Senolytics Reduce Age-Related Dysfunction and Extend Remaining Life Span by 36% Following Administration to Old Mice

This paper isn't open access, but is important enough to stand out from the many publications on clearance of senescent cells emerging these days. While the evidence is compelling for senescent cells to be a root cause of aging, and removal of senescent cells via senolytic therapies to reverse aspects of aging, many of the fine details remain to be robustly established in the science and the implementations. Measures of senescent cell levels are not yet advanced enough for clinical implementations, for example, and the life span studies have so far involved animals genetically modified to suppress senescence rather than administration of senolytics to normal animals. That has now changed: in this study, researchers demonstrate that the senolytic mix of dasatinib and quercetin produces noteworthy results on the remaining life span of old mice.

Physical dysfunction and incapacity to respond to stresses become increasingly prevalent toward the end of life, with up to 45% of people over the age of 85 being frail. The cellular pathogenesis of age-related physical dysfunction has not been fully elucidated, and there are currently no root cause-directed, mechanism-based interventions for improving physical function in the elderly available for clinical application. Here we report a potential strategy for addressing this need: reducing senescent cell burden.

Senescent cell burden increases in multiple tissues with aging, at sites of pathology in multiple chronic diseases, and after radiation or chemotherapy. Senescent cells can secrete a range of proinflammatory cytokines, chemokines, proteases, and other factors; together, these are termed the senescence-associated secretory phenotype (SASP), which contributes to local and systemic dysfunction with aging and in a number of diseases.

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.

Link: https://doi.org/10.1038/s41591-018-0092-9

Comments

Nice result. Is this maximal lifespan or median lifespan?

Posted by: Antonio at July 10th, 2018 9:55 AM

The numbers being compared are 140 days to reach 50% mortality following treatment with vehicle in old mice versus 190 days to reach 50% mortality following treatment with dasatinib/quercetin in old mice.

The mortality curves for the two groups have the same slope; the treatment curve is shifted right fairly consistently all the way down to 100% mortality.

Posted by: Reason at July 10th, 2018 10:42 AM

Thanks. So it's a 36% median lifespan increase but also there is a maximal lifespan increase. Nice.

Posted by: Antonio at July 10th, 2018 12:02 PM

Maybe this can win the Mprize, if it still exists (I can't find it in Methuselah Foundation's website)

Posted by: Antonio at July 10th, 2018 12:54 PM

Nice for mice. I would think we would hear from self experimenters by now as to anything dramatic.

Posted by: Chris Zell at July 10th, 2018 1:04 PM

It would be nice to test it in other mammals. Say pets like dogs or cats. Put dogs suffer from human lifestyle diseases. Like begging sedentary, overeating and percent stress.

I wonder if patients who take dasatinib are trying to boost it with quercetin.

Since dasatinib is quite toxic it cold be applied with slow release patches or injectables to limit the impact to a specific site.

There will be nothing original if the combination is injected in a chronically inflamed knee joints, for example...

Posted by: Cuberat at July 10th, 2018 8:49 PM

Can anyone explain why, when senescent cells were transplanted to young mice, their immune systems did not clear the senescent cells out?

Posted by: jim at July 11th, 2018 11:35 PM

@Jim: A very interesting question.

Posted by: Reason at July 15th, 2018 12:28 AM

MSCs (transplanted cells in the paper) are much less immunogenic compared to other cell types.This is another reason why MSCs are commonly used for transplantation for other clinical purposes. Also, with 1 million of cells at one time, it will be very difficult for the immune cells to clear them up in a timely manner. Moreover, these tranplanted cells will also spread senescence to host cells, making the situation even worse.Interestingly, they did different number of senescent cells transplantation, and 0.2 million senescent cells did not cause observable effects. That might indicate 0.2 million might be the max capacity for the immune system to clear up.

Posted by: Chris at August 24th, 2018 12:10 PM

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