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Ovariectomy uncouples lifespan from metabolic health and reveals a sex-hormone-dependent role of hepatic mTORC2 in aging

Arriola Apelo, Sebastian I, Lin, Amy, Brinkman, Jacqueline A, Meyer, Emma, Morrison, Mark, Tomasiewicz, Jay L, Pumper, Cassidy P, Baar, Emma L, Richardson, Nicole E, Alotaibi, Mohammed, Lamming, Dudley W·2020·eLife
DOI 10.7554/elife.56177PMC PMC7386906
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Abstract

Inhibition of mTOR (mechanistic Target Of Rapamycin) signaling by rapamycin promotes healthspan and longevity more strongly in females than males, perhaps because inhibition of hepatic mTORC2 (mTOR Complex 2) specifically reduces the lifespan of males. Here, we demonstrate using gonadectomy that the sex-specific impact of reduced hepatic mTORC2 is not reversed by depletion of sex hormones. Intriguingly, we find that ovariectomy uncouples lifespan from metabolic health, with ovariectomized females having improved survival despite paradoxically having increased adiposity and decreased control of blood glucose levels. Further, ovariectomy unexpectedly promotes midlife survival of female mice lacking hepatic mTORC2, significantly increasing the survival of those mice that do not develop cancer. In addition to identifying a sex hormone-dependent role for hepatic mTORC2 in female longevity, our results demonstrate that metabolic health is not inextricably linked to lifespan in mammals, and highlight the importance of evaluating healthspan in mammalian longevity studies.

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Metadata

Authors
Arriola Apelo, S. I., Lin, A., Brinkman, J. A., Meyer, E., Morrison, M., Tomasiewicz, J. L., Pumper, C. P., Baar, E. L., Richardson, N. E., Alotaibi, M., & Lamming, D. W.
Affiliations
  • Department of Dairy Science, University of Wisconsin-Madison, Madison, United States
  • William S. Middleton Memorial Veterans Hospital, Madison, United States
ORCID
Lamming, Dudley W
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2020-07-28
Volume
9
ISSN
2050-084X
DOI
10.7554/elife.56177
PMC
PMC7386906
Cited by
34
References
7
Language
en
Licence
Funders
  • American Federation for Aging Research
  • National Institute on Aging (AG041765, AG050135, AG051974, AG056771, AG062328, AG000213)
  • American Diabetes Association (1-16-PMF-001)
  • National Center for Advancing Translational Sciences (UL1TR002373)
  • Glenn Foundation for Medical Research
  • U.S. Department of Veterans Affairs (I01-BX004031)
  • School of Medicine and Public Health, University of Wisconsin-Madison

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