ROCHESTER, Minn. -- The presence of senescent or dysfunctional cells can make young mice age faster. And using senolytic drugs in elderly mice to remove these rogue cells can improve health and extend life. These findings from Mayo Clinic researchers and collaborators provide a foundation on which to move forward in this area of aging research. The results appear in Nature Medicine.
"We can say with certainty that senescent cells can cause health problems in young mice, including causing physical dysfunction and lowering survival rates, and that the use of senolytics can significantly improve both health span and life span in much older naturally aged animals," says James Kirkland, M.D., Ph.D., a Mayo Clinic geriatrics researcher who heads Mayo Clinic's Kogod Center on Aging. Dr. Kirkland is senior author of the study.
The first senolytic drugs --compounds that remove senescent cells from the body -- were discovered at Mayo Clinic. The senolytics used in this study are a cocktail of dasatinib, which promotes cancer cell death, and quercetin, an antioxidant found in apples and other foods. In effect, senolytics act by allowing senescent cells to "self-destruct" rather than damage healthy cells nearby and throughout the rest of the body.
How the study was performed
The researchers transplanted senescent cells into young mice and a group of middle-aged mice that had aged naturally. 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.
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. Remaining life span was extended by 36 percent, compared to the norm for this strain of mice. And the increase in life span 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. Furthermore, the senolytics killed human senescent cells within 48 hours in fat samples taken directly from the operating room.
Translating to humans
The researchers caution these senolytic agents 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.
Collaborators on the study are from Newcastle University, Newcastle upon Tyne, U.K.; Indiana University Bloomington, Bloomington, Indiana; The University of Alabama at Birmingham, Birmingham, Alabama; The University of Texas Health Science Center at San Antonio, San Antonio, Texas; South Texas Veterans Health Care System, San Antonio; The Scripps Research Institute, Jupiter, Florida; and the University of Connecticut Center on Aging, UConn Health, Farmington, Connecticut.
The research was supported by multiple grants from the National Institutes of Health, as well as the Connor Group, Robert J. and Theresa W. Ryan, the Glenn/American Federation for Aging Research, and the Ted Nash Long Life and Noaber Foundations. Some of the researchers have a financial interest in the outcomes of this research, and Mayo Clinic has patents on senolytic drugs. Details and full author list appear on the paper.
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