I’m still confused. My biology knowledge is probably lacking, so maybe that’s why, but I had a similar thought to dkirmani after reading this: “Why are children born young?” Given that sperm cells are active cells (which should give transposons opportunity to divide), why do they not produce children with larger transposon counts? I would expect whatever sperm divide from to have the same accumulation of transposons that causes problems in the divisions off stem cells.
Unless piRNA and siRNA are 100% at their jobs, and nothing is explicitly removing transposons in sperm/eggs better than in the rest of the body, then surely there should be at least a small amount of accumulation of transposons across generations. Is this something we see?
I vaguely remember that women are born with all the egg cells they’ll have, so, if that’s true, then maybe that offers a partial explanation (only half the child genome should be as infected with transposons?). I’m not sure it holds water, because since egg cells are still alive, even if they aren’t dividing more, they should present opportunities for transposons to multiply.
Another possible explanation I thought of was that, in order to be as close to 100% as possible, piRNA and siRNA work more than normal in the gonads, which does hurt the efficacy of sperm, but because you only need 1 to work, that’s ok. Still, unless it is actually 100%, there should be that generational accumulation.
This isn’t even just about transposons. It feels like any theory of aging would have to contend with why sperm and eggs aren’t old when they make a child, so I’m not sure what I’m missing.
My understanding is that transposon repression mechanisms (like piRNAs) are dramatically upregulated in the germ line. They are already very close to 100% effective in most cells under normal conditions, and even more so in the germ line, so that most children do not have any more transposons than their parents.
(More generally, my understanding is that germ line cells have special stuff going to make sure that the genome is passed on with minimal errors. Non-germ cells are less “paranoid” about mutations.)
Once the rate is low enough, it’s handled by natural selection, same as any other mutations.
Unless piRNA and siRNA are 100% at their jobs, and nothing is explicitly removing transposons in sperm/eggs better than in the rest of the body, then surely there should be at least a small amount of accumulation of transposons across generations. Is this something we see?
Increase of transposons is evolutionary disadvantageous so there’s selection pressure against increased active transposon count and for reduced active transposon count.
My impression is that DNA repair mechanisms get dramatically less effective with age, and that piRNA and siRNA (and other such transposon repression mechanisms) are effective but not 100% effective even in germ cells. Since germ cells in males continue to divide through the entire lifespan, my naive expectation would be that the children of very old men to age faster than the children of younger men (not just “have worse health outcomes in general” but specifically “express the specific marks of senescence earlier”).
Is that a valid prediction of the “transposons make more transposons and eventually the exponential increase in the number of transposons kills the cell” hypothesis?
Since germ cells in males continue to divide through the entire lifespan, my naive expectation would be that the children of very old men to age faster than the children of younger men (not just “have worse health outcomes in general” but specifically “express the specific marks of senescence earlier”).
Yes, but likely a few days or months and not years.
Let’s think through a scenario.
Imagine that each human has 100 active transposons. Then imagine each additional transposon reduces the amount of raised children by 0.01. If left alone this process would reduce the active transposon count to zero. If we assume the amount of transposons that exists is in equilibirum, the amount of new transposons produced in the germline because the transposon suppression systems aren’t perfect, is exactly the amount that’s needed to keep the active transposon count on average at 100 active transposons.
Given that most of the effect of aging happen a lot later then when humans get children, it would be surprising to me when a single additional transposon would reduce the amount of raised children by 0.01. I haven’t run the numbers myself but I wouldn’t be surprised if on average there’s only one or less additional transposon per generation (at normal childbearing age).
If transposons don’t produce aging you also need to present a different mechanism of how increased transposon count produces a problem that’s big enough for evolution to keep the amount of transposons at their current level. I can’t think of a different mechanism of how transposons create the evolutionary pressure to keep their numbers in check in a organism like humans where there seems to be more transposon activity in non-germline cells.
I’m still confused. My biology knowledge is probably lacking, so maybe that’s why, but I had a similar thought to dkirmani after reading this: “Why are children born young?” Given that sperm cells are active cells (which should give transposons opportunity to divide), why do they not produce children with larger transposon counts? I would expect whatever sperm divide from to have the same accumulation of transposons that causes problems in the divisions off stem cells.
Unless piRNA and siRNA are 100% at their jobs, and nothing is explicitly removing transposons in sperm/eggs better than in the rest of the body, then surely there should be at least a small amount of accumulation of transposons across generations. Is this something we see?
I vaguely remember that women are born with all the egg cells they’ll have, so, if that’s true, then maybe that offers a partial explanation (only half the child genome should be as infected with transposons?). I’m not sure it holds water, because since egg cells are still alive, even if they aren’t dividing more, they should present opportunities for transposons to multiply.
Another possible explanation I thought of was that, in order to be as close to 100% as possible, piRNA and siRNA work more than normal in the gonads, which does hurt the efficacy of sperm, but because you only need 1 to work, that’s ok. Still, unless it is actually 100%, there should be that generational accumulation.
This isn’t even just about transposons. It feels like any theory of aging would have to contend with why sperm and eggs aren’t old when they make a child, so I’m not sure what I’m missing.
My understanding is that transposon repression mechanisms (like piRNAs) are dramatically upregulated in the germ line. They are already very close to 100% effective in most cells under normal conditions, and even more so in the germ line, so that most children do not have any more transposons than their parents.
(More generally, my understanding is that germ line cells have special stuff going to make sure that the genome is passed on with minimal errors. Non-germ cells are less “paranoid” about mutations.)
Once the rate is low enough, it’s handled by natural selection, same as any other mutations.
Increase of transposons is evolutionary disadvantageous so there’s selection pressure against increased active transposon count and for reduced active transposon count.
My impression is that DNA repair mechanisms get dramatically less effective with age, and that piRNA and siRNA (and other such transposon repression mechanisms) are effective but not 100% effective even in germ cells. Since germ cells in males continue to divide through the entire lifespan, my naive expectation would be that the children of very old men to age faster than the children of younger men (not just “have worse health outcomes in general” but specifically “express the specific marks of senescence earlier”).
Is that a valid prediction of the “transposons make more transposons and eventually the exponential increase in the number of transposons kills the cell” hypothesis?
Yes, but likely a few days or months and not years.
Let’s think through a scenario.
Imagine that each human has 100 active transposons. Then imagine each additional transposon reduces the amount of raised children by 0.01. If left alone this process would reduce the active transposon count to zero. If we assume the amount of transposons that exists is in equilibirum, the amount of new transposons produced in the germline because the transposon suppression systems aren’t perfect, is exactly the amount that’s needed to keep the active transposon count on average at 100 active transposons.
Given that most of the effect of aging happen a lot later then when humans get children, it would be surprising to me when a single additional transposon would reduce the amount of raised children by 0.01. I haven’t run the numbers myself but I wouldn’t be surprised if on average there’s only one or less additional transposon per generation (at normal childbearing age).
If transposons don’t produce aging you also need to present a different mechanism of how increased transposon count produces a problem that’s big enough for evolution to keep the amount of transposons at their current level. I can’t think of a different mechanism of how transposons create the evolutionary pressure to keep their numbers in check in a organism like humans where there seems to be more transposon activity in non-germline cells.