They’ve stopped dividing, yet they refuse to die. No, they’d rather persist in a zombie-like state, secreting pro-inflammatory factors, worsening age-related conditions, and accelerating aging itself. They are senescent cells, and getting rid of them is a tempting prospect, especially now that an experimental drug combination has been shown to benefit both artificially and naturally aged mice, improving their physical function and increasing their lifespan.
The new findings were generated by a research team led by James L. Kirkland, M.D., Ph.D., of the Mayo Clinic. These scientists deployed a combination of senolytics, drugs that selectively eliminate senescent cells. Specifically, the scientists used dasatinib (D), which is used to treat some forms of leukemia, and quercetin (Q), which is a plant flavanol found in some fruits and vegetables.
In mice that were artificially aged—that is, young mice that received injections of senescent cells and subsequently developed physical debilities—the D+Q combo restored vigor. In mice that were naturally aged, the D+Q combo extended both lifespan and healthspan.
Detailed results appeared July 9 in the journal Nature Medicine, in an article entitled, “Senolytics improve physical function and increase lifespan in old age.” According to this article, transplanting even small numbers of senescent cells was sufficient to cause the mice to become frail and reduce their survival. Fewer senescent cells were needed to cause these effects in older mice than younger mice or in high fat-fed than in lean mice.
This means that obesity worsens the effects of aging. Problems were prevented or reversed in the mice transplanted with senescent cells by treating these mice with senolytics.
“The senolytic cocktail … decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue,” wrote the article’s authors. “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%.”
In naturally aged mice, roughly equivalent to 80 human years, administering the senolytic cocktail orally improved physical function. The mice were better able to run on a treadmill and maintain a stronger grip strength, and they had increased daily activity.
In these mice, the extension of lifespan did not come at the cost of a prolonged period of frailty near the end of life. Death from age-related diseases as a group was delayed and was generally due to old age rather than any single age-related disease, such as cancer.
“We can say with certainty that senescent cells can cause health problems in young mice, including causing physical dysfunction and lowering survival rates,” says Dr. Kirkland. “The use of senolytics can significantly improve both health span and life span in much older naturally aged animals.”
Additional work demonstrated that the senolytics killed human senescent cells within 48 hours in fat samples taken directly from the operating room. Nonetheless, the researchers cautioned that such senolytics should not be taken by people, unless their safety and effectiveness is demonstrated in clinical trials. They say if these agents turn out to be effective and safe in such clinical trials, senolytics could help alleviate physical dysfunction and frailty in older people, while increasing independence in later life.
