The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Zmpste24−/− Progeria Mouse Model

Abstract

Aging leads to several geriatric conditions including osteoporosis (OP) and associated frailty syndrome. Treatments for these conditions are limited and none target fundamental drivers of pathology, and thus identifying strategies to delay progressive loss of tissue homeostasis and functional reserve will significantly improve quality of life in elderly individuals. A fundamental property of aging is the accumulation of senescent cells. Senescence is a cell state defined by loss of proliferative capacity, resistance to apoptosis, and the release of a proinflammatory and anti-regenerative senescence-associated secretory phenotype (SASP). The accumulation of senescent cells and SASP factors is thought to significantly contribute to systemic aging. Senolytics—compounds which selectively target and kill senescent cells—have been characterized to target and inhibit anti-apoptotic pathways that are upregulated during senescence, which can elicit apoptosis in senescent cells and relieve SASP production. Senescent cells have been linked to several age-related pathologies including bone density loss and osteoarthritis in mice. Previous studies in murine models of OP have demonstrated that targeting senescent cells pharmacologically with senolytic drugs can reduce symptomology of the disease. Here, we demonstrate the efficacy of senolytic drugs (dasatinib, quercetin, and fisetin) to improve age-associated degeneration in bone using the Zmpste24−/− (Z24−/−) progeria murine system for Hutchinson–Gilford progeria syndrome (HGPS). We found that the combination of dasatinib plus quercetin could not significantly mitigate trabecular bone loss although fisetin administration could reduce bone density loss in the accelerated aging Z24−/− model. Furthermore, the overt bone density loss observed in the Z24−/− model reported herein highlights the Z24 model as a translational model to recapitulate alterations in bone density associated with advanced age. Consistent with the “geroscience hypothesis,” these data demonstrate the utility of targeting a fundamental driver of systemic aging (senescent cell accumulation) to alleviate a common condition with age, bone deterioration.

Therapeutic Perspectives for Inflammation and Senescence in Osteoarthritis Using Mesenchymal Stem Cells, Mesenchymal Stem Cell-Derived Extracellular Vesicles and Senolytic Agents

“…These results suggest that senescent macrophages may play a significant role in the development of muscle dystrophy by impacting the function of muscle stem cells and that the senolytic elimination of these cells may be a promising therapeutic strategy. We have recently shown that the elimination of senescent cells with senolytic treatment (Fisetin) can improve bone health in a progeria animal model that develops premature osteoporosis [40]. Together, these results suggest that senolytics may have the potential for use in the treatment of human age-related musculoskeletal disorders, including OA.…”

“…Increased numbers of senescent osteocytes have been observed in both murine and human models [37,38], and induction of senescence in murine and human osteocytes has been shown to increase RANKL-dependent bone resorption [39]. We have recently shown that the elimination of senescent cells with senolytic treatment can improve bone health in a progeria animal model [40]. Senescent cells have also been shown to accumulate in osteoarthritic joints [41][42][43].…”

The potential for senotherapy as a novel approach to extend life quality in veterinary medicine

“…Relevant to orthopedic disease , one study found that treatment with dasatinib and quercetin decreased osteoclastic activity while promoting osteoblastic differentiation in mouse models of osteoporosis ( 102 ). Conversely, in another mouse model (accelerated aging Z24–/– model) dasatinib and quercetin treatment did not mitigate trabecular bone loss ( 103 ) while another study indicated dasatinib and quercetin treated mice may actually improve bone production of aged bone marrow derived mesenchymal stem cells ( 104 ). Dasatinib and quercetin treatment have facilitated growth of aged muscles through SC clearance and altered Igf1, Ddit4, Mmp14 gene expression in a mouse model of blunted muscle hypertrophy ( 105 ).…”

Plant-Derived Senotherapeutics for the Prevention and Treatment of Intervertebral Disc Degeneration and Aging

“…It has been shown to reduce senescence markers in multiple murine and human tissues in a cell type-specific manner, to restore tissue homeostasis, to attenuate age-associated pathologies and to extend lifespan after its administration in progeroid and old mice [ 152 ]. Regarding its beneficial effects against pathological conditions of the musculoskeletal system, fisetin has been shown to counteract osteoporosis in in vitro and in vivo preclinical studies across animal species [ 153 ], to inhibit IL-1β-induced inflammatory response in human OA chondrocytes through activating SIRT1 and to attenuate the progression of OA in mice [ 154 ], as well as to ameliorate bone degeneration in the Zmpste24 −/− progeria murine model for Hutchinson–Gilford progeria syndrome [ 155 ].…”