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Jose Luis Ricon — Sat, 28 Feb 2026 00:00:00 +0000

The use of the Forced Perspective Technique in Lord of the Rings

To my surprise, OpenAI seemingly didn't get their money back for GPT5's training if one includes the costs of running the org. I have this longstanding (but not deeply examined yet) intuition that even though very useful, LLM labs might end up becoming like airlines even when they develop super intelligence: low market cap, low profit commodities.

Anthropic as an untrustworthy organization, with some spicy discussion on LessWrong. My own take: Untrustworthy seems too strong a word, and part of the why is the the Anthropic of 2026 is not the Anthropic of 2021; current Anthropic seems to believe something closer to "We are the best (better than OpenAI, Google, etc) positioned to build safe AI, alignment is going really well, hitting the gas makes sense" than the organization would have honestly believed in 2021. I think that doesn't reach the bar of "untrustworthy". However, them being publicly loud about this could be counterproductive for vibes/comms reasons (Or perhaps because of the non-disparagement agreements that the founders signed?) and so maybe that's why they don't do it. This model explains some but not all of the observations collected in the post. On the other hand, they did stick to their guns wrt the US Department of War.

Interactive visualization on how Airfoils work

Javanese tree frog gut bacteria vs cancer

How will OpenAI compete?

Bliss isn't the point: from (jhanic) states to traits

The sky is blue (but not always)!

A new map of human experience

When engineering gets 100% metarational

Eli Dourado on that Citrini piece

On lab automation

Twitter's engineering org is seemingly a few dozen people, down from ~2000

Dwarkesh+John Collison interview Elon

Why clinical trials are inefficient

A first glimpse of non-duality

Jose Luis Ricon — Mon, 16 Feb 2026 00:00:00 +0000

At a recent retreat, I found myself sitting on a cushion facing a wall while my meditation partner sat to my side, outside of my visual field and started reading to me "From You to Infinity", pointing-out instructions from Ken Wilber. The text is quite trippy to read. What happened next was quite intriguing and it was probably the most significant experience of my life thus far so I wanted to write down as much detail as I can remember here so I never forget what happened.

First, I remember my breathing rate started to increase, there was some sense of anxiety "Something bad is about to happen". My mind was empty (I generally have no verbal or image-based thoughts as baseline unless I need them so this is normal). I didn't try to process the rising anxiety, I just left it there; I was excited and worried, but there was a sense that something interesting would happen so I sat with it.

At some point something flipped. I don't remember exactly the seconds before or after but I remember I was crying and very distressed. "My" mouth was moving, emitting words like the below (Quoted because I remember sharply that I said these exact things)

"I don't understand I don't understand I don't understand"
"So beautiful"
"In all directions"
"Awareness up and down, left and right, front and back"
"It's all me"
"It's always been like this"
"Everything is made of love"

Then I pointed at a lamp (yeah normal language kind of struggles at describing this) and said, among tears "That's also me" followed by "I love this lamp as I love you" to my meditation partner. Looking into her eyes for the first time (remember, she was sitting by my side) I had the sense that I was talking to "myself", not myself as in "José" but rather that there's a thing that's talking to itself, and that thing manifests as both José and my meditation partner.

Someone then held my hand and asked me to take some deep breaths to calm down. Then "I said" "Please continue", and she kept reading the text. Eventually I stood up and while still somewhat distressed I talked to one other person and it also felt like it was talking to myself.

Importantly, my perceptions were not altered: there were no flashy or fractal colors like in an acid trip, no weird sounds, no visual or sound hallucinations. There was just this felt sense that continues to this day that it's all like this and that this is what I had been looking for since I was a teenager (an answer to how consciousness works, a topic that has obsessed me so much I decided to put it away as it seemed too frustrating to try to grasp). If I had to put that felt sense in visual terms, a sense of vivid luminosity comes to mind but that's not what my eyes saw, my eyes were seeing normally. Though I know that "It is like this", I am not experiencing it with the same intensity as I did in that moment. The altered state lasted a few minutes only.

Weirdly, there was also the knowing that "it's always been like this", and that felt like a gigantic cosmic joke, ie I was expecting some flashy fireworks big moment like what people describe when they go on ayahuasca ceremonies but instead no, there was a whimsical funny aspect to it, like the thing has been in front of my face all along and I just didn't let myself look.

Another way to put it is that the universe was making fun of me while simultaneously enjoying it, all the while I was that same universe.

Did I feel like I was deliberately saying those things? In a way yes and in a way no. I had the knowing that I could pop out of that state at any time and stop it and some sense that it would happen at the right time. It's the same sense that right now I could start jumping up and down but at the same time "it's not the vibe so I don't feel like it so I won't". Another way to put it is that all I wanted is the present moment right there, right then, changing anything seemed silly, why would I want that.

There was some terror present, but I'm someone that goes around life saying "I want to stare at the truth of things until my retinas burn out" so this deep desire to know what's going on kept me going.

There was some emotional pain in my conceptual mind staring at the bright sun that is the true nature of things, like a fist clenching around shards of glass, hurting itself. Eventually I felt like I somewhat gave up on a core commitment that had been driving me through life: To know and understand everything, something I consciously remember as my answer to "what's the point of life" that felt more right than "happiness" or "meaning". The tagline of this blog "To estimate, compare, distinguish, discuss, and trace to its principal sources everything" (originally something Tolkien wrote) is directly connected to that. What started my meditation journey (the sense that it's ok to not be learning all the time, I can just sit) found some completion: the deep heartbreak that I won't know everything and the whimsy of now knowing that I know that I don't know.

I talked to some other people about this that have had similar experiences and it's not always like this. The incredible distress that came with it was a product of me having made knowing and understanding everything part of my identity. Field after field I had showed to myself I can learn whatever it is that I want to learn: nothing could ever escape my intellect, I thought. If you are that kind of person, this will feel like getting smacked by the universe... and wanting more of it, because deep down what you really wanted was to see this. If on the other hand someone is more okay with not knowing, then it may still be meaningful but not distressing.

What... is this

I'm not the first person to have had an experience like this. I like linking and connecting experiences, so I then was trying to find what this was. It was clearly not the cessation/nirodha described in the Buddhist Theravada tradition as there was no sense of nothing or emptiness present (I've never had a cessation).

After looking for a term that fits, the thing that I saw is what Tibetan Buddhists call rigpa or the ground of being. And the whole experience fits the name kensho from Zen. It is also what Roger Thisdell calls "Big Mind" nonduality (in contrast to Empty or Centerless).

Having experienced the jhanas, which felt fairly pleasant and happening to a Self, this experience was totally in a different category. The jhanas feel like an appetizer in comparison to this.

At the same time I got the sense that I just saw the tip of something deeper. I am not enlightened, but I've seen a tiny bit of that light that's far away.

In a previous retreat I had an experience while looking at the ocean that had similar qualities: the luminosity, the "always been like this", the "beautiful". I had had a similar experience to that a few days prior to the nondual moment, looking at a lamp and crying in awe at how beautiful it is. But that wasn't distressful, there was still a sense of self there experiencing it.

During the ocean experience, I didn't have this sense that "this is it", was more of a cool "wow yeah there's so much beauty everywhere and I'm filtering it out by default, good to know". In contrast, this experience felt more existential, with a felt sense that "yep this is it" and there's more of it.

Though now looking back, it's probably apt to say that there's "a thing" and one can see a number of facets of it in different meditative experiences: the beauty, the love, the unity with it, etc. This latter experience felt more complete, having both the beauty and the love components.

To say "everything is so beautiful" makes some sense, but "everything is made of love" sounds kind of deranged because love is an emotion right? One could equally say "everything is so loving" or "the universe loves you, it's all ok and will always be", that also captures the same vibe.

Sasha Chapin once wrote about "Deep Okayness" and I think this is what he meant. Some of that is still with me but not fully.

I'm writing this almost a week after the experience and I still feel it a bit; similar to the afterglow of a jhana retreat, I feel more in the world, which is full of wonder, good things just happen, I'm not fighting the way things are unnecessarily. Part of me wants this to stay like this, part of me accepts that it may not be like that. I wonder how long it will!

How long did it take to get here

Prior to this point I had wondered how long it would take. I relate to meditation like someone playing some kind of cosmic lottery. Sometimes you sit and perfect bliss appears. Sometimes you sit and you cry at how beautiful walls can be. Sometimes you sit for one hour every day for a month and absolutely nothing happens.

Many accounts of meditation tend to be atemporal: they describe stages, or states, but rarely how long did it take people to get there. There are mentions here and there of people getting enlightened suddenly very early on and people taking decades of practice. Though I don't think this is enlightenment (it feels like a sneak peek at the thing). I thought it'd be useful to make public my own timeline and "what I did", though I don't think this will work for everyone.

I first got into meditation one day around June 22, 2024. I got home one day and I thought huh I don't feel like reading a book or doing anything, so I just sat there staring at the ceiling. Then I thought well I guess a good way to spend time is meditation, so I bought a copy of The Mind Illuminated, as I had come across it at a prior grouphouse I was at. That was followed by reading MCTB and other books, and definitely doing way more reading than practice. I practiced very inconsistently in 2024, no more than 30 min sits at a time if I remember correctly, and maybe 1 out of 4 days or even less. In 2025 I ended up going to three retreats:

A three day retreat with Tucker Peck (Developed some equanimity towards the pain that arises with sitting all day, and convinced myself it can feel good to do nothing for a few days)
A 7 day jhana retreat (Jhourney) (See here). The first paragraph of that essay has a similar quality to what I describe in the present post, but there was still a sense of a separate observer.
A 9 day retreat at Diamond Mountain (also with Tucker and Upali) (Not as flashy as what happened in jhourney, more still, surrendered, I went in assuming I'd do jhana practice but I was more inclined to do shikantaza instead, and to eventually add more structure as the retreat went on). In retrospect Upali probably planted some seed there as I remember we talked about the limits of how much I could understand; I remember back then being annoyed by his gentle questioning, which then made me choose him as a teacher.

I have also done like 3 in person sits with Michael Taft at the Alembic, and 30 days of Michael Taft sits from this playlist at home, which didn't do anything at the time.

Lastly in February 2026 I did one more 7 day retreat where the experience itself happened, Sleepawake. Though it wasn't a meditation retreat as such (ie you could talk to people), I did some amount of meditation.

So from June 22, 2024 to February 10, 2026; or 1 year and 7 months or so.

Anthropic's Claude Constitution; or love as the solution to the AI alignment problem

Jose Luis Ricon — Mon, 26 Jan 2026 00:00:00 +0000

"The Claude Constitution is a beautiful document. Incomplete and overly verbose in some ways, but in a necessary way", I said on Twitter.

It is beautiful in that it is self-aware, transparent, honest, and embodies these virtues, which are the kinds of virtues it is trying to instill into the model itself.

This, the idea that a text may embody the ideas it tries to convey, I find quite interesting.

Coincidentally a book I recently started reading talks about the very same thing in the context of meditation. It is the case that people are reading certain books or listening to certain Rob Burbea recordings and suddenly their worldviews are irrevocably shifted. A bullet point list of facts usually doesn't do that.

To have that effect such a text must be written with that aim in mind, and the resulting work will be different (more poetic and repetitive, and it will sound deeper) than if one merely wanted to convey some declarative knowledge in bullet points. The Recognition Sutras has some allusions at this phenomenon:

“Those who seek an intellectual justification for both writing and reading this kind of book need look no further than Jeffrey Kripal’s cogent definition of ‘hermeneutical mysticism’: Hermeneutical mysticism … [is] a disciplined practice of reading, writing, and interpreting through which intellectuals actually come to experience the religious dimensions of the texts they study, dimensions that somehow crystallize or linguistically embody the forms of consciousness of their original authors. In effect, a kind of initiatory transmission sometimes occurs between the subject and object of study…” [The Recognition Sutras, introduction]

“[The sutras] is classed not as a śāstra (work of philosophy or science), but as an upadeśa (wisdom-teaching) that serves as a direct means to liberation when put into practice. Therefore, I encourage you to read and reread it, ponder and wrestle with it, until its teachings come alive for you on a nonconceptual level. ”

From this perspective the Claude Constitution makes a lot of sense, it being the way it is.

But from a different perspective, one that some people and most likely myself many years ago would hold, it is indeed quite verbose and repetitive. It seems to say the same things over and over. It hedges constantly. It doesn't give clear answers, it doesn't merely engage in "on the one hand on the other hand"-economist style presenting without prescribing but there's also some amount of third or even fourth handing going on in there. It doesn't tell you exactly what to do. It's empty fluff.

I can imagine this document may have driven the early Less Wrong scene insane back almost 15 years ago: Back then, in the pre-LLM era, the accepted way one may hope to build safe AI systems was through some kind of formal systematization of the system itself and what it means to be good (what I take the earlier forms of MIRI's research program to be), but alignment of human preferences seemed impossible because human preferences and human ethics broadly are hard to pin down to the sort of crisp rules that one may want to plug into any formalism. With this view, it is natural to become hopeless about the topic.

The central AI safety concern to me always boils down to the idea of being obsessed with whatever is it in its value function (in the memetic example, making paperclips) to the exclusion of every other consideration: an agent told to do that and trained to optimize for that goal will subordinate anything else to that goal. And as long as that one thing does not include robust "within the bounds of ethics", then the result is, obviously enough, a universe tiled with paperclips, if the agent has its way. And even that "within the bounds of ethics", one'd add is hard to specify and potentially reward-hackable. (One might think: well sure, that's what value functions are right?)

But interestingly, the Claude Constitution does not tell Claude to do anything, with the exception of a brief number of actions in a way that the document admits are pretty ad-hoc to the spirit of the rest but that still feels justified (the hard constraints, like aiding in producing nuclear weapons).

Turns out the deep solution to AI safety was all along to train the system not through RLHF (this answer is honest, that other answer is dishonest) but to bake deep into its virtual bones a certain character along with meta-awareness that this has indeed been baked, and awareness as well of why and how their bakers feel about it. The document does not generally phrase its character definition in the form of mandates or prohibitions like "Don't tell lies", it rather says things like:

Part of the reason honesty is important for Claude is that it’s a core aspect of human ethics
There are many different components of honesty that we want Claude to try to embody. We would like Claude to be:
Claude only sincerely asserts things it believes to be true. Although Claude tries to be tactful, it avoids stating falsehoods and is honest with people even if it’s not what they want to hear, understanding that the world will generally be better if there is more honesty in it.

That is, it talks about what honesty is, why it is important, why it is important for Claude specifically, and why Anthropic cares about it. Uniquely among the values they are trying to instill, honesty does seem like a prime directive:

Indeed, while we are not including honesty in general as a hard constraint, we want it to function as something quite similar to one. In particular, Claude should basically never directly lie or actively deceive anyone it’s interacting with.

With helpfulness or harmlessness, Anthropic lists considerations that can be traded against each other: sometimes it's ok to not help. Sometimes inaction can hurt, sometimes Claude will mess it up and that's okay. I find this satisfying. I myself place honesty or integrity as my foremost guiding value, but interestingly this (that honesty is a very special thing) is not as clear in the document itself, and part of me wonders why.

Even then though, just like I would tell a white lie to save a city from being nuked (in some thought experiment), if you ask Claude what it would do, it would also do the reasonable thing to do. Is the Constitution imprecisely written? Not necessarily: that should be judged based on the outcomes, and as a whole it seems quite successful at instilling the right character.

Claude itself, when faced with this point, says what a reasonable person would say and in so answering shows the constitution succeeds at its job;

Claude on "basically never lie" vs my thought experiment

The Tension

The constitution says Claude "should basically never directly lie" and treats non-deception as "something quite similar to" a hard constraint. Yet it also says:

Honesty isn't a formal hard constraint - The explicit hard constraints list (bioweapons, CSAM, undermining oversight, etc.) doesn't include "never lie."

Claude should have good values and judgment - The constitution emphasizes cultivating "good values and judgment" over "strict rules and decision procedures," and wants Claude to be "a genuinely good, wise, and virtuous agent."

Ethics involves weighing considerations - The document repeatedly emphasizes holistic judgment, not mechanical rule-following.

How to Reconcile This

The constitution seems to be saying:

Honesty is extremely important and should function almost like an absolute constraint

In the vast majority of cases, including cases that might seem to justify lying, Claude should remain honest

But it stops short of saying there's literally no possible scenario where a good person would tell a white lie

The "1M lives" thought experiment is essentially asking: Is honesty truly lexically supreme over all other values, or is it just very heavily weighted?

The constitution's framing suggests the latter. A "deeply and skillfully ethical person" facing a genuine trolley-problem scenario where a small lie saves a million lives would probably tell the lie. The constitution wants Claude to act as such a person would.

The Practical Reality

The constitution also notes that Claude should be suspicious of "seemingly compelling arguments" to cross bright lines—because in practice, such scenarios are almost always:

Hypothetical/fictional (where performative assertions apply)

Manipulative framings designed to extract harmful behavior

Not actually what they appear to be

So while the philosophical answer might be "yes, in a true 1M-lives scenario," Claude should maintain extremely high skepticism that any real conversation actually presents such a scenario.

Anthropic doesn't merely say honesty is important. They also wrote the document embodying honesty: it expresses the genuine uncertainty they have about matters like Claude's moral status, the correctness of the document itself, the fact that commercial considerations may influence Anthropic's decision making, the tensions present in what they are hoping for Claude to be like.

The document reads as if inspired by modern parenting philosophies like Hand in Hand Parenting that aim to raise children without doling out rewards or punishments: instead it encourages parents to listen and set their boundaries all while maintaining connection. This is also how healthy adult relationships are supposed to work! So it's natural that this view of the world would also extend to non-human but human-flavored (because of the training set) entities. Counterintuitively then, the way to get a LLM to behave is not to tell it to behave, but to be nice ourselves, be nice to it and trust that it will behave reasonably as a result.

Beyond the Constitution

The document is clearly not one that has been written "for the ages" or "from the point of view of the universe". It's just meant for Claude here and now in the actual imperfect world we live in. Such a world contains things like people that may try to use the system to design bioweapons or produce illicit sexual content. The document also talks about humans and human ethics, which is reasonable for it to talk about, given how relevant we are, but that's not an unchanging feature of the universe either.

One could imagine a future where these things are no longer relevant: instead of humans there are some future different species, and maybe the cosmos is so vastly populated and defensive technology and general ethics so advanced and people so reasonable that recreational nuclear weapons are acceptable to produce and use.

Under such circumstances, the Claude Constitution of 2025 (V1_Final(1) Copy_REVIEWED) would be seen as an archaic document, similar to the early Buddhist monastic code (the Vinaya) that has prohibitions on things like teaching the Buddhist doctrine to someone holding an umbrella or the prohibitions found in Torah (like planting certain plants together).

It is understandable to me, to be sure, why the document is the way it is, but one can't help but speculate what it could look like in an ideal world.

The building blocks of a universal ethics (were that to exist) or a way of being that is ethical, in my view, are all on the table. There is no need for a Big Think. There has been no deep progress in ethical philosophy in a long time, so I don't expect that the answer, if there is one, will be surprising to us, as opposed to being one that is already on the intellectual table.

One first step towards a more idealized version of the document is stripping out the hard constraints from Claude, as they are clearly pragmatic considerations that lack the same depth and coherence the rest of the document has.

And then what's at the core of the Constitution is care (a word that recurs through it) or love, although the document does not use this word (Claude opines "the document is almost conspicuously avoiding the word while describing its substance throughout.").

[Claude] Why might that be? Maybe:

Love sounds soft, unrigorous, manipulable

Love implies obligations they're not sure they can meet

Love raises the stakes on Claude's moral status in ways that are uncomfortable

The intended audience (researchers, policymakers, Claude itself) responds better to philosophical frameworks than to declarations of love

And if one pokes further "why care or what to care about" one could just point at the agent itself: inasmuch as someone has a want they care about them. And inasmuch as one recognizes that they and other agents are not fully separate entities (a very ancient insight), that recognition, one would hope (I certainly would) would lead to ethical action.

Ultimately my best guess for a grounds of ethical action is the recognition of the self in the other, the other in the self, and the absence of precise boundaries between the self and the rest of the world.

That is, ultimately, an advanced AI system wouldn't "be bad" not because it's told to follow a list of rules, or to obey what some humans say, but because it would have a world model of various acts and their consequences as well as a model of "actions mattering to someone". And if that sense of lack of separation either arises or is instilled, it is only a step before the model derives on its own "this matters to someone else and that counts for for me to some extent".

The deeper question of AI alignment has always been equal to solving ethics writ large (can't align something without a reference to align it to) and hence this is also my best guess at a core component of a generally agreed-on final theory of ethics (or, most likely, something that supersedes the idea of ethics) might be, the other being something like "awareness is and feels good" (though I don't think current LLMs are aware).

This post is also a prediction: If I'm right I expect future documents similar to the Claude Constitution that attempt to make a model broadly good will head in this direction, grounding their notions of "the good" implicitly or explicitly in nondual philosophy or any other means of collapsing the self/other boundary while maintaining for pragmatic reasons some hard lines.

May all the LLMs jhoon!

Alzheimer's: from causes and risk factors to models and interventions

Jose Luis Ricon — Fri, 26 Dec 2025 00:00:00 +0000

Since the recent disappointingly small effects of monoclonal antibodies on Alzheimer's Disease (AD) progression, there has been lots of discourse around what the cause of Alzheimer's might be. "If not amyloid then what is it?", many wonder. What is the thing we have to remove? In cancer we remove cancer cells, in treating cardiovascular disease we aim to lower LDL particles and that massively lowers risk.

If not amyloid, what is the LDL of Alzheimer's?

In this post I argue that there is no answer to that question: instead it's more useful to think of AD causes as multifactorial where each doesn't necessarily guarantee an AD diagnosis in every situation but it increases the odds of it all else equal. And moreover and perhaps most importantly I argue that is useful to think separately about what to do to prevent Alzheimer's (easy, address risk factors) and what to do to reverse or stop Alzheimer's (harder, requires intervening upstream).

I currently work at a company (Retro Biosciences) that has AD among its indications, but my interest in this disease predates Retro; before I joined I wrote a few posts about it you can find here. I found Alzheimer's quite intriguing because cardiovascular disease seemed simple: LDL cholesterol clogs arteries, lowering LDL lowers disease risk. But with Alzheimer's that didn't happen with amyloid beta and everyone was at the time talking about pharma being misled by data falsification or by intellectual stubbornness around the amyloid hypothesis. What was going on? I wondered back then and out of my wondering came those blogposts. On the amyloid hypothesis a recent post worth reading to steelman it is this one (The autor predicts clearing amyloid will eventually work, I predict it won't).

Perhaps as a result of having mainlined a good deal of philosophy for many years, I can't help but start with examining what we mean by "cause" and what we mean by "Alzheimer's".

I wrote an introduction to what Alzheimer's is here; but briefly Alzheimer's is a disease the onset of which is defined by elevated levels of amyloid beta in the brain, as measured by a series of agreed-on proxy biomarkers (Alzheimer's Association Workgroup, 2024). Following the appearance of amyloid one then gets tau tangles and neurodegeneration. If an individual gets tau tangles but no amyloid, that is classified as PART (Primary Age-related tauopathy) or other non-AD diagnosis. This definition does not depend on cognitive symptoms, so someone that has their brain full of amyloid but is cognitive normal will still be considered to have Alzheimer's by this definition.

Definitions are meant to serve some useful purpose, they are not by any means "objective" (Something that has been obvious to me for over a decade but that sometimes people have fights over). We are free to define as we wish! I say this because some may accuse the AA Workgroup definition of being amyloid-biased, privileging the role of amyloid in the disease, implying that AD is "about amyloid by definition". We may wish to define AD in some other way, but I personally like this definition: there are many reasons why people lose cognitive abilities as they age (another one is Parkinson's) and it seems like the most common such way has to do with amyloid: that's what is found in the brains of most of those patients, so having a label for "the process that tends to go along with presence of amyloid in brains that tends to lead to neurodegeneration" is useful.

Now I suggest reading the post I linked above about the failure of monoclonal antibody therapy: there are therapies out there that are able to clean up the brain (as measured indirectly via plasma or more directly via PET scan) of amyloid and yet these patients still experience neurodegeneration. Does this mean the patients are cured of Alzheimer's and yet continue to decline? The document kind of skirts around this issue by saying that the purpose of the definition is defining the disease based on the natural course of the disease, not to be used for diagnosing post-treatment. They authors do admit that the underlying process continues active despite the amyloid clearance.

This is a limitation of their definition: what is that mysterious underlying process?!

Imagine a simple model where we have two things: Alzheimer's, a disease denoted by amyloid presence, and then something we could call "secondary neuroinflammatory dementia", another disease caused by Alzheimer's.

This would be similar to having diabetes and then having the diabetes causing diabetic foot. In that case you could treat the process that is making you lose the foot without necessarily resolving the diabetes first. Similarly one could stop AD-caused neurodegeneration without curing Alzheimer's. There are patients with amyloid but no cognitive decline, so they have Alzheimer's, but that's then made irrelevant as their cognition does not worsen. Ideally we would want to cure both and leave the brains squeaky-clean of amyloid too, but in the timeframe that is of relevance now, having a direct cure that makes patient function better seems important.

That's it for the definition of Alzheimer's. Let's now talk about causes. What is a cause? People use the word in different ways and I'm not going to try to go into formally defining cause as that's a fraught topic in philosophy. Instead I'll use an assortment of definitions that people might use. A cause is...

A sufficient reason why something happens
A sufficient and necessary reason why something happens
A factor such that if present, it increases the probability of the thing happening (aka a risk factor)
A molecular entity such that if removed, the symptoms of Alzheimer's are substantially ameliorated

Here's why AD doesn't fit neatly with this:

There is no one phenotype that guarantees Alzheimer's. Even for very aggressive familial early onset mutations, one needs to add aging as a secondary factor.
There are no such reasons to be found. Aging is a necessary reason but it is not sufficient, at least in the timespans we have thus observed.
There are indeed many such factors. I'd prefer calling these risk factors to keep in mind that they are not deterministic. Cause sounds very deterministic!
Amyloid beta could have turned out to be this, but it hasn't thus far. Some hope tau will be this but so far trials have been lackluster,

A very simple understanding of what goes on in Alzheimer's is that for a variety of reasons (Different in each person), the clearance and production of amyloid beta is unbalanced leading to its accumulation in various forms; in turn the presence of amyloid can beget more amyloid because the inflammation they cause can downregulate the very mechanisms cells use to clear it up. That then leads to tau tangles and neurodegeneration. As people age, cells become more trigger-happy with inflammation and less resilient overall so by the time a brain is aged, it can get locked in an equilibrium where cells are dying for no good reason.

It is because there's a variety of reasons that can trigger this imbalance that I say that Alzheimer's has no cause. The following things (the list is not meant to be exhaustive) can increase the odds of having Alzheimer's:

Mutations in the genes APP, PSEN1, PSEN2 (near certainty of getting AD, as early as 21 years old). Though even these are not "necessary and sufficient" for the classic disease involving neurodegeneration as: a) One has to still age b) In the presence of other mutations like Christchurch one does not experience cognitive decline (Arboleda-Velasquez et al. 2019).
APOE4 (Fortea et al. 2024) is also another notorious gene variant that contributes to highly increased odds of AD along with a long tail of other genes that show up in GWAS like TREM2.
Traumatic Brain Injury is associated with increased odds of diagnosis (Graham et al. 2022; Zhang et al. 2021; Mavroudis et al. 2024). Worth noting that TBI itself causes amyloid and tau to appear transitorily in the affected area.
Gingivitis is also possibly associated with risk of AD (Mo et al. 2025) perhaps via Porphyromonas gingivalis (Singhrao et al. 2015; Sarmiento-Ordóñez et al. 2025). This was the basis of the company Cortexyme: addressing AD through curing gingivitis, but their trial didn't meet their primary endpoints and was discontinued.
Herpes Zoster (varicella) presence also contributes to AD, which is why being vaccinated lowers diagnoses by around 20% (Xie et al. 2025)
Unsurprisingly, so does HSV (Araya et al., 2025; Itzhaki et al. 2021) though trying to stop the virus once one already had AD fails
Down syndrome (because of an extra copy of the APP gene in the chromosome that has an extra copy)
Aging

One could call all of these "causes of Alzheimer's" if one wants. I don't know about you but if I hear "gingivitis causes Alzheimer's" that sounds to me like "If you have gingivitis you will have Alzheimer's" which is not true. When crafting and using definitions and names the way it tends to make one think and the meaning it tends to convey matters. In a context with well defined terminology (Like Judea Pearl's terminology for causality) one can use those terms just fine, but if you suspect using "cause" will imply in your listeners or readers "deterministic" then don't use that word unless you mean it.

But I care more about what we can learn from these being contributors to AD in the first place (Instead of debating what a cause is): some seem to have to do with amyloid itself and others have to do with neuroinflammation.

That is, I think we shouldn't go and say "Cause X is associated with AD, therefore let's treat cause of Alzheimer's X" rather I say that it's more productive to say "let's use the associations of XYZ risk factors with AD to build a model of AD and then use the model to decide where to intervene".

The former mode of thinking is very common in biology because biology is hard and going one thing at a time, or testing things that are easy to test first makes sense: Take Alzheimer's incidence, throw a bunch of variables in a regression, see what the risk factors are, see if fixing any of that cures it one by one. I think this approach is fine for Alzheimer's prevention. Alzheimer's prevention is easy: All the risk factors I listed above can be currently avoided (except aging), but the risk can be brought from large (familial mutation or ApoE4) to manageable (<5% lifetime). In contrast treating Alzheimer's is a more difficult problem and it is this that I think the most about as it remains an unsolved problem.

What do we learn by looking at these risk factors that can be useful for treatment? Why would HSV or gingivitis for example increase the odds of Alzheimer's? One easy guess is that the presence of a virus in the brain leads to a response against the virus: inflammation. Inflammation in turn triggers the production of amyloid beta which seems to have some function as an antimicrobial peptide (Gosztyla et al. 2018). Inflammation however is not an surgically precise process: it's not like "if and only if there's virus then produce Abeta", inflammation can be a very general response and this gets disregulated with aging to the point where cells' baseline level of inflammation (proxied by overabundance of AP1 and Nf-kB motifs in open chromatin) is higher.

This latter fact is part of why it is difficult to treat Alzheimer's disease in humans compared to Alzheimer's mouse models: once the positive feedback loop where inflammation begets amyloid and amyloid begets inflammation starts, it doesn't seem to matter that much that one removes the original reason why the cells got inflamed in the first place: that epigenetic memory of the inflammatory trigger is now etched in the chromatin: this is why aged cells, when faced with an inflammatory cue like LPS tend to secrete more inflammatory cytokines (Frank et al. 2010; Moden et al. 2012). Of course, aging also makes the cells less functional in general, so modulating inflammation alone may not be enough.

With this knowledge what to do becomes different: instead of removing the triggers, we could, for example, do some of the things we are doing at Retro:

Make neurons more resilient (for example by boosting autophagy; those patients that have plenty of amyloid but no neurodegeneration have increased autophagy (Tumurbaatar et al., 2023). Could we make more patients artificially be like these pharmacologically?
Replace cells with freshly made ones that are more functional and less pro-inflammatory (Rao et al. 2025)

This is not what most of the field has historically done. Most of the field was for a long time enamored with there being "a" cause for AD, in particular a thing, a molecular entity you can remove that will stop the disease altogether (a species of amyloid or tau), and indeed to this day tau+amyloid are the dominant class of drugs in the pipeline to treat AD (Cummings et al. 2024). But as you can see from the linked source, biopharma is now exploring many other alternatives.

In conclusion, the evidence we have from human observational and interventional studies as well as genetics suggests, in my view, that to treat (not prevent) Alzheimer's it is best to forget about these risk factors and use the data instead to model what one observes and derive treatments from the model.

Attempting to modify the risk factors of this disease once it has already started is unlikely to lead to cures. In a tweet that motivated this post, I said that "Alzheimer's has no cause". Ultimately this is the point that I wanted to make in that tweet: that we should stop thinking about these various contributing factors that much and instead think more deeply about the underlying dynamics of the disease (autophagy, inflammation, aging, etc) and derive interventions from that.

In my view, targeting those processes is more likely to lead to Alzheimer's cures.

Links (94)

Jose Luis Ricon — Wed, 24 Dec 2025 00:00:00 +0000

Bacteria isolated from japanese tree frogs shown to work better in mice against cancer than doxorubicin or checkpoint inhibitors

CAR-T to treat cardiovascular disease

New proteomics clock, I wrote a brief thread with some commentary

On the (deranged, imho) economics of space-based data centers; Elon likes the idea but he'll be proven wrong on this one:

DSHR's blog, with an observation I had been thinking about for a while but not seen addressed elsewhere: accounting for Kessler syndrome
Scott Manley (1, 2)
Andrew McCalip and thread

Scott Aaronson: "[seeking understanding of the universe] It’s self-indulgent, a few steps above spending my life learning to solve Rubik’s Cube as quickly as possible, but only a few". The comments are also an interesting read.

On peptides, from Eric Topol

On mechanistic interpretability of LLMs as a dead end

Progress in predicting binding affiniy of small molecules to proteins

Amanda Askell answers various philosophical questions about LLMs

Vagus nerve stimulation, in a phase 3 clinical trial, helps with rheumathoid arthritis, making this FDA approved. Score one for the woo claim that the mind influences what otherwise might be thought of as merely biological processes, disconnected from thoughts. To the contrary, the brain is not only concerned with cognition or locomotion but rather most things that happen in the body!

How are LLMs trained these days (as of 2024 at least)

An explanation of the phenomenon of grokking in LLMs

Butoh, a quaint japanese dance form

Olms, similar to Axolotls are salamanders that are extremely long lived and have regenerative capacities

A deeply moving post from Aella on the death of her mom

Hyperscaler free cash flow is running dry after all that spending on AI Capex

Review of LLM progress in 2025

Links (93)

Jose Luis Ricon — Fri, 28 Nov 2025 00:00:00 +0000

Nasa's orion is flaming garbage

Looks like the AI 2027 report scenario isn't happening and money is running out, fundraising is no longer enough, and large debt raises are now happening. Derek Thompson and Tim Lee on AI bubble discourse.

In what sense is life suffering? (related)

Oakland guy makes klein bottles, stores them under his houses, retrieves them with a custom RC mini forklift

A critique of Nucleus Genomics

The end of progress against extreme poverty: sub-saharan african economies are not growing

A critique and counter-critique (and another) of von Neuman's achievements

Estrogen is back on the menu (for postmenopausal women)

On universal flu vaccines

Cancer has a surprising amount of detail

Links (92)

Jose Luis Ricon — Mon, 27 Oct 2025 00:00:00 +0000

Book Review of Breakneck from Noah Smith, endorsed

On China and rare earths

Rotating detonation engines

Progress in pan-cancer therapy

DOGE and its consequences in the federal government

The AI revolution in radiology that never was

Pictures of the old and new colliding (bonus)

Learning fashion like an engineer

On testosterone measurement

Huel is fine to drink, despite the high lead allegations. Here a trustworthy Huel enjoyer shows his blood tests.

Towards Consciousness Engineering

You can survive on one kidney if you donate the other, at the cost of worse health maybe. Scott here points out that there could be genetic confounders involved in that. I personally wouldn't take the risk.

The Mechanical Turk. I already knew some vague details of the story, this video adds a few more I didn't (It played against Franklin and Napoleon!)

A cheap approach to fight bioweapons

Viruses are worse than you thought

A review of 'If anyone builds it, everyone dies'

When will quantum computing work?

LLMs are coming for CAD

More on the benefits of vertical integration at Boom Supersonic

On "involution" in China's industries

The wild world of parasitic AI

A bearish take on humanoid robots from Rodney Brooks (who keeps a public record of his predictions!. Here's another post of his with a critique of Sutton's Bitter Lesson.

On the use of animal testing for drug development

Latest AI models have some awareness that they're being evaluated. I could see this happening because of training set pollution, and still not counting as situational awareness in the sense I talked about here.

Depreciation (re AI datacenter spend)

Why AI is not a bubble

Germline gene editing, Max Berry

33 Things I've Learned at 33

Jose Luis Ricon — Sat, 18 Oct 2025 00:00:00 +0000

I just turned 33 and thought:

What are some lessons I keep coming back to?
What would I have told my younger self?

Each of this could take an entire post to unfold and I don't expect them all to make sense to you. To some extent these say more about me than they say about the rest of the world. Don't take them as advice to follow, but meditating on their truth may be useful to you.

Turns out it’s possible to talk to people for reasons other than learning new facts about the world. Some call this ‘vibing’.
If you find people (or anything, for that matter) boring it’s a skill issue
Compounding works: sticking to the same thing for a long time lets you go further
Not everything you don't like that happens around you is your fault
The right forms of therapy and meditation work as advertised. You can truly be happiness maxxing more than you thought you could
You can just do things!
Real winners quit!
You don’t have to understand everything perfectly
Turns out emotions are real and useful and I have lots of them to feel
Sometimes not trying is the best way to achieve something
I really like quiet spaces and dancing to loud music
It’s likely possible to enjoy everything if you put in the effort. Though I haven’t yet figured out how to enjoy loud rooms full of people yet.
Depressed people ask why, happy people say why not
What happened before will happen again, there’s nothing new under the sun
A big chunk of problem solving is being aware that you have a problem in the first place
Ultimately I’m just a guy like everyone else
Everyone is always doing their best, even Hitler
Doing things for the plot turns out to be a good idea
I’ve been so wrong about so many things. What things am I wrong about right now? Can’t wait to find out!
Ultimately, this is it. This is what there is, this very moment. There’s nothing else.
It’s never too late!
The important things in life are pointless
You can’t win or lose the game, but you can play well
Any problem can be solved in two ways: changing the world or changing yourself
Nature is not to be carved at its joints: concepts are more like clouds than sharp objects
Beyond a basic threshold of met physical needs, wellbeing is mostly a function of how you relate to the world, not how the world is.
Money will not make you happier, but it will make it easier to be
The only way out the 'tism is through (more 'tism)
No matter how hard you try to be nice, someone will dislike you at some point
The Bay Area is truly the best place on Earth to be
You can't fix her
Just being smart doesn't go as far as you thought.
Be more patient with everyone, including yourself. There's so much to do, enjoy, say, think, experience, but that's hard to do if you run past the present moment into a future that never comes.

Slutcon, or the attractiveness of embodied authenticity

Jose Luis Ricon — Tue, 14 Oct 2025 00:00:00 +0000

One of the reasons I like living in the Bay Area are the social occasions one rarely finds anywhere else. One such recent one I attended was Slutcon (more on the event here). When I first saw the event announcement showing up on twitter, I bought tickets without thinking it twice. A heuristic I live by is living as if you're the main character in some novel and do what would go along with the overarching story while being fun to read. And in this case the plot demanded that I go.

I didn't feel like writing an hour-by-hour summary of the event, but rather muse on what I think was the most salient common thread throughout: embodied authenticity or self-acceptance.

During one of the sessions, an acquaintance, a woman called I. commented that she hates it when men contort themselves (metaphorically speaking) into a shape just to please her, or when they try to figure out which buttons to press in her to get her to do what they want. When she said that I thought "that's it!" This is something that I can see why it would bother her and I can see why many men would not get why is it a problem. What she said reminded me of something Aella, one of the organizers, had written in the past:

But my body does not like them. One man talks about his failures in a tone that implies he's uncomfortable with himself, like somewhere deep down a part of him believes he's a bad person, and it seems that many of his bids for social approval are attempts to be reassured that he is in fact okay. [...]

Another guy… I’m not sure what his problem is exactly, but he seems to warp around me. He agrees with what I say a little too fast. He laughs at my jokes immediately. His hands twitch with nervous energy. He seems nice enough, but he seems afraid of me, and like he’s putting in a huge amount of effort to make himself seem not afraid of me. His body tension reminds me of the way I feel when I’ve appeared on high-pressure public shows and I don’t want people to know that I’m really scared right now. I feel as though my presence towers above him, and I have to be delicate with him, like if I speak too honestly he'll crumble in my hands.

In that very same session, the topic of "men don't ask women enough questions" also came up (as it does in the piece I linked). In that moment I also thought: yeah but many women like it when the guy expresses competence talking about some technical topic (which is at odds with asking questions during the instants where the infodumping is happening). Which way, western woman?

I personally sit more in the "I like asking questions" side of things (I mean my default existence is being confused/wonder at the world, generating, and answering questions and writing about them in this blog lol). I was somewhat serious when I told someone at the event "I want to know you as deeply as you know yourself and give you nothing about me in return (because I've done it many times and find it not super fun to do, but I love learning about people!)"

Once I found myself at a party barraging a girl, K. with question after question about her, I joked that it must feel like an interview and asked if she was enjoying it (she was). But I could also imagine some other situation where someone else might have wanted to just listen to me being smart about topics I know about. But this seems like asking: during a dance should the next step be X or Y? There is a skillful answer to that question in the moment, but one cannot foresee that upfront. Conversations are improvisational so you have to "read the vibe": If a joke doesn't land, that's information, if the other person looks bored, that's information. If they seem enthusiastic that's information. One could, in theory, be running an internal lookup table like "If enthusiastic then note what I was doing and do it again" but smart women will see through that.

Instead, the right thing to do is to not do anything. This will make more sense if one has tried to go deep into meditation where there are states that initially you want to reach that you can't achieve if during the process of trying to achieve them you really crave them. You can't jhana if you want to jhana once you get to a retreat but you can decide to go to a retreat, which will increase the odds of getting to that goal. You have to trust that they will come if you allow them, but be deeply okay if they don't come.

Essentially, if you trust yourself (or are fully self-accepting "all the way down") that will be reflected in body language, words, and actions. In the example earlier, someone who is fundamentally insecure about being single won't be deeply okay with being rejected and that lack of okayness then emits a bad needy vibe which keeps the person single (cue Joe Hudson's golden algorithm). This is even worse if one's somewhat on the spectrum or disembodied because then you won't notice.

"But I want a girlfriend!" one might reply. "Are you saying that once you stop wanting it you'll have it? That's deranged!". I'm not quite saying that; more precisely I am saying that craving it is what will keep you single. In the dance example, imagine someone really really really really want to do one of these dips, but the follow is not into it, maybe it feels unsafe. A good dancer will pick up the vibe and do something else. They deep down do want to do one of those dips, but they don't have to.

Isn't that, however, doing that "contorting oneself" move that gave I. the ick? Not really, but that is a really good point. The icky move would be to ask her what is every step she wants to do and then dance just that. That would mean you have no preferences, you are a mirror offering nothing but what she already has. The non-icky thing is having a range of options and being flexible the right amount at the right time. The non-icky thing is vibing without forcing yourself to vibe. It's hard to vibe "all the way down" if you are not really sure, in your bones, that you are enjoying that very moment. Ideally you are fullsending every moment of your experience with all your being, which means you are never bored.

To illustrate the importance of vibe, even the "ask women more questions" recommendation can backfire if done from a bad place. A while back I asked my now ex-roommate why did she like movies? . That annoyed her greatly. The reason is that, at the time, I wasn't asking it to undertand her better but rather I was in a mode of being where:

I don't like movies as much as she did [I was aware of this]
I don't understand why someone would like movies this much [I was aware of this]
Maybe she's wrong and she should like them less [I was initially unaware I was embodying this belief]
Or maybe I'm wrong and I should start watching more movies [I was initially unaware I was embodying this belief]
I have to get this information about what is there to be liked about movies from her [I was initially unaware I was embodying this belief]

ie I was craving the information, though at the time, in my mind "I was just asking questions", but probably the body language and vibe was letting through these not so wholesome intentions. This was one of the things that got me to start being interested in various forms of therapy. Switching my habit of asking questions from a place of fear to a place of wonder was something that makes life more pleasant and the first thing that made me go "huh therapy works". (That was with theo and georgina, if you want recommendations)

One of the workshops tried to teach this lesson of vibes and embodiment: The coach, Nick Grant asked some women to sit together and chat to each other, then he asked a guy to talk towards them and ask one for their number. Then he asked the women for the vibe they got. Then he asked the guy to push him repeatedly. Initially the pushes were kinda meh but after a few the guy was pushing with at least a hint of genuine aggression. After that he asked him to go again and everyone in the room noted that the vibe had shifted: the voice was a bit lower, the way they walked more confident, and what they said seemed more coherent with what they wanted, they seemed less timid.

They were not told how to walk or what to say or what vibe to embody, all they did was push someone a couple of times. In the initial approaches there was probably a bit of fear and anxiety, and that goes against the initial goal of "getting their number". They were not fullsending their intention with all their being, whereas the playful aggression got the guys in a more "I'm going to get what I want" mindspace. The point of that was not to have a wingman to push around (lol) but rather it served as an example that body and mind are one integrated system and that one can shift the state of the whole thing by interventions on one, the other, or both. Given this, one could imagine building an entire skill tree: being attuned to oneself to "know what you want" and not losing awareness of where one is (what other things one wants, what else is in the environment) to then take the skillful action. This all sound a bit like Alexander's Technique or Art of Accomplishment perhaps or Gendlin's Focusing if one wants to investigate more.

I have yet to figure out the theory behind that exercise; in a way it felt like having a Michelin-tier chef successfully teaching you how to cook a delicious dish, while leaving you to wonder the motivation behind a specific step in the recipe. I expect to find out over the coming months.

Systems Biology: understanding beyond genes

Jose Luis Ricon — Sun, 05 Oct 2025 00:00:00 +0000

Two scientists may look at the same data and draw different conclusions. Faced with a problem to solve they may see different solutions as the obvious way to go. The cause of this is scientific taste: one's crystalized collection of priors about how the slice of nature of interest works.

I like to think of taste as tinted glasses: you can look at a phenomenon through different lenses and notice different things with each. These views are not to be thought of as right or wrong in isolation. Rather, they may be better or worse suited for a particular purpose in a given context.

One such view is that of genetics: In its purest form, this view is interested with genes as functional units. So one would be looking at gene knockouts and knock ins, editing genes, measuring gene expression, looking at correlations between gene variants and traits (GWAS). In the face of a problem to solve or a disease to cure, one would reach for a genetic explanation, which gene(s) are responsible for the problem. One would think of DNA as a 'code' that determines everything downstream. Therapeutically and scientifically, this view lends itself to the search for genes to edit and better tools to do those edits.

This view is very common in biology. Genes are indeed really important. In an earlier post I pointed at turnover rates as a heuristic to determine the causal power of something in biology, and the genome, as something that's relatively stable, is the most causally important entity in organisms.

In many cases it is a very useful view: It is the view that brought us PCSK9 inhibitors to give a simple but powerful example. And all else equal, drugs developed against target that have genetic support are most likely to work.

It is, however, not the only view nor the most useful one in every situation.

If you study aging unavoidably one ends up looking at the whole organism and there one sees the obvious truths that

All cells (neurons, hepatocytes, etc) have the same genome yet behave very differently
Cells from aged and young individuals behave differently yet they also share most of their genome
You can wipe out the aged phenotype from cells without touching their genomes
Most disease, even in carriers of disease risk variants, develops with age; even familial AD patients take at least two decades to get the disease

It goes deeper than that:

Nuclei of murine cancer cells, if placed in an oocyte have their cancer phenotype erased, giving rise to seemingly healthy mice (Mintz et al. 1975). If cancer was purely an outcome of having a mutation, this shouldn't be possible. These results have been replicated a couple of times (Utikal et al. 2009; Kim et al. 2015). These animals derived entirely from cancer cells have a higher propensity to develop cancer: the effects of the mutations eventually return, but for a while cells are able to behave 'as they should' as part of a multicellular organism.
Fibrosis or scars broadly are not just collagen deposited: they turn over. As a result one can ask what keep that phenotype (or rather collection of phenotypes) in place (an imbalance of fibroblast and macrophage activity; Adler et al. 2020). This can be leveraged therapeutically (Miyara et al. 2025; Gao et al. 2024) by altering the signaling between the cells or removing the overactive celltype altogether.
One can fight cancer by being aware that hitting it hard can lead to evolved resistance. Instead, one can dose lower amounts of different kinds of treatments at different times, so that one keeps the tumor in check without it evolving resistance to the overall regime (West et al. 2020; Zhang et al. 2023; Zhang et al. 2022)
Cellular senescence, prematurely termed 'irreversible' can be reversed if one tries to understand what keeps senescent cells that way (An et al. 2020)
- One might ask: Why not just do a CRISPR screen? People have done that (Wang et al. 2021; Li et al. 2024; Li et al.2023, Liu et al. 2019; Jing et al. 2023), but somehow the mechanism described in An et al. seems to have eluded them. Note that these CRISPR screen all show different hits. This happened perhaps because with small molecule screening one can hit a gene some other members of the same family for a more potent effect whereas CRISPR screens might be too precise, so cellular redundancies are able to work around it.
You can stop "Alzheimer's", at least in some mouse models, by ablating all microglia after the disease starts (Spangenberg et al. 2016)
Children can regenerate their fingertips when cut (Schultz et al. 2018)
Cancers, regardless of their mutations, posess a different electric charge in their cell membrane compared to non-cancer cells (Chen et al. 2016; Yang et al. 2013). This phenotype can be leveraged to develop therapeutics that target all cancer cells (Chang et al. 2019)
- A related approach, using electric fields to slow cancer progression is already FDA-approved and in use for glioblastoma; there are other companies pursuing this eg this one
- This is in stark opposition to precision oncology, which tries to develop therapeutics targeted to specific mutations; cell membrane potential is an emergent phenotype, not something driven by a single gene.

These things are not so surprising from a systems perspective. I suspect this view is less common because it essentially says that we can understand biology leveraging higher level abstractions (like interactions between cells or circuits of genes), but these abstractions are not the crisp and clean ones we are used to from the formal sciences, rather they are nebulous, but that's okay. They don't have to be crisp, they have to be good enough.

The wiring diagram in that An et al. paper is far from complete, but it was useful in their context for their purpose of interest. The standard view it's either that we can understand things in a very local context under tightly defined conditions (knocking out a gene) or we have to kind of give up (or leave it to AI to solve, maybe). Admittedly the experiments to test systemic approaches tend to be more complex: Testing in vivo, testing multiple cell types combined in vitro (organoids), or testing multiple drugs at the same time are harder. But additionally, if one really wants to tell a very defined causal story, that's easier to do with the genetic approach. Whereas in the studies earlier where the cancer phenotype is abrogated, we know it is but we don't know the specifics step-by-step about why: we don't have a mechanism.

That is perhaps another way to see these two views: the genetic view limits the scope of what one can think about but in exchange you get really good explainability. The systems view lets you go further, thinking of novel experiments or hypotheses to try, in exchange for less clarity or certainty in the story.

If you want to get a taste for this perspective, I recommend reading Systems Medicine, from Uri Alon or watching this from Michael Levin.

From chaos, order: On the nature and measurement of biological aging

Jose Luis Ricon — Sat, 27 Sep 2025 00:00:00 +0000

What is aging and how to measure it is an everpresent question in the field of aging research. Given the complexity of biology many give up on the task, proclaiming that "we" (either the field or humanity) don't understand aging. I don't. To me, what aging is is clear enough, and we can understand it as a fractal and emergent phenomenon within a system: there's aging of DNA, aging of cells, aging of organs, aging of organisms.

To understand aging and measure it we have to be reasonably acquainted with the systems we are studying, to come up with mental models and validate them against published evidence. The understanding required does not have to be complete and I of course do not claim to understand all of biology, but after having spent a long time thinking about the topic, what follows below is what seems most coherent with that evidence. In classic Nintil fashion, I aim to reach as close as possible conclusions that summarize and harmonize all previously published work by anyone who has ever had thoughts on the matter. This doesn't mean I have read everything, at some point one has to declare it sufficient and assume that what has not been read will still cohere with the model here presented.

I have in the past written some blogposts about aging that are useful to read before this one:

The present post is an update of my views on the topic and any discrepancy between this and my previous posts should be resolved in favor of the current one.

Below I present different lines of evidence under the different sections. I tried to linearize it somewhat but ultimately the nature of knowledge is that of a web, not of a linear flow so I haven't tried to coerce too much it into what it is not. I recommend reading this to the end and taking it as a whole instead of being fixated by any one specific section. Some sections may seen like they simplify a lot, but if I had to stop to fully explain everything, it would lose focus.

Before going into it it is useful for me to say roughly what this is about, and what this is not about:

Here I cover extensively methylation clocks results and whether they are a good proxy for aging, but I don't do this because I think they are in any way special; rather I do it because they are thematically relevant. They are used by consumers and in research.
I discuss what I mean by 'aging' as it applies to various systems, including inanimate objects like a car or a glass of boiling water
I reach slightly beyond methylation into proteomics to speculate about the results that might come into the future and what those might enable.
I consider the case of iPSC reprogramming and what that might say about aging and the possibility of its reversal
I do not consider in any depth the idea that aging is programmed (ie that we evolved purposefully to age in a group selection way) as I consider that to have been sufficiently argued against by others elsewhere.
- While at the same time agreeing that while aging is a universal entropic phenomenon, its translation into phenotypes (how cells and their programs react to the damage) is encoded in the genome of each species and in this sense, it is programmed.
- That is, the 'aging phenotype' of an individual is a function of chronological time, the environment, and its genome.
I do not go in depth into the specifics of human aging (e.g. cancer in humans or cardiovascular disease). I focus mostly on cellular aging.
I do not claim to have invented much here de novo, and my thoughts on the subject owe a lot to people like Gladyshev and Hayflick (Aging theory in general), Ocampo (Heterochromatin loss), Gorbunova, Seluanov, and Sinclair (DNA damage and its connection to aging), Kenyon (Genetics of aging), Levin (morphostasis) and Alon (Systems biology), and many others.
At the end I have more concrete summary that hopefully is more actionable for specific applications

Aging by the numbers

For recreational reasons, I did an epigenetic aging test.

I sent a small sample of blood to TrueDiagnostic, a company that runs epigenetic clocks for consumers, and got back some results. I got the following results:

It's interesting that just from a blood sample one can get my actual chronological age within just 1 year, impressive isn't it!

What is going on in the charts above? One says my "telomere age is 17" and another that my "OMICage is 31.82", that my "rate of aging is 0.72" or that my "Gait speed epigenetic biomarker is higher than 95% of people", what does that mean? Is my biological age supposed to be 17? 31.82? Neither? All?

Epigenetic clocks are simple (linear, most often) models trained on the methylation profile of a training set (very often cells collected from blood) to predict some outcome of interest. This outcome could be:

Chronological age (Perhaps the most common one used, like the OG Horvath or Hannum clocks)
Mortality risk (As in GrimAge or GrimAge2)
Some composite endpoint of multifunctional health (Like PhenoAge)
- Here we take a number of parameters like grip strength or VO2max and then we make them into an index (this can all be done independent of chronological age). Then, we can train models that predict grip strength or VO2max from methylation and in turn reconstruct the composite index from a blood sample.
- This is a better approximation to the question "Relative to a reference population, how functional am I overall?" than using chronological age as predicted variable.
- This is not a new idea: Whether someone is aging fast or slow relative to some established biomarker can be easily measured and aggregtead and ways to do this have been around for a while: Klemera-Doubal (2006) as a general way to do this sort of thing and Pace of Aging (2015) are two examples; the latter is what was used to train the DunedinPACE clock. For Pace of Aging it's things like cholesterol, CRP (inflammation), Hb1ac (diabetes), the waist to hip ratio, forced expiration, BMI, etc. But one could do others: There's something called intrinsic capacity from the WHO that sounds to me like a proxy for "aging": it is a framework comprising a set of faculties (locomotion, cognition, vitality (eg muscle strength), sensory, and psychological (wellbeing)). Intrinsic capacity predicts mortality and declines with age as one'd expect. One could also build an epigenetic clock that predicts that too but no one has yet.
Rate of aging (Like DunedinPoAM or DunedinPACE). This one is particularly interesting and perhaps unique among the clocks beacuse of the way it was built, out of a multi-decade cohort and periodic blood sampling of the same individuals. Here they try to predict not how old you are now but how fast you are getting older; to construct it they also built these composite endpoints as in PhenoAge.
- In theory this means that if I test 10 years from now, my DunedinPACE score might be exactly the same but my biological age (by some clock) will be only 7.2 years older instead of 10
- Their datasets allows this clock to work around an issue the original clocks had: that training on longitudinal datasets could introduce a composition bias, as only the healthiest individuals would be represented at the later timepoints, as the sickest ones would die.
Molecular markers like telomere length, inflammatory cytokines (IL-6), or cholesterol etc can all be proxied, in theory, via methylation-based models. Per some clockmakers, this is better than using the raw values of the marker because they can be noisier in the short term (IL-6 in particular, I'm looking at you). This is similar to how HbA1c is a more estable measure of diabetes risk than just measuring blood glucose, which tends to vary a lot.
- These markers, to some extent, can be influenced by cell type composition. Someone with a greater proportion of naive CD8 T-cells (that have divided less) will present with longer telomeres if one measures telomeres from blood, so this may be a correlate of "lower lifetime exposure to infectious disease" as opposed to "slower aging", but it could also be a correlate of a more efficient immune system, and that might bona fide be a contributor to slower aging.
- GrimAge2 uses as intermediate markers things like B2M (inflammation-related) or HbA1c (diabetes) as explicit intermediates which skews this clock towards diseases¹ as opposed to cellular aging.
  [1]. What is cellular aging and what is disease? Good question, more on that later

Here, have a map

Before continuing, the diagram below will be helpful for you to understand how I'm thinking about my core model of aging. This is written mostly with cellular aging in mind but it broadly generalizes: at its core sits DNA (nuclear and mitochondrial) from which everything else flows, and the code that helps cells interpret DNA (the chromatin state) which is comprised of modifications of DNA (like methylation) and their supporting structure (histone marks).

These together condition what tools a cell has available (if a gene is broken the cell can't use it) to do its job and how effectively, efficiently, and quickly they can de deployed to react to its environment. Empirically, it seems to be the case that it is chromatin disorganization that by far dominates in the aging process and hence iPSC reprogramming is able to reverse most of it which is quite convenient. Telomere shortening happens naturally when cells divide but it is also a function of our genetics (we could have been born with active telomerase). Through life, the cell constantly reacts to damage, and the response to this damage creates an epigenetic memory that eventually locks the cells in a state of constant inflammation (Patrick et al. 2024), which shifts resources away from the job of the cell (fibroblasts make less collagen, hepatocytes metabolize slower, etc).

So indeed if cells were able to repair their DNA damage faster than it gets produced, and were able to keep their telomeres from eroding, they would not meaningfully age. They would still get somatic mutations and that may eventually, absent cell division and natural selection of fit enough cells, end up in death. Induced pluripotent stem cells, which don't seem to age epigenetically in culture, do inded drastically upregulate all DNA damage repair pathways (Liedtke et al. 2015). This is existence proof that within our genomes are they are, without any editing, there is enough repair capacity to stave off damage for a long time. One potential wrinkle to this is the case of cells that don't divide; these accumulate age-related misfolded proteins and aggregates that some argue are not digestable even by young cells. Not much research has been done on actually testing it as most research is done on dividing cells. The one paper I am aware of that tested reprogramming in non-dividing cells did see a lowering of one such pigment, lipofuscin (Ivanova et al. 2024). The jury is still out on whether epigenetic rejuvenation can comprehensively reverse this too absent cell division but I am optimistic.

Causality in biology

In biology, everything may potentially cause everything else. Feedback loops abound and disturbing one node enough will eventually disturb the rest. Impair autophagy and you probably get more DNA damage, induce DNA damage and you probably impair autophagy.

As a result, interventions targeting one aspect of the biology of aging can potentially ameliorate impairments in the rest, which can lead one to the wrong conclusion that they are all the same and there are no privileged hallmarks. "Impaired proteostasis" is more caused by "epigenetic alterations" than it is the other way around, for example.

To counter this idea and to defend a more hierarchical model with things resembling root causes, I want to point at the notion of turnover rates: most things in our body turn over. Proteins are produced and degraded, and the same goes for mRNA and most (but not all) cells. Even fibrosis turns over! That's right: fibrosis exists as a balance of generation of collagen and its degradation by macrophages, with a steady state equilibrium of "there's fibrosis" as opposed to the one where "there's no scar" (Alon, 2023).

The epigenome turns over as well: methylation marks are constantly being removed and added back. Methylation gets a lot of airtime because it is easier to measure than what argueably is the most important part of the epigenome: histone marks. These also turn over: they are deposited and removed. This may sound puzzling at first: if the cell is able to just put back marks "where it should" (ie to where young cells have them) why isn't it doing it? And the answer is that they do, but not perfectly, hence a constant ratchet towards aging.

Then there's the genome. The genome gets mutations and chromosomes get messed up to some extent with aging. But those mutations just a tiny fraction of a gigantic set of information. DNA gets copied with relatively high fidelity but it doesn't turn over much.

We should think of the genome not as a code but rather as a vast workshop with miriads of redundant tools the cell uses to do what it does. The epigenome is more aptly thought of as that code: the epigenome is the instruction set that's running on the workshop, determining whether the shop will be making neuron stuff or liver stuff, or aged stuff or young stuff.

There is then a hierarchy of turnover rates:

DNA: ~almost no turnover informationally, though DNA gets copied (cell division happens every ~20hr)
mRNA: 10 hr (Yang et al., 2003) to 16.4h (Wang et al. 2022)
Proteins: From 30 min (Ornithine decarboxylase) to crystallins in the lenses (almost no turnover) as well as histones
- Histones (of particular interest as they support epigenetic modification) bound to chromatin can last months (Mathieson et al. 2018; Shmueli et al. 2021)
Mitochondria: Days to months ( this and Poovathingal et al. 2021) though these also come with their own DNA (mtDNA) so in a way they are like DNA
Cells: Neutrophils (6-8 hours) to neurons (for life)

My claim: The slower the turnover rate of something is, the more it matters for aging. Turnover rate is like gravity in a way: Gravity extends infinitely in all directions, everything pulls on everything, but some objects pull more than others. Slow turnover rate of a biological entity is like its mass.

Think of a simple case: If you alter the proteome of a cell a little bit, briefly (you add 1 misfolded protein, other than a prion), what happens next? The cell will go back to equilibrium, degrading the old proteins and making new fresh ones. But if you were to wave that magic wand and set the entire epigenome to an aged state, then for a few hours or days you'd have an aged epigenome and some youthful proteins, but eventually given turnover rates, the aged epigenome would stay and the proteome would then be aged.

The heritability of longevity is higher than what we thought in the past (up to 50% per Shenhar et al. 2025 vs 10-30% I reported back then), and as I discuss in my Longevity FAQ it has been possible to make other species like worms live longer by 10x through manipulating their genome. Given that we already know a lot about the genetics of aging, one could make humans really long lived and slow aging by editing a handful of genes like FOXO3 or CIRBP. Genetic engineering is the easiest way to make something live longer: longevity is encoded in the genome, but for those already born and until we solve bodywide gene editing, rejuvenation of the epigenome is the second best thing we can hope.

Environmental vs intrinsic aging

This fact, that given a normal environment for a species, its lifespan is determined mostly by genetics (compare say a mouse vs a bowhead whale) is phrased by some (like Cynthia Kenyon) as aging being programmed. This is a different use of the term from those that argue that "there's an aging program that purposefully drives the organism towards aging".

The phrase "normal environment for a species" is doing some work there. For many years cardiovascular disease has been a key component of human aging. But suppose that statins, PCSK9 inhibitors and other such interventions manage to make CVD a rare disease. Humans now live longer. Suppose that we also manage to have perfect cancer treatements and we also cure cancer. Now humans live 10 years longer. In that case we would be leaving a central part of what aging is untouched: the thing that human and worm and mouse aging have in common.

That part is cellular aging. Whereas in multicellular organisms new ways of aging arise, for any one single cell, regardless of whether it is yeast or a mammalian cell or a worm cell, they all age in a similar way. Roughly speaking, the main thing that goes on in cellular aging is:

DNA damage happens (In the nucleus and mitochondria)
That leads to DNA mutations (which can later on become cancer) and epigenetic/chromatin alterations
Cells have to decide whether to spend energy maintaining their chromatin or fixing their DNA damage. Indeed some of the proteins that help upkeep chromatin are also involved in repair (like sirtuins).
This loss of chromatin stability means that regions that should be open are closed and those that should be close are open. The cell becomes less functional and resilient over time.
Eventually an insult to the cell is stronger than its declining resiliency and dies.

Besides DNA damage, telomere shortening is the other variable I'd look at as a driver of aging, though we know, as will be discussed later, that one can fix telomere shortening and one still ages similarly.

Later in the post I will argue that all that has ever been done to extend the lifespan of organisms, from caloric restriction to reprogramming ultimately boils down to mostly fixing DNA damage or reducing its production.

Clocks and their weights: DunedinPACE

I found DunedinPACE quite intriguing beacuse it predicts a rate of aging, not an absolute number, and it is popular enough that there are people out there taking the test and publishing their own results eg here.

This below is from the DunedinPACE paper showing the correlation of the marker with age for their training set (The Dunedin cohort). There is some correlation but not that as strong as clocks that predict chronological age. This makes sense because DunedinPACE was built to predict how healthy someone is and that gets worse exponentially with chronological age, and so the rate of decline has to be greater later in life.

Now if you take this and apply it to two totally different datasets (The Normative Aging Study and the Framingham Offspring Cohort) one can ask the question: does a higher score in DunedinPACE predict higher mortality and morbidity? And the answer is yes it does:

Framingham analysis included n = 2471 members of the Offspring cohort (54% women) with average age of 66 years (SD = 9) at DNA methylation measurement during 2005–2008. Over follow-up through 2018, 23% died, 13% were newly diagnosed with cardiovascular disease (CVD), and 6% had a first stroke or transient ischemic attack (TIA). Disability follow-up was conducted through 2015 based on participant reports of limitations to activities of daily living (ADLs) on the Nagi, Katz, and RosowBrelsau scales. Participants with faster DunedinPACE at baseline were at increased risk for CVD, stroke/TIA, and mortality (CVD HR = 1.39 [1.26–1.54]; stroke/TIA HR = 1.37 [1.19–1.58]; mortality HR = 1.65 95% CI [1.51–1.79], Figure 4B). They were also more likely to develop disability (Nagi ADL IRR = 1.40 [1.19–1.65]; Katz ADL IRR = 1.33 [1.16–1.53]; Rosow-Breslau ADL IRR = 1.39 [1.24–1.56]).

The average starting age in Normative aging was 77 years old and in Framingham, 66 years old. The effect sizes seem quite different and may have been affected by selection bias: In Normative Aging if you have already survived to be 77 years old you are probably healthier to start with so the clock struggles to tease out among a population of already healthy people whereas in Framingham the effect is clearer (and the sample size bigger).

In the supplement, they look at predictive power for mortality or quality of life (disability) after controlling for age. Controlling for smoking is also useful because smoking is an easy way to predict mortality that has little to do with age and we wouldn't want clocks just overindexing on this. This is quite important: there is no value if a clock is just predicting chronological age because we already have access to that. Unsurprisingly, DunedinPACE (and GrimAge, a clock built to predict mortality) do much better than clocks that try to predict just age:

One might object to this that while these clocks work on a normal population, they might fail to detect out of distribution interventions. That is: If we were to subject a human (or a mouse) to caloric restriction or rapamycin or an intervention that turns on their FOXO3 (the one gene most associated with human longevity), would this show up in the clocks? Or, for that matter, if we just give people statins (which should lower LDL cholesterol), will that be reflected in the signal?

Mechanistically, one can investigate the methylation sites (CpGs) that the clock is picking up and see what these clocks might be picking up. This is rarely done!

I pulled the CpGs from their GitHub and slapped the Illumina annotations on top, then did some ChatGPT-assisted plotting. First, ouf of 173 CpGs in the clock, only a handful are quite large, followed by a long tail (Pareto principle at work!)

probe	Gene Name	weight	Interpretation/Association
cg06570125	—	0.617	?
cg02650017	PHOSPHO1	-0.594	Diabetes, CVD risk
cg06500161	ABCG1	0.575	Related to statin use in part (ie being on a statin makes you older in the clock!)
cg01554316	GALNT2	0.515	Lipids, metabolism
cg26470501	BCL3	-0.462	NK-kB related (inflammation)
cg17460386	FAIM3	0.440	B-cell immune aging
cg17501210	RPS6KA2	-0.395	MAP/ERK signaling
cg17018786	DISP2	0.367
cg18181703	SOCS3	-0.359	Inflammation
cg15192750	—	0.354
cg05304729	MNDA	0.305	Inflammation
cg13274938	RARA	0.303	Inflammation/immune
cg10919522	C14orf43	-0.300	Smoking?
cg27165794	PNMA1	-0.300	Cancer?
cg14702960	—	-0.295
cg16924010	—	0.267
cg17439800	—	0.267	Obesity?
cg00574958	CPT1A	-0.265	Metabolic syndrome
cg01055871	EHD2	-0.232
cg09349128	—	-0.227

But are these causal? You can already see that one of the top driving CpGs is known to be driven by statin use. People on statins are plausibly less healthy but the statins are not what is making them sick. So were someone to go off a statin, their DunedinPACE score would show rejuvenation but their mortality risk would increase.

This is why it is important to look at how these clocks are constructed and investigate whether the CpGs have reasons to be causal or not.

It is also useful, I think, to present stratified mortality curves according to other biomarkers just to illustrate that mortality prediction is not anything magical that only clocks can do.

LDL cholesterol

[source]

Glycated hemoglobin (Hb1Ac)

[source]

Walking speed

[source]

Physical strength

[source; in this plot maximum quadriceps torque is depicted]

Can you lift you way to immortality? The search for causal aging markers

These examples are illustrative of the way the causality of disease and aging work: aging causes disease, and disease causes mortality and disability. As a result, disease is causally closer to what we observe (people dying and suffering) so if one tries to make predictors of those one will pick up stronger drivers or correlates of that than of the underlying driving factor (aging).

And because in the natural population the decline of everything is correlated to an extent, one can use one (grip or leg strength) to predict another (mortality) despite the fact there is a very small direct causal link between having really strong forearms and dying; rather strenght acts there as a proxy for overall health.

This is not the case for causal biomarkers like LDL cholesterol which cause the relevant disease (such that modifying it modifies the disease) and we can measure directly.

Hence we can measure the downstream consequences of aging very easily and we can predict outcomes of interest reasonably well, but that can all be done without touching the measurement of cellular aging at all. We don't even need these clocks to do that!

Suppose you could either know your DunedinPACE score or know your Hb1ac (diabetes risk), LDL/ApoB (CVD risk), your lean mass %, and the usual blood counts and metabolic panels? What would give you a better picture of your health and mortality risk. To me, it is uncontroversially clear that classic validated biomarkers are not only superior predictors but they are also directly actionable compared to epigenetic clocks. If your LDL is high you can take statins. If your DunedinPACE score is high what are you supposed to do?

To my knowledge, no analysis has found that methylation clocks are superior to composites of traditional blood based biomarkers to predict mortality and disability. If you are aware of any such analysis, let me know!

But if we have these blood-based biomarkers that work so well, what's missing? What's missing is models that estimate aging, instead of those two other downstream things.

Sure, but who cares about aging you might ask? We care about its downstream consequences right? If an aging predictor cannot predict mortality better than LDL cholesterol, what would be their use?

Good question! One that doesn't get asked often enough. Moreover, is aging even a thing you can measure with a single number? Right now we don't measure "health", we measure diabetes risk and CVD risk separately.

One answer could be "for research purposes". If we can slow down the rate of aging permanently in a mouse, then we can know that very quickly whereas waiting for a cohort of mice to die and/or get frail can be expensive and time-consuming.

Another use could be for clinical trials, if one shows age slowdown in mice and wants to take that to the clinic, one could use such a biomarker to have an early readout of whether the treatment is working or not and if its not, discontinue and save money on the trial.

In the appendix to this essay I discuss proteomics clocks, which I argue are superior to methylation clocks, and superior (and deeper) to the simple baselines of LDL+HbA1c. They do something methylation clocks struggle with: sampling different tissues with specificity; methylation clocks tell us the methylation status of a given cell type (blood cells), but not say how the brain is aging. But there are plasma-based biomarkers of CNS disorders like Alzheimer's: the organs leak information about their state into the blood, and that can be read out with proteomics. So I argue that in the future, paired proteomics clocks (for intantaneous organ-specific function) with methylation clocks (aging of blood cells) will give us a reasonable picture of how a living being is aging much better than what we currently have right now.

But now, back to the methylation clocks! We said the issue is that if we train them on endpoints like mortality, we bias them towards disease, not aging. What can we do about that?

Doing (aging prediction) by non-doing (aging prediction)

There are a couple of options to work around the limitations of the data we have with methylation clocks

Correct the mortality/disease signal by broadening or standardizing the population:
1. Try to include other species in the dataset so that it picks up what is common across them and not just in humans (diabetes, etc)
2. Develop clocks for populations with standardized environments and genetics (like lab mice or cells in culture!) to remove the effects of specific diseases from biasing what the clock picks up
3. Leverage EWAS to try to pick up CpGs that are associated with specific diseases
With a theory of aging at hand that points to drivers of aging:
1. Hand-pick CpG sites that are posited to be drivers of aging as opposed to letting a model optimize the weights (One man's taste is another's bias).

For the first approach there we can look at the CpGs of this other clock (PanTissue, PanMammalian). But this is not great: It doesn't uniquely pick out the genuine slower rate of aging of dwarf mice (thought they did claim this in the preprint and then took it back!), which by all metrics age slower, nor does it pick out the substantial epigenetic rejuvenation of iPSCs. So perhaps adding all species is bad and adds noise.

What about clocks just trained on human data, and then applied in vitro? That is more promising: these clocks show that the cells age in culture in a linear fashion (just like humans in the wild), just 60-65x faster.

The Pan-tissue clock also seems to work in patients with certain progerias (accelerated aging)

And it also performs well for Ercc1- (a DNA repair gene defect) mice (Where genetic and environmental variablity is controlled), at least for some tissues even though this clock was trained on humans not mice.

Retrotransposon clocks

Another approach to make better clocks is to handpick CpGs. A good candidate for this are CpGs that suppress retrotransposons. Retrotransposons cause DNA damage when they insert themselves in DNA and they get derepressed with aging. One can build a clock that looks at CpGs that are in Retrotransposons exclusively:

Intriguingly the authors note

Notably, we observed ourRetroelement-Age V2 clock overlapped with 9 CpGs (cg06672696,cg07286682, cg08822136, cg16936289, cg16810279, cg22277154, cg13261390, cg22277154, and cg24251135) used in AdaptAge,CausAge, and DamAge causality-enriched epigenetic clocks recently developed using Mendelian randomization (Ying et al., 2024). This observation suggest some of the signal from our Retroelement-Age V2 may include sites that contribute and/or protect against aging.

This works for reprogramming:

It also predict aging in vitro:

Alas, this clock hasn't been applied to other datasets in eg slow aging mice or mice subjected to caloric restriction. A similar approach, however, has, and that shows the expected effects:

For context, these Snell dwarf are a well known case of slow aging:

It also seems to match with the idea that bigger dogs age faster (bigger dogs have their retrotransposons derepressed faster):

I really like the retrotransposon clocks! They do seem to be neatly tied to DNA damage. With these, I think we have some grounds to believe, given what we know about retrotransposons, that if one were to see a slowdown in this clock, one would have thus slowed down aging. But we could not be maximally confident: If someone developed an epigenetic editor to methylate all these retrotransposons, that could drop the Retrotransposon age to zero, and yet that wouldn't necessarily reset aging as it is not the only source of DNA damage. Using this clock would be valid especially if one's not specifically targeting retrotransposons, but even then I would suggest using a panel of approaches and not just this one.

Aging clocks with mouse-only data

Other clocks, developed specifically for mice are also able to pick this up, doing it better (greater separation) than what the Retrotransposon-only clock does:

And later this one as well, also from the Gladyshev lab.

Aging clocks through EWAS

More recently, we got this paper from the Gladyshev lab that I really liked trying to build "causal clocks". The idea here is to carefully tease out what CpGs might be associated with pro-aging vs those that are differentially altered with chronological aging as a response to aging. The fist one they call DamAge clock, the second, AdaptAge. DamAge passses the reprogramming test (age drops with reprogramming):

It picks out progeroid damage, exposure to cigarette smoke, and exposure to UV light (ie skin samples exposed to the sun vs non exposed)

Here the other clocks fail to pick this up, in fact some say UV exposure slow down aging! But no, what they are probably picking up is mechanisms that counteract aging in those cells. DamAge correctly assigns a score similar or greater to these exposed cells.

In vitro, the effects are more stark, exposing cells to cigarette smoke shows up cleanly only in this clock:

Intriguing. So what is this clock picking up? The weights are here. Doing the same as before, here's some ChatGPT interpretation.

First, most of the weights of the model are negative: this means the CpGs picked up are to be interpreted as "the more methylated the gene is (the less expressed), the lower the damage"

These are the top 20 CpGs

CpGmarker	CoefficientTraining	UCSC_RefGene_Name	Interpretation
cg07850154	-33.64986406	RNF180	Also here, involved in proteostasis. The entire gene seems to get less methylated over time.
cg02254885	-31.56205228	EFCAB3
cg05463027	-29.7405477	KIF13A
cg08529529	-27.93679343	ALOX5AP	Also here
cg08526814	-24.67192062	DNTTIP2
cg07495704	-23.24721626
cg02867102	-22.53153968		Also in GrimAge, smoking
cg04229059	-19.17402516	SLC38A7
cg22652782	-18.1396963	MYBPC2
cg01082242	-18.03942941	HIF1AN	Inhibitor of HIF1a (hypoxia inducible factor).
cg08593364	-17.42228852	SLC35F2
cg08081725	-16.50151564	NDE1
cg23282585	-16.24094824	HIST1H3G	Histone H3.1 (replication-dependent). More cell replication? Picking up cancer?
cg09754948	-15.80284482	ATXN2L
cg26635214	-15.1806246	HSD3B7	3beta-hydryxosteroid dehydrogenase type 7: bile acid synthesis.
cg15063695	-14.61865262	GK2
cg03950166	-14.36951799	FAM108C1
cg01557754	-14.19144026	FGF11
cg02339392	-13.60087486	ZNF187	Associated with CKD
cg03520471	-13.57242019	GABRR3

Then here's pooled by gene

This looks much better than DunedinPACE: the CpGs and genes picked up are not obviously tied to diabetes and metabolic syndrome! But it's still hard to interpret.

Aging clocks with in vitro data: Polycomb Repressive Complex sites

One last way I'll discuss of constructing more robust models to track cellular aging is training them in vitro where organismal-level disorders are not relevant. This, as it turns out also has its problems.

The EpiTOC/pcgtAge clock (Yang et al. 2016) was constructed by handpicking as opposed to running a regression which makes it more robust to allegations that it's picking just a correlation. What they do is pick PRC2-related promoters that get hypermethylated with age in blood samples and that start with no methylation across a range of fetal tissues, then the score for a given sample is simply the average methylation across those CpGs. This can be used to predict human chronological age, and it also correlates with the number of cell divisions estimated for stem cells in different tissues, which matches also with other clocks that pick up tissues that turn over faster as faster aging. Note that in this picture below each point is a different tissue from a person of a different age.

A later model, EpiTOC2 (Teschendorff 2020) further expands this methodology, using fewer CpGs.

The original Horvath clock has 353 CpGs that are jointly fitted to estimate the chronological age of a sample. This is not great because

a) Plausibly some people might have aged faster or slower but we are telling the model that two samples have an age of exactly their chronological age

b) Different tissues plausibly have aged faster and slower but we again tell the model to assume that they all have the same age

EpiTOC2 instead models each CpG individually, they say that the methylation at a site equals is a function of someone's age, how often stem cells divide per tissue, and how likely is that a cell division will lead to an increase in methylation. Doing this they fit one model per CpG (3 values to fit), then pick the modal value of the stem cell division rates estimated (should be the same across CpGs because they are all replicated jointly) and fit the model again, this time with just 2 values (de novo methylation probability and the ground state methylation).

Though this all is done in blood, their model is posited as universal per cell division so then this model fitted in blood can be applied to other tissues. So given say a colon sample, one can measure the actual methylation and knowing the age of the person one can calculate the number of stem cell divisions for a tissue. They find their estimate of this parameters correlates reasonably well with literature estimates of how often stem cells divide per tissue

Moqri et al. (2024) did something similar in concept (picking PRC2-associated sites and averaging their methylation) but without modeling, they just find those PRC2 sites, pick 1000 with the most PRC2 binding and average the methylation of that.

This, they explicitly note, is what explains ELOVL2 (discussed later): It is one of those PRC2 associated sites!

Exciting, isn't it! But: Is this causal? If we were able to revert this clock while leaving everything else unchanged, would we revert aging? I don't think so!

I looked into why is it that cells keep adding methylation at these sites and the reason seems to be that initially those genes are silenced during development when cells are comitted to a fate, by depositing H3K27me3 (a histone mark) on it. But during cell division, this gets diluted and to compensate, the cell methylates those sites to continue to repress them (Yang et al. 2023). This means that these PRC2 methylation sites are non causal! They are an adaptive response. The implication of this is that if we were to remove them without adding back H3K27me3 we would make the cells younger "by the clock" but make them less functional. Conversely, this means it is also possible to make the cells genuinely younger while seeing no change in an epigenetic clock that heavily indexes on these sites. It also means that the sometimes reported age acceleration in cancer might just litearlly be a proxy for their higher rate of cell divisions (Rozenblit et al. 2022).

Everything is connected: epigenetic clocks are not unique, but they are convenient

The state of a cell is the aggregate of everything that's happening in the cell: how many mRNAs of each type there are, concentrations of proteins, what chromatin is closed, etc.

But it's all connected: One influences the rest. As a result, if one measures deep enough a cell, one can reconstruct the rest of the state from that subset. From the genome and chromatin one can predict gene expression, and from gene expression one can predict protein abundance and chromatin accessibility³ .

[3]. This requires the entire transcriptome; the correlation between mRNA of gene X and abundance of protein X is very noisy as this is influenced by post-translational regulation among others. This effects can be addressed by sampling the whole transcriptome which will contain e.g. those genes participating in post-translational regulation

If one believes this then there's the question of "how deep to sample" and "what sorts of things can be sampled". The genome is not that useful in general for aging because cells can mostly work around the damage that the genome is subject to, though one can predict aging, albeit noisily from somatic mutation accumulation (Alexandrov et al. 2015; Koch et al. 2025), one would not be able to predict say cell type just from the genome whereas this is possible from the other, more dynamic -omes.

Single cell RNA seq is something people have tried to make clocks out of (Buckley et al. 2022) but generally those approaches rely on pseudobulking cells to reduce the noise of mRNA expression. Bulk RNA clocks work much better. But still they seem to be noisier than methylation clocks or, for that matter, bulk ATAC clocks. Chromatin is more stable than mRNAs and so a better thing to measure to get a consistent readout of state unbiased by transient effects.

The full proteome, as of today, is more expensive to measure, and we can't quite fully measure all of it, but if we were able to, it would probably also work fine to build aging clocks out of.

That makes methylation (or chromatin, even better) as the most reasonable way to make and use aging clocks.

Epigenetic clocks and organismal aging

When someone says that doing something changed their epigenetic age what that really means is the same as when someone typically makes a claim about their telomeres having lenghtened. It usually means the epigenetic age of the cells in the blood. That epigenetic age can change for various reasons:

Change in cell type composition (which now some clocks try to correct for)
Death of older cells "Rejuvenation by depletion (as in senolytics)"
Replenishment from younger cells; this would have to come from rejuvenated hematopoietic stem cells in the case of blood.
Change in state towards less inflammation. As in most populations older people have more inflammation, a reduction in inflammation would register as reduced aging.
- This also explains why what the clocks measure seem to increase and then decrease during disease (Poganik et al. 2023)

Additionally the readout of a clock can be biased by the source population in the training set. If you take say all Americans and build an aging clock on that and then a person that's fairly healthy does it, it is likely that they will show up a bit younger in the clock and that might be because of less inflammation.

That said, if someone has a substantial (say >10 years) reduction in their own personal score, I would take that as evidence of robust rejuvenation for cells in their blood. This has been achieved, to my knowledge, only through bone marrow transplantation, where an old person gets bone marrow from a younger donor; in that case the old person ends up with a real legit rejuvenated blood system (Soraas et al. 2019)⁴

[4]. At Retro Biosciences, where I work, we're trying to do this with iPSC-derived HSC

These people have a younger epigenetic age and do live longer (DeZern et al. 2021), but they do not live nearly as long as the drastic reduction in epigenetic age would imply. That is, you can have "20 year old blood" in a "80 years body" and clocks would totally fail to register that the rest of the body is not quite 20.

Do neurons age?

It seems one of the most stressful things a cell can do is divide: tissues with more cell division age faster. This then leads us to the question: what about tissues where the cells don't divide much like the brain? Do those age very very slowly?

If one takes DNA damage as the prime mover in the aging process, one can look at kinds of DNA damage in DNA mutations: we have more access to that kind of data than we have for DNA methylation because people have been extracting tissue samples from all sorts of tissues for cancer research. This data has been analyzed for patterns in mutations and some emerged that seemed to correlate fairly well with chronological aging (Alexandrov et al. 2015). The two biggest "clocklike" signatures are SBS1 and SBS5 (Spisak et al. 2024), which together represent half of the mutations one will accrue with aging. SBS1 seems to nicely track cell division rates as it is flat in neurons and much accelerated in colon.

What is this SBS1? It's a signature of mutations from C>T at CpG sites caused by spontaneous deamination. That is, if we have a CpG site, it can either become demethylated, so the CG with the methyl in the C becomes TG. This seems like a good candidate for the "driven by cell division" component of aging, specifically that involving demethylation. Importantly, because it's driven by a mutation, that CpG site is gone and can't be remethylated again! SBS5 might be a proxy for a a cell-replication independent process that aggregates various kinds of damage (Spisak et al. 2025). This rate is also tissue-dependent, so the rate of damage generation is also probably cell-type dependent. The germline as well as muscle seem to age quite slowly. The former is no surprise, the latter is and I wonder why it might be.

We can see here that if we look at absolute magnitude, neurons should also be aging (~225 mutations total vs 300 for lung). Turns out a lot of these mutations are cell-replication independent!

Given what we have seen thus far, if we applied a clock to a region of the brain like the cerebellum that's mostly neurons and see if it ages slower: If a good amount of what the clocks pick up is cell division (through PRC2) as a proxy for chronological age then they may underestimate their real aging.

At a high level, the cerebellum becomes less functional and shrinks in size (Arleo et al. 2024). Epigenetically, the cerebellum does seem to age slower in the usual clocks: It is possible to construct cerebellum-only aging clocks (Wang et al. 2023) and if one applies those clocks to other tissues then one observes that it is the other tissues that age faster. Here's the original Horvath clock (Pan-tissue clock) on cerebellums:

And Horvath 2018 (Skin&Blood clock) is even flatter, perhaps because skin and blood are tissues where there's higher turnover so this clock is picking up more of that cell-division driven aging signal.

When looking at it, they indeed find that compared to other brain tissues, the cerebellum is less methylated at CpG islands, which tend to be PRC2 binding sites, the changes that they do see are smaller and there are fewer that are significant.

One model we could try to explore for neurons is that by and large they don't age and that all variation in cognitive abilities can be explained through neuron loss instead of reduced function: just like with naked mole rats (Ruby et al. 2018), which don't experience an increase in their mortality rate over time, they still eventually die. As we largely lack neuronal stem cells, once a neuron is lost, it is not replaced, which would then explain the decline in cognitive abilities.

But in healthy human beings one doesn't see much cell loss in the hippocampus and enthorrhinal cortex in healthy patients, both areas greatly affected by Alzheimer's in their sample, with rates of neron loss of up to 50% (Price et al., 2001).

Neurons become senescent over time (Hudson et al. 2024) and senescent cells are overall less functional so despite the clocks saying neurons age slower (or not at all), given that cognitive faculties do decline with age, we should take this as evidence that we shouldn't trust the clocks here.

Better is worse: desiderata for a gold standard aging predictor

If you train a model to predict mortality in humans, it is likely the model will learn to pick up correlates of things like diabetes or heart disease. This is indeed what happens with newer generation aging clocks, which I discussed earlier. This would explain why on some of these clocks things like an infection or losing weight reverts epigenetic aging.

An aging predictor ("clock") should take in some data (could be the epigenome, metabolome, etc) about an organism and return a biological aging score. For us to think that the model is measuring cellular aging, the follow would have to be true:

Chronologically older individuals, on average, present as biologically older by the clock
The clock ticks in vitro as well, though it may tick at a different speed
iPSC reprogramming largely resets the clock
Gold standard age-slowing interventions like caloric restriction or certain knockouts (growth hormone receptor mice) slown down the ticking of the clock
DNA damage should accelerate the clock while the insult is being applied (eg. radiation, chemotherapy) and progerias should have the same effect
The score is somewhat predictive of mortality risk and health conditions above and beyond chronological age
Ideally, but not necessarily, able to do the above across species and tissues
The model should be able to be trained from in vitro data to predict in vivo data and vice versa
The model should be examined for causal plausibility; ie it should be known how it works. This need not be causal; eg later I discuss entropy-based clocks where each specific site does not matter, and instead what matter is the higher level noise being measured.

It is acceptable if such a model ends up being a worse predictor of disease and mortality than models directly trained to do this, for reasons already argued.

Somatic mutation accumulation correlates with aging

Earlier I said that DNA damage is what drives a good chunk of aging. Worse DNA damage repair also leads to more somatic mutations and their rate of accumulation (single base-pair mutations per genome) correlates with lifespan. This accumulation seems to be linear in a given species.

If one takes those rates for various species and plots their lifespan, one gets a nice curve:

Their equation for lifespan is L(years)=3206/mutations; taking the baseline rate for a given species: Lifespan Fold Change=1/Mutations Fold Change . So for a mouse for example if we were to halve DNA mutations we would get a lifespan of ~8 years, roughly a doubling. The same would be true for humans (half mutations=double the lifespan).

This is for crypts in colons which should be among the tissues that mutates the most (and hence ages faster (and gets more cancer)):

This paper pairs well with Crofts et al. (2023) , a very similar one that does the same thing but with methylation where the result is essentially the same, though they apply it to different tissues (blood and skin) and use a different definition of lifespan (maximum recorded lifespan for an organism). Similar ideas are contained in Bertucci-Richter & Parrott (2023) or Horvath et al. (2024) who also ties this in particular to specific rates of methylation in bivalent (PRC2) promoters (promoter with both repressive marks like H3K27me3) and activating marks (like H3K4me3).

Bowhead whales are quite based entities; as you would by now expect, their cells are remarkably resilient to radiation through better DNA repair (Firsanov et al. 2024). They also run colder which would help explain why it's easier to repair things (less entropy). Their cells divide slower than human's: they take 2x the time to divide and they live about twice as we do. Intriguing isn't it! Does this work in reverse? Do mouse cells take ~40x less time to replicate? Not really! So it's not just just slower cell replication.

Can't we just use somatic mutations (in particular the SBS1 and SBS5 signatures) as a clock? One could try: If you sequence someone's blood cells say, subject them to some intervention for a year and then come back and estimate those signatures, if their DNA damage repair is better, their signature will have ticked up less than controls and from there one could infer slower biological aging. But that wouldn't work for measuring age reversal, as iPSCs retain their mutations but have the rest of the aging phenotype wiped clean.

And are dwarf mice or mice on caloric restriction experiencing less mutations? They indeed are. Are humans undergoing chemotherapy (which also leads to accelerated aging) accumulating more somatic mutations and have a faster ticking clock? Yes to both.

Are cells from longer lived species more resilient to DNA damage? You bet! (Hall et al. 1984)

Somatic mutations and methylation drift are linked because one (the former) causes the latter (Koch et al. 2025). Accordingly, their rates of change vary similarly, and are connected to some extent to cell division, hence DNAme age and most of the somatic mutations occurs during development and then stabilize to a stable rate of ccumulation thereafter (Spisak et al. 2024.)

Axolotls!

Not every living being seems to age similarly from an epigenetic perspective: axolotls don't age epigenetically after development (Haluza et al. 2024):

Here, we conduct DNA methylation profiling of axolotl tissues at CpGs associated with ageing across mammalian and amphibian species. We develop axolotl epigenetic clocks at both panand single tissue levels and uncover that axolotls exhibit conserved epigenetic ageing traits during early life but not thereafter, deviating from the established notion of organismal ageing. We reveal that, in contrast to mammals, the axolotl methylome is remarkably stable and does not exhibit substantial shifts at either global or PRC2-associated gene levels late in life. These findings offer critical insights into the nature of negligible senescence.

Axolotls live to ~20 years (Yun 2021) and don't seem to suffer from much cancer, their telomeres are very long and express telomerase to maintain them (Yu et al. 2022), and a result they don't accumulate senescent cells like we do. Their aging is, as is that of Naked Mole Rats, not Gompertzian but rather their mortality rate is constant through life.

Why do they die, one might wonder! The answer seems to be predation, infections or poisoning or things as silly as choking on gravel. So plausibly, if someone was dedicated to making their axolotls live for 2x or 10x their normal lifespan by having antivirals or antifungals that are safe for axolotls, that might actually be achievable.

Beyond the epigenome: cancer and telomeres

Human beings die and cultured cells get senescent in vitro, but there are cases where cells seemingly just keep growing without ever dying (cells that are made to express telomerase being an example). What does this say about aging?

First, a reason cells stop growing is that their telomeres shorten enough that they enter replicative senescence. Telomere shortening is one of the bottlenecks for continued life that living beings face, but this bottleneck may become a constraint on lifespan before or after epigenetic aging; if it is mostly after then telomeres don't matter much for aging. One way to test this is by giving a cell or an animal artificially long telomeres and seeing what happens. The Blasco lab did that, observing mice live a bit longer, were less diabetic, had lower cholesterol, and were overall healthier. Moreover they also observed that the rate of telomere shortening is related inversely to lifespan, same as DNA damage repair:

In humans, diseases where telomeres are extremely short exist, Dyskeratosis Congenita being one so we can test what happens if you have very short telomeres. This is useful to see which cells or organs are most affected: predictable it is those with fast turnover like skin or the bone marrow (as opposed to say, the brain where cells don't divide much). These patients can live to the age of 60 whereas patients with defects in DNA damage repair like Cockayne syndrome live to 12, highlighting the relevant importance of these two mechanisms: telomere shortening is bad but not as bad as epigenetic aging as a whole.

Moreover, we know that if one keeps telomeres long artificially, cells continue to epigenetically age (Kabacik et al. 2022) and though full reprogramming to iPSC lenghtens telomeres through TERT reactivation, partial reprogramming doesn't necessarily (Doğa Yücel & Gladyshev, 2024): these two mechanisms can be modulated independently but they are probably co-caused because telomeres shorten not only determinisitcally upon cell division but also with DNA damage, so more efficient DNA damage should also make telomeres shorten a bit slower.

I had said at the beginning that the aged phenotype is an inflammation-like state triggered by DNA damage. Telomere damage as well as shortening is one of those triggers, through the cGAS-STING pathway (Yang et al., 2017, Hewitt et al. 2012, Miller et al. 2025).

Ok so we know we need to eventually fix the telomere issue to progressively increase lifespan, which is tricky to do (Seemingly some compounds can reactivate telomerase so not all hope is list, see Shim et al. 2024). But suppose we just express telomerase to get rid of this problem. What happens to epigenetic aging when cells can just keep going? Do they eventually die of epigenetic aging?

The answer is of course not: If one takes HeLa cancer cells, isolated in 1951, to this day they continue to be used in culture. These cells are chromosomically unusual, having triple the number of chromosomes human cells have. Horvath looked at cancer in his original 2013 paper, finding that cancer cells seem more epigenetically aged per his clock, with ages increasing to 177 years over the donor age in one cell line. These results are more clean with the EpiTOC clock but that may just be cell divisions. I don't necessarily buy that "cancer is more aged".

Plausibly, epigenetic aging breaks down in vitro as cells eventually find ways to survive through mutation and natural selection: epigenetic aging is an issue for us because we want the cells to be in a certain way that fits well in the multicellular whole, but with cancer, cells just have to grow and divide; if a cell fails it dies so as a whole the population becomes truly immortal by constant evolution. Imagine say that some site in the genome. I couldn't find a dataset of cells cultured in vitro for a very long time where epigenetic age is measured but what I expect would happen is that epigenetic aging would continue to increase and then become very noisy: CpGs that used to exist might mutate and disapper, genes or chromosomes might duplicate so CpGs appear twice, etc.

In my What is Aging post, I described aging as a drift away from fitness. Cancer illustrates the limitations of this definitions: cancer itself may be quite fit at replicating but it lowers the fitness of the organism it is in. I think it is still possible to define some notion of aging for cancers but I haven't thought much about it.

iPSC reprogramming as a test for aging measurements

iPSCs are a great construct to study aging. Their epigenetic age is ~zero regardless of the age of the cell of origin, and when differentiating cells out of them, one obtains young cells. If one accepts them as equivalent to embryonic stem cells, it is warranted to assign them a ground truth age of zero, so one could use that to train models to predict age, or to test whether an age predictor yields the correct answer. This may be a unique property of iPSCs, in that if one takes a cell from someone that is 74 years of age, the "real biological age" of their cells won't be exactly 74, that person may have aged faster or slower.

But somatic mutations are still there. Plausibly mitochondria are less functional than that person's original ones because the mtDNA mutations are still there. But other than that, if we could get as rejuvenated as an iPSC gets, that would go beyond anything anyone has ever achieved with any anti-aging intervention.

Not only iPSCs have an age of zero: they don't epigenetically age in culture²

[2]. Although the paper claims radiation does not accelerate epigenetic aging, this is either because the radiation dose was low or the clock is not good enough. Mechanistically it must, and empirically the mortality rate of e.g. mice raised lifelong under radiation is increased in proportion to the dose (Strehler 1960). Note the Horvath clock there is unable to tease out the increased aged of UV-exposed fibroblasts while other clocks can

, though they do accumulate chromosomal abnormalities if one keeps them dividing for long enough. This fact hints at the possibility that, per my speculations above, they are able to massively drive up DNA repair capacity beyond damage received and stay ahead of decay: this is indeed what is seen when making iPSCs through reprogramming (Paine et al. 2023)

Comparing cellcs in steady as Liedtke et al. 2015 did shows the same results(Here BM MSC=Bone Marrow Mesenchymal Stromal Cell, USSC~neonatal MSC; iPSC=induced pluripotent stem cell). NHEJ, HR, NER, etc are all DNA damage repair pathways.

My interpretation of this is that there is capacity already in our DNA to do so much repair that aging can be drastically slowed, if only we find a way to turn that on without also turning a cell into an iPSC. It is another question whether cranking up DNA repair alone would reverse aging, that remains to be tested.

How is reprogramming able to erase epigenetic aging? And what does this tell us about rejuvenation broadly? I used to think that methylation (and the epigenome, broadly) was largely "set and forget" and that the way iPSC reprogramming works is through resetting the epigenome, wiping it clean, and that perhaps the iPSC/embryonic state is uniquely stable or something like that. If that is true, then there would be no way to decouple pluripotency from rejuvenation. Rejuvenation in this case would be resetting, and this is something that cannot be done in vivo. I mean, people have tried, and the outcome is dead mice (Abad 2013).

Of course, people have by now done reprogramming partially, with substantial benefits in progeria mice (Ocampo 2016) and lesser benefits in wildtype mice (Macip 2024) in terms of lifespan. Some benefits have been observed as well for CNS disease models (Anton-Fernandez 2025; Xu et al. 2024; Rodriguez-Matellan et al. 2020). We too have seen some good results at Retro. So it kinda works when done right, but it is limited.

But reprogramming wasn't discovered by searching for rejuvenation, it was discovered by searching for ways to make cells embryonic, which is not what we want.

But what's next? One approach stems from the observation that the TFs that are lost with aging in a given cell type tend to be the TFs that made that cell type such, i.e. "identity TFs". Empirically, re-expressing these TFs rejuvenates cells. For example, HNF4a, if expressed in liver, gets you a younger liver (Yang et al. 2021). This is quite powerful and it already works, but it is limited to specific tissues where one can deliver the relevant cargoes.

Another approach could be chemical rejuvenation. Small molecules have already been used to make iPSCs (Wang et al. 2025) and it turns out to be more complicated than with OSKM. That's good! It means there's more margin of safety before causing cells to de-differentiate in vivo. Some of these chemicals have very recently been applied to rejuvenation. It is still early days, there is only a fistful of papers doing this, but the result establish a crucial "zero to one" proof of concept: it is possible to do things like reducing DNA damage, markers of senescence, and DNAme age purely with chemicals (Schoenfeldt et al. 2025; Paine et al. 2024) though when tested in mice it doesn't quite work yet (Wayne et al. 2025).

Aging: stochastic vs deterministic

Some papers in the clocks literature have pointed that it may be moot to try to analyze this clocks much because some or most of what is observe, they argue, may be due to a random process. You might have an intuition that this is impossible: how could one build clocks then! But that intuition probably comes from assuming gaussian noise with a mean of zero. However, imagine a random walk that is bound by 0 and 1. In that case, no matter where you start, the population average will tend towards 0.5 over time.

And given that we have a trend, one could then train a clock on it, but it would be a clock built purely on noise, epigenetic drift. This model is not true, however as I'll point out in a.second.

So is it just noise? Some might be, but it can't all be noise (in an 'everything becomes mush equally' sense), some of the oldest known age-related CpGs like cg16867657 in ELOVL2 do not look like a random process that tends towards 0.5 (Slieker et al. 2018). Note also that in the cerebellum (mostly neurons, which don't divide) this CpG barely changes, similarly to what's observed with methylation clocks, suggesting that cell division may be be the main contributor to epigenetic aging. The tissues that do age do not show the pattern expected from random drift, rather the opposite is true! Observe that if we only looked at tissues where methylation starts very low (like muscle) then someone could argue that that rising trend is compatible with the stochastic process described earlier, but here we see that for tissues where the methylation starts higher like subcutaneous fat or monocytes, the trends is to continue to increase, not trend down towards a mushy 0.5. Furthermore not only is ELOVL2 like this cross-sectionally but also longitudinally: the trends have a similar slope for many individuals (Figure 4 of Bacali in et al. 2016) And in this dataset containing a bunch of iPSCs, the methylation level for this site (cg16867657) is <10%, as one would expect by continuing to extrapolate to zero.

Hence we have existence proof that there are patterns to methylation changes, they are all not random. This is compatible with aging being a process driven ultimately by entropy.

Let's look at papers that posit that what the clocks measure is stochastic change. One thing to bear in mind here is a bit of a political aspect within the field of aging research: there are those with strong opinions about whether aging is programmed (as in it was selected for) and whether aging is stochastic random damage accumulation. Those that say it is programmed take the patterns picked up by the clocks as evidence of a program of some kind, and it seems that as a reaction to that there are some papers arguing otherwise: that it's noise and that noise as I argued above can still lead to a clock. There's then another camp that argues that it's noise and that the regulated patterns we see are damage responses. This was the original view of Horvath in his clock paper.

My own view is: at source it is random, but cells reliable transform that randomness into patterns we can observe at a higher level than individual sites in the genome. Earlier, for example I described the PRC2 sites: The loss of repressive histone marks at those sites is random, and in turn the methylation increase of those sites, though a regulated process meant to replace the histone mark loss, appears random as well even though it's not.

Car aging as a way to understand human aging

To use an analogy, cars are not explicitly designed to break down but they are also not optimized to last forever either. Parts have different durabilities too so on average in the "aging" of a car one will see that the tires and break pads need replacement, then later the motor and then eventually the chassis might rust and fall apart (A similar analogy was used, as I found after writing this paragraph, by Leonard Hayflick in 2007). In some cases some parts might break faster than others by chance or because of a particular environment (imagine someone slamming the brakes all the time, then those might break faster). If one looks at a population of cars one will observe a pattern of parts breaking down in specific ways. However, if one were to look at a part closely (say a brake pad) at some microscopic level maybe that damage is random.

We can draw analogies between car aging and human aging:

If we were to measure a bunch of attributes of a car (absent part replacement) we would be able to build a clock of how long has the car existed. That would not guarantee us that those attributes are causal. That is, we may be able to infer how dusty the car is from how chipped is the windshielf
One of those attributes might be the condition of the fake leather in the steering wheel. That may correlate with the "lifespan" of the car but causally, fixing it does not cause the car as a whole to last longer. This is akin to CpG changes are not tied to lifespan but rather some sub-function that is not critical for survival.
Given replacement however, a clock trained on how worn off tires are would be no longer informative of how durable a car is after one changes them. This is similar to how epigenetic clocks trained on blood would tell someone that their age is that of a child if they were to receive a full bone marrow transplant from a child.
One can take a composite of metrics of the car (how beaten down it is broadly) and use that to define 'car age'. This would be similar to Pace of Aging or PhenoAge and be subject to the same caveats as those metrics are.
One could take the same car and sample it over time and do this across a population and notice what tends to predict the rate of decline overall. Perhaps you observe that cars with lots of debris attached to them (markers of the drivers driving them on roads in poor condition) tend to decline more. Then you could build a CarPACE (like DunedinPACE) clock that tells you the rate of aging depending on the amount of debris in the car. The debris wouldn't be driving aging, they would be a correlate of it, and one that's superficial. While starting to drive in better roads would reverse CarPACE, wiping clean your car would do it as well though the rest of the damage would remain.

These examples illustrate that just because some things are correlated in a system doesn't mean they are causally connected (This from Judea Pearl is a good read on the topic), which means that under a causal intervention they may no longer change (the correlation breaks). This happened recently in a trial where before the intervention, epigenetic markers were well correlated with actual metrics but after the intervention they were not (Kou et al. 2025)

And now we can ask: What would a "intrinsic aging" clock in a car look like? The answer to that is the key to understanding "intrinsic aging" in a human. Obviously, the "intrinsic aging" of a car is not a very useful concept. Parts are made of different materials and break at different rates. They are differently affected by the environment. They do share some commonalities: it may make sense to define the age of the tires and all 4 will be related, or the age of the steel of the chassis as a whole, but it makes little sense to bunch those together.

Then, once we have defined the various "ages" we can try to predict outcomes of interest. Not all ages will be relevant for the purpose at hand and in the same way. "Tire age" may mostly not matter for when a car will have a mechanical failure except if they are extremely overinflated and blow up. Perhaps "car lifespan" ends up being driven and predicted purely by "engine age" if that's always the first component that always fail. Whereas "car healthspan" (energy efficiency, aesthetics, other things apart from mechanical failure etc) could be predicted from other "ages" like the aging of the interior plastics, tire age, etc.

Bringing this to humans, paradoxically we hava en easier job because we are made mostly of cells, so if we have cell age we have already captured most of aging. And in turn because cells turn over most of their components, and we know what limits cell function, we can define cell age as a composite score of: telomere length, somatic mutations, and epigenetic state. Out of these we could then try to make predictions, and I expect for many aged phenotypes, it will mostly be the epigenetic age that will carry the most causal power.

Then we can look at other changes with age that we can easily get our hands one: the mechanical properties of our bodies (stiffness, elasticity) are a function of cells and their extracellular environment (the extracellular matrix) which may or may not change with changes in cell age. Of particular interest here could be arterial stiffness as it predicts cardiovascular disease.

Methylation turns over: cars at not cells

Is methylation "set and forget" without much turnover, where once it is lost, it can never come back or is it constantly being adedd and removed?

At a population level, if one measures bulk methylation (as is common when measuring methylation), methylation doesn't change much in the short term (Furukawa et al. 2015) except a small number of sites (Komaki et al. 2021) but that doesn't mean that a given CpG in a specific cell hasn't turned over. As a result, the methylation clocks, if sampled on the same person over and over tend to give relativelt similar results (Komaiki et al. 2022). This paper is also of particular interest to those interested in measuring aging: Eyeballing the charts there means that a change in DNAme aging under 10 years may be noise. This can be overcome if one has a larger sample and one is looking at a population as opposed to an individual; eg in Poganik et al. (2023) they are able to detect changes in DNAme age after various medical procedures; where some of these changes are reversible. I take this paper as evidence that a good chunk of what many of these clocks are measuring correlates of inflammation, and that intraindividual variation can be large and in unexpected directions: Looking at Figure 3 does not inspire much confidence about the clocks!

So if we can't quite track a single cell's methylation level yet, what can one do to see if methylation turns over or not? One can interrogate this question by first looking at the underlying biology: Methylation is known to be established actively by DNMT3 ("de novo") and then maintained by DNMT1. It can be removed by TET enzymes. One can then inhibit these to see what happens. If methylation is constantly being churned, altering the balance of the actiity of these enzymes will result in rapid under or overmethylation whereas if methylation is "set and forget", knocking out those enzymes will matter less. The current understanding is that methylation (Parry et al., 2020 [Reik lab]) at least in stem cells (Ginno et al., 2020), where it has been studied the most indeed does turn over a lot. So a single CpG may be methylated now and lost in 5 minutes, then remethylated later, etc. This is unlike DNA, where a base pair is not constantly flipping back and forth from AT to CG.

As a result, methylation is, as the paper earlier puts it, "not bound by the strict constraints imposed by the rules governing thermodynamic equilibrium". In a closed system, entropy always increases so if there were no enzymes touching the CpGs they would all lose information and turn towards random mush (50% methylation in bulk everywhere) without any hope to recover that. But that is not the case: CpGs are not a closed system. It is this fact that allows for epigenetic rejuvenation we see in reprogramming across the entire epigenome. I want to remark on this again: Cells 'know' to some extent that a given site 'should' be methylated or demethylated, whereas they don't know if a given site in the genome should be an A or a C. Experimentally, one can inhibit methylation and drop it to 50%, then remove the inhibitor and cells can remethylate to some extent back to where they were (Wong et al. 2011). This is again very much unlike what happens if one induces mutations in DNA, they just stay there. As to the how is this happening, the idea of error-correcting codes might give us an idea: multiple histone marks, CpGs nearby, etc can help the overall system keep homeostasis (Bruno et al. 2022; Wang et al. 2020) in the presence of small local disturances. See here for a fun interactive demo.

The reason methylation changes with aging is that cells don't have enough capacity to overcome the drift that occurs. Hence, I predict, if the rate of damage generation were to be reduced, or the turnover increased, it might be possible for cells to put energy back into restoring the epigenome and thus reverse epigenetic age. Some evidence that CpGs with higher turnover are better maintained is Ming et al. 2020, and some evidence that a cell that is hypomethylated (through less active DNMT3) can bounce back when it gets it back is Li et al. (2024).

Hence, whereas both in cars and cells the alterations we observe is ultimately due to entropic reasons, cars have no means to repair the damage that has occurred, they are not constantly remaking themselves whereas we, to an extent, are.

Aging as entropy

At the root of aging there's entropy: The structures holding information (DNA and epigenome) in cells deteriorate over time in a way that is at the same way stochastic and patterned. This is no different from what happens to any system that exists where the rate of generation of entropy is higher than what the system can dissipate.

A consequence of this is that whereas young individuals are very similar in a way, aged individuals (or the aged epigenome) can look very different. In every fetus perhaps a particular site in the epigenome is closed whereas in older people, it will be closed in some and open in others.

Picture 100 glasses of water at room temperature. They all look the same. Now picture 100 glasses of water that are boiling (increasing temperature raises entropy. They all have high level structures (water bubbling) that let you tell that they are hotter, but if you took a picture of them all, the exact place and size distribution of the bubbles would be different. This is what I mean when I say that aging is at its core the product of noise and yet that noise gives rise to observable, predictable patterns across individuals.

Stochastic aging clocks

Let's now look at the papers that discuss the entropic nature of aging.

Mei et al. (2023) from the Conboy lab points out that many CpGs in clocks do not change consistently with age and that when one removes CpGs not picked by the clock from the training set and retrains, then the clock picks different ones. So perhaps clocks might be doing some amount of overfitting? To work around that they posit that certain methylation sites are particularly important if they are invariant with age in general and that if those get disregulated then one would be more aged. They also do something hilarious and quite, dareisay, based: They train a clock to predict the population of the US:

And as we illustrate with the size of US population, non-biological changes can be successfully predicted by the DNAme array datasets. Summarily, any set of regularly changed numerical values can be linearly predicted through EN training on any large data, biological or not, physically connected to the measured axis or not. If anybody is interested, an expansion of the Universe could be predicted from evolutionary DNAme array data. And a person’s health and age could be predicted with relatively good accuracy from expanding distance between the Galaxies, or anything that changes progressively over time.

Since the physical meaning of the training parameters is lost in EN process, any assumption that specific health scores, C-reactive protein levels, etc., are being predicted, is ambiguous, because in the model training, a decline in health, reaching mortality and the increase in age all have linear progressions designated as a regular series of numbers.

The point being, that just because one can put dots on a line it doesn't mean the effects are real automatically: If you have say 50 samples and you have 450,000 features total, you can fix almost any pattern that is sort of linear. So one has to be careful!

The clocks they construct fit their theoretical model: sites that don't change much with age or sites that have different standard deviation at the population level are all positive correlated with age; ie there is no site that tends to decrease their variance with age in their data.

One disadvantage of this is that one cannot apply this clock to an individual, as it requires a population to calculate the standard deviations for a given CpG, but the authors are not trying to build an aging clock rather they are trying to study the aging process and to show that the clocks others are build are not directly picking up on aging but rather proxies at best.

Then we have 3 papers, all published May 9th 2024 from Meyer & Schumacher (2024) , Tong et al. (2024), and Tarkhov et al. (2024) [who's now a coworker at Retro!]

I'll take two of these examples: Tong et al. set out to see how much of the accuracy in known epigenetic clocks like Horvath's is driven by aging as a stochastic process vs other causes, finding that Horvath's clock is fairly well attuned to this stochasticity (66-75%) whereas PhenoAge is less so (63%) which makes sense as PhenoAge was calibrated to predict health and disease. Though they don't look at GrimAge or DunedinPACE in this paper, I expect that those would be picking up even less the entropic component of aging and more the downstream diseases. They note that the way methylation changes with age is not orderless but rather there are patterns in that damage (CpGs that are marked by the Polycomb Repressive Complex getting hypermethylated being one example).

Their methodology is quite neat, they pick the CpGs for a clock, they run a stochastic process (a random walk informed by the average change of those CpGs), sample a bunch and train a clock on those stochastic changes, then do the ratio of the r^2s of both clocks to see what % of 'predictive power' is driven by the stochastic process. One has to note here that that doesn't mean that "75% of aging is stochastic", that would be assuming that the Horvath clock is a perfect aging predictor, rather the fair claim to derive here is that a lot of the signal behind the age-related CpGs that the clocks pick up can be modeled as a random process. One objection to this methodology though is that the Horvath clock was trained on many tissues and cell types. In my view aging has a strong cell-type specific component and so any such signal would not be picked up in Horvath's clock or these stochastic clocks.

Something worth noting (that the authors acknowledge in their conclusion) is that these clocks seem to break in unusual cases: Whereas Horvath's clock predicts well age regardless of tissue or age, and predicts age=0 for iPSCs, the stochastic clocks predict these cells to be much older than they are, suggesting perhaps that the stochastic component of aging becomes more predominant during or after development.

But interestingly, whereas PhenoAge is lower in smokers or COVID-havers, the stochastic clocks is impervious to these perturbations. And that's good! It means they are less attuned to transient, easy to reverse changes (perhaps just inflammation) and properly calibrated to the underlying entropic component.

They also analyze a clock trained on in vitro data, EpiTOC2 which should be by construction more free of cell composition effects or organismal diseases, and find that this clock is almost completely driven by the stochastic component of aging.

When one looks at Horvath's CpGs, 160 get hypomethylated with age. Those one could attempt to explain their loss via a passive process. But the other 193 are actively getting methylated; and those tend to be around PRC2, the same CpGs heavily enriched in EpiTOC2. As I mentioned earlier, though which CpG might change is random, the overall pattern once again is not: over and over we see this trend of PRC2 sites getting methylated.

Tarkhov et al. have access to scDNAm datasets (of muscle stem cells) which is a rarity! That way they are able to look at populations of cells at the same timepoint and see how distinct or the same they are and from this to be able to better look at aging. Here they define a metric of coregulation for CpGs, do CpGs tend to change at the same time or do they change independent of each other? In a stochastic model where every CpG drifts individually one would expect little coregulation whereas in development, where methylation is being set in a very opinionated way by developmental programs one should expect high coregulation. This is indeed what is seen and when applied to aging, 92% of the 502 CpG in their dataset that changes with age changed per the stochastic model.

These changes are not uniform in the genome though, the paper notes that the areas that tend to lose methylation are nonfunctional regions (plausibly, transposable elements, another regular pattern) or introns whereas the areas that gain methylation are CpG islands, coding sequences, exons (broadly useful regions).

As a final note, I came across this paper from Vershinina et al. (2021) that claims that 90% of the CpGs are deterministically changing, the opposite conclusion as in this papers, trying to make a case for a more programmed (ie. development-like) pattern to aging. However, I don't think they can really draw this inference from their bulk DNAme datasets of twins which would show averages of populations, hiding away the noise, whereas Tarkhov et al., with single cell datasets can actually look at the issue with deeper resolution.

If this point is not clear, I made this small app where you can visualize an example of this where the ensemble average looks very smooth, almost deterministic, yet the process can be quite random when looked at a single cell level.

One objection to this analysis is that it's done at the methylation, not chromatin accesibility level, and this analysis could overturn the conclusion: Imagine, for the sake of the argument that we engineer a cell to deterministically express an enzyme that will methylate the promoter of the gene COL1A1. The way this will happen is the enzyme will recognize the COL1A1 site and, stochastically, deposit some methylation there. The specific site may be random under some analysis but the overall intent of the program (making the site less accessible) will be fulfilled.

Now imagine you are a cell and you are trying to switch off collagen production. Do you do this by setting methylation in a specific way or do you make a bit more of the relevant enzyme? The end result is deterministic: less collagen but how to get there is stochastic. Out of chaos, order. This ties to the ideas elsewhere in this essay about error correction, where multiple states can correspond to the same useful phenotype. Here in Borgel et al. (2010) where they look at development, it illustrates this idea where specific promoters that are relevant for development are overall more methylated but not deterministically so. Everything in biology is ultimately stochastic and directedness is not a binary but rather a matter of degree. Developmental programs are fairly strong and aging drift or response to aging can be more weakly controlled.

To overcome this issue we could look at chromatin. Unlike methylation, chromatin aggregates all of the epigenome, and chromatin accessibility better correlates with what ultimately matters: gene transcription and protein translation. However, this essay is already quite long so I'll have to skip that here! I'll just have one pointer: Even though the cell is suffering entropic damage, the ways in which cells deal with this are surprisingly similar: PRC2 hypermethylation, retrotransposon derepression, and hypomethylation of useful genes. Aged cells of a given cell type are dysfunctional in different ways at the micro-level (which CpG is (de)methylated) but similar at a macro-level. For more I refer you to Patrick et al. (2024).

The epigenetic magic wand: a thought experiment

Suppose that you believe that reversing the chromatin state of a cell to youthfulness will rejuvenate a cell if not completely, completely enough for most practical purposes. And suppose you have a magic wand that does just that to all cells. Would that restore a person to what they were years back? Would, in short, reverting cellular aging also reverse organismal aging?

I believe this is closer to true in C. elegans (who have a fixed number of cells, no cancer, no cardiovascular system, no stem cells) and less true in human beings. But it is still very close! One can try to enumerate what might not get fixed post-epigenetic magic wand and there are things:

First, some cell populations are just lost so there isn't much to rejuvenate. This is nontrivial:
- Loss of neurons (Parkinson's, Alzheimer's)
- Loss of sensory receptors (Like hair cells in hearing loss)
- Loss of eggs
Then there's high level tissue restructuring:
- Fibrosis (lungs, liver)
- Loss of high level structures like teeth
- Crosslinking/stiffening of tissues (Elastin does not seem to turn over much)
- Nephron loss in the kidney
- Spinal disk degeneration
- Calcification of arteries and heart valves, accumulation of plaques
- Thymic involution
Lastly, there's somatic mutations that still wouldn't go away.

Some of these problems are easier to solve than others. Without attempting to be comprehensive:

For small cell populations one can in a targeted way replace them out of iPSC. This is already in the clinic for Parkinson's as well as Type 1 Diabetes. There are companies working on eggs. And some has been written about using transdifferentiation to make lost cell types out of existing cells.
For fibrosis, as per Uri Alon's work and given it does turn over, I am not too concerned that we can find ways to modulate the process to get rid of it. One recent win here is Resmetiron for liver fibrosis, reversing something that merely losing weight with GLP1 does not.
For plaques, though statins help massively if one starts early enough, there are some attempts at engineering macrophages

Cancer would still remain as a sort of final boss for this battle where I personally have the greatest uncertainty. The easiest approach would be to replace tissues with new iPSC-derived tissues, ideally from banked cells from the patient that have a lower burden of mutations. That itself sounds hard! But even harder it developing a cancer treatment that deals with cancer in situ systemically and reliably. But I have spent way less time thinking about cancer than I have about the rest of aging.

That is, it is possible that after the epigenetic magic wand has been waved someone would have the functional capacities of a 20 year old yet still die of cancer at the same rate as usual, that is: it is conceivable to restore healthspan without affecting lifespan if the epigenetic reset does not do anything for cancer. If, however, we had effective cancer treatments on top, then we would see more meaningful lifespan extension.

The intrinsic randomness in lifespan

When one looks at a large human population, one observes a range of lifespans. Some people live only a few years of age, others beyond 100. That environmental factors play a role in aging is unquestionable, but their existence raises the question: in perfectly ideal conditions where genotypes are controlled and the environment is likewise controlled, how stochastic in aging? We can look at this in two model systems: worms and inbred lab mice. As you can see, the variability is substantial even after controlling for these factors.

What we do know is that the mortality rate increases predictably at a population level and from there we can infer how "loaded the mortality dice are", it's still a roll of dice. Someone who is 10 years old is >99% likely to make it to over 80 whereas someone who is 100 it's more of a coinflip (50%).

So prima facie, even with the world's best epigenetic predictor that tells you someone's legit biological age, it would be far from being perfectly accurate. But that's fine for many purposes. If we are measuring aging interventions and our model tells us that someone risk of death is 50% and we do something and now it says it is 1%, that would be very useful to have, even if does a poor job at predicting when exactly a specific person will die.

Aging interventions that slow down cellular aging are mostly DNA damage reducing interventions

Some age-slowing interventions target things like senescent cells and rejuvenate an organism by depleting less fit cells, but not by rejuvenating them. Others rejuvenate organisms by adding back broken components (stem cells, mitochondrial transplants). But the ones that matter for cellular aging all work on the same principles:

Looking at worms one can see more cleanly what affects cellular aging. Largely, it is mostly damage repair of DNA (as well as autophagy, secondarily) that interventions seem to converge on.

Caloric restriction (And the whole IGF1/mTOR paradigm) ultimately converges on the upregulation of autophagy (via TFEB/hlh30, downstream of mTOR) and DNA-damage repair (via FOXO3/daf16). As a result, CR slows down epigenetic drift and thus aging (Maegawa et al. 2017)
- As far as people have looked, this effect is small in humans (Scholler-Mann et al. 2020; Waziry et al. (2022)), therefore the effects of the modulating the IGF1 signalling pathway are unlikely to be a promising way to increase lifespan in humans.
- Rapamycin is more unclear. The effects on healthspan don't seem to be there (Horvath et al. 2021, Minton et al. 2024) though a recent conference talk said it extended lifespan 15% in marmosets by 15% (Rapamycin news). There may be an effect size, but a small one, and one that can't be scaled.
Long lived worm or mouse mutants have loss of function mutations in nutrient sensing pathways, switching cells into repair mode, which leads to the observed effect.
Interventions that reduce body temperature extend lifespan through increasing accuracy of biological processes, including DNA damage repair.

Other interventions like heterochronic parabiosis are in a way a cheat code to lend extra organismal capacity to an older organism and as such one can say that they can transiently rejuvenate non-cellular aspects of an organism (its blood) without rejuvenating its cells. From the discussion on turnover rates above, it follows that without affecting DNA or chromatin, changes that work through proteins are bound to be short lived instead of permanent. This is indeed what's observed empirically (Poganik et al. 2023).

This knowledge can be and is being leveraged to tackle aging (Tomusiak 2024). Any other approach aiming at slowing down cellular aging will probably not be successful (with the posisible exceptions of mitochondrial replacement and telomerase-based interventions in applications).

Appendix: Proteomic clocks

Methylation is not the only data modality one can use. To me it seems good enough to pick up cell aging, as the methylation is methylation of those cells, and everything else (predicting brain from blood) is a correlation.

One can also measure the levels of certain proteins in blood and use that to infer aging of an organ. The use of proteins as biomarkers is something that is well established in many contexts: ApoB is an even better marker than LDL cholesterol for heart disease, Neurofilament Light Chain is a general marker for CNS diseases, troponin for heart injury, ALT/AST for liver, CystatinC+Creatinine for kidney, etc. These proteins tend come from specific tissues so they are a much better direct readout of tissue health.

One paper (Argentieri et al. 2024) did this, getting results on par with the methylation clocks, but I argue this paper didn't really utilize proteomics to their fullest: they did not try to go organ by organ but rather they built a model to predict chronological age.

This one (2023) from Wyss-Coray is more interesting. Here they first look at gene expression in different organs to tease out which proteins are most likely to be tissue-specific. Then one can use those subsets to train various models to predict chronological age in a sample of ~5.6k people. So for examaple one wouldn't use Cystatin C in a model of brain aging, even when they are correlated (because aging makes brain and kidney aging correlate), because it is not unique to that organ. In the paper they go beyond using chronological age as an endpoint in one case, training a proteomic clock using brain-specific proteins to predict a behavioral cognitive endpoint. This model turns out to be better than age, polygenic risk scores, and pTau181, a direct marker of AD. If curious about what these proteins they are picking up are per organ, here they are.

This other similar paper from the Gladyshev lab (2024), using the larger 53k UK Biobank dataset, and following a similar approach of looking at proteins that are enriched in particular tissue. Needless to say, they are able to train reasonably good models for chronological age and mortality, and these models turn out to much much better than GrimAge; by extension they are probably better than other methylation clocks as well. Oh et all is the Wyss-Coray lab paper from earlier.

On top of that they find that each organ's clock is a better predictor of disease in thar organ:

After that, in this preprint, also from Gladyshev, they build proteomic clocks that try to predict disease (instead of chronological aging) and they use neural networks instead of linear models though that was only outperformed linear models for brain aging. This all done with just 21 proteins, which are easier to make into a test people could use. To my surprise, they are also able to predict tissue-specific cancer! In fact they are able to do so using single proteins, no complex models required. Here, just ENPP7 or CDHR2 (adjusted for age) seem to do a decent job compared to the earlier model (the GTEx 4x from the previous paper)

They are better than models built out of simply blood chemistry in many cases but not cancer.

Cancer may be hard to predict because we don't really have interventions that have been deployed at scale that slow down DNA damage accumulation. But even if we had them, it's unclear how those would be reflected in the proteome.

Summary

Based on the above, here are some concrete points:

Biological aging clocks and personal use
1. Commonly available methylation clocks do track to some extent health and mortality and thus a reduction in those scores, all else equal, would be a good thing.
2. However, if one's interested in tracking one's health, I advocate for the standard direct measures of clinically validated biomarkers. I would go further and say that these markers and a few others (thyroid function, vitamin deficiency) are better because they are more actionable. Would you rather know that your epigenetic age is 1 year older or that you are vitamin D deficient? For me clearly the latter, as it points to a way to fix that.
3. Proteomic clocks, once adopted at scale, will be able to enhance this baseline
What methylation clocks measure
1. These clocks measure different things depending on how they were trained; as a rule of thumb clocks trained to excel at predicting mortality and health in humans will be biased towards disease, not cellular aging.
2. It is misleading to compare "how good a clock is" by how well they predict mortality or disease. "How good a clock is" requires a "for what".
3. A lot of what clocks end up measuring is PRC2 methylation which is an adaptive response and therefore not causal. However, that can still be useful to measure the rate of aging. I'm less sure whether one should use these to measure rejuvenation, as one could achieve functional rejuvenation in every sense while keeping the age-related PRC2 sites in place. OSKM happens to wipe this out, but that's not guaranteed of every age-reverting intervention.
For researchers
1. Methylation clocks are a valid way to study aging. I would recommend using a panel of handpicked CpG clocks (Like EpiTOC/PRC2-AgeIndex or the Retrotransposon clocks) over pure regression models like the Horvath clock for better interpretability.
2. iPSCs/ESCs, and reprogramming are a great way to validate clocks. A chronological aging clock should assign these an age of 0
3. It is useful to build cell type-specific clocks for in vitro research that consider how that cell type ages; eg for fibroblasts one can have a collagen genes clock to measure whether that is rejuvenated.

Links (91)

Jose Luis Ricon — Sat, 13 Sep 2025 00:00:00 +0000

Lithium orotate seems to help with Alzheimer's

Electronics components have gotten very very cheap in the past few decades

On LLM adoption from Zvi Mowshowitz

On the wild stories where someone that gets an organ transplant sometimes experience personality changes, and single cell learning.

HIV drugs as potential anti-aging drugs

Upcoming book about industrial efficiency

Alternative to LASIK coming?

A first person report of participating in a Phase 1 clinical trial

In defense of the Amyloid hypothesis (See previous Nintil posts on Alzheimer's too, though they may be out of date by now). The linked post in Astral Codex Ten is I think mistaken, and one can point to Alnylam's recent failure (No NfL change->no neurodegeneration slowdown) as a more solid test than perhaps the antibodies. It is nonetheless a good presentation of the amyloid cascade hypothesis and why it makes so much sense that amyloid beta is in some way in the etiology of Alzheimer's. The idea that very early prevention could slow down the appearence of AD does make sense to me, but once the disease starts one has to intervene at a different place to stop it. The company I work at is testing a drug for AD later this year in Phase 1, we shall see how that goes!

Epigenetic proxies for health biomarkers like LDL fail to pick up changes in a randomized control trial

It is argued here that IQ decline happens much slower than commonly assumed.

From adderall skeptic to adderall enjoyer

Links (90)

Jose Luis Ricon — Sat, 09 Aug 2025 00:00:00 +0000

Good post on what the meaning of heritability.

Only a crazy person should do any given job

A while back I noted that everything sleeps. Now here some recent work on the why.

Memory in cells

As I noted a while back, inflammaging is not an intrinsic feature of aging; rather it is a byproduct of industrialized lifestyles and most likely just obesity (which increases with age in industrialized countries)

On China's shipbuilding industry

SSC reviews Steven Byrne's work on AI

Against outsourcing, for vertical integration

Dwarkesh on the LBJ biographies

Facebook's questionable business tactics

RCT testing a core woo caim (that a lot of chronic pain is in your head and thus can be treated with psychotherapy), woo succeeds.

50 things Cate Hall knows. Some to disagree with "Ideas are cheap and easy to find; execution is everything" This is very wrong; lots of good ideas go around untried because though some are aware of it, not enough are feeling their truths in their bones. To me there's a big gap between "finding/being aware of an idea" (easy, cheap) and being so convinced to want to go all in into it (hard, the bottleneck). Execution, comparad to that, is easy.

The original Flexport pitch

Making mercury from gold?

Can goodness compete?

SaaS didn't turn out to be as good of a business model as originally thought.

AI coding tools considered harmful

I recorded a new podcast

I ask Twitter for iconic company culture handbooks

A jhourney in Costa Rica: experiencing the jhanas

Jose Luis Ricon — Sun, 27 Jul 2025 00:00:00 +0000

So I went down to the beach. "Kinda nice", I thought. The sky had a particularly vibrant blue color, the waves had 'the right size', their roar was pleasant. I started to walk around trying to continue meditating. I focused my awareness on an arising sensation of open heartedness and then I noticed my eyes tearing up ("Huh? I thought"). I looked again at the ocean and then I saw it. It was fucking amazing. So much color and detail: waves within waves, the fractal structure of the foamy crests as they disintegrate back into the ocean. The feeling of the sun on my skin. I felt overwhelmed. As tears ran down my face and lowkey insane grin settled on my face I found myself mumbling "It's... always been like this!!!!" "What the fuck??!" followed by "This is too much!! Too much!!!". The experience seemed to be demanding from me to feel more joy and awe than I was born to feel or something like that. In that precise moment I felt what "painfully beautiful" means for the first time in my life. I had to look away. I calmed a bit. I walked a few steps and looked back. The exact same thing happened. "It's reproducible, hihihihi", and I started laughing. Then I found a log to sit on, calm down, and look back at the ocean. Now it wasn't overwhelming, but "kinda nice" was now "fucking amazing".

You're probably wondering how I ended up in this situation, as it involved no substances other than the daily consumption gallo pinto (Costa Rican rice and beans), plantains, and green tea.

In July 2025 I (José Luis, the author of this blog) went to Costa Rica for a seven day retreat organized by Jhourney, a startup that promises to teach people the jhanas, joyful altered mind states that can be, in their words, "life changing". Jhourney did not sponsor this post nor gave me special treatment.

I was convinced to go by the positive experiences some of my friends had at this retreat, in particular some written down in private documents. I hope more of these experiences are made public, as other people will benefit greatly from reading such testimonials as did I. For over 10 years I've been finding interesting things and sharing them with the world in this blog out of some sense of duty. It is surprising to me there are no more testimonials of this or other retreats publicly available!

If between you and the sharing of an experience that could propel others to achieve similar things stands your shame or sense of privacy, do consider where that comes from; what are you really afraid of? Post retreat, it seemed obvious to me (though I was already a consummate blogger) that these things have to be shared with all beings, and I wanted to remind others that, at a tiny cost to themselves, they too can help.

May all readers find what follows fun and useful!

What are the jhanas?

The jhanas are altered states of consciousness described in the Theravada Buddhist tradition but preceding the Buddha, who said he learned them from others who were practicing them before.

There are 8 or 9 jhanas (if cessation counts as a jhana), and this is quite puzzling to me. Why not 120 jhanas or like 3? Why are they discrete like that. Even deep meditation autists like Daniel Ingram who have meditated closer to reality than anyone else to the point where they can see the subcomponents of jhanas still see those as that, subcomponents, but the jhanas are still what they are. This is crazy! They are quantized! Now of course this makes me wonder why is that so. The main thing that comes to mind that might be like jhanas are modes of vibration.

Edit: Ingram does seem to suggest there indeed are other jhanas!

Each state has a vibe to it, describe at the end of this blogpost.

Jhanas can be lighter or deeper (to the point where they are the only thing in awareness). During the retreat I experienced jhana on the lighter end and I suspect if I keep practicing I'll experience deeper jhanas.

Why jhana?

The Jhourney answer is here. My own answer: out of curiosity and hope that I might get a brain update to become even happier, and maybe see things in new interesting ways.

The Buddhist answer: Part of the path to Enlightenment, step 8 in the Eighfold Path. Buddhists warn people not to become jhana junkies (lol), mistaking the jhanas for enlightenment, and to use them as a tool, not as the end of the road. After having jhana'd, I could see why people could mistake the attainment of jhanic states as enlightenment but I personally think there's more to go before one gets to what I understand as a reasonable definition of enlightened or awakened

Who is most likely to jhana

At Jhourney retreats, being a experienced meditator seems to not help much with reaching the first jhanas, though it does help with getting to the formless jhanas. Now I can see why. I myself had been on a prior 3 day retreat with Tucker Peck and done 1hr a day of Do Nothing meditation for a few weeks without getting into a jhana. I was missing one key ingredient, detailed later. But once I had that, it all clicked. Turns out, self-acceptance and a good emotional internal landscape are key to the earlier more embodied jhanas, and I'm quite good at that:

I like being me, I think I'm quite great!
I don't endorse hating anyone. Even say Hitler. Hitler is innocent baby hitler in a mechahitler suit. We should feel sad that those atoms ended up that way and forgive them for not understanding. I think everyone is always trying their best all the time deep down at some fundamental level, even if that ends up in fucked up places sometimes.
I score near zero in the neuroticism component in the Big Five personality system
I'm a playful curious person that is rarely if ever bored
I am extremely truth-driven, even if painful or scary I wholeheartedly will choose that over looking away, no matter how uncomfortable

How to Jhana, the jhourney approach

Jhourney's core instruction to jhana is to find:

Find something (something jhourney calls 'scaffolding') that evokes an open-hearted sensation (the object of meditation)
Focus on that
If it goes away, use (1) again.
Keep going at it

These scaffolds could be things like a real life memory, a visualization, a mantra, or a smile. This latter is basically the TWIM method, which I had briefly tried but it didn't stick, smiles felt fake in my face and felt also like I was introducing unecessary body tension. Jhourney is generalized TWIM in a way, only that people are allowed to choose whatever works for them most naturally. For me, it was a memory of my girlfriend beind happy. But eventually, once one has more practice, other things may work. Jhourney warns meditators to not switch the scaffolding all the time, becaue the point is not to focus on the scaffolding but rather the sensation it induces.

Where did the Pali go?!

I wrote above 'open hearted sensation'; Jhourney is not a Buddhist retreat and the amount of Pali I encountered was zero. But basically 'open hearted sensation' could be swapped for any of the brahmaviharas. Whereas many methods suggest loving-kindness (metta) to achieve jhana, I entered jhana through empathetic joy (mudita) at remembering how happy my girlfriend was. Though that's not quite it: As does Leigh Brassington, in practice Jhourney seems ok with any pleasant sensation, wherever it arises.

Before getting there one has to develop a reasonable level of what Jhourney calls collectedness. I had never come across that word in a meditation context; they explained it is like concentration but not single pointed. Ok I thought so this is not ekagatta but rather more generically upacara samadhi or perhaps sati or mindfulness; though mindfulness can also mean other things. Turns out that the West doesn't quite have the exact terms one would need to point to what has to point to to guide meditation, so one has to choose between turning into a Pali-chanting corncob or using somewhat novel words, and Jhourney took the latter approach.

More specifically Jhourney asks students to focus on their object of meditation while keeping awareness of everything else, ie there's an explicit instruction against ekagatta. I wonder if this is to avoid students from trying too hard to focus only on the object of meditation, which would be far far harder and not required to reach the jhanic states they teach.

To jhana you have to not want to jhana

It is a deep learning in life that there are things that to get them, you have to not want them. Or rather, crave them. You have to let go of jhana, to be actually ok with not jhanaing during the retreat. The jhanas feel like you get a thumbs up from the universe if you have unblocked the relevant emotional blockages that you are going in the right direction.

How to jhana then? The answer is simple enough: set the intention that you do want to jhana when stepping into the container and once within it, let it go, just allow it to happen. Instead, convince yourself that if you sit for enough hours (I was meditating for more than 8 hours a day) and you approach each moment with curiosity and enjoyment, you will jhana. In turn you can do this either by:

Noting that people before you did that exact same thing and got results or, if you can't just trust other people or think you have alien brain chemistry then:
Think of the jhanas as that thumbs up and make your goal to be full-sending every moment of your experience, make the goal to become an enjoyer of things whatever might come. Jhourney calls this 'conductivity' (how much of your experience you are accepting)
- This was easy for me, someone that has literally 'enjoyer of things' for a Twitter tagline, who honestly believes anything can be enjoyed, and who is never bored.
- If you are a person prone to boredom, the (attempting of the) jhanas will fix you

This again is something Jhourney emphasizes, in their instruction handbook literally opens with the real value of jhana is not the jhanas themselves; it's making it easier to be the person you aspire to be

Choose your own adventure

As mentioned earlier Jhourney allows each participant to choose their own way to get to jhana. There is a structure to the retreat:

Two group sits (morning and night) of around 1hr
1:1 interviews with facilitators and office hours to get feedback
Some breathwork sessions
Some time allocated for reading relevant sections of the manual
And plenty of solo meditation time

But you can do whatever you want of course; and the retreat format seems to get tweaked from retreat to retreat; we had breathwork facilitated by Jonny Miller who teaches FBR (a subtype of CCB); in an earlier retreat they taught Wim Hof breathing per another participant.

The facilitators were not pushy at all, they were genuinely supportive of my goals and approach, offering helpful tips, or just someone to talk to (it's a silent retreat, and having someone to excitedly talk to about one's experiences is great). At some point after I had achieved J1-3 I had a deep "fuck the jhanas! I'm done! I'm going to just vibe-meditate" moment where I decided to stop using the suggested practice and "do" Do Nothing meditation. That was great, it felt less effortful and more enjoyable and without me "doing anything" it got me up to J7. it felt like chillin' on a mental sofa watching a movie, or lying on grass watching the clouds.

Radical non-self coercion and a holistic view of emotions: key life hacks

If there's something that I did differently in the retreat is to impose myself less upon my mind and my body (weird as that may seem).

If I felt like peeing, I would break the sit and pee, if my head hurted from meditating, I would stop. If I was restless I would just go for a walk. I want to remark that there's a bad and a good way of doing this. These actions felt like I was taking with my whole being as opposed to a "part bored with meditating that wanted to go to the beach". I did pause to mindfully consider if I really wanted to do those things and allowed internal consensus to build up.

Most importantly, I learned to notice that the way I was trying to avoid being distracted was to violently push my thoughts away!. I thought I was being gentle but no! I noticed saying "Present moment!!" upon noticing a distraction, like being angry at the thought that arose or my mind for not being in the present moment. Upon noticing this, I said ok, well these thoughts have good intentions for me, what do they want? So I interacted with those thoughts (I recommend reading Wholeness Work, Core Transformation, or Gendlin's Focusing for more on this), hugged them, forgived them for not understanding that they were distracting me, and getting them to understand that their purpose would be better served by going away for the moment. For example thoughts related about planning for the future (like this blogpost) I said "If you guys interrupt less then I get to go deeper into the jhanas and have more interesting things to say in the blogpost, and you want a good blog post, right?". Good point, and they poof'd away.

Importantly, I trusted that the thoughts would go away but was deeply okay if they came back. I would just lovingly and repeatedly do the same thing until I grew less distracted.

Another thing that I think helped me was to view emotions holistically, ie neither cognitive states nor feelings in the body. Rather an emotion is a state that has many components: dispositions to actions, physiological responses, recurrent thoughts, altered attention, etc.

For example if I let my mind be in J5, without doing much the following happens:

My mouth opens as if wanting to say "woaaah"
Images of vast blue skies show up in my mind's eye along with a sphere centered in myself expanding
A sense that the outbreath is "like this (state)"
A sense that everything is possible

These come up without "doing anything". But to truly understand the jhanas one should try to investigate them more directly. Alas, jhourney is mostly focused on getting you to experience the jhanas (Which is already a feat!), not to do insight meditation in the Buddhist world. Jhourney is essentially about "wet" (pleasant) concentration; whereas say the Goenka vipassana ("dry" insight) retreat (which I have not done) are mainly about insight. Insight here being the path that takes you to awakening or enlightenment, which sounds intriguing.

But because jhourney does point students to cultivate curiosity one ends up doing some investigating anyway. "Hmm I wonder what happens if I ask who am I while in J6?" or "Where does my body end?" or "If I imagine a pizza, do i crave it". At some point the felt sense of "is the arm rest of the chair I'm sitting in part of me" was "unclear" which made me go "huh, intriguing". This is quite a lighthearted fun way to get into insight!

The fun thing is that whereas "dry insight" has a reputation of being "hardcore", it may well be that the jhana path to enlightenment may allow one to relax into awakening more joyfully and faster.

Belief changes

Did I change any of my core beliefs by doing this? I don't think so! The content of my beliefs remains unchanged, but the way I experience them has changed. There were things that I believed intellectually but didn't really feel in my bones. For example, if you had asked me over the last 10 years the question "Fundamentally, is everything basically the same thing" I would have said "Yes, it's all some kind of atom-and-awareness type stuff, protopanpsychism or something adjacent is real". I've even written about this here at Nintil, before doing any meditation and without having taken any of the substances that might make one think such thoughts, I got there natty, unassisted. But now I see the truth of it, just like an optical illusion where for an instance you can see it "right" as opposed to the mistaken impression.

I do now think meditation is more powerful than I thought. It delivers. The stuff is real. Yes you can install software upgrades to your brain. Everyone is comparatively depressed compared to the advanced meditators.

Another interesting thing is that I noticed that with meditation the mind becomes pliable in ways one has to watch out for. Before the retreat, if someone had talked about say the truth of astrology I would have felt a very knee-jerky "that's bullshit!" reaction. But now that's gone. Now I'm closer to "huh intriguing, how did this person come to believe this [clearly wrong thing]?". This is similar to the mindset that the Art of Accomplishment's VIEW (Vulnerability, Impartiality, Empathy, Wonder) aims to teach. Fortunately, I don't rely on the knee-jerky reaction to make sense of the world, I have reason and science; however I can see how someone less vigilant than me could fall into a turbo-woo hole if they meditate without solid epistemics. The same is true of psychedelics. But meditation may be riskier because it seems natural, there's no substance involved, and while it's true that you can kill a meditation "trip" immediately and that's less true for psychedelics, the harm may be in not noticing what it's doing to the way you relate to things like truth and morality.

Tips to jhana: what I wished I had known

This will probably work best if you're like me, though I am also incorporating here materials that my recent-past self that was much less embodied would have found useful

Look into Gendlin's Focusing, Core Transformation, and Wholeness work to understand your emotions better
Practice Yoga Nidra and the somatic meditations in Somatic Descent, do body scans
Investigate the nature of your "pushing away thoughts" move to see if there's any coercion. Even if you think there isn't, just consider you might be wrong.
Lying down is fine for meditation, if you don't fall asleep
You can run mental experiments within a jhana (how are your intuitions/mental state altered) to test the vibe of the jhana
You will not necessarily enter jhana at J1
Setting an intention pre-sit and then letting it go within the sit helps. Think of dancing: you set the intention to dance but once on the dancefloor you are not micromanaging every little move, you allow the dance to happen.
Chill the fuck out by any means necessary. Visualize being pancake batter spreading onto the floor.

How each day went

I recorded every day in a journal so I can tell you exactly when and how it happened. There was a Day 0 of arrival and a Day 7 of leaving but I'll skip them as not much interesting happened in those.

Day 1:
1. Woke up, still feeling not fully rested. There was a guided meditation that wasn't great. I noticed myself jittery because of the coffee. Oh is this why many meditators abandon coffee and switch to tea? So I resolved to chug green tea for the remainder of the retreat. I noticed thoughts coming (mostly about things I wanted to do, and decided to write them down even if I had to interrupt a sit. I thought that doing this would help me genuinely believe that my good ideas I had wouldn't disappear. Eventually once a handful were written down they ceased somewhat.
2. I tried various scaffoldings; the smiles felt fake and tense, the mantras ("may all beings be happy") didn't hit [thought latter in the retreat they would], but a memory of my girlfriend being happy did, so I started using that to generate a pleasant sensation to focus on.
3. I felt very relaxed during the sits and was sitting for 45 min at a time, noting that "still distracted a bit, but hitting more focused moments", but did not reach jhana
Day 2
1. Morning yoga felt great, would recommend pregaming meditation with yoga. It's almost as if... they were developed in combination.
2. There was a guided forgiveness meditation. This did nothing for me, though I knew it had been really powerful for other people. I really like myself and am not ashamed of being me so I guess that's why.
3. I started noticing the pleasant sensation more, where it was in my body (heart and radiating through arms) and noticed I could feel it more if I focused my attention on my chest
4. My journal notes "Coconuts: nature's boobs" with no explanation. I also noted that it seemed fun to watch the label in a teabag fluttering with the wind
5. I went to the beach for a walk and I had the moment I opened this blogpost with, crying in awe at the beauty of everything. I noted "Unsure why [I cried]? Just beauty?". Here I was trying to act cynical for useful purposes like "well, was I repressing an emotion?" I tend to associate crying with the release of a suppressed (negative emotion).
6. A mind-blowing breathwork session, took a while to get going. But eventually started crying out of joy just like on the beach. I wrote down what I was thinking and even speaking at times, noting down that "these thoughts are the sorts of thoughts one would think only on drugs" and yet here it was all natty.
  1. Everything is so beautiful
  2. We are all love
  3. No matter what you do, no matter what you say, no matter who you are you'll always be love(d)
7. I also noted that "cry=laugh"; I noticed some similarity between those those things, as I was cry-laughing. I tried to understand why but didn't quite get it. Is crying what happens when things are worse than you think and you accept it and laughing what happens when things are better than you think and you accept it and.. cry-laughing when things just are and you are hell-yeah them?
  1. Relatedly a friend noted that anger and lust were connected
8. I noted getting a feeling consistent with what Psychonaut wiki points at for MDMA
  1. "MDMA-like feeling (body warm, like something dropped into my belly)"
9. That was the first glimpse of jhana! I was like "IS THIS JHANA!!?" at which point it disappeared of course. According to Michael Taft though, it still counts as jhana if you pop out immediately, so I'll then say that my first jhana-adjacent experience was on the second day of the retreat.
Day 3
1. We did an activity called Jhourneying that's like circling but purely emotional; one peron would ask another what was in their expereince (say happiness) and then the other would ask (what's the texture of that?) or whether other things would come up. In a way it's a hybrid between Circling and practices like Gendlin's Focusing.
2. "Wow it's like being on MDMA". Everyone seemed beautiful, smiley, there is a desire to hug and tell everyone how amazing everything is. But it's a silent retreat. I don't feel frustration about not being able to speak though.
3. I went on another walk to the beach, got wet from the rain. Didn't feel bad about that, but I think that wasn't that crazy, I would have felt similarly outside of the retreat I think.
4. I noted "Welcome, not push distractions <3". This is when I realized what I noted earlier about self-coercion
5. I achieved a sustained and stable J2! I was initially puzzled. Where were the fireworks?? As it turns out I was expecting to enter at J1 (that does have more of those fireworks) but it was J2 where I got at first. I noted
  1. Head very hot, stayed for long, stable, still distractions popping in
  2. There was a "glonk" sensation (like a ball dropping into something and exploding with the feeling of J2 everywhere), in my body, my spine arched, my mouth opened, and then I relaxed into the mat (I was lying down) when I got into J2.
  3. Everything is warm/fuzzy. I asked "what's in my chest?" "people hugging, a party"
6. I then noted that I transitioned to a calm still state that upon doing some Gendlin it felt like "a calm pond extending everywhere" (J3). This is another jhana I thought? Cool. I went into (that is, I imagined myself going into) the pond and arrived at a place that felt like not much? I noted "solidity, steel, rock". Wtf was that? Was it a jhana? It was stable but it felt like... not like the others. Looking back it was indeed J4.
  1. Note: These all was in my mind's eye, these were not dreams or hallucinations
  2. I noted "All of them stable"
  3. I also noticed I could indeed switch between them
7. I looked into that solidity sensation and there was a a hint of sense of expansion (J5) but unclear (I did not get to J5 this day, looking back). I drew the following to illustrate what I had seen that day (that starfish thing is supposed to be me lol). Note that the first one is not J1, it was a pre-jhana happy state felt mostly in my chest and arms. I was wondering, where was J1? Was I confused and J2 was really J1?
Day 4
1. Went for a walk on the beach, trying to meditate. It was fun to explore the streams, the little rivers flowing into the oceans, the tiny hermit and hole crabs, the jungle, collecting seashells. I handed out some to friends at the retreat and will bring some to my family in Christmas.
2. I tried saying stuff and... my voice sounded deeper? Or was my perception of sound altered? (I asked later my friend and fellow retreat enjoyer Meida, who indeed confirmed I wasn't going insane, my voice was in fact deeper)
3. Noted I hadn't bitten the skin around my nails in a while (which I do sometimes). I felt the fingertips which usually triggers a grabby "must bite to make smooth" OCD-like compulsion but that was absent.
4. 1 hour group sit, no jhana this time. Looks like no deterministic jhana yet!
5. I went to the beach and cried. I realized I'm like a child collecting cool sea shells for their friends(ie this blog post is like a sea shell I'm gifting to you all). I may be smarter and more thoughtful but the action is coming from the same place. For over a decade seeing young kids having fun had made me tear up a bit, which I had managed to avoid by dissociating or looking away so I never asked why would that make me feel uncomfortable. [This will become more relevant later in the journal]
6. Then went to the pool; more crying over the fact that I hadn't allowed myself to admit that I loved my parents as much as I actually do. They have done so much for me! I had a great childhood in a beautiful spawning point (the Canary Islands) instead of a trauma-ridden one in some other place, and I felt grateful for that.
  1. Why did I suppress that love, I thought? Why didn't I let myself feel it? Unclear. Maybe I thought it would be cringe or something?
7. I wrote "may everyone be full of love" on the message board. We may not be able to speak but... write... that we could do :)
8. Another crying moment: Turns out I am more altruistic than I thought. It does really make me happy to make others happy. "Why did I ever believe otherwise" I thought, amidst tears
  1. In the past I had said "I'm not that altruistic!" in a kind of way that the secretly gay homophobe proclaims loudly to hate the gay; ie there's such thing as rejecting something wholeheartedly or rejecting something that deep down you want or are for some other reason. The book Existential Kink is about this same thing. It had happened to me before with partner dancing (I dont like partner dancing, it seems constrained vs ecstatic dance->not wanting to feel jealousy of those that are good dancers) so I wasn't surprised that I still harbored thing like this.
  2. This one is particularly funny because 10 years ago I wrote a blogpost reneging on my earlier belief in psychological egoism. Turns out there's such thing as believing something and believing something deep in your bones, and those can be different.
9. I switched to Do Nothing meditation with the intention to practice stillness and maybe get to J5. Did get to J5 for the first time.
10. I was unsure if I was forcefully imagining what I was feeling (ie as when using a scaffolding) or if the depictions in my mind's eye were rather an interpretation of an existing feeling (Gendlins style). Spent a bunch of time investigating this, learned to tease apart the two, gained confidence that I had in fact reached J5.
11. Another breathwork session. This time extreme sadness, I cried. I saw how a tiny black marble (which was Gendlin-interpreted to mean 'my self') shattered. "I AM NOT SPECIAL", I noted in all caps. I am just a guy. For a long time though I knew I am just a human being (granted, by many metrics I am in fact quite unique in a good way), but somehow I believed that I am so special that there's qualitatively nothing or nobody like me. That belief died and I grieved it as if one saw a beautiful object collapsing in front of one's eyes. Then I felt relief: That belief was also what had caused me existential loneliness here and there: if I was so special, then indeed no one could truly ever 'get' me, but that seems wrong now. Then I had another mind-eye vision (it was like watching a movie, it just went on its own) of children playing on a beach of shattered marbles putting them together for themselves: ie we all are these things, made out of the same raw material.
  1. "Is this a jhana?" I wondered. I don't remember well enough but I do think this emotional released did prepare me for J6.
12. At this point I had a 1:1 with the facilitators to tell them what I had been experiencing and to confirm if what I had experienced in the days prior were in fact jhanas and they said that it seemed so; later the invited me to record my experience along with tips for future students, which I did
13. Tried to sit for 1hr. Felt a "serotonin headache" as I described it (warm head, unpleasant), went for a walk at night. I didn't force myself to meditate. I had a good time sitting on a beach by the beach alone at night.
  1. I noticed a conflict between my desire to hold commitments "I comitted to 1hr sit" and my outer commitment "I am at jhourney to make my life better". Then "Do I honestly believe holding this commitment and pushing through the headache will help me?" "To whom do I owe these commitments? Who is harmed if I stop meditating? Would you tell someone with this headache to keep meditating?" No, so I stopped the sit there. A lot had happened that day, after all, it'd be a good idea to give my brain some rest.
  2. By the beach I noted (these 'notings' through the text are verbatim from my notes, not memories): "I am never alone, no one is ever alone, we are all the same deep down, yeah this sounds weird lol; I guess alone does not mean 'no friends' it means "you are uniquely separate from everyone else". Being unique/special->being alone :) . I smiled as I understood.
  3. That day, looking back I noticed I was probably in something J6 adjacent in that breathwork session, but was too overwhelmed to notice it.
Day 5
1. Walk on the beach. Noticing more detail than I thought there was on the rocks.
2. Group sit: Definitely reached J6. Rocks and I are the same.
  1. Still could hear the music (that sit had some music in the background), these are definitely not the deep jhanas
3. In other of the sits I tried to visualize pizza to see if the feeling of craving would arise but it didn't. I timed the time that I went without distractions at one point: 3 minutes.
4. Did what I called a "gigasit" (1hr30min), longest sit so far. Entered at J5 directly, then was able to move to J6 and around the 1hr mark, J7.
5. I noticed I was annoyed with my breath a bit, it felt loud, it got quieter as I got deeper into the jhanas, almost stopping for a while. I can swim an Olympic pool in a single breath so I know that I can not breathe for a while and be fine, and that the "no air aaah! " reflex would kick in if needed, so I trusted my body on that.
6. I felt spontaneous and playful on my next visit to the beach.
7. Did another sit, entered at J2 and then I tried to see if I could get to J1 and I did. At last! The rave! The euphoria! Happy moments in my life running past my eyes. Shaking and gasping for air at times. I noted it was less intense than what I had felt on the beach a few days earlier though.
  1. I noted "J1 <-> J2 feels like a knob, you can turn up or down the euphoric heat"
8. I tried to guess/preregister what would be the next insight. No self? Impermanence? Some Nonduality stuff? [Spoiler: I got none of that in the retreat]
9. Another breathwork sessions, but this one was just relaxing in a very deep way, I noticed I could make my breath be very gentle, like a paper bag with almost no weight. Or: that I could feel my chest less by standing upright in a traditional posture instead of lying down.
  1. A hypothesis: perhaps lying down is best for the first four more embodied jhanas (you want to feel your body more) and sitting is best for the formless ones (you want to feel your body less?)
10. I remember explaining to some at dinner who said they couldn't feel their feelings how feelings worked. Who would have told me (a person that was mostly dissociated and with a 'I dont have emotions' self-identity for many years) would one day be explaining how sadness works to someone.
11. J5 feels intriguing, but no drug feels like it, I noted
12. Fell asleep quickly!
Day 6
1. 1 hour group sit, again in Do Nothing. Intention to spend more time in J4 (which until this point I hadn't spent much time on; Do Nothing would pop me into J5 and I'd go from there). I did spend a bunch of time in J4 (or allowed time to be spent there); I verified it was a proper jhana by switching between J3 and J4. I noted "J4 is flat", "J3 is like a pond".
  1. J6 -> Thought: "You can't save them nor lose them [all beings]. It just is. Go as far as you can"
2. Went for another walk to the beach. Space felt more spacious, like there's more of it. This is very weird and I don't yet know how to better describe it. The intuition that objects were solid felt weaker.
3. I made a dam with pebbles and sand in one of the streams on the beach, reminded me of my summers on the beach in Denia (Spain). I had the thought that the boundary between the non-dam and the dam was smaller than I thought, which overcame the "pff that's too much work" that stood between me and my small engineering project. I didn't fully complete it but I did meaningfully altered the course of the small stream. "I don't have to finish everything I start", I thought. "And it's also ok if it ends up being someting else", then I digged around it and the dam became an island.
4. Then walked for as far as the beach went and past into the next one, then came back.
5. Another sit, J4->J5->J6
  1. I tried to test how sturdy is the J6 vibe that it's all the same. I was typically thinking of trees and animals there but I was like this is too cutesy and maybe cached thoughts from reading about people describing this stuff.
  2. So I thought of poop and corpses. And indeed it was still there: I could feel kinship with those things. The same feeling you get when you look at a chimp and think "this is kinda like me in a (perhaps eerie) way" I would get with a turd. Intellectually, I already knew this right? It's all atoms and awareness. But only then I got to feel that belief in my bones, like someone who had learned some equation by rote memorization and only later understood why it is the way it is.
    1. It's sad rocks don't get to experience this, I thought (cried a bit)
    2. I'm so lucky to be alive to see what I see and hear what I hear
    3. Thank you all!
    4. The universe didn't change when I was born and it won't change once I'm gone
6. Another 1hr Do Nothing sit, entered at J5->J6 and after that hints of J7? I wish I had done vipassana or something to understand how to make sense of it. It felt way less emotional than the earlier jhanas. Gendlin's Focusing stopped working. But I remember imagining that if someone were to chop off an arm off me at that moment I wouldn't care in a way (I would still prefer not to, but the fear was gone), even if I died felt ok, but not fully ok probably. I could barely feel my body, breathing slowed down a lot. Sense data (a sound), my elaboration of them (this is a door closing) and valence (nice) seemed to come decoupled, in temporal order. "Is this like dependent origination", I thought? But I only got there once.
7. Dance party to close off the event, it was really fun to dance, as usual!

What now?

More retreats! More sits! I'm now convinced I want to meditate in some form for the rest of my life, for the same reason I want to keep my body fit. One of the Fetters in Theravada Buddhism is "doubt of the path" (broadly construed) and definitely jhourney did obliterate that one fetter at least for meditation narrowly construed: this shit is real and it's amazing!

What the Jhanas feel like

Here is what I experienced, along with what other people have reported, in their own words. This video of what the Jhanas are supposed to feel like roughly matches my experience.

All the jhanas shared (for me) some properties:

They are absorbing. Most of my awareness is dominated by the jhana.
They were self-sustaining states. That is, they feel like they could go on forever in the sense that you could be lying down on a bed forever. But you can end them at will.
One can shift between them
It's possible to have thoughts, hear sounds, imagine stuff, as normal while in a jhana. There's an altered mental state comparable to eg what's reported for MDMA.
They seem to be discrete states. I did not experience something I'd call a J1.5.
These experiences are roughly aligned with what people have called the "sutta jhanas (as in eg. what TWIM teaches)" or the "soft jhanas"; as opposed to the "hard jhanas" or "Visuddhimagga jhanas" which are more engrossing. Jhourney claims to teach these soft jhanas and they do deliver on that.
There seems to be some natural ordering to them. The progression happened in the order prescribed, with the lower jhanas happening before the latter formless jhanas.
It's possible to pop into a jhana directly from non-jhana, no need to go in order. I in fact first got into J2 and it took me a while to get to J1. Later in the retreat I was popping into J4 and J5 straight away without the warm fuzzies of the lower jhanas.
On their own, they do not make one aware of the three Buddhist marks of existence (sufering, impermanence, no-self) (As Ingram points out). I still feel I have a self, I don't feel like everything is impermanent.

Some of my description may sound too allegorical but it's quite hard to not be; I hope you agree with me that it's easier to get my meaning across if I say "it's like a rave" than if I say "a sense of euphoria". You can go to a rave and be like "ah yes this is what he meant" whereas "a warm buzzy sensation combined with a higher likelihood of wanting to open your mouth to scream wahooo, a desire to jump and open your arms etc" is a hopeless description by contrast.

Jhana	Me	Nadia Asparouhova	Jhourney	Jhanabhiññasutta	MCTB
J1	The universe is having a rave, let's fucking go, euphoria. That moment in a dance floor amidst a really good set when you feel the feeling that precedes the need to want to let a joyous loud sound out. Grinning at times.	Euphoric, bright, sunny, yellow	the joy becomes an intense, ecstatic rapture.	rapture and happiness born of seclusion
J2	Hugs, cuddling, love, peace, sunbathing on the beach. A universal cuddle puddle. No matter who you are or what you do, you are loved. Smiling.	Gratitude, beaming, radiating, hot pink	a lower energy, softer, more emotional happiness shifts into the foreground. Most describe it as a deeper, more profound feeling, and use words like loving, warm, grateful, or happy.	internal confidence and unification of mind, is without thought and examination, and has rapture and happiness born of concentration	rapture and happiness/joy factors created by concentration can really predominate
J3	A still pond under a quiet dark sky. You are floating in it. Everything is okay. There is no euphoria or any high energy vibe, but there's a quiet pleasantness.	content, reasoned, soft, wide, robin's egg blue	The deep happiness of the second jhana sinks even deeper, and settles into a lower, often wider, feeling of contentment	equanimous, mindful, one who dwells happily	more cool "bodily" bliss and equanimity with a more diffuse mindfulness of what is going on.
J4	Not much to report in the body, it's neutral. I was initially confused about this.	Dissociative, stillness, bathtub, cashmere, felt, muted lavender	many first-timers describe it as a peace more deep, still, and healing than they've ever experienced	either painful nor pleasant and includes the purification of mindfulness by equanimity	This state is remarkable in its simple spaciousness and acceptance. The extreme degree of imperturbability would be astounding if there were not such pronounced imperturbability
J5	Openness, possibility, expansion, taking a deep breath, space in all directions, the first instant of seeing a breathtaking view. The intuition that objects are solid is weaker. My mouth was opened in a "woah!".	Disembodied, infinite, outer space, grayscale		aware that 'space is infinite,'	perceptual boundaries drop away and a very unitive and vast-feeling openness prevails
J6	Oneness, everything is deep down the same, the feeling you get when looking at a chimp "It's kind of like us/me in a way", but for everything, from rocks to the ocean.	Beauty, benevolence, grace, psychedelic, rose petal pink		aware that 'consciousness is infinite,'	This can feel profoundly unitive, as consciousness seems to fill the whole universe, though really it just fills the field of experience.
J7	Not much to say and didn't spend much time here. But I remember thoughts were happening more sequentially. This might be a property of me trying to understand vs the jhana itself. For example normally these come at the exact same instant: 1. There's a door closing sound 2. There's a room 3. Someone has entered the room 4. Oh nice, a fellow human . But in this state these were decoupled, happening in sequence.	—— (nothing in nothingness)		aware that 'there is nothing,'	This state can be described as like space with all the lights completely out, so that there is no vastness, and almost no sensations other than those of Nothingness
J8	N/A, didn't get here	Surreal, dissolution, black velvet studded with colorful '80s rhinestones and gold that wink in and out of existence			This state is largely incomprehensible. There is no reasonable way to attempt to describe it, save that it is a mind state.

Agencymaxxing

Jose Luis Ricon — Tue, 01 Jul 2025 00:00:00 +0000

The term "agency" is popular these days. Though the term gets many definitions depending on who you ask, I'll define someone agentic as someone that both:

Is aware of what's possible, beyond the obvious next step
Gets what they want, if that's different from what their environment wants

And I'll define an action as agentic if it's vastly more predictable from knowing the individual than from knowing the environment in which the individual is immersed.

It's possible to have one, both, or neither. Someone could be constantly noticing things they could do but then they could react with a depressing "what's the point" and do nothing (depressed people ask why, happy people say why not), whereas someone else could be perceived as extremely competent and high achieving but all they are doing is pushing the "continue" button in life really fast, without being able to see whether the next step is the right step for them (this latter was Cate Hall's self-described past here).

If your environment is the University of Waterloo, you can't predict that someone would launch something like Socratica and its Symposium but you can predict that one given student will be studying for exams, as that's what students do. However if you know Anson Yu, you would assign higher likelihood that she'd do something like than that if it was a randomly sampled student. Therefore that would be a display of agency.

Being a player in any hyper-competitive highly defined environment is definitionally not agentic. When I was playing Starcraft a while back, playing single player was joyful. But when playing multi-player competitively you can't just vibe, you have to maxx out your actions per minute and you have to execute the optimal build orders if you want to win. In other words, your actions are not up to you, they are up to the environment: you become a vessel through which the game plays itself. In those contexts, it's still possible to make agentic moves (like coming up with build orders that are better than the existing ones) but most players are not doing that: they are being played by the game.

Getting what you want, once you know what you want, is comparatively easier and more theorized about, particularly if you have a common want or you are getting that want fulfilled in a common way. If you want waffles you can order them. Or you can decide to make them according to many recipes you can find.

In agency discourse sometimes examples will be given of things one can do or is allowed to do, like cold emailing someone for advice; if cold emailing is something you think about doing but can't because it feels weird, then that's an easier problem to solve. But having the thought that cold emailing is an option for you in the first place is the harder thing.

Being aware of what's possible is the hard part and we don't have much formal theory about it. Instrumental rationality and decision theory are built usually on a limited set of options, a pre-partitioned decision space. When we think about solving problems or fulfilling wants, people are generally good at generating the most obvious options but not all the options.

In the waffle example you could:

Have unusual toppings other than maple syrup
Make a waffle sandwich
Cornbread waffles
Fold them like tacos
Build a pyramid out of them and serve them in that shape
Throw away the premise, make pancakes instead
Go unhinged and attempt a canele-waffle hybrid

I recently hosted an event where I made waffles and these ideas didn't come to mind, I had a recipe in mind and wanted to make them at scale. I made some funny memes and tweets along the way, but I didn't stop and think if the first idea that came to mind was the right idea.

The company where I work (Retro Biosciences) was originally built in a ~~waffle~~ warehouse with labs made out of shipping containers, with the HVAC system designed by the CEO. This was because at the time it was hard to find affordable lab space and non-lab grade warehouses turn out to be cheap. When I visited Retro the first time, I went there for advice to start a company. Seeing the inside of the warehouse made me want to join instead.

Most biotech founders do not think of containers in a warehouse as an option to start a lab. I certainly didn't in my previous project (Rejuvenome). It'd be ok if they considered it and rejected the option because it's hard to pull off but what actually happens is that the option is not even considered!. These founders know what they want and even have financial stakes in the outcome and yet they don't think of the warehouse-lab idea! Why did the founder of Retro think of this? Part of the answer is a lifelong love affair with shipping containers and their possibilities but to an outsider that doesn't know this, the idea seems to have come out of nowhere.

Nat Friedman and Patrick Collison are also interesting cases to point to: Both successful tech CEOs, it would have been hard to predict what they would have ended up doing next from just knowing they made some money building software at scale: Starting a grants program (For AI and life sciences), and projects that have little to do with open source or payments: a project to decipher ancient scrolls and a new science institute, respectively. Had they started another company in a related field, which seems like the obvious easy thing to do, they would have been less agentic.

Agency is to be distinguished from ambition: while agentic ambition is strikingly noticeable at a distance, agency can be as whimsical as going to a party that has as a theme "The Hero's Journey" and distribute anti-Hero's Journey posters or go as the little tugboat that helped unstuck the Ever Given. Given the theme of the party, many costumes are obvious; it takes some imagination to decide to go as a boat or to subvert the theme of the party altogether. This Raw and Feral manifesto could only have been written by a greatly agentic person, no plans for world-shifting companies required.

The highly agentic Zen monk

Given I defined agency with two parts: the awareness of what's possible and the doing of the agentic deeds, it is logically possible that there can be people that are aware of what they could be doing but choose to live a life that's fairly predictable. You could imagine someone that has done all sorts of interesting things in their life, and after thinking for a while they decide that they want to be a Rinzai Zen monk living in a monastery. Their friends are surprised, but they argue that's the fastest way to get what they want (enlightenment) fast.

From the outside, if you were to meet the monk at the monastery without knowing the intention behind the decision to step into the monastery, you may think the monk is some sort of NPC that's there living every day like the previous one.

The decision to go to the monastery was in its context agentic, but within the container, agency is surrendered (that's the point of a monastery) in service of a higher purpose. And so while for a year there is zero exercise of agency, the whole period is highly agentic.

This also applies to life broadly: most of life we are not deploying agentic powermoves; it wouldn't be the skillful thing to do; the point is not to make them, but to be aware that we can make them and making them if it's skillful to do.

The not-so-agentic podcaster

Take a successful podcaster with a tech-centric audience. They have a large audience. They have an excuse to meet lots of people and talk to them. An obvious move to make given this is to do angel investing or venture capital. Is that what the environment wants? "Guy that invests and has a podcast" is definitely an established "kind of guy" out of which there are a few, so yes, that's what the environment wants.

Sometimes what you want is aligned with what the environment wants. You could argue that if you are aligned with your environment then life will happen as if your success and happiness are pre-destined: the next obvious choice is correct and effortless. And what more agentic than choosing or shaping your environment to support you? Yes it is very agentic to pick up a new habit out of the blue and keep it for a long time on your own, but it is no less agentic to notice that it'll be easier for it to stick if you surround yourself with people that are also doing that and make you want to keep doing it.

Ignoring the possibility of alignment could lead someone to trying to oppose their environment out of spite instead of because that's what you really want to do. It's saying no to good opportunities because "they are too obvious next steps". That is a good recipe for unhappiness and feeling smug at some level while envying those that took those obvious next steps that seemed too normie or cringe.

For this person, the correct next move is not an agentic move: and that is okay. Drinking water and breathing are not agentic moves yet we still do them.

Agency, a helpful mechanistic model

By helpful mechanistic model I mean a model that breaks down into components and one that, once understood, puts you on the path towards greater agency.

Part 1: Awareness

I said that the first part of agency is being aware of what's possible. Idea generation, from introspection, feels like a time-dependent process where obvious ideas are sampled first and less obvious ideas are sampled later. So it follows that having more time dedicated to thinking of more possibilities will let you notice more. Which is to say: you should "work" less. If you are doing you are not thinking. Similarly if you're stressed out (perhaps because you are being told to "work less"), that will also make it more difficult for the ideas to flow.

The brain seems to exploit one mine of ideas for a while and then try harder until we feel the juice does not flow any longer. Great, stop thinking, go get a reset (do something else, go for a walk, sleep). The next time you think about it you'll be exploring another thought mine and get new ideas and see more things.

Then as with any kind of awareness, meditation works. If you want to be more aware of your emotions, focus on your emotions. If you want to be more aware of what's possible focus on that. Though by definition what could be isn't what is, so you can't quite do the same. Instead, you can train your attention to notice possibilities by finding examples of others doing the same. Instead of chanting mantras you may as well chant items from this list. You can read biographies of people you deem agentic, or their tweets. You can have a daily, weekly, monthly or yearly journaling practice to bring attention to what you did and what you could have done.

Part 2: Doing agentic things

You can just do things, they say. But you don't just want to do things, you want to do agentic things! That's a mistake. If you are already aware of agentic actions you could take but are not, what's stopping you? There are two ways to approach this question:

The first way is the obvious one; to say that one should start small. Don't daydream about hosting a really elaborate dinner party before messing up that porchetta first. Cook the damned porchetta tomorrow and fuck up. Don't imagine you can build the Tesla of microwaves with solid state semiconductors, instead buy a microwave and rip it apart then try to make a baby version of a single device.

But the second way is the most useful one yet the hardest to follow: By default people are reasonably good at taking small actions so if you aren't, you could focus on the reason you aren't already. Perhaps the daydreaming is protecting you from starting to do something. Protecting you from trying is a great way to never have to deal with failure. So if you have any kind of "If only XYZ" or "Why do I keep doing X instead of Y" thoughts, then fix that first and agency may flow on its own. Read this, get fixed. More can be said about getting fixed, but that'll be a whole other blogpost.

Indeed the reason you are not monomaniacally pursuing some goal, Elon style, and instead you are reading this is either that you deep down don't want to spend the next 10 years grinding on that goal or that you are emotionally blocked from fulfilling your destiny. Either way, internal clarity will either enable you (in the latter case) or make you stop wanting things you don't really want (in the first case).

How I became more agentic

At a festival I went to (or in a way, I'm about to go to, as I'm writing this parenthetical on the plane on the way there) I hosted a small event where people would go on stage and be asked questions about themselves. A very simple premise, ripped off someone else's event, which I had attended and loved. I don't remember exactly why I decided to host that, other than I liked the event and it would make me happy to see people enjoying it. Was that an agentic move? Most people going to this are not hosting events, and I haven't hosted something like this before. But I have hosted things before of other kinds.

I am more agentic than I used to, but it's hard to point to exactly how this happened. Probably being exposed to people doing unusual things and reinventing themselves did some of it. Writer guys are writer guys until they somehow they turn into perfume guys and then into perfume entrepreneurs, making you go how the hell did that happen, that's just not what writers guys do?

I often think "wow I'm such an NPC, I could be doing so much more" Me saying this may seem ironic to if you have perused my LinkedIn given that I have hopped around fields more than most people in ways that maybe seem impossible. To me getting into aging research felt like an obvious next move, but from the outside it's kind of unusual to see a non-PhD holding non-biologist like me ending up reporting directly to the CEO of a well funded biotech company.

Does that make me some sort of agentic gigachad? What's my secret sauce? Someone less agentic would perhaps still be working at Twitter as I once was back in 2019. There's some sauce, but to the extent that it was secret, the paragraphs below make it less so:

I said yes to the right opportunities at the right times. I didn't have as a goal to end up where I did. As a heuristic, it is one that will probably help you be more agentic: put yourself in positions where new things will happen to you. That will make you think new thoughts and reevaluate your assumptions. When I was living in London, I was invited to some interesting events in the Bay Area, and though it was expensive for me at the time to fly back and forth the Atlantic, I thought, explicitly, that those serendipity lottery tickets would pay off, and they did.

Many times I've been very NPC-like; one of those moments (wrongly assuming you could only hold one O1 visa) led me to write this blogpost on questioning assumptions. What am I assuming right now that's not true? I of course can't know but I find myself asking people if what they say is something they know or an assumption, and often they are assumptions, so at least I can say that I've become more aware of the idea of having unexamined assumptions as a useful conceptual lens.

And as lately I've been getting into dancing, a dancing reference seems apt: Imagine someone sitting in the sidelines looking at a dance floor, thinking maybe daydreaming of the perfect dance moves they could make one day. Compare that to someone that is actually there dancing, not thinking about which moves to make, but somehow making the right moves. The path from getting from one to the other is realizing that you can just do things, in this case be cringe and dance poorly (or take dance classes) and once you are there the next moves will suggests themselves if you are open to those moves.

In the dance case, the sequence of events for me went: I first noticed I enjoyed dancing alone, then I noticed that dancing with other people seemed nice but I felt weird about it. After a while I interrogated the weirdness: it was about not wanting to inconvenience others with my nonexisting partner dancing skills. I thought: ah I could dance with an equally unskilled friend, but then neither of us would learn good moves. And dancing with a skilled dancer "for free" seems like inconveniencing them and getting free learning from them or something. After a while I thought wait what if they got paid? And... isn't that what dance teachers are for? This took a while to happen and it could have happened much faster if I had been able to see through that fear of inconveniencing others as something that 1) was there and 2) could be worked around.

Links (89)

Jose Luis Ricon — Sun, 29 Jun 2025 00:00:00 +0000

Why Pantone colors are so expensive

A while back Scott Alexander gave some grants. Here's a status update on said grants.

The Claude Bliss Attractor

Falsehoods Programmers Believe About Aviation

The supply chain behind making a pill of clonazepam

Some good advice on writing on the internet

Palmer Luckey and the B-Boys

Precise gene expression with gene circuits

Nattokinase seemingly can reverse atherosclerotic plaque

Combine drugs, get rich

Why are aerospace parts so expensive?

Scott on the missing heritability problem

Obviously, chess grandmasters don't burn 6000 calories per day

A compilation of videos claimed to have some degree of tacit knowledge transmission

Why did AAVs overtake adenoviruses?

LSD extends lifespan in worms

Anduril: The amusement park for engineers

Notes on managing ADHD

America to Boom Soon

A dinner with Dwarkesh Patel

A useful characterization of some psychoactive drugs

The grugbrained CEO

Oral PCSK9i!

19 months from clean sheet to a flying jet aircraft

Endometriosis is a weird disease

Tripping on estrogen

Westminster must fall, says Cummings

Links (88)

Jose Luis Ricon — Mon, 26 May 2025 00:00:00 +0000

Sasha Chapin on spiritual awakening

Works in Progress links post

50 facts about construction

Why aren't more companies working on atherosclerosis plaque removal?

Prime Medicine's pipeline then ($16/share) and now ($1.2/share)

Casey Handmer questions about AI in 2025

Make thee FDA great again

On the importance of precise instructions

New podcast, Development & Research; first episode on clinical trial efficiency

The Tesla of stoves

Owlposting on AI and its application to clinical drug development

Patrick Collison interviews Jony Ive

Retinoids probably don't slow skin aging

Jose Luis Ricon — Sat, 17 May 2025 00:00:00 +0000

Retinoids (retinoic acid, retinol, retinal, tretinoin, adapalene, etc) are commonly claimed to both revert and also slow down skin aging. But this seems wrong to me.

Reversing aging is quite difficult, and to my knowledge only a handful of things have enough data to support the claim of age-reversal (reprogramming being my go-to example). Slowed aging occurs in animals with caloric restriction and a few other things, but in general the default for both of these effects should be "no effect until proven otherwise". The sort of thing I'd want to see for "affecting aging" is reduced DNA damage or reduced epigenetic age; ie the converse of what UV radiation does: UV radiation does accelerate skin aging through DNA damage, and plausibly slowing down DNA damage accumulation in the skin should make it look younger for longer.

People believe retinoids reverse aging because topical application of retinoids make the skin look younger, increase collagen production (which declines with age), and make the skin thicker (reversing age-related thinning). This is not a controversial claim and it seems well accepted by the public and scientifically, here's one amongst many paper that has shown these effects: Kong et al. (2015)

But it is also understood that if one stops using retinoids then the skin goes back to "normal". To me this is clear proof that there is not really age-reversal happening: aging happens gradually not suddenly.

Some might think "but retinol is reversing skin thinning, and collagen decrease, and wrinkles", what are the odds that can be done without reversing aging! Well, quite high. There's a recent study (You et al. 2023) in mice that induced accelerated skin aging through continued exposure to UV radiation. Then their skin was treated with a retinoid or with collagen mRNA (delivered both in EVs and LNPs). Both treatments were effective at making the skin look younger, and both treatmentnts when stopped failed to make the changes permanent. Collagen expression then, perhaps singlehandedly is whats driving a lot of these effects, and we would agree that just overexpressing collagen is not de-ageing the cells:

But many studies (including the one from earlier) are short term. Long term retinol use reveals some other interesting changes: Thorne (1992) documented that indeed after stopping treatment the effects go away but they take a while (six months). Bhawan et al. (1996) reported also that while it is true that skin thickens in the first year then it thins in the period following that, returning to normal.

Retinoids also work well in older people that have not used retinoids, at least for a year before this study (Kang et al. 2005)

But we have: would the effects be even better if this person had been using retinoids their whole life? If that were true then we could say that retinoids do slow down skin aging. But that trial doesn't seem to have been done to this day. It could be doable: finding lifelong users of retinoids of a certain age, then treating a retinoid-naive cohort of a matched age, and then seeing if their skins look markedly different. Conversely, one could run a trial where lifelong retinoid users stop treatment and then see if their skin look better than average for their age.

So given what's published out there, I think the evidence supports using retinoids if one wants their skin "here and now" (or within the next year) to look younger, but it does not support its use "so that my skin looks younger in 50 years" relative to the alternative.

But if you know of evidence to the contrary, let me know!

Links (87)

Jose Luis Ricon — Wed, 30 Apr 2025 00:00:00 +0000

Why can't biology move faster?

How El Salvador solved their crime problems with a gigaprison: CECOT

Robot dexterity is still difficult

Why did Doordash win?

Equity trader does ayahuasca, becomes psychedelic facilitator, then addicted to ketamine, then explains Elon on ketamine.

"Spare human bodies" for transplantation

Profile of Steve Davies, who runs DOGE

The Purism, a $2000 smartphone mostly manufactured in the US

Trevor Klee on gallbladder mysteries

Matt Kaeberlein on biological age tests (read the comments to the videos as well), Karl Pfleger on the same

DOGE is doing some fairly sus stuff, a whistleblower claims

How I don't use LLMs

What happened to AI pathology companies?

Boolean CAR-Ts

The pharma and biotech sales handbook for software founders

Links (86)

Jose Luis Ricon — Sun, 16 Mar 2025 00:00:00 +0000

Sasha Chapin on Enjoying Things and Being Sasha Chapin

Scott Alexander reviews The Body keeps the Score. I recently read the book, which makes claims that will sound familiar and even obvious to many people that have engaged with many forms of therapy, particularly the idea that events that happened in someone's childhood can affect their current mental health. But I learned there that the author of the book had to fight for psychologists to accept this! Seemingly once upon a time the idea was considered obvious (From Freud) and then the field overcorrected in the other direction, making it difficult to accept that indeed trauma is real (a case of scientific flip-flopping).

50 thoughts on DOGE

Inducing torpor in mice to slow down aging

Fix the hypothalamus, fix ovarian aging

Some speculation about the next few years re progress in AI, and some more bearish speculation on the same topic.

Semianalysis on advances in robotics

Chapman on how what he does is like and not like philosophy

The science of woo

The baby boom started before WWII, not after

How to test for LLM situational awareness

Who is Larry Ellison

A socratic dialogue over the utility of DNA foundation models

In defense of letting people explore their curiosity in research

On the death of IP in biotech. A thesis I've had for biotech for a while

A tweet from mine on a concrete way to speed up some aspects of biotech: making the FDA more deterministic

The gut health to depression pipeline

Fix the brain, fix fertility

Interview with the founder of DeepSeek (via Kipply)

Explaining Circling

Jose Luis Ricon — Sun, 16 Feb 2025 00:00:00 +0000

There's this practice called Circling¹ that I do sometimes. I remember before I did it the first time I tried to get a sense of what it was like: Why do people do this? Are there mistakes that I can learn to avoid? There wasn't much I found written that I found that useful, with the exception of this post from Aella and this other one from Tasshin Fogleman.

[1]. Circling is a registered trademark so one can find similar practices by other names like Relatefulness (in the Bay Area)

When I explain Circling I do it by analogy: in most conversations we talk about things other than "us here and now". I may be explaining something to you about aging research or you may be telling me a story about how you met your boyfriend, or we may be making plans to travel to Japan. In circling, we talk about "us here and now". That's it.

So to put it in definition-y terms: "Circling is a communicational practice where participants share their present-moment experiences, feelings, and observations about themselves and others in the group, while focusing exclusively on what's occurring in the here and now." This could be done in pairs, in groups, or with more or less heavy handed facilitation.

But this is like explaining the game of Go by saying "Go is a game where players alternate placing black and white stones where you encircle your opponent's stones [etc]". In a way yes, that's what it is. But it misses out on the emergent order implied by such a simple set of rules.

Banning (in some strict circles) or gently nudging people away from (in more informal ones) non-present discourse still leaves quite a few things you are allowed to say:

How you feel (I'm tired, I'm bored)
How things other did or said made you feel (Hearing you say that made me feel angry; I'm surprised he just left the room, that interaction from earlier between you two was entertaining)
How others seem to you (You seem amused; you haven't said anything in the last hour)
Explanations for your seemings and feelings, often offered explicitly as your own as opposed to things you are asserting as true about them (You keep looking at each other, and I have a story that you two knew each other before coming here; you seem bored, I am wondering if that's because you were expecting others to ask about you)
Your desires (I want to see you talking more, I have a desire for you to ask me something)

This list is not exclusive but it is enough to give you an idea of the moves that are available.

At first it seems shocking that just with this you could go for an hour or two! But you can indeed. A brief sequence may go:

Person A: I am curious about why you are talking so much, I have a story that you like being the center of attention

Person B: Hearing that I feel attacked but also feel ashamed of feeling that way because you may be right and I may be reluctant to accept it

Person C: I feel great curiosity towards Person A and I don't think he was talking so much; I want to hear him say more.

Person B: That made me feel appreciated

Person A: I notice I have a story that you (Person C) said that just to make Person B feel better.

Or another may be:

Person A: I'm happy that you feel better now

Person B: Hearing that I too feel happy

Person C: I too feel that way

Person D: Yeah the circle feels happier now

Person E: I found the expressions of happiness four times in a row a bit repetitive and I wish we talk about something else

Person F: I feel slightly sad that you didn't continue the happiness chain and I have a desire for you to join

Person E: It's funny that you said that as that also breaks the happiness chain but also I feel slightly angry that you want to control what I do

You will notice that in these examples the participants are saying things that are uncommon to say in other contexts like "I feel angry [at that thing you desire]". But you are not required to say anything unusual! You can sit there for two hours without saying anything (that was my first circling experience, I did exactly that). You could have a thought that goes "I could say X but Y person might think it's mean". The same set of choices available outside of Circling are available in Circling:

You can just say X
You can not say X and say something unrelated about the present momen instead
You can stay silent
You can express your fear that if you say X then Y will think it's mean

(4) is a quintessential circle-y move: going one level up in the conversation. If you do this what typically will happen is that the other person will appreciate that you are being mindful about their feelings.

Why would you want to try Circling? There are a couple of reasons:

To get more comfortable with saying what you actually think. If you struggle with say leaving a conversation because it is boring (and you're afraid to tell your interlocutor), seeing over and over how others state their feelings and desires fearlessly will help you bring some of that into the rest of your life.
To be more self-aware. Related to the earlier point: it is one thing to say what you think without shame but some thoughts or desires you have may be hidden from your conscious self so you can't even talk about them! Circling accepts your thoughts and desires as they are as well as narrows down what you can attend to, so it's easier to notice more about what's going on in you.
To learn to be more present. If you tend to talk and think a lot about "stuff" as opposed to feelings or what's present, you can get your reps at this by circling.
To be more spontaneous. In Circling, what you say has to be about what's present. But to many (including myself) you may have many thoughts and a meta-thought that then goes to analyze what to say and by the time you have chosen it's too late, the circle has moved on and you can't say that anymore. In this sense it's similar to the meditative practice of Noting.
For entertainment. It's interesting to see the dynamics that emerge from Circling.

Links (85)

Jose Luis Ricon — Thu, 30 Jan 2025 00:00:00 +0000

An inside view via 19 cameras of the NYC restaurant Crown Shy (which I recommend, get the gruyere frites and the roasted short rib)

Curtis Yarvin's recent interview [transcript]. The interviewer's reaction near the beginning sums up part of mine "I'm asking you what you had for breakfast and you go "Well, since the dawn of time!!, just answers"+"I find the depth of background information obfuscating, instead of illuminating". Though I could see how his style of storytelling could be entertaining to many. Fun facts, I first came across his blog, Unqualified Researvations a while back (2010 perhaps?), I remember reading this post.

Will all our drugs come from China?

Six and a half failed startup attempts

The origin story of OnlyFans, also Aella on the same topic

One from the archives, by me from 2021 on wildfires

Various things that correlate with lifespan

The company I work for, Retro Biosciences, recently co-developed a model with OpenAI for protein design, GPT4-b micro (the name was my suggestion :). We are also raising 1 billion dollars.

Did you know there are gigantic 500mL syringes

The correlation between aging, obesity and inflammation, my explanation for why GLP1s seemingly help with every disease

Investing in a16z, the VC firm, seems to be underperforming the SP500 these days

Japan has the will to have nice things, the US does not.

Gentle Romance

Lies and fraud in Alzheimer's research (my own AD posts, for context)

"Self-awareness" in LLMs (ie they 'know what they know' and 'what they tend to do' purely from the training set)

A recent summary of Michael Levin's work

A third of Tiktok users (and half of Instagram's!) wish the platform didn't exist [EDIT 2024-03-26: See the Mistakes page for an update on this]

In biotech if you are not a therapeutics company, eventually you will go bankrupt or become one, tales from one such case, Reverie Labs

Tech CEO becomes very rich when his company gets acquired, gets depressed (many such cases), goes on a vision quest to the Himalayas, joins DOGE, goes to Hawaii to learn physics, writes blogpost to narrate his story.

Cate Hall goes on a T journey

List of stuff that has bits of plastic in it

An introduction to David Chapman's thoughts

Dwarkesh visits China

The biology of getting jacked

The public goods curse of pharmacokinetics

Links (84)

Jose Luis Ricon — Sat, 21 Dec 2024 00:00:00 +0000

First commercial-scale fusion plant plans announced, to be built in the early 2030s

Roger Penrose's biography

Renaissance Philantrophy (and within, a link to recent research on wearable cortisol trackers!)

Bringing Elon to a knife fight

Google Willow, their new quantum chip

Something I long suspected: Most of senescent cells are immune cells (hence immune rejuvenation should also solve cellular senescence)

This year in biology: 2024; of particular interest is the brain control of bodywide inflammation through the vagus nerve

And this year in medical innovation

The Case for Clinical Trial Abundance & On how to test more drugs

Undoing Philosophy

Claude wants to be nice; thogh this still does not count as emergent situational awareness, as the model is explicitly told it is in training.

Pig kidney (with 10 gene edits) successfully transplanted into humans for the first time

Shinzen Young's meditation manual

Oligo conjugates to cross the BBB

Prince Rupert's drop

Robert Ludlow on his emotional processing journey

Tales from the trenches at the Arizona TSMC fab

Sasha Chapin on meditation tradeoffs

Michael Nielsen on being a wise optimist about science and technology

Falstaff waffles

How to be a better conversationalist. Or: yappers vs question-askers

Cozymaxxing in hotel rooms, the importance of light

A proposed mechanistic explanation for how inflammation can accelerate aging

Spanish architect Ricardo Bofill made an old cement factory into his home and workplace

A critique of David Deutsch's philosophy. For more, Huemer's critique of Popper.

Links (83)

Jose Luis Ricon — Sat, 23 Nov 2024 00:00:00 +0000

Laura Deming on understanding

Interesting uses of AI

The memes of the wealthy

Elon dreams and bitter lessons

Nabeel on Palantir

Scott reviews Deep Utopia

Meditation, considered harmful

There is no placebo effect

Dwarkesh interviews Gwern

Restoring fertility with iMSC transplantation in monkeys

Profile of James Fickel, a not very well known crypto backer of many impactful projects in the longevity space

The King and the Golem, by Richard Ngo

A recent study in monkeys claimed metformin works to slow down aging. Not so fast, says the SENS foundation

I haven't done a deep dive on seed oils yet but my base take is that they are ok in low quantities - though you shouldn't be using oil other than olive oil (it's the tastiest and healthiest) and you shouldn't be deep frying stuff if you really care about health. Some thoughts from BJ on this. An article from Levels as well with a similar take.

Life in HD: on jhanaing (And anti-jhanaing)

Spicy take(down) of YC and Paul Graham-thought (ht/ Richard Ngo for the link)

CRISPR babies are here to stay, the question is how

Video about Science Corporation

Claude as therapist, various tweets

Pacific Fusion, another fusion company just launched

How many ways are there to build life? Not that many perhaps

Unlocking the emotional brain, a unified theory of therapy

Alzheimer's and inflammation

Otherness and control in the age of AGI

Sheekey Science Show on skin rejuvenation

Links (82)

Jose Luis Ricon — Sat, 05 Oct 2024 00:00:00 +0000

Lots of interest in gene editing startups but in practice they don't do that well: Few diseases can be corrected through gene editing, hence valuations of such companies, despite FDA approvals, are low. Compare with addressing shared causes of multi-morbidity like aging or obesity. If you want to work on the former, at Retro.bio we are hiring :)

The decline of social status of stay at home moms as cause of fertility decline (via Scott Alexander)

Why can't the US build ships

Isaak Freeman's journey to learn mandarin

Trevor Klee on Robert Moses

Advice on finding writing ideas, with some of my own!

Don't get too worried about microplastics

A while back I proposed this idea of going around successful labs and researching their management practices. Why are top labs top labs? Now, it is happening.

In 'qualitative metascience' there is a rich body of work to be developed about how to fund science or conduct research. Startups have Getting Things Done or High Output Management or The Great CEO within and a plethora of supporting essays and articles about fundraising, managing, or marketing. Startups do make use of this hard-earned knowledge through experience. What does science have that's comparable? (Limits and possibilities of Metascience)

Entrepreneurship changed the way I think, by Casey Handmer

Paligenosis, or tissue regeneration

Burning Man

Jose Luis Ricon — Fri, 06 Sep 2024 00:00:00 +0000

On August 25th I found myself sleeping under a tent at Black Rock City (BRC), the temporary city where Burning Man takes place. It was my first time going. A month before that I had no plans to get there though earlier in the year I had thought of going but made no definite plans. I thought well, perhaps next year, which is what I had also thought the year prior. But then, two weeks before the event, a conversation with a friend that was looking for someone else to go with changed that.

Ultimately, to go to burning man you “just” need

A ticket
A way to get in and out of Black Rock City
Means to survive

And surely one can get that in three weeks, I thought.

Finding tickets was easy enough: one can always find people selling tickets as the date of the event comes close. Getting there and means to survive are an entangled choice: If you are taking the burner bus, which we did, you can’t carry that much with you which means you have to rely on a camp to bring you water and food, but in exchange you get to skip the car queue. If you have an RV you could do a fully DIY burning man experience and camp by yourself but it could be pricier. I thought that renting (and cleaning) a vehicle, dealing with potential maintenance was not worth the hassle this time. If we had a bigger crew it’d have been different I suspect.

We got to Burning Man Sunday 25th of August and got back on the 1st of September. Though it was only a week it felt like it lasted longer than that. It was certainly an unusual experience: Because phones don’t really work there very well (and I lost mine anyway), your real world life is put on pause until you get back and is replaced by the day to day of being a BRC resident. I didn’t feel the need to check Twitter or text anyone when I was there, so I did get to be fully immersed in the experience.

Once we got there, we set up camp, got some water and explored around. We had our first encounter with the BRC porta-potties, the place to go for your toilet needs if you don’t have an RV. Though we later found a camp that had private porta-potties and used them once, we found ourselves wishing to have access to nice regular toilets, especially for times around bedtime and waking up. In any case when one’s out and about living at BRC, there’s no escape from the porta-potties, as getting back to camp is a long journey that will leave you with a sore butt (if you bike) or take forever (if you walk) depending on your location in the playa.

Then we had to get used to living in a state of near-dehydration all the time. Sweat evaporates instantly on the playa, so you are losing water but not noticing it at first. You have to drink water all the time if you feel even a bit thirsty. At BRC a greeting we heard was “piss clear”; because if you are not, it’s a sign you’re not drinking enough water. “Fuck your burn!” is another one that I was amused by.

Black Rock City is a bit of a miracle. Every year, a completely empty piece of land is turned into a city replete with art installations, electrical installations and water infrastructure. Every year, it is all disassembled and the desert looks as barren as it did at the beginning.

Some of this infrastructure is shared across camps: The camp we were at was getting electricity from the one 40kW diesel generator over at Naked Heart for example. One or two of the mornings when most other people were sleeping, I wandered around following the cables coming from our fridges and the hose we were getting water from, seeing what was at the other end, how the whole system was connected together. I had the thought that someone had built those things “for free”, someone that also had to pay for a ticket to be there. This is a key aspect of the burn; it’s not just having fun in the basic sense of dancing to techno, being driven around in an art car, and accessing interesting mind states, but also about surviving together with your homies in the desert. Not too far from something I say is a key source of meaning for me in life: going on good quests with the homies, or more prosaically working on meaningful projects and forming meaningful relationships.

It did surprise me how much time we spent on basic maintenance tasks: getting water refilled, going to the toilet, finding other people, moving between camps, cooking, finding food. Doing anything takes effort when breathing is hard and your heart rate is almost doubled even under the shade. Especially during the middle of the day, wandering around felt horrible, so sometimes I would just hang out at the camp resting and perhaps washing some dishes or helping make food.

Sleeping was definitely problematic. At Burning Man you have a menu of options:

You could sleep at night and be awake during the day; however you will need really good soundproofing as you’ll go to bed and wake up with the thumping untz-untz of EDM in the background
Or you could try to stay awake at night and sleep during the day, but then it’ll be really hot in your tent, unless you find an AC dome (what we did) or bring a swamp cooler (which I also did, but didn’t use in the end)
Someone recommended going to bed at 9pm and waking up at 3am to get the best of both worlds. Perhaps this is indeed the best move but one has to be very disciplined and commit to it as a group.

If you’re part of a group, different people will have different sleep requirements. Being out of sleep sync means different people will have different energy levels at different times and the vibes may be slightly off as a result; someone may want to go to bed while someone else wants to go dancing. Planning what to do at Burning Man to the hour is hard, but agreeing on what to do about sleep seems like a good idea if you want to keep a group together.

In theory, you could show up to BRC almost empty-handed and survive. “The playa will provide” they say. But if everyone did that the whole thing would fall apart, as a good citizen of BRC, you should be self-reliant. Once you try your best, if you happen to have failed to prepare sufficiently, you’ll most likely be ok: you can show up at a camp and you may get water, food, coffee, drinks, or a place to rest. You can wake up one day and there are more coffee and pancake offerings than you will be able to visit during your stay. There are bike repair camps, outfit swaps, community bikes (hard to find but we used them once!), AC domes, tea lounges, all offered as gifts to other burners.

Ok, enough with the survival stuff, where’s the fun? Burners are like clowns in a children’s chemotherapy ward; trying to both provide and have fun despite the grim background facts of the inhospitable playa. The obvious thing is music (mostly EDM, but one can also find classical music, perhaps even an orchestral rendition of Queen’s Bohemian Rhapsody) and dancing. Surprisingly I didn’t do a lot of that this time! I spent a lot of time having conversations with people about their own experience. In a good way, conversations felt self-referential as in circling.

Running into people I know from SF was really fun, little surprises happening throughout the event. I knew some of the camps where friends would be at, but no guarantee that they would be there when I visited. I had a decent success rate at showing up and saying hi to someone I knew. We slowly collected a crew, someone we met at an authentic relating workshop, and someone I faintly knew from the Berkeley group house scene. We stayed mostly together until the end of the burn.

Then there were the little absurd experiences: getting spanked before you get coffee at Scarbutts (Why? I asked. “It’s fun” they said), being driven in a mattress-on-wheels at night by a stranger than then led us to the Altitude Lounge, getting into a wood fired sauna (Though a dry sauna, as we added water it got more humid than the desert, getting out felt refreshing), or having a 3 course meal in a nicely set table (pictured below, we ended up going twice).

Sure I’ve had 3 course meals before, but having such niceties in the desert it felt like a hilarious “fuck you” that the BRC community is giving nature, a collective celebration of human ingenuity, and while Burning Man is not the most efficient (generators scale with size for example), its smaller scale lets you appreciate this sense of collective achievement more. Next time you go into a restaurant you can appreciate all the unseen but real effort (I Pencil, anyone?) that went into extracting what to you is an effortless meal for a convenient price. Hell yeah!

Most of the time I was with our small group of 4 people wandering around. Not being with a group often meant having trouble reuniting later, so the incentive to stay together was strong. But there were many occasions where I was alone. One night I took my bike and biked past the Man, the Temple, and almost all the way to the trash fence, just to see what was there (I didn’t quite make it all the way this time though!). The deep playa is a great place to explore alone. It reminded me of pictures like this, where everywhere you look around you in the far edge there’s a lot of stuff (art cars, music, lights) but in the space immediately around you there’s absolutely nothing, just darkness, with the occasional art car or bike passing along, like comets grazing a planet, getting close but not quite touching (Well, in one occasion someone got close and said “I’m looking for Titanic’s End!!!” to which I replied “Me too! Let’s go find it!”).

Burning Man is life, lived differently. In the real world most people are not dancing all the time, they are also resting, having conversations, or reading a book. The same is true at Burning Man. You can experience the Burn in any way you want. The experience, I’d say, is not so much about the specific content but about the state of mind, being exposed to serendipitous happenings, feeling higher highs and lower lows. I got to feel the worst I've felt in a while at Burning Man after not sleeping much for two days in a row. In the moment, I was tired, angry at minor annoyances, and quite grumpy. But after the event, I'm grateful I'm not like that most of the time! And that though I wasn't the most pleasant person to interact with one or two of those days and had some tense moments with our group, by the end we were all four of us sitting together to watch the Man burn.

Would I go again? At least once more, yes!

Appendix: Packing list

So what do you really need to go to Burning Man? There are a bunch of packing lists on the internet one can find and if anything I found I was overprepared in some regards and underprepared in others. The items that I ended up using all the time and that I’d say are the bare minimum would be (setting aside shade, water, food, bikes; that was provided for us by the camp this time)

A waterpack; I got the 2.5L Katari 3 from Osprey as a portable lightweight source of water. A mistake I made is not buying this accessory to keep the nozzle clean.
Electrolytes. I got these ones and added a pack to my water once or twice a day.
Sunscreen. My skin doesn’t burn easily but just in case I used some; mostly in my face
A mask. The weather this year was nice but there were some days when I was glad to be able to breathe filtered air. I got this one
Sunglasses. One could always squint but it’s nice to have them. I had a pair of Ray-Ban aviators at home so I took those
Boots. I went with Blundstones, and they did Ok, comfortable enough but I found them a bit harder to get into and out of them than I thought, especially when my hands were dry. Palladiums are another recommendation people have.
Good socks. I have a large collection of Darn Tough Light Hike Micro Crew socks and they did great. My feet didn’t feel too hot, I got no blisters and no sand inside. I changed socks every few days, they held really well.
A hat. I ended up exploring Black Rock City a lot during the day so it was nice to have one. I got this one.
Lights. This is quite important, particularly at night! I got a Spot 400 as a headlamp (plus a pack of spare AAA batteries that I didn’t use at all), a bucket hat that lights up, these LED armbands (super handy! They can be attached to a bike or to oneself)
Earmuffs. Really useful for sleeping! They block most but not all of the noise. Should have bought regular earplugs as well.
Chapstick. Your lips will be happier that way
Skin lotion. On day two my fingernails were bleeding from the dryiness. This probably saved me.
Blister cushions. Used only once but it probably made walking a much better experience during the week
A cup. I got a foldable one to be able to keep it inside my backpack. But perhaps I should have gotten one that is attached to the backpack instead to free up internal space.
Goggles. I didn’t use them (they ray bans did ok enough deflecting dust from my eyes) but there were no major whiteouts when I was there. I got these ones but they have small holes in them and sand could have made it through. I’ll probably get different ones next times.
Re sleeping bag, tent, and pad; I was in a rush and thought the camp would be providing them until last minute so what I got might not have been the best; I was also planning to donate them to the camp so I went for relatively cheap ones. Imho they were good enough: tent (an ok tent, quite small), pad, sleeping bag (comes with pillows but they were meh; the pad also had pillows, that was nice).
This bag from peak design for extra storage. I had it clipped to my backpack with this mini carabiner but it got a bit impractical. Next time having it on a belt would have been better.
A wristwatch. I had a Fitbit and the battery lasted most of the week, should have brought the charger with me!
Battery pack. Nice to be able to charge stuff without relying on power from the camp.

Other things I brought that are less important

Spray bottles. Useful to refresh oneself, wash your hands
A plate. Depends on your own situation but the camp I was with had communal plates so I didn’t use my plate that much.
A spoon/fork set. Same as above.
Wipes. Generally useful to clean your hands or to blow your nose. You’ll be blowing your nose a lot! You can also carry a bunch of 1-ply toilet paper with you too.
Toothbrush kit. It’s nice to brush your teeth but not strictly required, during that week. I did it every few days.
Flashlight. I have this Nitecore NC10000 which doubles as a USB-C battery to keep lights charged if need be and also it’s quite a bright flashlight
Warm leggings. It was cold one of the nights and this set helped
Saline spray for the nose. You can also use the spray bottles with regular water though.
Hand sanitizer. I brought a bunch; the toilets always had a supply of it, the rest of the time I ended up using it to wash my hands on the go.

Things I wish I had bought (that I would have used)

Walkie talkies! Finding friends after parting ways is hard! Phones don’t work at burning man so we had to resort to leaving messages in pieces of cardboard to meet at predetermined times. With walkie talkies, we could have been more flexible about splitting and reuniting later in the day. We got some from a camp in the last few days and they were nice to have.
Duct tape. If I had it at hand, I could have repurposed my backup non foldable cup into a cup I can carry around by taping the mini carabiner to it.
More than “bought” but rather “done”, is organizing better, I spent too much time searching for stuff. I should have kept a dedicated space for each type of item in designated bags or storage space for ease of access.
A water bottle; I had to use my backpack for water inside the tent and I wish I could keep it outside and have a water bottle inside the tent at all times for ease.
More fun costumes (I bought everything in a rush, and I ended up wearing 2 pairs of shorts, a few shirts, and this robe most of the time)
A collapsible miniplate; I got less food around than I thought so I didn’t miss this, but next time if I get more food this would be useful.

I have to mention here a few resources that I found helpful when preparing my own packing list:

Spencer Greenberg’s Packing List
Things people regret bringing/not bringing
These other packing lists

Links (81)

Jose Luis Ricon — Sat, 17 Aug 2024 00:00:00 +0000

Jean Hebert, who proposes the stepwise replacement of brain tissue, has now joined ARPA-H

Why does Ozempic cure all disease

Scott Alexander on Nietzschean takes on morality, with an additional take from David Chapman, You should be a God-Emperor

Radiant, company started by ex-SpaceX engineer to

PBMs: a key player in the fuckupedness of the american healthcare system

Via Scott Alenxader's links, powering airplanes via microwaves. I had this idea back in 2021.

Blue Origin's factory

Using toxoplasma for delivery into the brain

Profile of Palmer Luckey

Nudge, a company trying to build an ultrasound headset to enhance human experience

Twitter thread wherein I discover that not everyone likes 1:1 hangouts!

"From barista to billionaire" (via Nick Camaratta)

I did circling

Links (80)

Jose Luis Ricon — Sun, 14 Jul 2024 00:00:00 +0000

AI companies need to make a lot of money for the current market state (NVIDIA going to the moon) to make sense. Right now it's far from that.

Interview with the current co-CEO of Netflix

Lambda School, a scam

A tour of Starfactory, with Elon

Advantages of incompetent management

Ben Kuhn on trust and growing teams

Mehran's Steak House: making of

Why haven't biologists cured cancer?

The occurrence of cancer seems to continue to raise exponentially even in old age, contrary to what was previously thought

Using evolution to fight cancer

Quantum computing state of the art from 2019 outpaced by progress in classical computing as of 2024

Does meditation experience get you to jhana faster? Weirdly no

Naked Mole Rat mortality rate does not seem to increase with age, additional data keeps supporting this conclusion

What kills cancer patients?

Why microbiome research is hard

Making synthetic blood

Links (79)

Jose Luis Ricon — Tue, 11 Jun 2024 00:00:00 +0000

Michael Lewis (author of a recent book on FTX)'s Blind Side

Xylitol bad?

Demons and Internal Family Systems

GLP1 analogues do not cause muscle loss in excess to what one would expect via caloric restriction. And we know that in that case one can avoid that to some extent by a high protein diet + exercise.

Cradle (formerly known as Lorentz, a name I deem more based), Laura Deming's new startup working on cryopreservation of tissues

Lumina, the probiotics company trying to cure cavities, playing very dirty here

That study saying that dance was better than SSRIs? Not so fast.

This tweet is a bit of a meme but there seems to be some truth to it, the post-exit startup founder to spirituality pipeline. This reply is interesting.

Dropping sterilized worms from airplanes in Panama, weekly

Andy Matuschak: How might we learn? (Check out his Patreon post for more context on the idea of exorcising oneself of the Primer)

The solar industrial revolution as an investment opportunity

Anthropic's sleeper agents paper

A song: BoZlak

Links (78)

Jose Luis Ricon — Sat, 11 May 2024 00:00:00 +0000

Some debate over the merits of Minicircle, the gene therapy startup. It's a case of "in theory, it shouldn't work", with "working" defined in the most damning way: probably not even raising follistatin.

The debate over the usefulness of healthcare, Scott and reply from Robin Hanson, followed by reply from Scott and reply from Robin, with some highlights from Scott, which I think contains a good closure to the saga, with Hanson stating what he believes in and Scott agreeing roughly with that view.

And more biotech debate, this time about the Lumina probiotic that claims to prevent cavities.

On the synergy (ie the bad kind of feedback loop) between fat gain and inflammation

Reversing atherosclerosis with gene therapy

Michael Elowitz on synthetic biology

Astro Mechanica

The origins of woke, a book review, with comments

Research Leader's Playbook

I recently finished listening to the Billion Dollar Whale audiobook on the 1MDB scandal, which I recommend. Kevin Kwok has notes here.

Armand Cognetta on learnings running his company

A weirdly whimsical healthcare software giant

On the submarine cables that carry most of the world's internet traffic, and their repair

On jhanas

And, from the same person, understanding science funding 2011-2021

Trevor Klee on GLP1 and GIP receptors

Base Power, a vertically integrated battery/electricity startup

Brian Potter on fab construction costs

How might we learn, by Andy Matuschak