willbradshaw's Comments

Why We Age, Part 2: Non-adaptive theories

Interestingly, Other Minds (a recent popular science book about cephalopods) seems to mostly put credence in non-adaptive theories, and indeed has a very nice general exposition of these theories (the section of the book after the passages I quote in that link talks at length about octopus semelparity).

Why We Age, Part 2: Non-adaptive theories

I don't believe it.

  1. The Jundishapur Journal of Natural Pharmaceutical Products doesn't exactly scream "credible source" to me. My honest inclination is to ignore this paper and wait to see if the theory pops up somewhere more reputable. I somewhat doubt it, since this paper gives off pretty strong crank vibes.
  2. Even if we ignore the credibility signals, the paper doesn't show any effect of DDW on lifespan. The fact that they make claims about geroprotective effects without looking at lifespan is a big red flag. The paper is also just pretty bad and unconvincing in general (e.g. it appears to contain absolutely no statistics).
  3. Even if DDW did increase lifespan, there are lots of other things that increase lifespan in mice. There's no particular reason to just ignore all that and attribute everything to deuterium.
  4. Even if DDW was as effective in mice as all other ageing treatments combined (which would be a huge finding), it still wouldn't tell you why mice live so much shorter than naked mole rats (or humans).

So unless there's solid evidence that DDW makes mice immortal, as opposed to making their coats (maybe, subjectively) a bit glossier, saying that "aging could be simply caused by deuterium and evolutionary explanations would then be a red herring" is flagrant hyperbole, verging on making stuff up.

Why We Age, Part 2: Non-adaptive theories

I'm not sure about this. I have to think about it.

Why We Age, Part 2: Non-adaptive theories

But that sort of thing is pretty rare, so the claim that it happens in a particular species with no such obvious mechanism (or indeed in practically all animals) is a little harder to swallow.

I think it's important that the AP theory holds even if the early-life gain is very small and the late-life cost is very large; that should broaden the list of potential ways to achieve that trade-off.

More generally, the idea of antagonistic pleiotropy as a general phenomenon doesn't seem that surprising to me: trade-offs are everywhere in biology, and if one side of a trade-off is underweighted by selection then it'll get shafted. It's basically just overfitting: it would be surprising if the optimal set-up for growing, surviving and reproducing over a span of (say) 20 years were also the optimal set-up for doing the same over (say) 100 years, and natural selection is almost entirely optimising for the former.

I meant that I would expect a mutation that causes tissue repair function to degrade with age to decrease fitness (slightly) overall, since there's no obvious connection to some beneficial effect earlier in life.

One potential response to this is that this is systems thinking rather than genes thinking. Many genes do lots of things across lots of systems, so you could see a mutation that improves functionality in a way that's relevant to one system early in life, at a cost to another system in late life.

(I'm personally more of a fan of relaxed purifying selection, which seems like the more general and less contingent theory, but I do think antagonistic pleiotropy theory is solid enough that finding more concrete examples of it wouldn't surprise me.)

Why We Age, Part 2: Non-adaptive theories

Cells don't just die of nothing. Their deaths have causes: causes like telomere attrition, genomic instability, cellular senescence, mitochondrial dysfunction, or loss of proteostasis.

The paper is not trying to enumerate every thing that changes for the worse with age (it doesn't include immunosenescence, for example, even though that's among the most important systemic changes you see with age). It's trying to distill down to a list of things that cannot be adequately reduced to other processes.

Why We Age, Part 2: Non-adaptive theories

Isn't it fairly obvious why juveniles are smaller? They have to fit inside the mother, or inside an egg which had to fit inside the mother. Even if the egg could potentially grow, you're limited by the energy reserves you started with until you hatch and find more. Staying in the egg also seems very dangerous (can't hide or run away from predators, can't move away if temperature/water/etc levels aren't good, etc).

I can't tell whether or not your second paragraph is disagreeing with anything I said in my post.

Why We Age, Part 2: Non-adaptive theories

Antagonistic pleiotropy is certainly plausible in the abstract, but it's not obvious how it would work in humans.

Are you suggesting antagonistic pleiotropy is particularly non-obvious in humans (vs other animals), or that it's non-obvious generally but you particularly care about humans? This isn't directly related to your question, I'm just curious.

Something like tissue repair, for instance, is obviously beneficial in old age but it's hard to see how it would be harmful early on.

This sentence confuses me. Why would you expect it to be harmful early on? Antagonistic pleiotropy predicts mutations that are beneficial in early life and harmful later. Is this a typo (switching old and young)?

Also, it seems like this kind of explanation suggests we should be fairly pessimistic about finding a "cure" for aging, since there are likely many different unrelated causes.

Yeah, I think this is basically right. In general my impression is that most experts don't believe ageing is "one thing" – a single underlying cause we could neatly target. On the other hand it also doesn't seem to be, like, a million things: there is an enumerable list of key causes, on the order of ten items long, which together account for most of the physiological ageing we see in mammals. It's not obvious to me what to make of this theoretically.

(Of course, there are still plenty of people who like to claim they've found the single mechanism underlying all ageing, usually fortuitously closely related to the thing they study.)

Why We Age, Part 1: What ageing is and is not

Speaking for the intuition of wear and tear, it does seem surprising to me that an "embedded repair system" has enough redundancy to not get worn down by the real world.

I think this is a priori reasonable, but we do have existence proofs of animals that don't seem to age. Even if you think (say) naked mole rats are probably ageing a bit (just too slowly for us to detect on the timescales of our experiments) that doesn't address why all other rodents don't age at the same (very low) rate. I don't think wear-and-tear will get you anywhere when trying to address divergence in lifespans between related species.

As for bones, there are vertebrates that can regenerate whole limbs, so it's certainly doable.

Highlights of Comparative and Evolutionary Aging

Yup, agreed.

(Unless you're interested in how that kind of influencing is done, in which case it might make a useful case study.)

Highlights of Comparative and Evolutionary Aging

Remember, it's not that they're immortal, it's just that their chance-of-dying-per-unit-time stays flat; that still implies that the number of survivors drops off exponentially over time.

This is true, but does still raise the question of what exactly these 30-year-old mole rats are dying of. They barely get cancer, they don't seem to have high baseline rates of the kinds of intrinsic causes of death you see in humans (heart disease etc.), and in captivity they're not exposed to predation or starvation, so...inter-mole violence? Status anxiety?

According to this popsci article:

Naked mole rats generally don't get many chronic diseases that become familiar to humans as they age, like diabetes or Alzheimer's, Buffenstein said. In the wild, the animals might die by predator attack or from starvation, infection or lack of water, she said. In the lab, the cause of death is usually hard to find; the main issue that shows up in necropsies, Buffenstein said, are mouth sores, indicating the animals weren't eating, drinking or producing saliva well in their last few days and infection set in.

So as of 2018 the answer seemed to be ¯\_(ツ)_/¯.

(Buffenstein is a mole-rat PI at Calico.)

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