Senolytics Improve Physical Function and Increase Lifespan in Old Age

By Ming Xu, T. Pirtskhalava, J. Farr, B. M. Weigand, Allyson K. Palmer, Megan M. Weivoda, C. Inman, M. Ogrodnik, Christine M. Hachfeld, Daniel G. Fraser and 23 more. Nature Medicine, 2018

1,970 citations recorded by the source corpus.

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. Transfer of senescent cells into naive, young mice can induce physical dysfunction, and a senolytic can reverse this dysfunction and potently increase lifespan in aged mice.

Subfields: Physiology

View Paper: https://www.semanticscholar.org/paper/918fb15a620d71230dc7ee961c0c2cfce924e9a7

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Physiology

Citations in the corpus

Kidney fibrosis: from mechanisms to therapeutic medicines (2023, background): “Recently, several creative studies validated the efficacy and safety of senescent cell clearances, applying transgenic mice with selectively sensitive pharmacological agents,(92,93) or the mice access to antiapoptotic drugs.(92,94,95) Moreover, various strategies are being tested to prevent the form”
Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study (2019, methodology): “consistent with preclinical findings of marked improvements in treadmill endurance and frailty following the selective ablation of senescent cells in progeroid, naturally aged, and lung-injured murine models [5,11,24,26].”
Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease (2019, background): “Additionally, in old mice, D + Q delayed age-related diseases as a group and extended their remaining lifespan by 36% [28].”