Characterization of cellular senescence in aging skeletal muscle

Authors: ZHANG, XU - MAYO CLINIC; HABIBALLA, LEENA - MAYO CLINIC; AVERSA, ZAIRA - NEWCASTLE UNIVERSITY; NG, YAN ER - MAYO CLINIC; SAKAMOTO, AYUMI - OREGON STATE UNIVERSITY; ENGLAND, DAVIS - MAYO CLINIC; PEARSALL, VESSILINA - MAYO CLINIC; WHITE, THOMAS - MAYO CLINIC; ROBINSON, MATTHEW - OREGON STATE UNIVERSITY; RIVAS, DONATO - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY; DASARI, SURENDRA - MAYO CLINIC; HRUBY, ADAM - MAYO CLINIC; LAGNADO, ANTHONY - MAYO CLINIC; JACHIM, SARAH - MAYO CLINIC; GRANIC, ANTONETA - NEWCASTLE UNIVERSITY; SAYER, AVAN - NEWCASTLE UNIVERSITY; JURK, DIANA - MAYO CLINIC; LANZA, IAN - MAYO CLINIC; KHOSLA, SUNDEEP - MAYO CLINIC; FIELDING, ROGER - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY; NAIR, K. SREEKUMARAN - MAYO CLINIC; SCHAFER, MARISSA - MAYO CLINIC; PASSOS, JOAO - MAYO CLINIC; LEBRASSEUR, NATHAN - MAYO CLINIC

Submitted to: Nature Aging
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/8/2022
Publication Date: 7/15/2022
Citation: Zhang, X., Habiballa, L., Aversa, Z., Ng, Y., Sakamoto, A.E., England, D.A., Pearsall, V.M., White, T.A., Robinson, M.M., Rivas, D., Dasari, S., Hruby, A.J., Lagnado, A.B., Jachim, S.K., Granic, A., Sayer, A.A., Jurk, D., Lanza, I., Khosla, S., Fielding, R., Nair, K., Schafer, M., Passos, J.F., Lebrasseur, N.K. 2022. Characterization of cellular senescence in aging skeletal muscle. Nature Aging. https://doi.org/10.1038/s43587-022-00250-8.
DOI: https://doi.org/10.1038/s43587-022-00250-8

Interpretive Summary: Cellular senescence is a process related to the aging of many cells in our bodies and may be associated with the decline in walking speed and other measures of physical functioning and strength. Associations between markers of cellular senescence in the blood and measures of physical function and muscle strength were studied in older adults. Associations were found between many of the blood markers and measures of physical function. A panel of 10 blood markers effectively identified participants at the greatest risk for mobility loss. These findings highlight the association between senescence factors, physical performance, and muscle strength and future studies should examine whether cellular senescence can be modulated through diet and physical activity interventions.

Technical Abstract: Senescence is a cell fate that contributes to multiple aging-related pathologies. Despite profound age-associated changes in skeletal muscle (SkM), whether its constituent cells are prone to senesce has not been methodically examined. Herein, using single-cell and bulk RNA sequencing and complementary imaging methods on SkM of young and old mice, we demonstrate that a subpopulation of old fibroadipogenic progenitors highly expresses p16Ink4a together with multiple senescence-related genes and concomitantly, exhibits DNA damage and chromatin reorganization. Through analysis of isolated myofibers, we also detail a senescence phenotype within a subset of old cells, governed instead by p21Cip1. Administration of a senotherapeutic interven- tion to old mice countered age-related molecular and morphological changes and improved SkM strength. Finally, we found that the senescence phenotype is conserved in SkM from older humans. Collectively, our data provide compelling evidence for cellular senescence as a hallmark and potentially tractable mediator of SkM aging.