Senolytics Improve Physical Function and Increase Lifespan in Old Age

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.

Authors: Xu M1,2, Pirtskhalava T3, Farr JN3, Weigand BM3,4, Palmer AK3, Weivoda MM3, Inman CL3, Ogrodnik MB3,4, Hachfeld CM3, Fraser DG3, Onken JL3, Johnson KO3, Verzosa GC3, Langhi LGP3, Weigl M3, Giorgadze N3, LeBrasseur NK3, Miller JD3, Jurk D4, Singh RJ5, Allison DB6,7, Ejima K6,7, Hubbard GB8, Ikeno Y8,9, Cubro H10, Garovic VD10, Hou X11, Weroha SJ11, Robbins PD12, Niedernhofer LJ12, Khosla S3, Tchkonia T13, Kirkland JL14.

1.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. 2.The University of Connecticut Center on Aging, University of Connecticut Health, Farmington, CT, USA. 3.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.  4. Newcastle University Institute for Ageing and Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK. 5.Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. 6.Department of Epidemiology & Biostatistics, School of Public Health, Indiana University-Bloomington, Bloomington, IN, USA. 7.Nathan Shock Center on Comparative Energetics and Aging, the University of Alabama at Birmingham, Birmingham, AL, USA. 8.Barshop Institute for Longevity and Aging Studies and Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. 9.Geriatric Research Education and Clinical Center, South Texas Veterans Healthcare System, San Antonio, TX, USA. 10.Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA. 11.Department of Oncology, Mayo Clinic, Rochester, MN, USA. 12. Department of Molecular Medicine, Center on Aging, Scripps Research Institute, Jupiter, FL, USA. 13. Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. 14. Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.

Nat Med. 2018 Aug;24(8):1246-1256. doi: 10.1038/s41591-018-0092-9. Epub 2018 Jul 9.