Sure, but the vast majority of damage types are repaired (in the case of DNA) or removed (e.g. when a protein or cell turns over). So the question is which specific damage types are accumulating. Many kinds of damage increase in count with age, but the vast majority of them turn over too quickly to be a plausible root cause.
Damage/dysregulation to the control sites are more central to the network—repair genes/proteins like OGG1/ERCC1 or the upstream control factors of everything or kinases. For whatever reason, expression of most repair genes (and heat shock proteins) goes down with time.
Damage to structural components (like extremely long lived proteins) are harder to repair and simultaneously make it harder for repair proteins to properly localize to places where needed.
It’s not a matter of simple downexpression or up-expression—though if I were to bet I wouldn’t say that damage to the repair proteins or proteasomes are totally causal—it’s just the simultaneously distributed damage of everything that ultimately builds up and I don’t think it can be summed into any neat causes other than changed damage to repair ratio.
If I were to bet on one mechanism, it would be repair genes that get jammed/make errors during repair. Statistically speaking, some percent of DNA repair enzymes will screw up the process of repair (or introduce further damage), and liposomes/proteasomes will get traffic jams that are difficult to remove/clear.
Damage/dysregulation to repair genes/proteins like OGG1/ERCC1 or the upstream control factors of everything.
Nope, they turn over too quickly. You’d have to damage most copies at the same time in order for it to have a permanent effect; otherwise the remaining copies will bring us back to equilibrium. (And even if most copies were damaged at the same time, the whole cell should still turn over, so that would also need to be prevented somehow in order to prevent reequilibration.) If expression is decreasing on a timescale of decades, then something upstream must be changing the equilibrium expression level.
Structural genes like the extremely long-lived proteins in nuclear pore complexes don’t turn over (similarly, damage to nuclear histone proteins is very difficult to repair). Even small changes in these genes can affect the ability of mRNA and all of the spliceosome proteins to be properly assembled where they’re most needed ⇒ this gradually sums up to a corrosion of cellular information.
They do turn over when the cell turns over, which for most cell types is still way faster than the timescale of aging. They could be a plausible root cause in very long-lived cell types, but I would guess that in long-lived cells they usually do turn over on a timescale faster than decades. This paper, for instance, finds that nuclear pore turnover is slower than turnover of rat kidney cells, but rat kidney cells turn over in weeks IIRC. NPC could turn over in years, and that would still be fast compared to aging.
Sure, but the vast majority of damage types are repaired (in the case of DNA) or removed (e.g. when a protein or cell turns over). So the question is which specific damage types are accumulating. Many kinds of damage increase in count with age, but the vast majority of them turn over too quickly to be a plausible root cause.
Damage/dysregulation to the control sites are more central to the network—repair genes/proteins like OGG1/ERCC1 or the upstream control factors of everything or kinases. For whatever reason, expression of most repair genes (and heat shock proteins) goes down with time.
Spliceosomes are esp impt too, as are the upstream genes behind lysosome synthesis (https://en.wikipedia.org/wiki/TFEB) and proteaosome synthesis.
Damage to structural components (like extremely long lived proteins) are harder to repair and simultaneously make it harder for repair proteins to properly localize to places where needed.
It’s not a matter of simple downexpression or up-expression—though if I were to bet I wouldn’t say that damage to the repair proteins or proteasomes are totally causal—it’s just the simultaneously distributed damage of everything that ultimately builds up and I don’t think it can be summed into any neat causes other than changed damage to repair ratio.
If I were to bet on one mechanism, it would be repair genes that get jammed/make errors during repair. Statistically speaking, some percent of DNA repair enzymes will screw up the process of repair (or introduce further damage), and liposomes/proteasomes will get traffic jams that are difficult to remove/clear.
Nope, they turn over too quickly. You’d have to damage most copies at the same time in order for it to have a permanent effect; otherwise the remaining copies will bring us back to equilibrium. (And even if most copies were damaged at the same time, the whole cell should still turn over, so that would also need to be prevented somehow in order to prevent reequilibration.) If expression is decreasing on a timescale of decades, then something upstream must be changing the equilibrium expression level.
https://www.nature.com/articles/s42255-020-00304-4
Structural genes like the extremely long-lived proteins in nuclear pore complexes don’t turn over (similarly, damage to nuclear histone proteins is very difficult to repair). Even small changes in these genes can affect the ability of mRNA and all of the spliceosome proteins to be properly assembled where they’re most needed ⇒ this gradually sums up to a corrosion of cellular information.
They do turn over when the cell turns over, which for most cell types is still way faster than the timescale of aging. They could be a plausible root cause in very long-lived cell types, but I would guess that in long-lived cells they usually do turn over on a timescale faster than decades. This paper, for instance, finds that nuclear pore turnover is slower than turnover of rat kidney cells, but rat kidney cells turn over in weeks IIRC. NPC could turn over in years, and that would still be fast compared to aging.