What about telomere shortening? Are there other things that slowly break apart as they’re used (and not rejuvenated constantly) that could explain aging beyond a few slow changing cells?
Telomere shortening is an interesting case. (I’m going to give my current understanding here without trying to dig up references, so take it all with a grain of salt.)
It’s clearly a plausible root cause—it’s a change which could stick around on long enough timescales to account for aging. On the other hand, it is possible for telomeres to turn over: telomerase is active in stem cells, so telomere length should at least not be an issue for cell types which regularly turn over—the telomeres turn over with the cells, which are ultimately replaced from the stem cells. For long-lived cells, there’s a stronger case that telomere shortening could be an issue.
Telomeres do get shorter with age, BUT they get shorter even in cell types which turn over regularly. That’s a bit of a red flag—either the telomeres aren’t being fully replaced by telomerase in the stem cells (in which case the stem cells ought to die a lot sooner), or some other mechanism is making them short besides accumulated loss over lifetime. The alternative mechanism which jumps out to me is: DNA damage, and oxidative damage in particular, has been observed to rapidly shorten telomeres. DNA damage and oxidative damage rates are generally observed to be much higher in aged cells of most types, so that would explain why telomeres are shorter in older organisms.
In terms of actual experiments, telomerase-boosters have been experimented with a fair bit, and my understanding is that they don’t have much effect on age-related diseases (though of course there’s the usual pile of low-N studies which find barely-significant and blatantly p-hacked results).
Other things will eventually be covered later in this sequence.
That’s a tough question to answer; there’s an awful lot of stem-cell types and telomerase activity is not necessarily binary. I wouldn’t be shocked if some of the more-differentiated and/or slower-dividing types don’t express it.
We can do a back-of-the-envelope estimate: wikipedia quotes typical telomere length of 11k bp (base pairs) at birth, and one replication eats up 20 bp. That’s a limit of ~500 divisions, so any human stem cell which divides much faster than every ~(80 yrs)/500 = 60 days needs to express telomerase just to keep dividing throughout our lives. In practice, I’d expect that to be an extreme underestimate, since my understanding is that oxidative damage eats up telomeres considerably faster than replication does, especially for infrequently-dividing cells.
What about telomere shortening? Are there other things that slowly break apart as they’re used (and not rejuvenated constantly) that could explain aging beyond a few slow changing cells?
Telomere shortening is an interesting case. (I’m going to give my current understanding here without trying to dig up references, so take it all with a grain of salt.)
It’s clearly a plausible root cause—it’s a change which could stick around on long enough timescales to account for aging. On the other hand, it is possible for telomeres to turn over: telomerase is active in stem cells, so telomere length should at least not be an issue for cell types which regularly turn over—the telomeres turn over with the cells, which are ultimately replaced from the stem cells. For long-lived cells, there’s a stronger case that telomere shortening could be an issue.
Telomeres do get shorter with age, BUT they get shorter even in cell types which turn over regularly. That’s a bit of a red flag—either the telomeres aren’t being fully replaced by telomerase in the stem cells (in which case the stem cells ought to die a lot sooner), or some other mechanism is making them short besides accumulated loss over lifetime. The alternative mechanism which jumps out to me is: DNA damage, and oxidative damage in particular, has been observed to rapidly shorten telomeres. DNA damage and oxidative damage rates are generally observed to be much higher in aged cells of most types, so that would explain why telomeres are shorter in older organisms.
In terms of actual experiments, telomerase-boosters have been experimented with a fair bit, and my understanding is that they don’t have much effect on age-related diseases (though of course there’s the usual pile of low-N studies which find barely-significant and blatantly p-hacked results).
Other things will eventually be covered later in this sequence.
Is telomerasa active in all stem cells?
That’s a tough question to answer; there’s an awful lot of stem-cell types and telomerase activity is not necessarily binary. I wouldn’t be shocked if some of the more-differentiated and/or slower-dividing types don’t express it.
We can do a back-of-the-envelope estimate: wikipedia quotes typical telomere length of 11k bp (base pairs) at birth, and one replication eats up 20 bp. That’s a limit of ~500 divisions, so any human stem cell which divides much faster than every ~(80 yrs)/500 = 60 days needs to express telomerase just to keep dividing throughout our lives. In practice, I’d expect that to be an extreme underestimate, since my understanding is that oxidative damage eats up telomeres considerably faster than replication does, especially for infrequently-dividing cells.