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Senolytics improve physical function and increase lifespan in old age

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.

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Fig. 1: Transplanting small numbers of senescent cells induces physical dysfunction in younger mice.
Fig. 2: Aging exacerbates the effects of senescent cell transplantation.
Fig. 3: Senescent cells reduce resilience to metabolic stress in mice.
Fig. 4: D + Q reduces senescent cell abundance and decreases proinflammatory cytokine secretion in human adipose tissue.
Fig. 5: Eliminating senescent cells both prevents and alleviates physical dysfunction.
Fig. 6: Senolytics extend both health- and lifespan in aged mice.

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Acknowledgements

The authors are grateful to J. L. Armstrong and L. Thesing for administrative assistance, M. Mahlman for obtaining human adipose tissue samples, Z. Aversa for help with muscle analysis, the Pathology Research Core Lab at Mayo Clinic–Rochester for histology studies, and C. Guo for overall support. This work was supported by the Connor Group (J.L.K.) and Robert J. and Theresa W. Ryan (J.L.K.); the National Institutes of Health (NIH) grants AG13925 (J.L.K.), AG49182 (J.L.K), DK50456 (Adipocyte Subcore, J.L.K.), AG46061 (A.K.P.), AG004875 (S.K.), AG048792 (S.K.), AR070241 (J.N.F.), AR070281 (M.M.W.), AG13319 (Y.I. and G.B.H.), AG050886 (D.B.A.), AG043376 (P.D.R., and L.J.N.), AG056278 (P.D.R. and L.J.N.), and AG044376 (L.J.N.); a Glenn/American Federation for Aging Research (AFAR) BIG Award (J.L.K.); the Glenn Foundation (L.J.N.); and the Ted Nash Long Life and Noaber Foundations (J.L.K.). M.X. received the Glenn/AFAR Postdoctoral Fellowship for Translational Research on Aging and an Irene Diamond Fund/AFAR Postdoctoral Transition Award in Aging.

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Contributions

M.X., T.T., and J.L.K. conceived and designed the study. M.X. performed and analyzed most of the transplanted mouse experiments and human adipose tissue explant experiments. N.G. and T.T. contributed to the human adipose tissue explant experiments. J.N.F., D.G.F., J.L.O., and S.K. contributed to the study of aged mice treated with senolytics. A.K.P. contributed to the bioluminescence studies. M.B.O. and D.J. contributed to ear fibroblast isolation. T.P., M.X., T.T., and C.L.I. performed the survival experiments using senolytics in aged mice. B.M.W., M.M.W., C.M.H., N.K.L., H.C., V.D.G., X.H., S.J.W., K.O.J., M.W., L.G.P.L., G.C.V., P.D.R., L.J.N., and J.D.M. contributed to the mouse studies. R.J.S. contributed to androgen measurement. D.B.A. and K.E. contributed to lifespan analysis. G.B.H. and Y.I. contributed to mouse pathology analysis. M.X. and J.L.K. wrote the manuscript with input from all coauthors. J.L.K., M.X., and T.T. oversaw all experimental design, data analyses, and manuscript preparation.

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Correspondence to Ming Xu, Tamara Tchkonia or James L. Kirkland.

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Competing interests

J.L.K, T.T., M.X., T.P., N.G., and A.K.P. have a financial interest related to this research. Patents on senolytic drugs (PCT/US2016/041646, filed at the US Patent Office) are held by Mayo Clinic. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies. None of the other authors has a relevant financial conflict of interest.

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Xu, M., Pirtskhalava, T., Farr, J.N. et al. Senolytics improve physical function and increase lifespan in old age. Nat Med 24, 1246–1256 (2018). https://doi.org/10.1038/s41591-018-0092-9

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