Antagonistic pleiotropy is certainly plausible in the abstract, but it’s not obvious how it would work in humans. 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. From googling a little bit, I found some info suggesting:
The adaptive immune system (because it “runs out of capacity” late in life; see also the discussion here)
Genes associated with coronary artery disease that appear to be under positive selection (but it doesn’t say why)
A gene that causes premature cell senescence if you have multiple copies, but is useful for repairing UV-induced DNA damage
I’m curious if anybody knows of other examples of how this mechanism actually works out physiologically.
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. On the other hand, maybe it should make us optimistic about being able to gradually invent solutions to many of those causes individually, if they are created by selection rather than being fundamental/unavoidable consequences of our cellular metabolism or something.
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.)
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?
As far as proof that it can happen in general, I found the example of animals that live just long enough to reproduce pretty convincing. Salmon don’t live more than about four years, but it’s quite clear how they gain a fitness advantage from dying after they spawn. 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.
This sentence confuses me. Why would you expect it to be harmful early on?
I guess I put this sort of backwards. 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. Same with heart disease, sarcopenia, etc.
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.)
It seems to me unclear why loss of neurons and muscle cells which both are not much newly generated in human adults are not on that list. It would surprise me if the same wouldn’t be true for a bunch of other cell types as well.
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.
I’m curious if anybody knows of other examples of how this mechanism actually works out physiologically.
Consider telomeres. The body’s inability to repair telomeres can be considered as an adaptive mechanism protecting from tumor formation in early life.
A little thought experiment:
When you’re a unicellular organism, you want to make as many copies of yourself as possible to maximize fitness. When you evolve into a multicellular organism, this strategy ain’t working anymore. A multicellular organism with telomerase expressed in every cell of the body will eventually get a mutation in one of the cell division regulatory cascades which causes it to divide infinitely and kill the whole organism.
For this reason, telomere repair should be disabled in non-reproductive cells so that renegade mutant cells would run out of reproductive capacity and stop dividing. The only way large tumors would occur is due to 2 independent mutations: one for cell division and one for telomerase expression. This is vastly more unlikely. The downside is that lack of telomere repair would lead to gene deregulation and eventual aging.
But longer-lived animals get cancer less, not more. I’ve heard this theory before but I don’t quite understand it. It seems to predict that age would be bounded by a trade-off against child cancers. But in fact selection seems to make animals longer-lived pretty easily (e.g. humans vs homo erectus). Naked mole rats barely get cancer at all, afaik. Do baby bats get cancer more than baby mice?
Antagonistic pleiotropy is certainly plausible in the abstract, but it’s not obvious how it would work in humans. 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. From googling a little bit, I found some info suggesting:
The adaptive immune system (because it “runs out of capacity” late in life; see also the discussion here)
Genes associated with coronary artery disease that appear to be under positive selection (but it doesn’t say why)
A gene that causes premature cell senescence if you have multiple copies, but is useful for repairing UV-induced DNA damage
I’m curious if anybody knows of other examples of how this mechanism actually works out physiologically.
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. On the other hand, maybe it should make us optimistic about being able to gradually invent solutions to many of those causes individually, if they are created by selection rather than being fundamental/unavoidable consequences of our cellular metabolism or something.
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.
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)?
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.)
As far as proof that it can happen in general, I found the example of animals that live just long enough to reproduce pretty convincing. Salmon don’t live more than about four years, but it’s quite clear how they gain a fitness advantage from dying after they spawn. 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 guess I put this sort of backwards. 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. Same with heart disease, sarcopenia, etc.
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.
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.)
It seems to me unclear why loss of neurons and muscle cells which both are not much newly generated in human adults are not on that list. It would surprise me if the same wouldn’t be true for a bunch of other cell types as well.
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.
You don’t need an increased amount of cell deaths for the cell deaths to become an issue without regeneration.
I would expect that some cells regularly die to all kinds of injury.
Consider telomeres. The body’s inability to repair telomeres can be considered as an adaptive mechanism protecting from tumor formation in early life.
A little thought experiment:
When you’re a unicellular organism, you want to make as many copies of yourself as possible to maximize fitness. When you evolve into a multicellular organism, this strategy ain’t working anymore. A multicellular organism with telomerase expressed in every cell of the body will eventually get a mutation in one of the cell division regulatory cascades which causes it to divide infinitely and kill the whole organism.
For this reason, telomere repair should be disabled in non-reproductive cells so that renegade mutant cells would run out of reproductive capacity and stop dividing. The only way large tumors would occur is due to 2 independent mutations: one for cell division and one for telomerase expression. This is vastly more unlikely. The downside is that lack of telomere repair would lead to gene deregulation and eventual aging.
But longer-lived animals get cancer less, not more. I’ve heard this theory before but I don’t quite understand it. It seems to predict that age would be bounded by a trade-off against child cancers. But in fact selection seems to make animals longer-lived pretty easily (e.g. humans vs homo erectus). Naked mole rats barely get cancer at all, afaik. Do baby bats get cancer more than baby mice?