What do you think about the ability to predict age to surprising accuracy using ~350 DNA methylation sites? Sadly I can’t work out if the author has considered looking at the sites to see much of what the methylation is changing the transcription of, other than the PGCT genes which based on a cursory search seem to be linked by being targets of a specific process rather than doing a specific thing. Again this makes it unclear whether this is upstream or downstream of ageing.
Mitochondrial mutation accumulation seems to be a big thing, mitochondrial dysfunction is implicated in Alzheimer’s, and might be linked to a bunch of signalling around epoxyeicosatrienoic acids. This is confused by the fact that EETs might induce mitogenesis but are also also anti-inflammatory and regulate the vascular system (?!) because biochemistry just like this sometimes.
Oddly enough, mitophagy also seems to be a potential target of anti-ageing drugs. Possibly the (selective) turnover of mitochondria can be used to remove the most dysfunctional ones? Perhaps the two processes might be coupled in such a way that speeding up one speeds up the other. Also some people have suggested combining these before but then as far as I can tell just didn’t bother to check if it actually worked (!?!?)
Whether mitochondrial mutations are upstream or downstream of other things is unclear. I think Nick Lane has suggested a mechanism by which mitochondrial mutations could actually accumulate faster than by chance (definitely in “The Vital Question” but possibly elsewhere) but I don’t know if it has been tested.
(Posting as a top-level comment since I have a few points to say but the stuff about DNA methylation is sort of in response to comments below)
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.
What do you think about the ability to predict age to surprising accuracy using ~350 DNA methylation sites? Sadly I can’t work out if the author has considered looking at the sites to see much of what the methylation is changing the transcription of, other than the PGCT genes which based on a cursory search seem to be linked by being targets of a specific process rather than doing a specific thing. Again this makes it unclear whether this is upstream or downstream of ageing.
Mitochondrial mutation accumulation seems to be a big thing, mitochondrial dysfunction is implicated in Alzheimer’s, and might be linked to a bunch of signalling around epoxyeicosatrienoic acids. This is confused by the fact that EETs might induce mitogenesis but are also also anti-inflammatory and regulate the vascular system (?!) because biochemistry just like this sometimes.
Oddly enough, mitophagy also seems to be a potential target of anti-ageing drugs. Possibly the (selective) turnover of mitochondria can be used to remove the most dysfunctional ones? Perhaps the two processes might be coupled in such a way that speeding up one speeds up the other. Also some people have suggested combining these before but then as far as I can tell just didn’t bother to check if it actually worked (!?!?)
Whether mitochondrial mutations are upstream or downstream of other things is unclear. I think Nick Lane has suggested a mechanism by which mitochondrial mutations could actually accumulate faster than by chance (definitely in “The Vital Question” but possibly elsewhere) but I don’t know if it has been tested.
(Posting as a top-level comment since I have a few points to say but the stuff about DNA methylation is sort of in response to comments below)
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.