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

Senolytics improve physical function and increase lifespan in old age.

Author information

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

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.

PMID:
29988130
PMCID:
PMC6082705
[Available on 2019-01-09]
DOI:
10.1038/s41591-018-0092-9
[PubMed - in process]
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