It might be the case that mitochondrial/DNA mutations in stem cells result in a reduced capacity to regenerate through initiation of apoptosis and senescence in the resulting clones which are supposed to take the place of their fallen comrades. The tissues arising from damaged stem cells just don't function and move rapidly into senescence of apoptosis. This Nature paper by Fagagna associates telomere associated senescence with DNA damage.
A DNA damage checkpoint response in telomere-initiated senescence
d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP
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In regards to stem cell differentiation and mitochondrial damage with aging, Tom Kirkwood has an interesting study with intestinal tissue where he showed the change of crypt cells over time as the stem cells themselves aged. He showed explicityly how the same mitchondrial mutations were discovered in the crypt cells arising from the differentiation of cells from a single stem cell population which sits at the bottom of the crypt.
Mitochondrial DNA mutations in human colonic crypt stem cells-Free
Abstract
The mitochondrial genome encodes 13 essential subunits of the respiratory chain and has remarkable genetics based on uniparental inheritance. Within human populations, the mitochondrial genome has a high rate of sequence divergence with multiple polymorphic variants and thus has played a major role in examining the evolutionary history of our species. In recent years it has also become apparent that pathogenic mitochondrial DNA (mtDNA) mutations play an important role in neurological and other diseases. Patients harbor many different mtDNA mutations, some of which are mtDNA mutations, some of which are inherited, but others that seem to be sporadic. It has also been suggested that mtDNA mutations play a role in aging and cancer, but the evidence for a causative role in these conditions is less clear. The accumulated data would suggest, however, that mtDNA mutations occur on a frequent basis. In this article we describe a new phenomenon: the accumulation of mtDNA mutations in human colonic crypt stem cells that result in a significant biochemical defect in their progeny. These studies have important consequences not only for understanding of the finding of mtDNA mutations in aging tissues and tumors, but also for determining the frequency of mtDNA mutations within a cell.
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It has been shown that the decline in populations of endothelial progenitor cells in the blood is linked to the reduced ability to repair arteries and is thought to be a result of stem cell population fatigue.
Eurekalert Release - Age-related stem cell loss prevents artery repair and leads to atherosclerosis - PDF
It appears that more researchers are observing that DNA and mitochondrial damage in stem cells is a root cause of many diseases and IMO is the rooot cause of aging. Stem cells proliferate much more slowly than post mitotic giving rise to mitotic tissues through clonal expansion, but some tissues require faster replacement than others and these are indeed the tissues which appear to age the fastest.. thymic involution and the immune system are examples of reduced capacity to regnerate as well as the linings of our intestine.. I would imagine skin and lung to bear a similar acclerated progenitor exhaustion as a result of the higher replacement rate. The lower the demand of replacement on a stem cell population, the longer it maintains its 'pristine' proliferative capactity. Being able to removed damaged stem cells would be a good therapy while enhancing the populations of undamaged stem cells would be required as well to fully enhance healthy regenerative capacity.
