Journal
AGING CELL
Volume 18, Issue 5, Pages -Publisher
WILEY
DOI: 10.1111/acel.13014
Keywords
frailty; hypothalamus; mTOR; mTORC2; lifespanobesity; obesity
Categories
Funding
- National Institute on Aging at the National Institutes of Health [AG041765, AG050135, AG051974, AG056771, AG062328, AG043483]
- National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health [DK098656]
- Glenn Foundation Award for Research in the Biological Mechanisms of Aging
- University of Wisconsin-Madison School of Medicine and Public Health
- University of Wisconsin-Department of Medicine
- American Federation for Aging Research
- Crohn's and Colitis Foundation
- Saudi Arabian Cultural Mission
- Research Supplement to Promote Diversity in Health-Related Research [R00 AG041765-04S1]
- American Diabetes Association [1-16-PMF-001]
- Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS) [UL1TR002373]
- Penn Diabetes Research Center [DK19525]
- U.S. Department of Veterans Affairs [I01-BX004031]
- [DK076169]
- [DK115255]
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The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved protein kinase that regulates growth and metabolism. mTOR is found in two protein complexes, mTORC1 and mTORC2, that have distinct components and substrates and are both inhibited by rapamycin, a macrolide drug that robustly extends lifespan in multiple species including worms and mice. Although the beneficial effect of rapamycin on longevity is generally attributed to reduced mTORC1 signaling, disruption of mTORC2 signaling can also influence the longevity of worms, either positively or negatively depending on the temperature and food source. Here, we show that loss of hypothalamic mTORC2 signaling in mice decreases activity level, increases the set point for adiposity, and renders the animals susceptible to diet-induced obesity. Hypothalamic mTORC2 signaling normally increases with age, and mice lacking this pathway display higher fat mass and impaired glucose homeostasis throughout life, become more frail with age, and have decreased overall survival. We conclude that hypothalamic mTORC2 is essential for the normal metabolic health, fitness, and lifespan of mice. Our results have implications for the use of mTORC2-inhibiting pharmaceuticals in the treatment of brain cancer and diseases of aging.
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