Geriatric muscle stem cells switch reversible quiescence into senescence

Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline with ageing. Here we report that geriatric satellite cells are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and that this irreversibly affects their intrinsic regenerative and self-renewal capacities. In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16 INK4a (also called Cdkn2a). On injury, these cells fail to activate and expand, undergoing accelerated entry into a full senescence state (geroconversion), even in a youthful environment. p16 INK4a silencing in geriatric satellite cells restores quiescence and muscle regenerative functions. Our results demonstrate that maintenance of quiescence in adult life depends on the active repression of senescence pathways. As p16 INK4a is dysregulated in human geriatric satellite cells, these findings provide the basis for stem-cell rejuvenation in sarcopenic muscles. This study shows that ageing satellite cells undergo an irreversible transition from a quiescent to a pre-senescent state that results in the loss of muscle regeneration in sarcopenia; furthermore, increased expression of p16 INK4a is identified as a common feature of senescent satellite cells. When muscles grow old One of the properties crucial to the function of adult mammalian stem cells is the capacity to remain in a quiescent state for prolonged periods — and to respond when the need to regenerate arises. Loss of skeletal muscle mass and function are common features of advanced ageing in humans, associated with a loss of regenerative capacity of the skeletal muscle stem cells, known as satellite cells. Pura Muñoz-Cánoves and colleagues show that ageing satellite cells undergo an irreversible transition from quiescence to a pre-senescence state associated with increased expression of p16 INK4a , a tumour-suppressor protein that has been identified as a marker for senescence. Repression of p16 INK4a during adult life is shown to maintain satellite cells in a reversible quiescence state that allows muscle regeneration; p16 INK4a is dysregulated in human geriatric satellite cells and the potential for muscle regeneration is lost.