My guess is that the primary cause of human aging is a combination of “depleted” stem cells combined with a gradual disruption of regulatory homeostasis.
Consider spermatogenesis as a model. There is a primary pool of slow dividing stem cells which are maintained in that state by local signaling from neighboring cells. In these stem cells, telomerase is sufficiently active that telomere length is preserved. The primary stem cell pool slowly replenishes a pool of fast dividing secondary stem cells in which telomerase is slightly less active. These are stem cells as the pool is largely self renewing. The secondary stem cell pool also generates progenitor cells which divide and differentiate to become sperm. Telomerase activity is much lower in these later cell generations so telomere length shortens with each division.
My speculation...
Bone marrow niches contain a common primary stem cell pool which has the potential to restore the primary stem pools in local tissues such as the testes. E.g., conditions in testes would cause release of signaling molecules into the blood. Those molecules would stimulate a special bone marrow stem cell causing differentiation into a primary sperm stem cell which is released into the blood. From the blood the stem cell enters the testes where it takes up residence in the local stem cell pool. In a similar manner wound healing recruits a variety of stem cell types from the bone marrow. (This would explain why fast cell turnover tissues don’t acquire mutations or shorter telomeres at a significantly higher rate than slow turnover tissues.)
Average telomere length decreases when the primary stem cell pools become depleted. E.g., chronic inflammation or stress might deplete the primary stem cell pool so that the secondary stem cell pools aren’t replenished, leading to decreased telomere length in the daughter cells. I.e., short telomeres are a sign of primary stem cell pool depletion, not a cause of aging. (Note that removing chronic stress may result in average telomere length increasing for white blood cells.)
Potential causes of stem cell depletion:
1) Stochastic differences in initial stem cell state. Due to molecular events such as DNA methylation, histone modifications, and differing signaling gradients from the local neighborhood some stem cells will divide faster and produce a higher percentage of differentiated daughter cells. Over time the stem cell pool will consist of cells whose initial internal settings favored slow division and a low percentage of daughter cells. This depleted stem cell pool becomes less and less able to meet the tissue regeneration needs of the body.
2) Gradual dis-regulation of the stem cell niche causes non-optimal functioning of stem cell renewal and differentiation. (With age red, blood cell producing, bone marrow gradually transforms into yellow, fat cell producing bone marrow.)
3) Environmental factors that alter stem cell epigenetic state causing poor functioning.
A strategy for rejuvenation would be to supply new stem cells engineered to be in an optimal epigenetic state for tissue renewal. By itself this would not suffice since mouse studies have shown that merely providing young stem cells won’t cause old muscle to heal. Various grow factors and other signaling molecules must also be provided in the target tissue. Eventually the old cells would be replaced and the local tissue would return to a “young” signaling environment.
Not Telomeres?
Consider spermatogenesis as a model. There is a primary pool of slow dividing stem cells which are maintained in that state by local signaling from neighboring cells. In these stem cells, telomerase is sufficiently active that telomere length is preserved. The primary stem cell pool slowly replenishes a pool of fast dividing secondary stem cells in which telomerase is slightly less active. These are stem cells as the pool is largely self renewing. The secondary stem cell pool also generates progenitor cells which divide and differentiate to become sperm. Telomerase activity is much lower in these later cell generations so telomere length shortens with each division.
My speculation...
Bone marrow niches contain a common primary stem cell pool which has the potential to restore the primary stem pools in local tissues such as the testes. E.g., conditions in testes would cause release of signaling molecules into the blood. Those molecules would stimulate a special bone marrow stem cell causing differentiation into a primary sperm stem cell which is released into the blood. From the blood the stem cell enters the testes where it takes up residence in the local stem cell pool. In a similar manner wound healing recruits a variety of stem cell types from the bone marrow. (This would explain why fast cell turnover tissues don’t acquire mutations or shorter telomeres at a significantly higher rate than slow turnover tissues.)
Average telomere length decreases when the primary stem cell pools become depleted. E.g., chronic inflammation or stress might deplete the primary stem cell pool so that the secondary stem cell pools aren’t replenished, leading to decreased telomere length in the daughter cells. I.e., short telomeres are a sign of primary stem cell pool depletion, not a cause of aging. (Note that removing chronic stress may result in average telomere length increasing for white blood cells.)
Potential causes of stem cell depletion: 1) Stochastic differences in initial stem cell state. Due to molecular events such as DNA methylation, histone modifications, and differing signaling gradients from the local neighborhood some stem cells will divide faster and produce a higher percentage of differentiated daughter cells. Over time the stem cell pool will consist of cells whose initial internal settings favored slow division and a low percentage of daughter cells. This depleted stem cell pool becomes less and less able to meet the tissue regeneration needs of the body. 2) Gradual dis-regulation of the stem cell niche causes non-optimal functioning of stem cell renewal and differentiation. (With age red, blood cell producing, bone marrow gradually transforms into yellow, fat cell producing bone marrow.) 3) Environmental factors that alter stem cell epigenetic state causing poor functioning.
A strategy for rejuvenation would be to supply new stem cells engineered to be in an optimal epigenetic state for tissue renewal. By itself this would not suffice since mouse studies have shown that merely providing young stem cells won’t cause old muscle to heal. Various grow factors and other signaling molecules must also be provided in the target tissue. Eventually the old cells would be replaced and the local tissue would return to a “young” signaling environment.