The most obvious potentially detrimental effects of cell death are in postmitotic tissues, where cells are not readily replaced. Some postmitotic tissues such as certain regions of the brain or skeletal muscle can be replenished by recruiting stem or progenitor cells. However, such cells seem to have a finite replicative life span that eventually is exhausted, whether due to telomere dysfunction, stress-induced p16 expression, or other mechanisms (65-67, 140-142). Moreover, the tissue or systemic milieu of aged organisms compromises the recruitment and/or function of adult stem cells (42). Thus, eventually, cell death depletes postmitotic tissues of cells. Apoptosis, necrosis, and other forms of cell death have been observed in several age-related pathologies, such as sarcopenia and Alzheimer's disease (99,112,143).
Both apoptosis and necrosis may increase with age, owing to increased levels of oxidative or other forms of damage. Apoptosis may benefit young organisms by efficiently eliminating dysfunctional or damaged cells. As organisms age, however, cellular reserves may become exhausted, such that the loss of cells leads to tissue atrophy or degeneration.
In contrast to postmitotic tissues, there is evidence that apoptosis may become less efficient with age in some mitoti-cally competent mammalian tissues (144). The mechanism responsible for this change is unknown. Nonetheless, it is likely to increase the level of damaged or dysfunctional cells during aging. Interestingly, caloric restriction, which extends the life span of many species (145), increases the basal rate of apoptosis in some rodent tissues. This increase may in part explain why caloric restriction delays most age-related pathologies, including cancer (144).
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