Shots fired against my beloved partial reprogramming! 🙂 But it’s a complete misunderstanding of the serial cloning paper on Peter’s part…
It actually SUPPORTS partial reprogramming as a means of extending lifespan, because it shows that somatic mutations are a remarkably minor constraint on normal lifespan.
I mean, remember what their experiment put cells through. Each generation began from a single somatic cell, which then expanded into the TRILLIONS of cells making up an entire mouse. The next generation was bottlenecked back down to one cell, fixing that cell’s accumulated mutations into the founder genome of the next animal.
They repeated this 57 times: from one cell to a whole organism, then back to one cell, over and over. That is a mutational stress test orders of magnitude beyond anything an adult organism would ever experience. Even if you lived for thousands of years, your tissues would accumulate only a fraction of the mutational burden these mice carried.
And yet the mice continued to have normal lifespans across generations.
Also, 58 generations was not some fundamental biological ceiling. It was one unscreened lineage (one path through the mutational landscape) that likely failed because of just a couple of major chromosome-scale lesions: the near-whole-chromosome 4 loss of heterozygosity, followed in one late branch by a Chr4–Chr11 translocation.
That methodology had none of the quality control built into sexual reproduction: no recombination, no competition between gametes, no embryo selection, and no systematic screening to advance the cleanest lineage. If they had used PGT-like genomic screening at each generation and advanced only the cleanest nuclei, I strongly suspect serial cloning could have continued far beyond 58 generations.
So yes, epigenetic reprogramming does not repair DNA mutations. But the remarkable finding here is that mice tolerated an enormous inherited mutational burden while continuing to age at a normal rate. That weakens, rather than supports, the claim that unrepaired somatic mutations impose a low ceiling on epigenetic rejuvenation.
And invoking the second law of thermodynamics does not rescue the argument. Living organisms are open systems that continuously expend energy to repair DNA, replace proteins, heal tissues and maintain local order while exporting entropy into the environment.
Thermodynamics just tells us that repair has an energetic cost, not that repair is impossible. Whether a particular age-associated lesion can be reversed is an empirical and engineering question. Calling it “entropy” does not make it irreversible.
PS: people have been dissing partial reprogramming for close to a decade because the earliest OSKM studies did not produce dramatic lifespan extension. But that is a strange standard to apply to the first generation of an entirely new therapeutic paradigm. OSKM was discovered to create pluripotent stem cells, not as the optimal combination for safely rejuvenating every cell type. Partial reprogramming is ultimately much broader than OSKM: the goal is to shift old or dysfunctional cells toward younger, more functional gene-expression patterns without erasing their identity. That will likely require cell- and tissue-specific factors, doses and delivery systems, as I’ve been saying forever.
BUT despite all the naysaying, the field has continued making steady progress toward the clinic! Life Bio has now dosed the first patient, NewLimit is advancing a liver-targeted, cell-specific reprogramming therapy toward human trials, and at YouthBio we are advancing our neuron-targeted, inducible partial reprogramming therapy for Alzheimer’s following our FDA INTERACT meeting.
None of this guarantees clinical success, but it makes one thing clear: partial reprogramming is NOT a failed idea. Its first therapeutic generation is already reaching patients while a more precise, cell-specific second generation is being built.
Peter Fedichev @fedichev
Just published on Substack: Why Epigenetic Rejuvenation Won’t Give Us Radical Life Extension — Lessons from 58 Generations of Cloned Mice.
This is my take at the results of a landmark Nature Communications paper (20+ years, 1,200+ mice, 58 generations of serial cloning with full epigenetic reset) shows it still collapses. Mutations accumulated 3× faster. Epigenetic reprogramming works… until it doesn’t. There is an irreducible level of damage that cannot be undone.
To my taste, this is a very important study. Popular literature claims cloning erases aging signatures. In short-lived species it may look that way — the entropic damage simply doesn’t have time to kill. In longer-lived animals we expect the picture be very different (and there is an anecdotal evidence for that with a lot fewer generation before the collapse).
This is also why I dislike the language of “information theory of aging.” Flipping the sign on entropy and calling that "information" (changing from the Boltzmann to Shannon equation) doesn’t repeal thermodynamics.
Of course, you can still hope for better Yamanaka factors or else. My interpretation of the experiment is not yet a proof of anything - certainly not. However, the experiment removes a lot of ground under proponents of epigenetic rejuvenation.
If you want to keep your identity, better to stop aging than try to reverse it.
Challenge me. Subscribe, Like & repost. Link:
