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Depletion of Rictor, an essential protein component of m TORC 2, decreases male lifespan
Abstract
Summary: Rapamycin, an inhibitor of the mechanistic target of rapamycin (m TOR), robustly extends the lifespan of model organisms including mice. We recently found that chronic treatment with rapamycin not only inhibits m TOR complex 1 (m TORC 1), the canonical target of rapamycin, but also inhibits m TOR complex 2 (m TORC 2) in vivo. While genetic evidence strongly suggests that inhibition of m TORC 1 is sufficient to promote longevity, the impact of m TORC 2 inhibition on mammalian longevity has not been assessed. RICTOR is a protein component of m TORC 2 that is essential for its activity. We examined three different mouse models of Rictor loss: mice heterozygous for Rictor, mice lacking hepatic Rictor, and mice in which Rictor was inducibly deleted throughout the body in adult animals. Surprisingly, we find that depletion of RICTOR significantly decreases male, but not female, lifespan. While the mechanism by which RICTOR loss impairs male survival remains obscure, we find that the effect of RICTOR depletion on lifespan is independent of the role of hepatic m TORC 2 in promoting glucose tolerance. Our results suggest that inhibition of m TORC 2 signaling is detrimental to males, which may explain in part why interventions that decrease m TOR signaling show greater efficacy in females.
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“Whole body deficiency of mTORC2 signaling, or tissue-specific inhibition of mTORC2 signaling in the brain, liver, or adipose tissue, reduces lifespan in C57BL/6J mice 114–117.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [117]
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“Genetic inhibition of mTORC2 in one or more tissues of a mouse can result in frailty, hyperphagia, insulin resistance, hyperlipidemia, hypercholesterolemia, hyperglycemia, kyphosis, and/or obesity depending upon the specific tissues in which mTORC2 is inhibited 114–117, 68.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [117]
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Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span
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“We also tested insulin sensitivity in aged male and female mice by means of an insulin wt Rictor+/– FemaleMale wt RICTOR p-S473-AKT AKT p-T308-AKT p-T450-AKT β-TUBULIN p-S473-AKT AKT p-T308-AKT p-T450-AKT β-TUBULIN RICTOR Male Female wt L-RKO wt L-RKO RICTOR AKT p-S473-AKT Pr ot ei n ex pr es si on (% of w ild ty pe m…”
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TOR Signaling and Rapamycin Influence Longevity by Regulating SKN-1/Nrf and DAF-16/FoxO
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Self-citationmTORC1 controls fasting-induced ketogenesis and its modulation by ageing
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Sorted by citations
Sarcopenia: Aging-Related Loss of Muscle Mass and Function
Larsson, L., Degens, H., Li, M., Salviati, L., Lee, Y. I., Thompson, W., Kirkland, J. L., & Sandri, M. (2019) · Physiological Reviews · doi:10.1152/physrev.00061.2017 · Cited by 1,797
Molecular mechanisms of dietary restriction promoting health and longevity
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Self-citationmTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review
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The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging
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Self-citationTORC1 inhibition enhances immune function and reduces infections in the elderly
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Metadata
- Authors
- Lamming, D. W., Mihaylova, M. M., Katajisto, P., Baar, E. L., Yilmaz, O. H., Hutchins, A., Gultekin, Y., Gaither, R., & Sabatini, D. M.
- Affiliations
- Department of Medicine University of Wisconsin Madison WI 53705 USA
- Whitehead Institute for Biomedical Research Cambridge MA 02142 USA
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2014-07-25
- Volume
- 13
- Issue
- 5
- Pages
- 911-917
- ISSN
- 1474-9718
- 1474-9726
- PMC
- PMC4172536
- Cited by
- 111
- References
- 8
- Language
- en
- Funders
- National Institute on Aging (AG041765)
- American Federation for Aging Research
- Ellison Medical Foundation
- Howard Hughes Medical Institute
- Damon Runyon Cancer Research Foundation (DRG-2146-13)
- American Diabetes Association
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