One very important thing I don’t know about the work on methylation sites is whether they’re single-cell or averaged across cells. That matters a lot, because senescent cells should have methylation patterns radically different from everything else, but similar to each other (or at least along-the-same-axis as each other).
One thing I am pretty confident about is that methylation patterns are downstream, not upstream. Methyl group turnover time is far too fast to be a plausible root cause of aging. (In principle, there could be some special methyl groups which turn over slowly, but I would find that very surprising.)
Some key experimental findings on the mitogenesis/mitophagy stuff:
mitochondrial mutants are clonal: when cells have high counts of mutant mitochondria, the mutants in one cell usually have the same mutation.
it’s usually a mutation in one particular mitochondrial gene (figure 1 in this paper is a great visual of this).
(For references, check thesetwo papers and their background sections.) These facts imply that mitochondrial mutations aren’t random—under at least some conditions, mitochondria with certain mutations are positively selected and take over the cell. Furthermore, this positive selection process accounts for essentially-all of the cells taken over by mutant mitochondria in aged organisms.
Then the big question is: do mitchondria with these mutations take over healthy cells? If yes, then the rate at which mutant-mitochondria-dominated cells appear is determined by the rate of mitochondrial mutations. However, I find it more likely that the “quality control mechanisms” of selective mitophagy/mitogenesis do not favor mutant mitochondria in healthy cells, but do favor them in senescent cells. In that case, mutant mitochondria are probably downstream of cellular senescence. I don’t know of a study directly confirming/disconfirming that, but it matches the general picture. For instance, there are far more senescent cells than mutant mitochondrial cells. Also, the mitochondrial quality control mechanisms seem linked to membrane polarization, and in senescent cells the membranes of even healthy mitochondria are partially depolarized (that’s part of the feedback loop discussed in the post), so partial depolarization would no longer confer as large a selective disadvantage.
One very important thing I don’t know about the work on methylation sites is whether they’re single-cell or averaged across cells. That matters a lot, because senescent cells should have methylation patterns radically different from everything else, but similar to each other (or at least along-the-same-axis as each other).
One thing I am pretty confident about is that methylation patterns are downstream, not upstream. Methyl group turnover time is far too fast to be a plausible root cause of aging. (In principle, there could be some special methyl groups which turn over slowly, but I would find that very surprising.)
Some key experimental findings on the mitogenesis/mitophagy stuff:
mitochondrial mutants are clonal: when cells have high counts of mutant mitochondria, the mutants in one cell usually have the same mutation.
it’s usually a mutation in one particular mitochondrial gene (figure 1 in this paper is a great visual of this).
(For references, check these two papers and their background sections.) These facts imply that mitochondrial mutations aren’t random—under at least some conditions, mitochondria with certain mutations are positively selected and take over the cell. Furthermore, this positive selection process accounts for essentially-all of the cells taken over by mutant mitochondria in aged organisms.
Then the big question is: do mitchondria with these mutations take over healthy cells? If yes, then the rate at which mutant-mitochondria-dominated cells appear is determined by the rate of mitochondrial mutations. However, I find it more likely that the “quality control mechanisms” of selective mitophagy/mitogenesis do not favor mutant mitochondria in healthy cells, but do favor them in senescent cells. In that case, mutant mitochondria are probably downstream of cellular senescence. I don’t know of a study directly confirming/disconfirming that, but it matches the general picture. For instance, there are far more senescent cells than mutant mitochondrial cells. Also, the mitochondrial quality control mechanisms seem linked to membrane polarization, and in senescent cells the membranes of even healthy mitochondria are partially depolarized (that’s part of the feedback loop discussed in the post), so partial depolarization would no longer confer as large a selective disadvantage.