Tier 3 — preclinical

Senolytics Improve Physical Function and Increase Lifespan in Old Age

Ming Xu, Tamar Pirtskhalava, Joshua N. Farr, Bettina M. Weigand, Allyson K. Palmer, Megan M. 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 J. Singh, David B. Allison, Keisuke Ejima, Gene B. Hubbard, Yuji Ikeno, Hajrunisa Cubro, Vesna D. Garovic, Xiaonan Hou, SJ Weroha, Paul D. Robbins, Laura J. Niedernhofer, Sundeep Khosla, Tamara Tchkonia, James L. Kirkland
Nature Medicine 2018 Volume 24, Issue 8, pages 1246–1256

Bibliography

PubMed
PMID 29988130
PubMed Central
PMC6082705
DOI
10.1038/s41591-018-0092-9
Funding
NIH grants AG13925 (JLK), AG49182 (JLK), DK50456 (Adipocyte Subcore, JLK), AG46061 (AKP), AG004875 (SK), AG048792 (SK), AR070241 (JNF), AR070281 (MMW), AG13319 (YI, GBH), AG050886 (DBA), AG043376 (PDR, LJN), AG056278 (PDR, LJN), and AG044376 (LJN), a Glenn/American Federation for Aging Research (AFAR) BIG Award (JLK), the Glenn Foundation (LJN), and the Ted Nash Long Life and Noaber Foundations (JLK). MX received the Glenn/AFAR Postdoctoral Fellowship for Translational Research on Aging and a Irene Diamond Fund/AFAR Postdoctoral Transition Award in Aging.
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) 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.

Study snapshot

DesignPreclinical in vivo animal study and ex vivo human tissue analysis
ModelC57BL/6 mice (wild-type and transgenic) and human omental adipose tissue explants
SampleVarious cohorts (e.g., n=147 for mouse lifespan study; n=8 human adipose tissue donors)
InterventionDasatinib (5 mg/kg) plus Quercetin (50 mg/kg) administered via oral gavage, or senescent cell transplantation
DurationRanged from acute 3-day courses to intermittent bi-weekly administration for 4 months, up to lifetime survival tracking
EndpointsPhysical function (walking speed, grip strength, hanging endurance); Lifespan and mortality hazard; Senescent cell burden (SA-βgal, p16INK4A, TAF+); Pro-inflammatory cytokine secretion (SASP components)

What the study showed, in plain terms

As we age, a subset of our cells stops dividing but refuses to die. These "senescent" cells secrete inflammatory signals that damage surrounding tissues, a process heavily linked to the physical decline and frailty seen in old age.

In this landmark study, researchers proved that senescent cells directly cause physical dysfunction by transplanting a small number of them into healthy young mice, which subsequently developed frailty. Crucially, the researchers then used a "senolytic" drug combination—dasatinib and quercetin (D+Q)—to selectively kill these senescent cells. When given to naturally aging mice, intermittent D+Q treatment significantly improved physical function, walking speed, and grip strength, while also extending their remaining lifespan by 36% without prolonging the period of late-life morbidity.

Key findings

  • Causation of Frailty: Transplanting even a small number of senescent cells into young mice was sufficient to induce persistent physical dysfunction and spread senescence to host tissues.
  • Lifespan Extension: Bi-weekly oral administration of Dasatinib and Quercetin (D+Q) in very old mice (equivalent to 75-90 human years) increased median post-treatment lifespan by 36% and lowered mortality hazard by 65%.
  • Healthspan Improvement: Eliminating senescent cells alleviated physical decline, improving maximal walking speed, hanging endurance, and grip strength in aged mice.
  • Human Tissue Efficacy: In human adipose tissue explants, D+Q effectively reduced the burden of naturally occurring senescent cells and decreased the secretion of key frailty-related pro-inflammatory cytokines (SASP factors).

What this study can and cannot tell us

  • Preclinical Limitations: While the results in mice are highly promising, animal models do not perfectly replicate human aging, and robust clinical trials are necessary to confirm safety and efficacy in older adults.
  • Side Effect Profile: Dasatinib is a powerful chemotherapeutic agent known to have potentially severe side effects in humans (such as pulmonary edema), meaning the D+Q protocol requires careful monitoring and dosage optimization before clinical translation.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology