Senescent Cells in the Aging of Muscles and Bone
The common age-related degenerative conditions that affect muscle and bone are driven in part by the accumulation of senescent cells that takes place throughout the body with age. Senescent cells are created constantly throughout life, largely as a result of cells reaching the Hayflick limit on replication, but also due to forms of damage. In youth, these cells are cleared rapidly by the immune system, but this clearance falters with age allowing a population of lingering senescent cells to accumulate. These cells secrete pro-inflammatory, disruptive signals that degrade tissue structure and function.
Osteoporosis, sarcopenia, and osteoarthritis, three common musculoskeletal disorders that often coexist in the elderly population. The loss of bone and muscle mass and the progressive degradation of cartilage are the macroscopic effects of the complex pathological processes underlying these diseases, in association with an increased susceptibility to fractures and an elevated risk of falls. From a microscopic point of view, affected tissues are characterized by numerous cellular and molecular alterations that induce a state of replicative senescence, irreversibly compromising the quality of the musculoskeletal system. Not surprisingly, cellular senescence has recently emerged as a critical element in the pathophysiology of osteoporosis, sarcopenia, and osteoarthritis, highlighting the need for further studies to understand the intricate relationship between cellular senescence and musculoskeletal functions, as well as to develop effective strategies to mitigate and manage these debilitating conditions.
Cellular senescence has been suggested to be among the mechanisms responsible for the decline in regenerative function observed in muscle and bone stem cells with advancing age because of the up-regulation of certain proteins, including p16, p21, and p27, responsible for altered tissue metabolism. Particularly, senescent bone cells are known to release the senescence-associated secretory phenotype (SASP) that promotes osteoclast activity, inducing bone resorption and accelerating bone mass loss. In agreement, studies in mouse models have shown that the elimination of senescent cells improves bone mineral density and bone microarchitecture, counteracting the onset of osteoporosis. Furthermore, in skeletal muscle, the senescence of satellite cells, which are essential for muscle regeneration, significantly reduces tissue repair capacity. In this regard, experiments in mouse models have shown that the elimination of senescent cells improves muscle function and increases muscle mass, suggesting senolytics as potential strategies in the treatment of sarcopenia. Finally, the accumulation of senescent cells in joints has been suggested to contribute to cartilage degradation and synovial inflammation, exacerbating the joint deterioration that characterizes osteoarthritis.