Impaired function of muscle stem cells is presently thought to be the dominant contributing factor in the development of sarcopenia, the loss of muscle mass and strength that affects everyone with advancing age. The mechanisms that cause stem cell decline are less well mapped, both in terms of their relative effect sizes, as well as their positions in the complex web of cause and consequence that links fundamental forms of cell and tissue damage, the root of aging, to downstream manifestations of aging.

Adult skeletal muscle has its own stem cell population, namely muscle satellite (stem) cells (MuSCs). Under sedentary conditions in the adult stage, MuSCs are mitotically quiescent and reside beneath the basal lamina of the myofiber; this position between the myofiber and the surrounding extracellular matrix is crucial for maintaining the stem cell state. After muscle injury, quiescent MuSCs promptly get activated, resulting in proliferation and their differentiation into myoblasts. Hence, myoblast fusion is critical not only for skeletal muscle development but also for regeneration. However, the function of MuSCs gradually declines during physiological and pathological aging. Although loss of the muscular regenerative capacity in aging is partly due to this impairment of MuSC function, the precise mechanism of how stem cell function is maintained and impaired remains unclear.

Aged MuSCs are also more prone to undergo senescence or apoptosis than young MuSCs. In terms of the ability of MuSCs to differentiate, the adipogenic differentiation program is enhanced in cultured, aged MuSCs. In the context of acute injury, symmetric and asymmetric cell division promote the expansion of MuSCs and maintain homeostasis of the stem cell compartment. Impairment of this process in aged muscle leads to an impaired propensity to proliferate and produce myoblasts necessary for muscle regeneration. While there are reports demonstrating decreases in the number of MuSCs during aging, conflicting reports show no significant differences in the number of MuSCs between young and aged mice. Additionally, since MuSCs are very rare and the number of MuSCs differs in the type and location of skeletal muscles, it is difficult to reach conclusions on the frequencies of MuSCs within young and aged mice.

The decline of MuSC regenerative capacity is due to age-associated extrinsic/environmental changes as well as cell-intrinsic/autonomous changes. As extrinsic factors, inflammatory responses, extracellular components, and changes in interacting cell types definitely affect the function in MuSCs. MuSC function is also impaired by cell-intrinsic damages including oxidative stress, DNA damage, modified signaling pathways, damage to proteins, and altered metabolism. An accumulation of cell intrinsic damages leads to a “point of no return” in aged MuSCs as they go into a pre-senescent state or they undergo apoptosis. Alterations in several intracellular signaling pathways in aged MuSCs affect their self-renewability. The functional decline of MuSCs is partly due to the activation of FGF2, TGF-β, WNT pathways, JAK/STAT3, p16INK4a, and p38. Those pathway modulations could be a therapeutic target for muscle regenerative therapy in elderly.