Targeting senescent cells to prevent age-related bone loss

Estrogen deficiency is a seminal mechanism in the pathogenesis of osteoporosis. Mounting evidence, however,
indicates that cellular senescence, a fundamental aging mechanism that drives multiple age-related diseases, also causes osteoporosis. Recently, we systematically identified an accumulation of senescent cells, characterized by increased p16Ink4a and p21Cip1 levels, in mouse bone with aging. We also found similar results in bone biopsies from older versus younger women, indicating parallel findings in humans. We then demonstrated that senescent cells mediate age-related bone loss using multiple approaches, e.g., treating wild-type (WT) mice with “senolytics” (i.e., drugs that eliminate senescent cells) and reducing senescent cell burden using mice expressing the INK-ATTAC “suicide” transgene via drug (AP20187)-inducible caspase-8 driven by the senescence-associated p16Ink4a promoter. These approaches improved bone mass and strength by suppressing bone resorption and stimulating bone formation. We next investigated a possible role for estrogen in the regulation of senescence in bone using multiple approaches in both mice and humans. Our data establish that estrogen deficiency and cellular senescence represent independent mechanisms in the pathogenesis of osteoporosis. Therefore, senescent cells accumulate at the time and location of age-related bone loss, and have a causal role in the pathogenesis of osteoporosis. Further, from a therapeutic perspective, targeting senescent cells appears to offer advantages over conventional anti-resorptive therapy. In addition, our findings have important implications for testing novel senolytics for skeletal efficacy, as these drugs will need to be evaluated in models of aging, as opposed to the current FDA model of prevention of ovariectomy-induced bone loss. Finally, since eliminating senescent cells and/or inhibiting their pro-inflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis but also for multiple age-related co-morbidities.

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