Oct. 11, 2022
The loss of skeletal muscle mass and function with advancing age, called sarcopenia, has a major impact on the independence and quality of life of older adults. Researchers' understanding of the specific mechanisms and factors involved in sarcopenia is still evolving, however, and there are few preventative treatments available.
Animal studies suggest that strategies targeting senescent cells, which are in a state of growth arrest, could help combat age-related dysfunction, including sarcopenia. Led by Nathan K. LeBrasseur, Ph.D., M.S., a team of Mayo Clinic researchers is examining the role of senescent cells in sarcopenia, and the potential for development of senotherapeutic intervention to prevent or treat age-related skeletal muscle dysfunction. Dr. LeBrasseur is co-chair of Physical Medicine and Rehabilitation research at Mayo Clinic in Rochester, Minnesota.
Senescent cells secrete a mix of proinflammatory cytokines, chemokines and extracellular matrix-degrading proteins. Those secretions, known as the senescence-associated secretory phenotype (SASP), are an indicator of systemic senescent cell burden. In previous research, Dr. LeBrasseur and colleagues demonstrated that the SASP contributes to tissue dysfunction by inducing paracrine senescence and inflammation, stem cell dysfunction, and alterations in the extracellular matrix.
In an article published in Nature Aging in 2022, Dr. LeBrasseur and co-authors describe their efforts to better understand the mechanisms of skeletal muscle aging and test whether administration of a senotherapeutic drug could attenuate the molecular features of senescence in skeletal muscle and improve features of skeletal muscle health.
The researchers analyzed skeletal muscle of young and old mice using single-cell and bulk RNA sequencing and complementary imaging methods. They also tested the impact of a senotherapeutic cocktail on skeletal muscle health in old mice, and they investigated senescence markers in skeletal muscle from younger and older humans.
Key findings
- Older mice exhibited multiple markers of cellular senescence. Older mice showed a reduction in lean body mass and skeletal muscle weight, a reduction in myofiber cross-sectional area, and significant deficits in measures of skeletal muscle performance and physical function. Aligned with that, senescence markers increased dramatically in skeletal muscle with aging, including elevated expression of cyclin-dependent kinase inhibitors p16 and p21, DNA damage, SASP markers, and alternated chromatin organization.
- Administration of a senotherapeutic drug improved the molecular profile and function of skeletal muscle in old mice. The researchers administered either vehicle or a senotherapeutic drug combination (dasatinib plus quercetin) to 20-month-old mice for four months. Data from multiple analyses suggested that the senotherapeutic partially mitigated the senescent cell burden in skeletal muscle and improved some parameters of skeletal muscle quality.
Analysis of human skeletal muscle showed age-related increases in senescence markers. The cellular senescence phenotype appears to be conserved in skeletal muscle of older humans. Expression of P16, P21 and SASP observed in tissue from older participants was higher than that observed in tissue from younger participants.
"Collectively, our data provide compelling evidence for cellular senescence as a hallmark and potentially tractable mediator of skeletal muscle aging," explains Dr. LeBrasseur.
Dr. LeBrasseur notes that he and his colleagues are actively involved in additional research building on these findings. "Given the public and private sectors' interest in developing pharmacological approaches to this mechanism of aging, our findings may inform novel clinical approaches to address the loss of muscle health and function in the context of aging, disease or injury. With support from the National Institute on Aging and the Glenn Foundation for Medical Research to advance these initiatives, we continue to develop our understanding of exactly how senescent cells compromise skeletal muscle health and function, and whether interventions designed to alter their abundance or behavior convey therapeutic benefit."
For more information
Zhang X, et al. Characterization of cellular senescence in aging skeletal muscle. Nature Aging. 2022;2:601.
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