Highlights of Comparative and Evolutionary Aging

by johnswentworth2 min read22nd May 20209 comments

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AgingWorld Modeling
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Author's Note: the purpose of this sequence is gears, i.e. physiology and molecular/cellular-level mechanisms, not evolution. This post contains only some bare-minimum background information as context for the rest; check out Will Bradshaw's series for a short intro which does better justice to evolutionary theories of aging in their own right.

Many species do not age: hydra, some turtles, rougheye rockfish, naked mole rats, and probably many others which we just haven’t sat around and watched long enough yet. This does not mean these organisms are immortal - in the wild, they get eaten or infected sooner or later. But their physiology does not change with age; post-development, older organisms look physiologically identical to younger organisms. They don’t get more wrinkles, or weaker muscles, or inflamed joints. In particular, non-aging species are not more likely to die soon as they get older. We call it “negligible senescence”.

Contrast to humans:

This is the Gompertz-Makeham Law of mortality: after development, humans’ annual death rate increases exponentially with age (doubling time ~8 years). For naked mole rats and other non-aging species, this curve would be completely flat after childhood. (Side note: that bump around age 20 is the car-accident bump).

This raises an evolutionary puzzle: aging obviously entails loss of functionality and increased death rate. Surely those things can’t be beneficial to organism fitness. But we know it’s physiologically possible for organisms to not age, so if aging isn’t evolutionarily beneficial, why do organisms ever age? Why haven’t all organisms evolved negligible senescence?

Well, once an organism has reproduced, evolution doesn’t really care what happens any more. Sure, slowly breaking down over time won’t be beneficial, but it’s not a significant disadvantage either, as long as the kids are grown. And in nature, the vast majority of organisms will die to predation or disease or starvation pretty quickly anyway. So, whenever there’s an opportunity to gain some early-life advantage in exchange for aging later in life, that’s going to be an evolutionarily advantageous trade-off. This is the “antagonistic pleiotropy” evolutionary theory of aging: most organisms age because there’s little selective pressure not to, and there are advantages to be had from trade-offs in favor of early life.

This ties in to the general theory of “life history strategies”: some creatures produce large numbers of offspring but don’t invest much in raising the children, while others produce just a few offspring and invest heavily in them. Creatures which invest heavily in their children will be more evolutionarily useful post-reproduction, so we should expect them to have longer lives; creatures which don’t invest much won’t gain as much fitness by living longer. At the extreme, we see organisms which spend their entire metabolic resources on reproduction, maximizing the number of young produced, and die shortly after.

There is some impressive evidence in favor of antagonistic pleiotropy in comparative (i.e. cross-species) aging - life history strategies do turn out to correlate quite heavily with lifespan, by multiple measures, and the measures which we’d expect to better reflect life history tend to screen off those which reflect it less well. I’m not going to go into the details here, but Robert Arking’s “The Biology of Aging” has a decent chapter on it (chapter 4).

For humans specifically, there’s some evidence that we have higher-than-usual evolutionary pressure against aging. In particular, humans are quite long-lived for animals our size. In general, larger animals have longer lifespans - mice live ~3 years, lions and gazelles live 10-15 years, elephants live 50-70… yet humans outlive elephants. Our long life span is typically attributed to very long gestational periods combined with a very high degree of parental investment in children. In the antagonistic pleiotropy <-> life history picture, high-parental-investment strategies are generally associated with long species life-spans, and vice-versa: when organisms don’t invest in their progeny, they are less evolutionarily useful in old age. Since we humans invest extremely heavily in our offspring, we are unusually useful in old age, and thus have unusually long lifespans.

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Probably not as relevant to this specific post as the general sequence on aging but have you seen and read Lifespan by Sinclair & LaPlante? If so what is your assessment. I've just started reading.

Yup, read it a few months ago. Mini-review:

  • The core mechanisms they talk about make sense, in particular transposons as root cause, and the picture of stressors competing for sirtuin activity.
  • The review of aging in yeast was a highlight. That's a great example where the mechanisms were pretty clearly nailed down, and Sinclair was one of the people who figured it out.
  • I'm much more skeptical of the particular treatments discussed, and especially the proposal that NAD boosters ameliorate age-related diseases by boosting sirtuin activity specifically. NAD is a fairly general-purpose molecule, there's a ton of other things it could be doing, and I don't recall a demonstration that sirtuin activity mediates their effects. (If there is a mediation experiment, then that part is much stronger.)
  • Sinclair in general seems to fit the "great experimentalist, mediocre theorist" mold; the blabber about information loss and aging being epigenetic was thoroughly confused. He has a bad case of obsession-with-his-favorite-gene-class (namely the sirtuins). In this case that gene class seems to be adjacent to an actual root cause (transposons), but Sinclair himself doesn't seem to have the conceptual framework in place to organize that knowledge.
  • The entire second half of the book is semipolitical fluff.

I think I would claim that the semipolitical fluff is probably the most valuable part of the book. In terms of moving the needle on mainstream acceptance, having a Harvard professor say fairly directly that "ageing is bad and we should cure it" is something I'd expect to make a significant difference.

Yeah, to be clear, semipolitical fluff is often valuable, and I agree that that's likely the case here. But I don't expect LWers to find anything new or interesting in that part of the book, nor is anything interesting there about how aging works. It's for a different audience and a different purpose.

Yup, agreed.

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

The Wikipedia for naked mole rats claims a maximum age of 30 (32?), why is that if they can live forever?

Following the citation on wikipedia, sounds like that's the longest one has lived in captivity. 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.

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.)

Thanks, that's the right question to ask and some great info on it.