There are many overlapping mechanisms involved in the age-related loss of stem cell function in muscle tissue that leads to loss of muscle mass and strength. To name a few: the mitochondrial dysfunction that occurs in all tissues, or the chronic inflammation produced by senescent cells and the aging immune system. The authors of this open access review paper choose to divide approaches to treatment of loss of muscle stem cell function, whether compensatory or actual rejuvenation, into those that affect stem cells versus those that affect the stem cell niche. Research has suggested that the fact that muscle stem cell populations become less active with age is more a matter of changes in the niche and systemic signaling rather than inherent damage to the stem cells themselves, but these changes must still originate in damage elsewhere in tissue.
Ex vivo manipulations of aged satellite cells have proven to be effective strategies to reverse some of the intrinsic alterations limiting their regenerative potential. These manipulations include genetic interventions to silence p16INK4a expression, thereby restoring quiescence and regenerative capacity to the aged satellite cell. Similarly, ex vivo pharmacological inhibition of p38 MAPK signaling decreases the expression of cell-cycle inhibitors, such as p16INK4a, and restores asymmetric division in satellite cells, contributing to enhanced regenerative potential of aged satellite cells in muscle transplantation experiments.
In vivo, local and systemic interventions have also shown promise in reversing age-related satellite cell defects. For example, systemic pharmacological treatments to restore basal autophagy flux preserved quiescence and muscle stem cell regenerative capacity in old muscles. Similarly, systemic delivery of oxytocin restores age-related regenerative capacity in old muscles, promoting satellite cell activation and proliferation, while systemic delivery of WISP1 during a regenerative event improves myogenic commitment and regenerative success. Moreover, systemic delivery of exogenous α-Klotho improves muscle stem cell bioenergetics and improves regenerative capacity in aged animals.
Rejuvenating interventions able to target the whole organism have also a positive impact on satellite cell function during aging. Successful interventions include caloric restriction, rapamycin treatment, supplementation with the NAD+ precursor nicotinamide riboside, senescent cell ablation, and in vivo reprogramming. These studies anticipate the existence of common hallmarks of aging associated with satellite cell loss of function in old animals, which can be considered common targets for intervention. Consistently, targeting chronic inflammation (a shared feature of several age-related pathologies) through systemic treatment with an inhibitor of NFκB activation improves myogenic function in aged satellite cells.