I have long argued that reduction in average telomere length with age is a downstream measure of aging, not an upstream cause of aging. Telomeres are the caps of repeated DNA sequences found at the end of chromosomes. A little is lost with each cell division, and when telomeres get too short then the cell become senescent and is destroyed. This mechanism limits the number of times a cell can replicate. The vast majority of our cells are somatic cells that are limited in this way. A tiny number of stem cells can maintain lengthy telomeres via use of the telomerase enzyme and thus divide indefinitely. This is how near all multicellular species keep the risk of cancer low enough to survive long enough to reproduce - only a tiny minority of cells are privileged with unlimited replication capacity.
Average telomere length is thus a measure of how rapidly cells divide and die, combined with how rapidly stem cells divide to deliver new daughter somatic cells with long telomeres to make up the losses. Stem cell function declines with age, a result of both molecular damage direction and indirectly via a changing balance of signals that are reactions to that damage. Fewer daughter somatic cells with long telomeres means shorter average telomere lengths in tissues. Telomere length is thus a measure of declining function.
Nonetheless, many groups are very enthusiastic about using telomerase to artificially lengthen telomeres. This extends healthy life span in mice, despite the fact that it is a matter of putting damaged cells back to work. This outcome, alongside the fact that stem cell therapies are beneficial, suggests that evolution has not produced a fine balance between declining function and cancer risk. There is some room for cells to act more vigorously in later life than they will do naturally. This is not, however, a reversal of aging. It is pushing the damaged engine harder. If we can, then let us take the benefits offered, but cautiously.
The research here is most interesting, as it causally links loss of mitochondrial function to telomere attrition via a mechanism that doesn't appear to have to involve telomerase activity. Mitochondria are the power plants of the cell, vital in the sense that they produce the chemical energy store molecules needed to power cellular activity. Failing mitochondrial function is implicated in age-related diseases of the energy-hungry brain and muscles, for example, though the degree to which this decline results from inherent damage in mitochondria versus reactions to damage elsewhere in tissues is an open question. Being able to demonstrate that age-damaged mitochondria are responsible for some fraction of telomere attrition puts a different twist on benefits in mice that result from lengthening those telomeres again. I'd like to see a paper with more of a focus on stem cells and somatic cells in this context rather than cancer cells, however.
Here we report an epigenetic mechanism by which mitochondrial dysfunction plays a role in inducing telomere attrition through acetyltransferase activity of hnRNPA2. Our results show that hnRNPA2 mediated H4K8 acetylation is a signal for telomere shortening. Additionally we provide evidence that alterations in the telomere length in response to mitochondrial dysfunction is dependent on histone acetylation status because mutant hnRNPA2 proteins, which show vastly reduced histone acetylation activity, cause a rescue of telomere length. This is in agreement with previous reports in cancer cells where telomere histone acetylation has been shown to correlate with telomere length. While our results show the causal role of mitochondrial dysfunction in telomere length maintenance by a novel epigenetic mechanism, prior studies have reported mitochondrial dysfunction as the result of telomere attrition, providing evidence for the close association between mitochondrial functions and telomere dynamics.
Mitochondria are highly susceptible to damage from numerous factors including free radicals, environmental chemicals, radiation exposure, and lipid peroxides produced by defective electron transport chain, the hypoxic environment prevalent in solid tumors and defective mtDNA transcription and replication machinery. These cellular and environmental stressors can cause mitochondrial defects such as reduction in mtDNA copy number, mtDNA mutations/deletions and impaired electron transport chain activity. In fact, defects in OXPHOS and accumulating mtDNA mutations are associated with aging and age-associated cancers. A common pathological feature of both of these diseases is shortened telomere DNA leading to DNA damage.
The consequence of telomere shortening in aging and cancer remains unclear. The prevailing view is that in aging, telomere shortening continues until cells senesce and finally die, while in cancer, the attrition stops when the telomere DNA reaches a critical length, and cells continue to divide and proliferate. It is suggested that induced telomerase activity in cancer cells is a critical factor, which prevents cell senescence and promotes tumor proliferation. It may be seemingly contradictory that mitochondrial dysfunction in immortalized cancer cells induces a proliferative phenotype in spite of mitochondrial stress induced telomere attrition. In a recent study tested the telomerase activity in these cell lines and found that mitochondrial stress induced signaling simultaneously activates telomerase in these cells. This provides a plausible explanation for these cells to maintain the critical telomere length for resisting senescence. In support, in IMR-90 cells, which do not express telomerase, we show that induction of mtDNA depletion results in hnRNPA2 activation and telomere shortening resulting in senescence. This suggests that the rescue of telomere length is possibly attributable to the reduced telomere histone acetylation but not due to activation of telomerase.