Senescent cells across the muscle niche drive sarcopenia, and senotherapies may offer a way to reverse it

Sarcopenia, the progressive loss of muscle mass, strength and quality, contributes to frailty, disability, falls, hospitalization and higher mortality in older adults. As populations age, understanding what drives it is a priority for healthspan. This review from the Chinese University of Hong Kong argues that cellular senescence is a central mechanism. Senescent cells are stably arrested, resist apoptosis, and secrete the senescence-associated secretory phenotype (SASP), a mix of inflammatory cytokines, chemokines, growth factors and matrix-modifying enzymes that can spread senescence to neighboring cells.

The authors synthesize roughly a decade of literature, emphasizing single-cell and multi-omic studies. They note the limits of classic markers: SA-β-gal can appear in non-senescent cells, and p16INK4a and p21CIP1 vary by cell type and trigger. Key datasets include Zhang et al. (mouse single-cell RNA-seq), Perez et al. (p21-expressing myofiber nuclei found only in aged human muscle), Kedlian et al. (first human muscle aging atlas), and Lai et al. (multimodal atlas across ages and fitness levels). Li et al. combined single-cell RNA and ATAC sequencing in aging human muscle and built a unified senescence scoring method. They showed that SASP composition differs considerably between cell populations.

Senescence appears in many cell types. Muscle stem cells show impaired proliferation and differentiation, with loss of autophagy and mitochondrial dysfunction implicated, and enhancing autophagy can restore function. Fibro-adipogenic progenitors (FAPs) are a major senescent population, with a p16-high subset showing DNA damage and chromatin changes. Loss of the FAP-derived signal WISP1 impairs stem cell function, and restoring WISP1 rescued regeneration in aged mice. Senescent FAPs also secrete TGF-β, which aggravates fibrosis.

Post-mitotic muscle fibers can also adopt a senescence-like state. A subset of old fibers shows p21-driven features, DNA damage and chromatin reorganization, possibly triggered by mitochondrial DNA release and cGAS-STING activation. Macrophages, endothelial cells and Schwann cells also take on senescent features. Senescent macrophages have been linked to ferroptosis and muscle atrophy in osteoarthritis. Together, these changes disrupt the muscle niche and sustain chronic inflammation.

On therapy, the review distinguishes senolytics, which eliminate senescent cells, from senomorphics, which suppress the SASP. In progeroid and naturally aged mice, clearing p16-positive cells genetically or pharmacologically attenuated age-related dysfunction, including in muscle. Oral ABT263 (navitoclax), a BCL-2/BCL-xL inhibitor, depleted senescent cells in aged mice and rejuvenated muscle stem cells and hematopoietic stem cells. The supplied text ends partway through this section, so details on other senolytic and senomorphic agents are not covered here.

The main caveat is that the evidence is largely preclinical and mouse-based. The review is narrative, with no pooled effect sizes, sample sizes or p-values. Marker limitations make it hard to identify and target senescent cells precisely, and the authors say mechanisms in post-mitotic fibers remain unexplored. Human trials in sarcopenia are needed before clinical use.