دورية أكاديمية
أعرض في EDS

Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans.

التفاصيل البيبلوغرافية
العنوان: Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans.
المؤلفون: Smith HJ; Dept. Molecular Metabolism, Harvard TH Chan School of Public Health, Massachusetts, United States of America., Lanjuin A; Dept. Molecular Metabolism, Harvard TH Chan School of Public Health, Massachusetts, United States of America., Sharma A; Dept. Molecular Metabolism, Harvard TH Chan School of Public Health, Massachusetts, United States of America., Prabhakar A; Dept. Molecular Metabolism, Harvard TH Chan School of Public Health, Massachusetts, United States of America., Nowak E; Dept. Molecular Metabolism, Harvard TH Chan School of Public Health, Massachusetts, United States of America., Stine PG; Dept. Molecular Metabolism, Harvard TH Chan School of Public Health, Massachusetts, United States of America., Sehgal R; Dept. Molecular Metabolism, Harvard TH Chan School of Public Health, Massachusetts, United States of America., Stojanovski K; Institute for Cell Biology, University of Bern, Bern, Switzerland., Towbin BD; Institute for Cell Biology, University of Bern, Bern, Switzerland., Mair WB; Dept. Molecular Metabolism, Harvard TH Chan School of Public Health, Massachusetts, United States of America.
المصدر: PLoS genetics [PLoS Genet] 2023 Sep 18; Vol. 19 (9), pp. e1010938. Date of Electronic Publication: 2023 Sep 18 (Print Publication: 2023).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE
أسماء مطبوعة: Original Publication: San Francisco, CA : Public Library of Science, c2005-
مواضيع طبية MeSH: Caenorhabditis elegans*/metabolism , Caenorhabditis elegans Proteins*/genetics , Caenorhabditis elegans Proteins*/metabolism, Animals ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Longevity/genetics ; Multiprotein Complexes/genetics ; Reproduction/genetics ; Mammals/metabolism
مستخلص: mTORC1 (mechanistic target of rapamycin complex 1) is a metabolic sensor that promotes growth when nutrients are abundant. Ubiquitous inhibition of mTORC1 extends lifespan in multiple organisms but also disrupts several anabolic processes resulting in stunted growth, slowed development, reduced fertility, and disrupted metabolism. However, it is unclear if these pleiotropic effects of mTORC1 inhibition can be uncoupled from longevity. Here, we utilize the auxin-inducible degradation (AID) system to restrict mTORC1 inhibition to C. elegans neurons. We find that neuron-specific degradation of RAGA-1, an upstream activator of mTORC1, or LET-363, the ortholog of mammalian mTOR, is sufficient to extend lifespan in C. elegans. Unlike raga-1 loss of function genetic mutations or somatic AID of RAGA-1, neuronal AID of RAGA-1 robustly extends lifespan without impairing body size, developmental rate, brood size, or neuronal function. Moreover, while degradation of RAGA-1 in all somatic tissues alters the expression of thousands of genes, demonstrating the widespread effects of mTORC1 inhibition, degradation of RAGA-1 in neurons only results in around 200 differentially expressed genes with a specific enrichment in metabolism and stress response. Notably, our work demonstrates that targeting mTORC1 specifically in the nervous system in C. elegans uncouples longevity from growth and reproductive impairments, and that many canonical effects of low mTORC1 activity are not required to promote healthy aging. These data challenge previously held ideas about the mechanisms of mTORC1 lifespan extension and underscore the potential of promoting longevity by neuron-specific mTORC1 modulation.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Smith et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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معلومات مُعتمدة: P40 OD010440 United States OD NIH HHS; R01 AG051954 United States AG NIA NIH HHS; R01 AG067106 United States AG NIA NIH HHS; R01 AG044346 United States AG NIA NIH HHS; F31 AG076296 United States AG NIA NIH HHS; R01 AG059595 United States AG NIA NIH HHS
المشرفين على المادة: EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
0 (Multiprotein Complexes)
0 (Caenorhabditis elegans Proteins)
تواريخ الأحداث: Date Created: 20230918 Date Completed: 20240129 Latest Revision: 20240210
رمز التحديث: 20240210
مُعرف محوري في PubMed: PMC10538657
DOI: 10.1371/journal.pgen.1010938
PMID: 37721956
قاعدة البيانات: MEDLINE
الوصف
تدمد:1553-7404
DOI:10.1371/journal.pgen.1010938