In recent years, researchers have provided evidence to suggest that cellular senescence mechanisms are partly involved in the decline of stem cell activity in aging. It is an open question as to how this interacts with other signaling mechanisms also recently shown to influence the suppression of stem cell tissue maintenance. This is one part of a larger discussion over the degree to which loss of stem cell activity is due to internal factors localized within the stem cell populations, such as cellular damage, or external factors such as changes in cell signaling systems that are a reaction to more widespread damage in tissues:
Regeneration of skeletal muscle relies on a population of quiescent stem cells (satellite cells) and is impaired in very old (geriatric) individuals undergoing sarcopenia. Stem cell function is essential for organismal homeostasis, providing a renewable source of cells to repair damaged tissues. In adult organisms, age-dependent loss-of-function of tissue-specific stem cells is causally related with a decline in regenerative potential. Although environmental manipulations have shown good promise in the reversal of these conditions, recently we demonstrated that muscle stem cell aging is, in fact, a progressive process that results in persistent and irreversible changes in stem cell intrinsic properties.
Global gene expression analyses uncovered an induction of p16INK4a in satellite cells of physiologically aged geriatric and progeric mice that inhibits satellite cell-dependent muscle regeneration. Aged satellite cells lose the repression of the INK4a locus, which switches stem cell reversible quiescence into a pre-senescent state; upon regenerative or proliferative pressure, these cells undergo accelerated senescence (geroconversion), through Rb-mediated repression of E2F target genes. p16INK4a silencing rejuvenated satellite cells, restoring regeneration in geriatric and progeric muscles. Thus, p16INK4a/Rb-driven stem cell senescence is causally implicated in the intrinsic defective regeneration of sarcopenic muscle. Here we discuss on how cellular senescence may be a common mechanism of stem cell aging at the organism level and show that induction of p16INK4a in young muscle stem cells through deletion of the Polycomb complex protein Bmi1 recapitulates the geriatric phenotype.