The senolytic drug fisetin mitigates age‐related bone density loss in the progeroid mouse model Zmpste24−/−

Abstract

Senescence is a cell state defined by loss of proliferative capacity, increased metabolic activity, and importantly, resistance to apoptosis. Senescent cells can release pro‐inflammatory cytokines/chemokines, proteases, and other factors, otherwise known as the senescence‐associated secretory phenotype (SASP). The SASP can adversely affect not only neighboring cells, but also likely contributes to driving systemic aging. Senolytic compounds such as dasatinib (D), quercetin (Q), and fisetin (FIS) were recently found to target anti‐apoptotic pathways known to be upregulated in senescent cells. Several reports have found significant improvement in healthspan indices including decreased frailty, neurologic dysfunction, and bone loss in vivo following intermittent treatment with senolytic agents. Our lab routinely uses the accelerated aging model Zmpste24−/− (Z24−/−) mice to investigate age‐related pathologies as they have a maximum lifespan of ~6 months. For the first time here, we examined the effects of another significantly safer senolytic compound, the flavonoid FIS, on spontaneous bone density loss associated with age using the Z24−/− model.Z24−/− mice begin to exhibit significant musculoskeletal decline associated with increased senescent cell burden as early as 2 months including weight loss and reduced cartilage proteoglycan and bone levels in skeletal preparations (Fig. 1). Importantly, we previously found that senolytic drug treatment restored cartilage in Z24−/− mice in a dose dependent manner. These data demonstrated for the first time the therapeutic potential for senotherapuetic drugs for the treatment of age‐associated knee OA. Fisetin, a newly characterized senolytic drug was recently demonstrated to significantly extend lifespan and healthspan, including musculoskeletal function, in progeroid mice. We thus next evaluated if FIS, a less toxic alternative to dasatinib that targets several senescence associated pathways, might better prevent bone loss in rapidly aging Z24−/− mice. Indeed, we found that weekly dosing of FIS for weeks starting at 3 months of age could significantly attenuate bone density loss in Z24−/− mice as evidenced by micro‐CT analysis (Fig. 2). Future studies will examine if more chronic dosing of FIS at younger ages.Aging is associated with sever musculoskeletal decline including OA and osteoporosis for which there are few treatment options none of which that target shared fundamental mechanistic drivers. We previously found that the senolytic drug cocktail DQ could prevent articular cartilage degeneration. The main objective of these studies was to investigate the efficacy of senolytic drugs, principally FIS, to attenuate age‐associated loss of bone density in progeroid Z24−/− mice. In agreement to previous reports, we found senolytic drug treatment could mitigate bone density loss in aged/progeroid mice. However, we report this for the first time using FIS, a much safer alternative to chemotherapeutic agents with similar efficacy. FIS may thus be a more clinically viable option for senotherapeutic treatment.Support or Funding InformationNIA (5P01AG043376‐05).Musculoskeletal pathology in Z24−/− mice is improved with DQ treatmentFigure 1Effects of senolytic drugs on trabecular bone in Z24−/− miceFigure 2