So, here’s the surprising bit, which I think even a lot of biologists haven’t fully absorbed: it’s not DNA damage itself that’s accumulating in a non-equilibrium manner. DNA damage events happen at a very fast rate, like thousands of times per day per cell (at least for that particular type of damage; there’s several types). It’s also repaired at a fast rate (true of all types, as far as I’ve seen). With that sort of half-life, if DNA damage were out of equilibrium, it would be out of equilibrium on a timescale much faster than aging. If DNA damage increases with age (and there’s a lot of indirect evidence that it does), then it’s a steady-state level that’s increasing, which means that either the damage rate is increasing or the repair rate is decreasing.
In other words, DNA damage itself isn’t the root cause—there is indeed something else upstream. You’re exactly right on that. (Though, with respect to variance in timeline, bear in mind that many processes play out in parallel across cells—if cells “go bad” one by one, then large number statistics will smooth out the noise a lot.)
The most promising potential culprit I’ve heard about is transposons: “parasitic” DNA sequences which copy themselves and reinsert themselves into the genome. The human genome has loads of these things, or pieces of them—I’ve heard a majority of human DNA consists of dead transposons, though I don’t have a reference on hand. Normally, they’re actively suppressed. But the transposon theory of aging says that, every once in a while, one of them successfully copies. Usually it will copy into non-coding DNA, and then be suppressed, so there’s no noticeable effect. But over time, the transposon count increases, the suppressor count doesn’t increase, and eventually the transposons get out of control. The DNA damage is a side-effect of active transposons—one of the main ingredients of a transposon is a protein which snips the DNA, allowing the transposon itself to sneak in. In particular, this may be an issue in stem cells—most cells would enter apoptosis/senescence once DNA damage level gets high, but if a stem cell has a transposon count slightly below the cutoff, then it will produce cells which rapidly apoptose/senesce.
Anyway, I’m sure this sequence will get around to theories of the root cause of aging eventually. There’s a number of them, although most have been ruled out.
I hadn’t heard the transposon theory of aging before. If true, that would explain why aging hasn’t been selected out by evolution: the transposons themselves have evolved, under different incentives than their host genome’s incentives.
Hold that thought—there’s a post on evolution of aging coming up pretty soon. It’s one of the better-understood areas, since we can get a ton of information by comparing across species.
https://apomorphic.com/2020/01/12/why-we-age-2-nonadaptive presents a theory on that. Tldr (mostly from memory) would be that with no biological aging, we still have more kids when we’re young, so evolution cares more about us when we’re young, so there’s very little selection pressure against mutations that only damage us when we’re old, or especially which help us when we’re young and harm us when we’re old.
Thanks Phil. I should probably just put these on LessWrong to be honest.
The lens-growth phenomenon sounds like it might be a neat case of antagonistic pleiotropy as applied to developmental rates: a process calibrated to give good results in early adulthood might be selected for even if it gets wildly out of whack in later life. IIRC Williams gives the example of male Fiddler crabs, whose major claw grows faster than the rest of the body: the difference is calibrated to give them big sexy (but still manageable) claws in early adulthood but can severely impede movement in late life (I have not independently validated this example). One could imagine something similar happening here.
>Usually it will copy into non-coding DNA, and then be suppressed, so there’s no noticeable effect. But over time, the transposon count increases, the suppressor count doesn’t increase, and eventually the transposons get out of control.
Wouldn’t it expand the size of the genome and potentially affect the distance between promoters/enhancers and target genes, causing a loss in a cell’s ability to appropriately regulate translation in response to perturbation?
I know some people (like genesis lung) who actively take lysine or antiretrovirals to suppress transposon activity—antiretrovirals may be aassociated with longevity./
Wouldn’t it expand the size of the genome and potentially affect the distance between promoters/enhancers and target genes, causing a loss in a cell’s ability to appropriately regulate translation in response to perturbation?
To some extent, though presumably the vast majority of copies will be into non-functional sequence, and copies into functional sequence will often result in a defective cell which is quickly removed. The expansion of the genome size shouldn’t be significant until the count is already way out of control; a transposon is tiny compared to the whole genome.
So, here’s the surprising bit, which I think even a lot of biologists haven’t fully absorbed: it’s not DNA damage itself that’s accumulating in a non-equilibrium manner. DNA damage events happen at a very fast rate, like thousands of times per day per cell (at least for that particular type of damage; there’s several types). It’s also repaired at a fast rate (true of all types, as far as I’ve seen). With that sort of half-life, if DNA damage were out of equilibrium, it would be out of equilibrium on a timescale much faster than aging. If DNA damage increases with age (and there’s a lot of indirect evidence that it does), then it’s a steady-state level that’s increasing, which means that either the damage rate is increasing or the repair rate is decreasing.
In other words, DNA damage itself isn’t the root cause—there is indeed something else upstream. You’re exactly right on that. (Though, with respect to variance in timeline, bear in mind that many processes play out in parallel across cells—if cells “go bad” one by one, then large number statistics will smooth out the noise a lot.)
The most promising potential culprit I’ve heard about is transposons: “parasitic” DNA sequences which copy themselves and reinsert themselves into the genome. The human genome has loads of these things, or pieces of them—I’ve heard a majority of human DNA consists of dead transposons, though I don’t have a reference on hand. Normally, they’re actively suppressed. But the transposon theory of aging says that, every once in a while, one of them successfully copies. Usually it will copy into non-coding DNA, and then be suppressed, so there’s no noticeable effect. But over time, the transposon count increases, the suppressor count doesn’t increase, and eventually the transposons get out of control. The DNA damage is a side-effect of active transposons—one of the main ingredients of a transposon is a protein which snips the DNA, allowing the transposon itself to sneak in. In particular, this may be an issue in stem cells—most cells would enter apoptosis/senescence once DNA damage level gets high, but if a stem cell has a transposon count slightly below the cutoff, then it will produce cells which rapidly apoptose/senesce.
Anyway, I’m sure this sequence will get around to theories of the root cause of aging eventually. There’s a number of them, although most have been ruled out.
I hadn’t heard the transposon theory of aging before. If true, that would explain why aging hasn’t been selected out by evolution: the transposons themselves have evolved, under different incentives than their host genome’s incentives.
Hold that thought—there’s a post on evolution of aging coming up pretty soon. It’s one of the better-understood areas, since we can get a ton of information by comparing across species.
https://apomorphic.com/2020/01/12/why-we-age-2-nonadaptive presents a theory on that. Tldr (mostly from memory) would be that with no biological aging, we still have more kids when we’re young, so evolution cares more about us when we’re young, so there’s very little selection pressure against mutations that only damage us when we’re old, or especially which help us when we’re young and harm us when we’re old.
Thanks Phil. I should probably just put these on LessWrong to be honest.
The lens-growth phenomenon sounds like it might be a neat case of antagonistic pleiotropy as applied to developmental rates: a process calibrated to give good results in early adulthood might be selected for even if it gets wildly out of whack in later life. IIRC Williams gives the example of male Fiddler crabs, whose major claw grows faster than the rest of the body: the difference is calibrated to give them big sexy (but still manageable) claws in early adulthood but can severely impede movement in late life (I have not independently validated this example). One could imagine something similar happening here.
>Usually it will copy into non-coding DNA, and then be suppressed, so there’s no noticeable effect. But over time, the transposon count increases, the suppressor count doesn’t increase, and eventually the transposons get out of control.
Wouldn’t it expand the size of the genome and potentially affect the distance between promoters/enhancers and target genes, causing a loss in a cell’s ability to appropriately regulate translation in response to perturbation?
I know some people (like genesis lung) who actively take lysine or antiretrovirals to suppress transposon activity—antiretrovirals may be aassociated with longevity./
To some extent, though presumably the vast majority of copies will be into non-functional sequence, and copies into functional sequence will often result in a defective cell which is quickly removed. The expansion of the genome size shouldn’t be significant until the count is already way out of control; a transposon is tiny compared to the whole genome.