Cellular senescence in age-related musculoskeletal diseases

Cellular senescence—an irreversible cell-cycle arrest coupled with the production of pro-inflammatory secretions known as SASP—is now viewed as a central driver of musculoskeletal aging. Accumulation of these senescent cells in bone, cartilage, intervertebral discs and skeletal muscle correlates with osteoporosis, osteoarthritis, disc degeneration and sarcopenia. While transient senescence aids embryogenesis, wound healing and tumour suppression, its chronic presence disrupts tissue homeostasis and creates a self-propagating “bystander” effect that accelerates systemic ageing.

Senescence can be triggered by telomere attrition, DNA damage, oxidative stress or oncogene activation and is enforced by the p16^INK4a^/RB and p53/p21/RB pathways. Mitochondrial dysfunction and impaired autophagy reinforce the phenotype, whereas epigenetic alterations such as reactivation of endogenous retroviruses amplify inflammatory signals. SASP molecules include cytokines, matrix-degrading enzymes and lipid mediators that recruit immune cells yet, when sustained, foster chronic low-grade inflammation—“inflammaging”—and spread senescence to neighbouring stem and progenitor cells.

In bone, senescent osteocytes, osteoblasts and bone-marrow mesenchymal stem cells accumulate with age and after menopause, tipping the balance toward resorption. Genetic or pharmacological elimination of p16^INK4a-expressing cells in INK-ATTAC mice increases bone mass, whereas p21-targeted clearance improves fracture healing. NAD⁺-boosting compounds, vitamin D receptor agonists and SIRT1/3 activators rejuvenate osteoblast differentiation and suppress SASP. Estrogen deficiency, vitamin D shortage, oxidative stress and ferroptosis all accelerate osteoblast and BMSC senescence; conversely, enhancing autophagy or correcting splicing factor YBX1 mis-regulation restores youthful potency.

Osteoarthritis involves senescence not only in chondrocytes but also in synoviocytes, meniscal cells and infrapatellar fat-pad adipocytes. Senescent chondrocytes display shortened telomeres, DNA damage and mitochondrial ROS, accompanied by up-regulation of MMP-13 and ADAMTS that degrade type II collagen. Mechanical stress, ECM stiffening and lysosomal cholesterol accumulation activate mTORC1 and NF-κB, reinforcing SASP and cartilage attrition. Clearing p16^INK4a^ cells with senolytics or blocking IL-17, MMP-13 or JAK/STAT signaling attenuates cartilage loss in pre-clinical models.

Intervertebral disc degeneration is similarly fuelled by senescent nucleus pulposus and annulus fibrosus cells that exhibit mitochondrial fragmentation, mitophagy imbalance and cGAS/STING-mediated inflammation. Compression stress, oxidative stress and impaired nutrient diffusion drive this process. Over-activation of PINK1/Parkin-mediated mitophagy or its suppression can both precipitate senescence, highlighting the need for tight regulation. Senolytic treatment (dasatinib plus quercetin) or antioxidant therapy targeting the Nrf2/GPX4 axis rescues disc height and matrix content in mice.

Sarcopenia arises from senescence in muscle stem cells (MuSCs) and fibro-adipogenic progenitors. Ageing shifts MuSCs from quiescence to a p21-driven senescent state; loss of transcription factor Slug or mechanosensitive Piezo1 signaling, and re-expression of embryonic Hoxa9, accelerate this transition. Accumulation of senescent FAPs impairs muscle regeneration and promotes fibro-fatty infiltration. Eliminating these cells with BCL-2 family inhibitors or reactivating autophagy via NAD⁺, CPEB4, or Nanog restores MuSC self-renewal and force generation.

Therapeutic strategies therefore focus on either removing senescent cells (senolytics) or suppressing their secretory phenotype (senomorphics). Dasatinib plus quercetin, navitoclax and FOXO4-DRI peptides have shown benefit in murine bone, disc and muscle ageing, but human trials reveal modest or transient effects, partly due to heterogeneity in senescent cell markers and limited drug specificity. CAR-T cells directed against uPAR or NKG2D ligands offer long-lived senolytic activity, yet the potential for off-tissue toxicity and the beneficial roles of senescence in repair and tumour suppression caution against indiscriminate clearance.

Future success will depend on refining biomarkers that capture the diverse senescence states in each musculoskeletal niche, optimizing intermittent dosing schedules, and integrating lifestyle interventions such as exercise and caloric restriction that naturally modulate autophagy and NAD⁺ metabolism. By selectively dampening the deleterious arm of senescence while preserving its physiological functions, it should be possible to extend the structural and functional lifespan of the musculoskeletal system and reduce the burden of age-related frailty.