Neuronal MML-1/MXL-2 regulates systemic aging via glutamate transporter and cell nonautonomous autophagic and peroxidase activity.

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  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Aging*/genetics ; Neurons*; Animals ; Amino Acid Transport System X-AG ; Autophagy/genetics ; Caenorhabditis elegans/genetics ; Peroxidases ; Caenorhabditis elegans Proteins/genetics
    • Abstract:
      Accumulating evidence has demonstrated the presence of intertissue-communication regulating systemic aging, but the underlying molecular network has not been fully explored. We and others previously showed that two basic helix-loop-helix transcription factors, MML-1 and HLH-30, are required for lifespan extension in several longevity paradigms, including germlineless Caenorhabditis elegans . However, it is unknown what tissues these factors target to promote longevity. Here, using tissue-specific knockdown experiments, we found that MML-1 and its heterodimer partners MXL-2 and HLH-30 act primarily in neurons to extend longevity in germlineless animals. Interestingly, however, the downstream cascades of MML-1 in neurons were distinct from those of HLH-30. Neuronal RNA interference (RNAi)-based transcriptome analysis revealed that the glutamate transporter GLT-5 is a downstream target of MML-1 but not HLH-30. Furthermore, the MML-1-GTL-5 axis in neurons is critical to prevent an age-dependent collapse of proteostasis and increased oxidative stress through autophagy and peroxidase MLT-7, respectively, in long-lived animals. Collectively, our study revealed that systemic aging is regulated by a molecular network involving neuronal MML-1 function in both neural and peripheral tissues.
    • Comments:
      Erratum in: Proc Natl Acad Sci U S A. 2023 Nov 21;120(47):e2318184120. (PMID: 37967225)
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    • Contributed Indexing:
      Keywords: C. elegans; autophagy; longevity; redox homeostasis
    • Accession Number:
      0 (Amino Acid Transport System X-AG)
      EC 1.11.1.- (Peroxidases)
      0 (MML-1 protein, C elegans)
      0 (MXL-2 protein, C elegans)
      0 (Caenorhabditis elegans Proteins)
    • Publication Date:
      Date Created: 20230918 Date Completed: 20230928 Latest Revision: 20240319
    • Publication Date:
      20240319
    • Accession Number:
      PMC10523562
    • Accession Number:
      10.1073/pnas.2221553120
    • Accession Number:
      37722055