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.
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.