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m TORC 2‐ SGK ‐1 acts in two environmentally responsive pathways with opposing effects on longevity
Abstract
Summary: The nematode worm Caenorhabditis elegans provides a powerful system for elucidating how genetic, metabolic, nutritional, and environmental factors influence aging. The mechanistic target of rapamycin (m TOR ) kinase is important in growth, disease, and aging and is present in the m TORC 1 and m TORC 2 complexes. In diverse eukaryotes, lifespan can be increased by inhibition of m TORC 1, which transduces anabolic signals to stimulate protein synthesis and inhibit autophagy. Less is understood about m TORC 2, which affects C. elegans lifespan in a complex manner that is influenced by the bacterial food source. m TORC 2 regulates C. elegans growth, reproduction, and lipid metabolism by activating the SGK ‐1 kinase, but current data on SGK ‐1 and lifespan seem to be conflicting. Here, by analyzing the m TORC 2 component Rictor ( RICT ‐1), we show that m TORC 2 modulates longevity by activating SGK ‐1 in two pathways that affect lifespan oppositely. RICT ‐1/m TORC 2 limits longevity by directing SGK ‐1 to inhibit the stress‐response transcription factor SKN ‐1/Nrf in the intestine. Signals produced by the bacterial food source determine how this pathway affects SKN ‐1 and lifespan. In addition, RICT ‐1/m TORC 2 functions in neurons in an SGK ‐1‐mediated pathway that increases lifespan at lower temperatures. RICT ‐1/m TORC 2 and SGK ‐1 therefore oppose or accelerate aging depending upon the context in which they are active. Our findings reconcile data on SGK ‐1 and aging, show that the bacterial microenvironment influences SKN ‐1/Nrf, m TORC 2 functions, and aging, and identify two longevity‐related m TORC 2 functions that involve SGK ‐regulated responses to environmental cues.
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“In worms, mTORC2 inhibition has most often been associated with reduced lifespan, while in flies increasing mTORC2 activity through overexpression of Rictor extends lifespan 21,111–113.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [112]
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“Inhibition of mTORC2 signaling extends the lifespan of C. elegans under certain temperatures and dietary conditions111,112, has anti-tumor effects 128–131, is beneficial in mouse models of mitochondrial disease132,133, and has been shown to inhibit or reverse senescence in human cells 134,135.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [112]
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Sorted by citations
Molecular mechanisms of dietary restriction promoting health and longevity
Green, C. L., Lamming, D. W., & Fontana, L. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00411-4 · Cited by 714
SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans
Blackwell, T. K., Steinbaugh, M. J., Hourihan, J. M., Ewald, C. Y., & Isik, M. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.008 · Cited by 622
Self-citationmTOR: Role in cancer, metastasis and drug resistance
Murugan, A. K. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.07.003 · Cited by 483
Targeting the biology of aging with mTOR inhibitors
Mannick, J. B., & Lamming, D. W. (2023) · Nature Aging · doi:10.1038/s43587-023-00416-y · Cited by 372
Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension
Zhou, B., Kreuzer, J., Kumsta, C., Wu, L., Kamer, K. J., Cedillo, L., Zhang, Y., Li, S., Kacergis, M. C., Webster, C. M., et al. (2019) · Cell · doi:10.1016/j.cell.2019.02.013 · Cited by 220
Metadata
- Authors
- Mizunuma, M., Neumann‐Haefelin, E., Moroz, N., Li, Y., & Blackwell, T. K.
- Affiliations
- Joslin Diabetes Center Harvard Stem Cell Institute Harvard Medical School Department of Genetics Boston MA 02215 USA
- Renal Division University Hospital Freiburg Freiburg 79106 Germany
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2014-07-09
- Volume
- 13
- Issue
- 5
- Pages
- 869-878
- ISSN
- 1474-9718
- 1474-9726
- PMC
- PMC4172656
- Cited by
- 92
- References
- 5
- Language
- en
- Funders
- Japan Society for the Promotion of Science
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