Thread

Loss of cell identity drives human aging: Two new papers

369 points · 184 comments · bookofjoe

rotbart · 1791018164 · focus · HN ↗
The strongest evidence we have of the reversibility of epigenetic aging, as well as its limitations -- are embryos which undergo an epigenetic reset.
After fertilisation, the embryo strips the father's DNA of its age-linked chemical tags and swaps its packaging, destroys his mitochondria, rebuilds telomeres, and clears damaged proteins, though it can't undo the DNA mutations sperm gather as men age.
(those that result in an non viable embryo result in miscarriage.)
1. darkerside · 1791021494 · focus · HN ↗
  Hmmm seems high stakes
  1. dzonga · 1791030535 · focus · HN ↗
    pregnancies are high stakes.
    it's actually surprising they happen at all given the very low probability of everything going right.
    le-mark · 1791061424 · focus · HN ↗
    > very low probability of everything going right.
    Looking around at 8 billion+ people on this planet, is the probability that low?
    mitxela · 1791110064 · focus · HN ↗
    It's about the same as the probability that your computer happens to only execute valid instructions.
  2. K0balt · 1791030627 · focus · HN ↗
    Yeah, as a 58 year old fetus…that sounds problematic.
2. jijijijij · 1791030973 · focus · HN ↗
  Embryogenesis is an early fail-fast process. The vast majority of mutations and instabilities are caught through developmental checkpoints. Every living human passed a ruthless selection process in the womb.
  So part of the magic of that aging reversal is simply abandoning what doesn't stick. You can't do that to a grown human, obviously.
  1. someonebaggy · 1791032000 · focus · HN ↗
    You can at the cellular level. There's a hypothesis that low levels of caloric restriction or oxidative stress are essential, because they weed out underperforming cells, which are replaced.
    pasquinelli · 1791033035 · focus · HN ↗
    do you mean to say low levels of caloric restriction, or low levels of caloric intake?
    someonebaggy · 1791039112 · focus · HN ↗
    A small amount of adverse conditions.
    tclancy · 1791045212 · focus · HN ↗
    If that works, just think what a heroic amount could do!
    wizzwizz4 · 1791045955 · focus · HN ↗
    It can weed out all your cells!
    meowkit · 1791046256 · focus · HN ↗
    Common response and completely misses the point. Its about dosage.
    Water will quench your thirst. You can also drown in it.
    Fire will warm your hands. Sticking you hands in a fire is a bad idea.
    Acute stress, induced by exercise / caloric restriction, is feedback to trigger beneficial cellular behavior.
    Chronic stress, no exercise / eating poorly through starvation or overconsumption (a “heroic dose”) will certainly kill you sooner.
    gozucito · 1791054057 · focus · HN ↗
    I think it was a joke :)
    jijijijij · 1791037243 · focus · HN ↗
    This is not at all comparable to the extent of embryonic rejuvenation. Lol.
    Caloric restriction etc. just aids cellular housekeeping. The processes in maintaining gametic immortality are much more radical and transformative. Somatic and gametic genetics are governed completely differently.
    agumonkey · 1791043442 · focus · HN ↗
    Do you have books or articles to read about this ?
    jijijijij · 1791049714 · focus · HN ↗
    All of it is a matter of active research, as this relates to the evolution of sex/sexual reproduction, which, contrary to popular belief, is still an unsolved problem in biology. Classical evolutionary theory cannot explain sexual evolution. Any book about "why?" will either be highly opinionated, agenda-driven, out-dated, or simplistic (as are my comments here).
    I am not a biologist, so I can not refer to or evaluate any meaningful recent papers on the matter. However, I can recommend the podcast 'Big Biology', which dives into current biology research, theory and philosophy, including sexual evolution.
    You may start here: <a href="https://en.wikipedia.org/wiki/Evolution_of_sexual_reproduction" rel="nofollow">https://en.wikipedia.org/wiki/Evolution_of_sexual_reproducti...
    Richard Dawkins' 'The Selfish Gene' is also an excellent read/audiobook. His specific theories of the evolutionary "unit" have been disproven, but his argumentation teaches a lot about "evolutionary thinking". I really wish he stuck with biology and science education instead of becoming this reactionary giga twat.
    agumonkey · 1791050866 · focus · HN ↗
    thanks a lot, i'll start with those.
    if you know other websites or podcasts similar to big biology i'd be glad, i've been trying to setup some list of sources on that topic
    thanks again
    jijijijij · 1791054227 · focus · HN ↗
    Sorry, it's not my main interest right now, so I am out-of-the-loop.
    Last time I checked, Big Biology was kinda unique going beyond basic popsci, while still remaining interesting and engaging. I think biologists are not the most technically inclined, not really drawn to podcasting. And it's also not the hottest of topics right now, specific research PR and educational voices aren't funded well. There are some journal/university etc. associated everybody-has-a-podcast-now podcasts, but I found them to be rather boring and dry. Individual episodes of the Huberman/Lex Fridman type edgelord podcasts may also be occasionally interesting, but the signal to noise ratio is poor, with a heavy bias towards overconfident and narcissistic guests speaking with false authority, lots of explanatory speculation presented as facts, pronounced political confirmation bias.
    Maybe take a well presented episode on Big Biology and see where else respective guests speak or publish?
    Ratelman · 1791053822 · focus · HN ↗
    What do you mean when you say sexual evolution?
    jijijijij · 1791056081 · focus · HN ↗
    The evolution of sex and sexual reproduction, as opposed to other means of reproduction. It is inherently tied to the difference in genetic maintenance/repair mechanisms between germline and somatic cells. See wiki link above.
    yrjrjjrjjtjjr · 1791064298 · focus · HN ↗
    Sexual reproduction can remove bad mutations. Imagine two parents. One has bad mutations m1. Other has bad mutation m2. They have three children. The first gets only m2. The second gets both and dies. The third inherits neither.
    Even though neither parent was fully healthy, one of the children was. Asexual reproduction cannot do this.
    jijijijij · 1791072763 · focus · HN ↗
    The scenario you are painting only exists with sexual reproduction, so it's circular reasoning.
    mitxela · 1791109888 · focus · HN ↗
    Organisms can only have bad mutations if they reproduce sexually?
    jijijijij · 1791124684 · focus · HN ↗
    No, of course not. But having diploid, paternal and maternal DNA is something you need sexual reproduction for.
    Apart from that, it's also wrong because sexual reproduction did not get rid of anything. Just one offspring not affected, but the premise already established the fitness of partial carriers, so that mutation is gonna remain in the gene pool.
    yrjrjjrjjtjjr · 1791134856 · focus · HN ↗
    Let me rephrase to be more neutral. Imagine two genetic lines. Both lines have one bad mutation. Survivable, but makes the individual less fit. With asexual reproduction evolution has to pick one or the other. With sexual it can get rid of both.
    jijijijij · 1791138142 · focus · HN ↗
    Why does evolution have to pick one of them?
    You are not really thinking this through. How would a fitness reducing mutation become a feature of a genetic line in the first place in asexual reproduction? The "silent" partial carrier dynamic of genetic defects is a problem exclusive to sexually reproducing organisms.
    How can sexual reproduction "get rid of them"?
    Play it out for a few generations, you will see, there is a frequency equilibrium. We've done this in school with paper, but if you know some programming, it's an easy exercise. Anyway, unless being very detrimental for partial carriers, the bad allele is gonna stay in the gene pool.
    mitxela · 1791144933 · focus · HN ↗
    Imagine a flax bush with a mutation that causes smaller leaves and a separate one that makes it live longer. Remember, mutations are completely random. In asexual reproduction it's probably going to be about as prevalent as the wild type (the default without these mutations). In sexual reproduction the repeated shuffling of genes will eventually (quite quickly in this case) produce one with the longer life but without the smaller leaves.
    jijijijij · 1791148590 · focus · HN ↗
    You are shifting the goalpost. It's not the original argument anymore.
    yrjrjjrjjtjjr · 1791172949 · focus · HN ↗
    > How would a fitness reducing mutation become a feature of a genetic line in the first place in asexual reproduction?
    A random mutation. Especially when combined with the founder effect or some other genetic bottlenecking.
    rsync · 1791056493 · focus · HN ↗
    I think the Nick Lane books are quite good - especially:
    <a href="https://en.wikipedia.org/wiki/Power,_Sex,_Suicide" rel="nofollow">https://en.wikipedia.org/wiki/Power,_Sex,_Suicide
    which, IIRC, discussed the notion of an semi-autonomous population of mitochondria in long lived tissues (like muscle) which could be curated over ones lifetime by high intensity exercise stress. Future mitochondria in these long-lived tissues would then not be descended from the poorer performing members who were weeded out through apoptosis.
  2. HexPhantom · 1791033466 · focus · HN ↗
    An adult therapy has to rejuvenate the cells you already have, in place, without breaking tissue function or creating cancer. Much less room for error
    jijijijij · 1791036682 · focus · HN ↗
    Yes, that's my point. Although, I wouldn't say "less room for error", but rather less room for handling error.
    Early embryogenesis seems to activate weird genetic pathways, whose function scientists suspect evolved for the sake of complexity alone, to be a genetic integrity stress test.
    Mind you, mutation in sexual reproduction isn't at all just accidental "bit flips". The cross-over stage in meiosis always recombines the chromosomal information randomly (to increase environmental adaptability, off-setting the slow rate of sexual reproduction). There is no concept of a "gene" there, the cuts can happen in the middle of anything important, too. This intentional instability needs to be accounted for, biologically.
    Before anyone even detects pregnancy, a lot of non-viable genetics have been aborted by the body. As tragic as they are for the becoming parents, miscarriages are a good thing, not misfortune. It's exactly this fail-fast selection process weeding out failed random recombination attempts, which likely would have caused severe functional problems later anyway.
    The body isn't a lump of omnipotent cells, but a complex system of functionally primed cells. You cannot do a selective genetic stress test on a developed organism like that. Without radical selection, the rejuvenation process wouldn't be safe, rather a guarantee for cancer and metabolic dysfunction. At any point in time, there are malignant cells somewhere in the body, which are constantly snatched by the immune system. In fact, "rejuvenation"/immortality is a hallmark of cancerous transformation. And let's not forget, embryonic development isn't fully self-governed. The mother's body also checks the embryo's signaling and may abort anything funky. A developed organism doesn't have this external oversight. Auto-immunity and genetic checkpoints is all there is and those mechanisms can become malignant, too.
    Did you know, with age, men's somatic cells increasing lack the whole Y-chromosome? It's not at all mission critical and just got lost at some point during mitosis, no biggie, but I think it shows the extent of accumulated genetic disarray in somatic cells.
    soyboy_supreme · 1791184543 · focus · HN ↗
    [dead]
    LogicFailsMe · 1791046023 · focus · HN ↗
    If you cracked this and gave everybody another ~50 years, that's probably enough time to crack cancer across the board. But not everybody is going to want those extra years. And I'd only want them if they were healthy active years.
  3. lostmsu · 1791050882 · focus · HN ↗
    It is not that ruthless though, is it? Because it is limited by the number of egg cells.
    jijijijij · 1791055040 · focus · HN ↗
    Given the fact the large majority of embryos die early after conception, I would call it quite ruthless. And of course, there is intense gamete selection beforehand too.
  4. Terr_ · 1791081495 · focus · HN ↗
    > Every living human passed a ruthless selection process in the womb.
    Ruthless and adversarial: <a href="https://aeon.co/essays/why-pregnancy-is-a-biological-war-between-mother-and-baby" rel="nofollow">https://aeon.co/essays/why-pregnancy-is-a-biological-war-bet...
3. HexPhantom · 1791033313 · focus · HN ↗
  Embryos are probably the clearest proof that at least some of what we call biological aging is reversible rather than simply accumulated irreversible damage
  1. jjallen · 1791034681 · focus · HN ↗
    Is this just a summary of the parent post? Seems like you just repeated what they said.
    anamexis · 1791035349 · focus · HN ↗
    I'm glad they did!
    [deleted] · 1791040337 · focus · HN ↗
    [deleted]
    DenisM · 1791049436 · focus · HN ↗
    I see this a bit recently. Karma grinding?
4. jarjoura · 1791056695 · focus · HN ↗
  Apparently mammal DNA lost its ability to self-repair adult cells somewhere along the way, maybe when we evolved to evade threats post-dinosaurs.

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