Thank you for the insightful conversation! My intention is to initiate a discussion & make some attacks, as I think this field deserves more discussion on such important issues. Based on the available data, it is difficult for me to understand how one can come to the conclusion that #aging in human is primarily controlled by an epigenetic program, as @ydeigin states, & its consequences can also be reversed by partial reprogramming. This lack of understanding on my part arises from the following points, among others: From minute 25 Deigin describes that it is possible to remove an old cell from the tissue and rejuvenate it both epigenetically & physiologically. But the devil is really in the details here, because I was realy confused for quite a while when I first read about this: It is not a single cell that is removed, but a very large number of cells, & this (partial) reprogramming takes place in a very small proportion of these cells (0.1 to max. 10%). These rejuvenated properties (= youthful like biomarkers) are then often measured in an entire cell population. Fittingly, whole-body exposure to Yamanaka factors for partial reprogramming in wild-type mice in vivo has not yet led to an extension of the mean lifespan by more than 25%, let alone to an extension of the maximum lifespan ... This puts it behind calorie restriction in mice, which in turn is unlikely to have any effect on the type of aging we observe in normal humans. Mice have adapted their nutrient sensitivity to their specific ecological niche & therefore have the genetic potential to modulate their growth & damage/repair rate to some extent. Another reason for the results on calorie restriction is the poor health of the control mice (obesity). A good general discussion of the problems with "anti-aging" results can be found here xitter.cf/lex_sviridov/status/17… & @AlexanderMWolf7 has also written quite a bit about this recently. From around minute 60, I believe that the role of damage to the extracellular matrix (ECM) & long-lived molecules in the aging process is downplayed, e.g. with the argument that cancer cells can modulate the ECM to their advantage in old age. However, this argument overlooks the fact that the ECM initially fulfills essential functions in multicellular structures, which is why the cancer argument is not really accurate. I think @afedintsev & @Replacing_Aging have a lot to say about this. For example, the accumulation of damage to long-lived molecules and cellular ‘waste’ such as lipofuscin, which cannot be enzymatically degraded in the wild type, is not remedied by partial reprogramming, as even young cells cannot degrade these substances. They simply accumulate over time and only develop their harmful effects, which contribute to the aging phenotype, after sexual maturity. If old cells are made to ‘behave’ transcriptomically like young cells, they are still confronted with such irreversible damage that does not occur in young cells due to the lack of time for accumulation and for which they also have no repair strategies. So to what extent can significant improvements be expected from partial reprogramming alone? @aubreydegrey It is also mentioned that after partial reprogramming, cells quickly lose their youthful properties and revert to their old state. So instead of discussing this as a possibility that aging is not primarily an epigenetic programmen and that many reversible epigenetic changes might rather be adaptive responses to an underlying remodeling process, the rebound is rather discussed as a technical problem. Even if old cells could be epigenetically rejuvenated, they could not maintain this state due to irreversible damage, presumably because of the high burden of irreversible changes in long-lived stable molecules (especially in long-lived species this becomes dominant) such as the ECM or other possible damages of entropic nature as proposed in @fedichev's models that may dominate the aging process in humans.