It seems like a key question is something like the rate of turnover vs. the rate of damage proliferation. We also need to factor in the potential for damage to inhibit turnover (among other repair mechanisms). After all, turnover is a complex set of processes involving identification, transport, destruction, and elimination of specific structures. The mechanisms by which it is effected are subject to damage and disrepair.
We also need to consider the accuracy of regeneration after turnover. When a cell dies and is replaced, the new cell will not anchor in the exact same position in the ECM. On larger scales, this might average out, but it might also lead to larger anatomical dysfunction. Individuals that survive from meiosis into maturity may do so because they’ve been lucky in avoiding random anatomical fluctuations that kill their less fortunate brethren. If the body does not have adequate mechanisms to maintain precise numbers, arrangements, and structures of organelles, ECM, tissue, and gross anatomy over time, then turnover won’t be able to solve this problem of “structural decay.”
This is to some extent true of the proteins and cells of the body. Malformed cells and proteins are targeted for destruction. So the survivors are similarly selected for compatibility with the body’s damage detection mechanisms, even though the best way of being compatible with those mechanisms is to evade them entirely.
So we have several things to investigate:
Structures with a slower rate of turnover than of damage accumulation
Example: cortical neurons, lens proteins
Forms of damage that impair or evade turnover
Example: mutations/epigenetic changes that eliminate apoptosis receptors in cancer cells, inert protein aggregates that cannot be degraded by the proteasome and accumulate in the cell, preventing turnover of yet other proteins. As a second example of protein evasion of turnover, loss of lysine or methionine would eliminate a site for ubiquitination, impairing the marking of proteins for destruction by the proteasome.
Forms of damage that accelerate damage proliferation
Example: metastatic cancer
Forms of damage that turnover cannot fix, such as structural decay.
Example: perhaps thymic involution? I am not sure, but I am confident that this is a real phenomenon.
That said, I think it’s a very valuable insight to keep in mind that for any form of damage, we always have to ask, “why can’t turnover fix this problem?”
It seems like a key question is something like the rate of turnover vs. the rate of damage proliferation. We also need to factor in the potential for damage to inhibit turnover (among other repair mechanisms). After all, turnover is a complex set of processes involving identification, transport, destruction, and elimination of specific structures. The mechanisms by which it is effected are subject to damage and disrepair.
We also need to consider the accuracy of regeneration after turnover. When a cell dies and is replaced, the new cell will not anchor in the exact same position in the ECM. On larger scales, this might average out, but it might also lead to larger anatomical dysfunction. Individuals that survive from meiosis into maturity may do so because they’ve been lucky in avoiding random anatomical fluctuations that kill their less fortunate brethren. If the body does not have adequate mechanisms to maintain precise numbers, arrangements, and structures of organelles, ECM, tissue, and gross anatomy over time, then turnover won’t be able to solve this problem of “structural decay.”
This is to some extent true of the proteins and cells of the body. Malformed cells and proteins are targeted for destruction. So the survivors are similarly selected for compatibility with the body’s damage detection mechanisms, even though the best way of being compatible with those mechanisms is to evade them entirely.
So we have several things to investigate:
Structures with a slower rate of turnover than of damage accumulation
Example: cortical neurons, lens proteins
Forms of damage that impair or evade turnover
Example: mutations/epigenetic changes that eliminate apoptosis receptors in cancer cells, inert protein aggregates that cannot be degraded by the proteasome and accumulate in the cell, preventing turnover of yet other proteins. As a second example of protein evasion of turnover, loss of lysine or methionine would eliminate a site for ubiquitination, impairing the marking of proteins for destruction by the proteasome.
Forms of damage that accelerate damage proliferation
Example: metastatic cancer
Forms of damage that turnover cannot fix, such as structural decay.
Example: perhaps thymic involution? I am not sure, but I am confident that this is a real phenomenon.
That said, I think it’s a very valuable insight to keep in mind that for any form of damage, we always have to ask, “why can’t turnover fix this problem?”