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Developmental biology - Aging|
Reversing Damage Caused By "Old" Cells
"This study provides compelling evidence that targeting a fundamental aging process - in this case, cell senescence in mice - can delay age-related conditions, resulting in better health and longer life. This study also shows the value of investigating biological mechanisms which may lead to better understanding of the aging process."
Many normal cells continuously grow, die, and replicate. Cell senescence is the process in which cells lose function, including an ability to divide and replicate, but resist cell death. Such cells have been shown to affect neighboring cells through the secretion of several pro-inflammatory and tissue remodeling molecules. Senescent cells increase in number in many tissues with age; they also occur in organs associated with many chronic diseases and appear after radiation or chemotherapy.
Senolytics is the name given a class of drugs that selectively eliminate senescent cells. In this study, Kirkland's team used a combination of dasatinib and quercetin (D+Q) to test whether this particular senolytic combo could slow physical dysfunction caused by senescent cells. Dasatinib is used to treat some forms of leukemia; quercetin is a plant flavanol found in some fruits and vegetables.
• To determine whether senescent cells cause physical dysfunction, researchers injected young (four-month-old) mice with either senescent (SEN) cells or non-senescent control (CON) cells. As soon as two weeks after transplant, SEN mice showed impaired physical function in walking speed, muscle strength, physical endurance, daily activity, food intake, and body weight. Additionally, they saw increased numbers of senescent cells above the number injected, suggesting senescent cells propogate into neighboring cells.
• They then analyzed whether a senolytic compound could stop or delay physical dysfunction, by treating both SEN and CON mice for three days with the D+Q compound mix. They found that D+Q selectively killed senescent cells and slowed the deterioration in walking speed, endurance, and grip strength in SEN mice.
• In addition to young mice injected with senescent cells, researchers also tested older (20-month-old), non-transplanted mice with D+Q intermittently over 4 months to find D+Q alleviated normal age-related dysfunction, resulting in higher walking speed, treadmill endurance, grip strength, and daily activity.
• Finally, researchers found treating very old (24- to 27-month-old) mice with D+Q biweekly led to a 36 percent higher post-treatment life span and lower mortality than in control mice. This indicates senolytics can reduce risk of death in old mice.
"This is exciting research. This study clearly demonstrates that senolytics can relieve physical dysfunction in mice. Additional research will be necessary to determine if compounds, like the one used in this study, are safe and effective in clinical trials with people."
Researchers note that current and future preclinical studies may show that senolytics can be used to enhance life span not only in older people, but in cancer survivors treated with senescence-inducing radiation or chemotherapy, and with a range of senescence-associated chronic diseases.
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.
Authors: Ming Xu, Tamar Pirtskhalava, Joshua N. Farr, Bettina M. Weigand, Allyson K. Palmer, Megan M. Weivoda, Christina L. Inman, Mikolaj B. Ogrodnik, Christine M. Hachfeld, Daniel G. Fraser, Jennifer L. Onken, Kurt O. Johnson, Grace C. Verzosa, Larissa G. P. Langhi, Moritz Weigl, Nino Giorgadze, Nathan K. LeBrasseur, Jordan D. Miller, Diana Jurk, Ravinder J. Singh, David B. Allison, Keisuke Ejima, Gene B. Hubbard, Yuji Ikeno, Hajrunisa Cubro, Vesna D. Garovic, Xiaonan Hou, S. John Weroha, Paul D. Robbins, Laura J. Niedernhofer, Sundeep Khosla, Tamara Tchkonia and James L. Kirkland
The authors are grateful to J. L. Armstrong and L. Thesing for administrative assistance, M. Mahlman for obtaining human adipose tissue samples, Z. Aversa for help with muscle analysis, the Pathology Research Core Lab at Mayo Clinic–Rochester for histology studies, and C. Guo for overall support. This work was supported by the Connor Group (J.L.K.) and Robert J. and Theresa W. Ryan (J.L.K.); the National Institutes of Health (NIH) grants AG13925 (J.L.K.), AG49182 (J.L.K), DK50456 (Adipocyte Subcore, J.L.K.), AG46061 (A.K.P.), AG004875 (S.K.), AG048792 (S.K.), AR070241 (J.N.F.), AR070281 (M.M.W.), AG13319 (Y.I. and G.B.H.), AG050886 (D.B.A.), AG043376 (P.D.R., and L.J.N.), AG056278 (P.D.R. and L.J.N.), and AG044376 (L.J.N.); a Glenn/American Federation for Aging Research (AFAR) BIG Award (J.L.K.); the Glenn Foundation (L.J.N.); and the Ted Nash Long Life and Noaber Foundations (J.L.K.). M.X. received the Glenn/AFAR Postdoctoral Fellowship for Translational Research on Aging and an Irene Diamond Fund/AFAR Postdoctoral Transition Award in Aging.
About the National Institute on Aging: The NIA leads the federal government effort conducting and supporting research on aging and the health and well-being of older people. The Institute's broad scientific program seeks to understand the nature of aging and to extend the healthy, active years of life. For more information on research, aging, and health, go to http://www.nia.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
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Treating very old (24- to 27-month-old) mice with a combination of dasatinib and quercetin (D+Q) biweekly led to a 36 percent higher than average life span, selectively killed senescent cells and
slowed deterioration in walking speed, endurance, and grip strength in senescent mice with
lower mortality than in control mice. Image: Pinterest.