@davidasinclair
“The Information Theory of Aging” was published today in Nature Aging. Free copy at link below:
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Death Becomes Her, or Why Aging is an Epigenetic Program
Evidence in support of the Strong Epigenetic Theory of Aging
https://yurideigin.medium.com/death-becomes-her-or-why-aging-is-an-epigenetic-program-c55a32fd8c74
Source Post: https://x.com/ydeigin/status/1735873878553972878?s=20
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I don’t think aging being a developmental program is incompatible with aging being caused by genomic damage. It could be that the developmental program is to shut off maintenance of genomic integrity. This would lead to genomic damage, which would in turn alter the transcriptome, alter cellular identity, and ultimately lead to loss of tissue function.
Transcript length alone explains most of the age-associated transcriptional changes in mice and humans. If a gene is twice as long, then all else being equal, it’s twice as likely to suffer an RNA polymerase-stalling lesion, or an exonic indel. Additionally, the longest transcripts are enriched for longevity-associated genes and vice-versa, which again suggests that perhaps long-lived individuals can stave off genomic damage for longer, and continue to produce longer transcripts that are necessary for cell function. [ref1] [ref2] This is extremely compelling evidence for the DNA damage theory of aging.
Of course, just because aging is caused by damage, doesn’t mean that a developmental program isn’t coordinating the occurrence of said damage. Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction provides evidence for such developmental program in much simpler eukaryotes than ourselves.
The heat shock response (HSR) is essential for proteostasis and cellular health. In metazoans, aging is associated with a decline in quality control, thus increasing the risk for protein conformational disease. Here, we show that in C. elegans , the HSR declines precipitously over a 4 hr period in early adulthood coincident with the onset of reproductive maturity. Repression of the HSR occurs due to an increase in H3K27me3 marks at stress gene loci, the timing of which is determined by reduced expression of the H3K27 demethylase jmjd-3.1 . This results in a repressed chromatin state that interferes with HSF-1 binding and suppresses transcription initiation in response to stress.
Also, if aging is due to DNA damage (programmed or otherwise), then it should be possible to slow it down by improving DNA repair, and this has in fact happened. The Bowhead and Right whales diverged only 4-5 million years ago, and the Bowhead MLS has tripled within that time. This appears to be due to enhanced DNA repair, as well as altered cell cycle dynamics. [ref1] [ref2]
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It’s really sad “that no matter how hard we try to keep ourselves young by leading a healthy lifestyle, it seems that by a certain age we will still catch up with our less disciplined peers in terms of decrepitude. That is, our aging trajectories will inevitably converge.”
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But it is still a better quality of life in the process. 
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I disagree with Sinclairs approach. I think the gradual reduction in functional gene expression is caused by a mixture of damaged and inefficient mitochondria and the effects of SASP. The body is not programmed to “age” instead cellular function deteriorates. DNA damage is also an issue, but a different one.
It is definitely sad, but we’re alive in a time where thinking maybe we can do something to make that slightly less true is actually a realistic possibility. That’s an amazing thing.
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I fully agree with what you said. Aging is truly unavoidable, especially after the age of 70. For most of us, both external appearance and internal organ aging tend to be consistent.
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I doubt an exercising pescetarian non-smoker’s aging trajectory will ever intersect with a sedentary ultra-processed-food-eating smoker’s.
I firmly believe there is a way to live longer and healthier.
The sickest among us start to die in large numbers in their 50s and 60s. The healthiest of us start to die in large numbers in their 80s and 90s. That’s about a 60% difference and non-negligible. It averages out to our current lifespan of 77-85. I plan to be in the latter group. 30 years is a generation, and I want it.
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I don’t agree with this.
There are various aspects of aging. Some I think can be reversed to some extent. Others are harder to deal with.
Hence Mitochondrial inefficiency can be repaired, the lack of acetyl-CoA caused by SASP can be rectified, but DNA damage is hard to repair and it may be that there are simply cells that we are best off without. There are probably other stochastic elements to aging, but I think the majority of the aging phenotype comes from the issues with protein production.
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But what is the cause that deteriorates the cellular function? Per Sinclair, it’s Epigenetic glitches (due to UV radiation, CT scans, etc). Per Deigin, it’s epigenetic glitches caused by a program, not by external influences as Sinclair says. Per Blagosklonny, it’s a hyper function of everything (but he doesn’t explain what causes the hyper function). Hyperfunction could be a result of the innate program (Deigin). I like Deigin’s theory more.
I have my own hypothesis which I have mentioned a number of times including in a summary form in the post to which you are responding.
I don’t mind writing a longer response, but some people might be bored with it.
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Thank you, I’ll read it! I thought that you would just answer in one sentence
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I read somewhere that there are 3 stages of aging. The first happens at 38, the second - at 64 or so, and the third one - at 78. And surprisingly, most ppl look very similar at each stage.
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And in the meantime, some of our undisciplined peers will have passed.
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