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.

Independent Roles of Estrogen Deficiency and Cellular Senescence in the Pathogenesis of Osteoporosis: Evidence in Young Adult Mice and Older Humans

“…Indeed, in recent years, several groups have shown that genetic or pharmacological selective elimination of senescent cells has a remarkable therapeutic impact across multiple organ systems in mouse models of aging and chronic pathological diseases, including metabolic dysfunction, atherosclerosis/cardiovascular disease, hepatic steatosis, pulmonary fibrosis, osteoarthritis, and sarcopenia/frailty . Furthermore, as noted earlier, our group has demonstrated that targeting senescent cells in old mice has beneficial effects on bone mass and microarchitecture with the beneficial effects of targeting senescent cells due to increased bone formation on endocortical surfaces and suppressed bone resorption .…”

The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline

“…It has been previously demonstrated that pre-adipocytes are one of the main cells that become senescent in vivo [10–12]. Thus, we next tested the possibility that conditioned medium derived from senescent human preadipocytes (PDPs) induces the expression and activity of CD38 in mouse BMDMs.…”

Moving Frailty Toward Clinical Practice: NIA Intramural Frailty Science Symposium Summary

“…Mitochondrial function decline, cellular senescence, and stem cell dysfunction were identified as among the biological domains where intervention development is moving forward and may hold relevance for the prevention or treatment of frailty . Indeed, many studies have already demonstrated that altered markers of stress response and energy metabolism are closely related to physical frailty .…”