Senolytics improve physical function and increase lifespan in old age

Ming Xu, Tamar Pirtskhalava, Joshua Farr, Bettina M. Weigand, Allyson K. Palmer, Megan Weivoda, Christina L. Inman, Mikolaj B. Ogrodnik, Christine M. Hachfeld, Daniel G. Fraser, Jennifer L. Onken, Kurt O. Johnson, Grace C. Verzosa, Larissa G.P. Langhi, Moritz Weigl, Nino Giorgadze, Nathan K LeBrasseur, Jordan D Miller, Diana Jurk, Ravinder Jit SinghDavid B. Allison, Keisuke Ejima, Gene B. Hubbard, Yuji Ikeno, Hajrunisa Cubro, Vesna D Garovic, Xiaonan Hou, Saravut (John) Weroha, Paul D. Robbins, Laura J. Niedernhofer, Sundeep Khosla, Tamara Tchkonia, James L Kirkland

Research output: Contribution to journalArticle

220 Scopus citations

Abstract

Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell–transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.

Original languageEnglish (US)
Pages (from-to)1246-1256
Number of pages11
JournalNature Medicine
Volume24
Issue number8
DOIs
StatePublished - Aug 1 2018

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Xu, M., Pirtskhalava, T., Farr, J., Weigand, B. M., Palmer, A. K., Weivoda, M., Inman, C. L., Ogrodnik, M. B., Hachfeld, C. M., Fraser, D. G., Onken, J. L., Johnson, K. O., Verzosa, G. C., Langhi, L. G. P., Weigl, M., Giorgadze, N., LeBrasseur, N. K., Miller, J. D., Jurk, D., ... Kirkland, J. L. (2018). Senolytics improve physical function and increase lifespan in old age. Nature Medicine, 24(8), 1246-1256. https://doi.org/10.1038/s41591-018-0092-9