A major problem during aging is that the functional capabilities of mesenchymal progenitor cells in bones and skeletal muscles decline. Senescence is a state of “stable” growth arrest in response to telomere erosion, DNA lesions, reactive oxygen species (ROS), and other mitogenic and metabolic stressors [39]. Activation of p16^INK4a/retinoblastoma protein (Rb) and/or p53/p21 tumor suppressor pathways plays a central role in senescence induction. Together these mechanisms of senescence limit excessive or aberrant growth of malignant cells. Interestingly, several senescence-inducing stressors are implicated in theories of aging (i.e., telomere erosion, DNA damage and mutation, protein aggregation, and ROS). However, instead of preventing the growth of cancers, the accumulation of senescent cells with advancing age negatively affects tissue structure and function and ultimately leads to tissue pathology. Thus, cellular senescence is an example of antagonistic pleiotropy, that is, a biological mechanism that increases odds of survival and reproduction in early life, but may have deleterious effects in later life.

Indeed, biomarkers of senescent cells (i.e., p16^INK4a and senescence-associated β-galactosidase (SA-β-gal)) increase in multiple tissues with chronological aging [40, 41]. Senescent cells are metabolically active and secrete a broad repertoire of cytokines and chemokines, matrix remodeling proteases, and growth factors, collectively referred to as the senescence-associated secretory phenotype (SASP) (reviewed in [42]). Though modest in number, senescent cells are presumed to underlie (a) age-related tissue deterioration due to their accumulation, loss of regenerative potential [43], and degradation of the extracellular matrix through the SASP; (b) age-related hyperproliferation, or the growth and spread of cancers, paradoxically, through components of the SASP including growth factors and matrix remodeling proteases; and (c) inflammaging, as cytokines and chemokines are prominent features of the SASP. Recently, it was demonstrated that targeted deletion of p16^ink4a-expressing cells improved multiple parameters of physical health and function, at least in a mouse model of accelerated aging [44]. Thus, cellular senescence has emerged as a potential unifying mechanism of aging and age-related diseases [45].

The contributions of cellular senescence to the aging of skeletal muscle and bone have not been thoroughly investigated. In adult skeletal muscle, satellite cells are mitotically quiescent. In response to injury and homeostatic demand, satellite cells are activated and reenter the cell cycle to generate muscle progenitor cells that repair or regenerate mature muscle fibers as well as self-renew to replenish the satellite cell population. Interestingly, the number of satellite cells does not appear to be significantly affected by aging. Instead, evidence suggests age-associated changes in the environment, or niche, which surrounds a satellite cell, compromise its ability to activate, regenerate, and replenish. While the SASP from neighboring fibroblasts, preadipocytes, endothelial cells, or other cell types may contaminate the “soil,” recent data suggests that cellular senescence may also directly impact the “seed,” or satellite cell. Specifically, in very old mice with sarcopenia and compromised muscle regeneration, p16^INK4a expression was significantly increased in satellite cells. However, when p16^INK4a was genetically silenced, satellite cell activation, proliferation, and self-renewal were restored [44]. The effects of eliminating senescent cells on bone strength were not assessed in this study, but there is substantial evidence that osteoblasts undergo cellular senescence during aging [46]. Modulators of SASP and cellular senescence hold great promise for increasing the health of bone and skeletal muscles.

In summary, reductions in skeletal muscle and bone occur with age and are linked to increased falls and fractures. An increased understanding of the underlying cellular mechanisms of aging, particularly cellular senescence and stem/progenitor cell renewal, is needed to stall if not reverse the effects of aging on the musculoskeletal system.