Cellular senescence and the skeleton: pathophysiology and therapeutic implications

Abstract

Cellular senescence is a fundamental aging mechanism that is currently the focus of considerable interest as a pathway that could be targeted to ameliorate aging across multiple tissues, including the skeleton. There is now substantial evidence that senescent cells accumulate in the bone microenvironment with aging and that targeting these cells prevents age-related bone loss, at least in mice. Cellular senescence also plays important roles in mediating the skeletal fragility associated with diabetes mellitus, radiation, and chemotherapy. As such, there are ongoing efforts to develop "senolytic" drugs that kill senescent cells by targeting key survival mechanisms in these cells without affecting normal cells. Because senescent cells accumulate across tissues with aging, senolytics offer the attractive possibility of treating multiple age-related comorbidities simultaneously.

Figure 1. Hallmarks of aging grouped by whether they are primary causes of damage; compensatory or antagonistic responses to it; or the end result (integrative) of the previous two hallmarks.

Adapted with permission from Cell (9).

Figure 2. Working model of the senescence pathway based on a large number of in vitro and animal studies.

The top box lists cellular stressors that trigger activation of key senescence inducers (p16^Ink4a/Rb and p21^Cip1/p53). This leads to activation of senescence mediators, which, in turn, promote the secretion of the proinflammatory SASP, resulting in tissue dysfunction. Senescent cells also activate senescent cell antiapoptotic pathways (SCAPs) that are the target of “senolytic” drugs. By contrast, “senomorphic” drugs do not kill senescent cells but rather inhibit the production and/or secretion of the SASP.

Figure 3. Working model of our current understanding of the contribution of cellular senescence to skeletal aging.

Senescent cells accumulate in the bone microenvironment with aging and secrete a proinflammatory SASP. The contribution of the SASP from non-skeletal sites as well as the possible systemic effects of the SASP from the bone microenvironment in modulating non-skeletal aging remains unclear. The increased proinflammatory SASP in the bone microenvironment acts on osteoblasts to impair bone formation, on osteoclasts to increase bone resorption, and on MSCs to skew their lineage commitment toward adipocytes and away from osteoblasts, consistent with skeletal aging across species.