Cellular Senescence in the Aging of Bone

Senescent cells accumulate with age, and disrupt tissue function via the signaling that they generate, the senescence-associated secretory phenotype (SASP). In bone tissue, the SASP contributes to breaking the balance between the activities of osteoblast cells, constantly building bone, and osteoclast cells, constantly deconstructing bone. Osteoclast activity in older people outweighs osteoblast activity, leading to a progressive loss of bone mineral density and eventual osteoporosis.

Maintaining lifelong mobility is one aim of healthy aging that allows independence and autonomy. However, falls and fragility fractures, which tend to occur in clusters toward the end of life, represent common hazards for the mobility of the aging population. This period comes with a substantial loss of quality of life and causes an enormous socioeconomic burden for patients and their families. While there has been tremendous progress in our understanding of osteoporosis due to sex hormone deficiency or medications, insights into how cell-intrinsic mechanisms contribute to the aging process of the skeletal system are still limited.

Over the past decade, emerging bone research has focused on the biology of osteocytes, the least accessible yet most common bone-resident cell type. Osteocytes are specialized bone cells that orchestrate skeletal remodeling. Senescent osteocytes are characterized by an activation of cyclin-dependent kinase inhibitor p16Ink4a and have been implicated in the pathogenesis of several bone loss disorders.

Researchers have now shown that systemic removal of senescent cells (termed senolysis) prevented age-related bone loss at the spine and femur and mitigated bone marrow adiposity through a robust effect on osteoblasts and osteoclasts, whereas cell-specific senolysis in osteocytes alone was only partially effective. Surprisingly, transplantation of senescent fibroblasts into the peritoneum of young mice caused host osteocyte senescence associated with bone loss. This refined concept of osteocyte senescence and the effects of remote senolysis may help to develop improved senolytic strategies against multisystem aging in bone and beyond.

Link: https://doi.org/10.1172/JCI169069

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