The "what is aging" question is a recurrent one in geroscience (I have my own take here), but everyone would agree that if we take something that we deem old, do something to it, and then we have no way of telling that apart from a younger version of itself, then it's fair to say we have solved aging for that thing.

If you are a single cell on a dish, cellular reprogramming is great news: Take a cell, reprogram it to a pluripotent stem cell (iPSC) and then back to the original cell type, recapitulating in a cell what an immortal jellyfish naturally does. The result is a cell that is indistinguishable from a young one. There are some caveats to this result: Do all cells in the plate get reprogrammed or are we seeing a selection effect where very damaged cells die? Probably there's some of the latter going on too.

One early paper from Lapasset et al. (2011) goes as far as claiming that these cells have been completely rid of their former aged cellular phenotype.

This result cannot be translated to humans (or mice, for that matter) directly. The equivalent of full reprogramming in a human would involve turning all cells into stem cells and back. In practice, doing that in vivo leads to pervasive cancer unless one gets the dosage and the targeting right as with this recent preprint. It is not guaranteed that we will be able to fully decouple rejuvenation from loss of cellular identity, but the possibility of it makes me optimistic as I wrote here. We just (that just is a massive understatement) need to find a safe way to partially reprogram, and find ways to deliver reprogramming throughout the body.

Reprogramming is also interesting for a reason that wasn't as obvious to me back then: Rejuvenation by full reprogramming is some evidence that cells have in them all they need for cellular rejuvenation. This claim is actually too strong; we already know that DNA mutations are not magically fixed by reprogramming, but the claim is not far from what the evidence seems to be showing so far: reprogramming rejuvenates mitochondrial function, the epigenome, telomere shortening, and altered gene expression. Reprograming takes old cells and makes them into cells that, as far as we can measure, are young. As long as the burden of mutations is not too high this can work.

It didn't have to be that way, it could have turned out that there are too many kinds of cellular damage that the cell just can't deal with, which would then require engineering novel enzymes, knocking in genes from other species, and other sorts of radical genetic engineering that eventually we would have to do in in vivo in adult humans. We don't yet know for sure if this is true, no one has looked at, for example, whether cells can get rid of lipofuscin when reprogrammed, but we do know that given a drug cells can be coaxed into it (Julien & Schraermeyer 2012, Fang et al. 2022). It used to be believed that cells were not able to do this.

Taking the fact that cells have in them all they need for rejuvenation as a fact then leads to the question of finding sets of perturbations for accomplishing this safely: we know there is a combinations of levers we can pull to get to the goal, the question is what levers, not whether they are there. These combinations do not necessarily have to involve the Yamanaka factors.

Fixing cellular aging then leaves non-cellular forms of damage that would also need to be repaired. I don't know of any comprehensive catalogue of these, but off the top of my head we need to address as well:

• Arterial calcification (Chelating agents? Elastrin)
• Cholesterol plaques (Repair Bio and Cyclarity Tx)
• Thymic and adrenal atrophy (Would reprogramming reverse this? There's the Fahy paper but we'd want to have something more robust ant targeted. I include this here because this is programmed, not due to damage)
• Sarcopenia (Why does sarcopenia happen?) I include here also diseases where the issue is that cells die (We lose muscle fibers), as opposed to the same cell aging.
• Cancer (Eventually we will all get it. DNA mutations seem to be unavoidable)
• Hair graying (A more mysterious topic than it seems!)
• Various kinds of crosslinks (Revel)
• Shift in cell populations with age within tissues (As exemplified by the skew towards the myeloid lineage in HSCs)
• Senescent cells (In theory they can be reprogrammed too, or removed)

Absent from this list is anything having to do with mitochondria. Damage to mitochondrial RNA is one of the targets of the SENS program; as with nuclear DNA, damage to mtDNA is irreversible. However, cells have only one nucleus, but many mitochondria. Each mitochondria has multple copies of its DNA. If cells can select healthy ones and selectively replace damaged mitochondria with new ones, and if reprogramming favors this process we may not need to do anything about mitochondria that reprogramming is not fixing already, with the possible exception of so called rho-0 cells where all mitochondria are dysfunctional. Empirically, full reprogramming completely restores function in mitochondria (Suhr et al., 2010, Lapasset et al., 2011).

Is partial reprogramming the only way to effectively rejuvenate cells? A positive answer to this question would mean that geroscience should focus on this almost exclusively. It would mean that if partial reprogramming does not pan out, aging cannot be solved. In that scenario, aging can still be slowed down (we already know that from multiple studies that extend life in e.g. mice using rapamycin) which is a consolation prize in the form of some additional years of healthy lifespan in humans.

There may be other ways that do not involve reprogramming but so far we haven't found any other intervention where a one-off hit of the therapy causes a generalized reversal of aged phenotypes in a cell. I suspect this will continue to be the case with single interventions: By now it seems clear to me that there is no rejuvenation without fixing the epigenome (which reprogramming addresses directly). A rejuvenated epigenome is then able to rebalance protein concentrations and get the cell to act young again. This rejuvenation is across thousands of sites in the genome. Increased autophagy may be one of the downstream effects of improved cellular function, but this is only one function among many that would need to be improved. I do think it is still possible to find a combined intervention that mimmicks what reprogramming does. I also think it's possible to have rejuvenation at the organismal level without having it at the cellular level: By replacing old organs with new ones, and removing damaged cells, and having stem cells replace those with undamaged cells it may still be possible to achieve the same effect. This is more difficult, and it would be interesting to calculate how long would it take for us to turn over all the cells in our body out of stem cells, as opposed to fixing already existing cells.

I take it as a given that partial reprogramming (or related interventions) is the way to work to rejuvenate cells but not everyone will think the same. To better focus efforts, we should converge towards thinking the same, and better data is the way to get there: There are obvious experiments that could be done here to validate the idea of whether cellular rejuvenation necessitates reprogramming or whether there are other interventions that could do it: Take two or three cell types from old patients, measure five-six biomarkers upfront (Ideally also get the transcriptomes), dose the cells with various interventions, then see what gets reversed or not. Get some young samples of the same cell type as a comparison, see how close the rejuvenated cells are to the young phenotypes.

Answers to some questions

After I posted this on Twitter, there were some questions and objections to the point I made here. I wanted to first restate that the core point of this short post is that full reprogramming is reasonable evidence that cells have in then the machinery required for near complete (as complete as we can reasonably hope to get) cellular rejuvenation. I am not saying much here about the translatability of full reprogramming as it exists right now, and it may well be that if there is a way to make this point into a therapy, that way does not involve the Yamanaka factors.

1. That something solves aging is something the aging community has seen before with telomerase and antioxidants. Why is this time different?
   1. I am well aware. I discuss both cases here. This old book I linked to in my Links captures some of the early enthusiasm
   2. One can judge reprogramming based on historical priors (Nothing the community has been enthusiastic about in the past has solved aging in cells) or one can go and look at the evidence we have now. The claim I'm making is not that reprogramming looks promising and that it might solve cellular aging in the future. The claim I am making is that the evidence has already shown this so we don't need to speculate. What reprograming does is something telomerase or antioxidant cocktails were never able to do. Immortalized cells continue to drift towards an old phenotype (Kabacik et al., 2022)
2. The experiments I cite here are not about aging
   1. The point I am making involves full reprogramming experiments (Usually from fibroblasts to iPSCs) followed by differentiation back to the cell type of origin. If this is done to old cells the result at the end is a young cell of the same type. This illustrates the point that the cell has the capacity to fix whatever makes it old (DNA mutations aside)
   2. It may feel like it's cheating because in some sense we are "destroying" the cell by making it into something else (a stem cell) before recreating it again: this would never work as a therapy. I agree with that, but it's one thing to discuss therapeutic viability, and another to discuss whether cells have in them all they need to reverse their age.
   3. I am taking "indistinguishable from a young version of itself" as a litmus test for whether some intervention successfully de-ages a cell or an organism
3. There's a selection bias during reprogramming: Some cells die
   1. Yes, this happens. At the same time, some cells do make it all the way to the end. The point I want to make here still carries through in this case.
   2. It remains an open question how damaged a cell has to be for reprogramming to be completely unable to undo the damage
4. Reprogramming adds novel somatic mutations. Reprogramming leads to loss of function and accelerated aging.
   1. That reprogramming leads to more somatic mutations is true.
   2. One has to balance the benefits with the costs: If one thinks as I do that a youthful transcriptome, or recovered mitochondral function, or broadly anything closer to function is what weights more when thinking about whether the intervention worked then on net we can still say that reprogramming reverses aging.
   3. An analogy: Suppose a patient undergoes a surgical procedure and has cancer removed, that patient is left with a scar. We would say that the patient is cured of cancer and we would mostly overlook the scar.
5. "I think it's a trap to use the same words ('aging', 'younger') to describe desired states across different layers of organizational complexity, where the meaning is not the same. Like asking 'this deacetylase can make a histone molecule 'younger', so will it rejuvenate a cell?'"
   1. I use the word aging in accordance to what I wrote here. My use of the word for cellular aging does not imply that solving cellular aging in vitro therefore makes it obvious to solve cellular aging in vivo or organismal aging
   2. Is there a definition of "aging" on which it is not true that reprogramming cannot be said to rejuvenate a cell? I don't think so?