The development of cancer is strongly affected by the presence of senescent cells. Cellular senescence is a tool of cancer suppression in the earliest stages at which cancers emerge from cell damage, attempting to halt replication in damaged cells as well as call in the immune system via inflammatory signaling to destroy potentially cancerous cells. Senescent cells are also involved in wound healing and coordination of regeneration, however, and this capacity can be subverted by an established tumor to support its growth. Once a cancer is established, the accumulation of senescent cells in and around tumor tissue creates a more favorable environment for plaque growth via growth factor signaling.
Because of this connection between senescent cells and cancer, many successful chemotherapeutic drugs that were developed before the modern understanding of the relevance of senenscent cells to cancer and aging are turning out to be successful precisely because they kill senescent cells or suppress the pro-inflammatory, pro-growth signaling of senescent cells. The early senolytic drugs demonstrated to selectively kill senescent cells and reverse aspects of aging were all repurposed chemotherapeutics. Researchers continue to identify ever more compounds in the long list of approved and potential chemotherapeutics established over past decades as senotherapeutics that could be repurposed to treat age-related diseases by destroying or suppressing the activities of senescent cells.
As the cellular micro-environment changes with age, senescent cells begin to secrete senescence-associated secretory phenotypes (SASPs) factors. These include pro-inflammatory cytokines [e.g., interleukin (IL)-1α, IL-1β, IL-6, and IL8], chemokines [e.g., C-C motif ligand 1 (CCL1), CCL2, and CCL5], proteases (e.g., matrix metalloprotease and serine protease), and growth factors (e.g., PDGF). SASP factors exhibit dual roles: they contribute to tissue regeneration, tumor suppression, and immunosurveillance, but can promote inflammation, tissue damage, and cancer progression. Consequently, extensive research has focused on anti-aging strategies that target senescent cells.
Bone homeostasis is maintained by a delicate balance between bone-forming osteoblasts and bone-resorbing osteoclasts. With aging, particularly post-menopause, this balance is disrupted, leading to impaired bone formation and increased resorption, thereby increasing the risk of osteoporosis and fractures. In aging bone, mesenchymal stem cells are more likely to differentiate into adipocytes rather than osteoblasts. Moreover, SASP factors such as tumor necrosis factor-alpha (TNFα), IL1α, IL1β, IL6, and CCL2 are secreted by senescent cells, fostering a pro-inflammatory microenvironment within bone tissue. TNFα, IL1α, and IL6 specifically impair osteoblast differentiation and enhance osteoclastic bone resorption. These findings highlight the importance of therapeutic strategies targeting senescent cells (senolytics) or modulating SASP activity (senomorphics) to prevent age-related osteoporosis.
In this study, we screened cabozantinib, a tyrosine kinase inhibitor approved for medullary thyroid cancer, for its anti-aging effects in bone-related cells, specifically osteoblasts and osteoclasts. Cabozantinib demonstrated the ability to activate osteoblasts and inhibit osteoclasts by suppressing the secretion of SASP factors from these cells. Additionally, it prevented bone loss in estrogen-deficient, ovariectomized mice. Our findings indicate that targeting senescent osteoblastic and osteoclastic cells using cabozantinib could be a potential therapeutic approach for treating age-related osteoporosis.
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