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Neuronal CRTC-1 Governs Systemic Mitochondrial Metabolism and Lifespan via a Catecholamine Signal
Open accessAbstract
Low energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modulate longevity via the CREB regulated transcriptional coactivator (CRTC)-1 in C. elegans. We show that CRTC-1 specifically uncouples AMPK/calcineurin-mediated effects on lifespan from pleiotropic side effects by reprogramming mitochondrial and metabolic function. This pro-longevity metabolic state is regulated cell nonautonomously by CRTC-1 in the nervous system. Neuronal CRTC-1/CREB regulates peripheral metabolism antagonistically with the functional PPARα ortholog, NHR-49, drives mitochondrial fragmentation in distal tissues, and suppresses the effects of AMPK on systemic mitochondrial metabolism and longevity via a cell-nonautonomous catecholamine signal. These results demonstrate that while both local and distal mechanisms combine to modulate aging, distal regulation overrides local contribution. Targeting central perception of energetic state is therefore a potential strategy to promote healthy aging.
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“knockdown of CRTC-1 in C. elegans extends lifespan (Burkewitz et al., 2015).”
From The Aging Epigenome (2016) · cites this paper as Burkewitz et al., 2015
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Self-citation
Metadata
- Authors
- Burkewitz, K., Morantte, I., Weir, H. J. M., Yeo, R., Zhang, Y., Huynh, F. K., Ilkayeva, O. R., Hirschey, M. D., Grant, A. R., & Mair, W. B.
- Affiliations
- Harvard University (US)
- Duke University (US)
- University of Michigan (US)
- Corresponding author
- Mair, William B.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 160
- Issue
- 5
- Pages
- 842-855
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4392909
- OpenAlex
- W2064550415
- Cited by
- 186
- References
- 47
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 14 · 2023: 14 · 2022: 24 · 2021: 19 · 2020: 23 · 2019: 17 · 2018: 15 · 2017: 21 · 2016: 20 · 2015: 6
- FWCI
- 8.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Diabetes Association
- Ellison Medical Foundation
- National Institutes of Health
- National Institute on Aging (R01AG045351, R01AG044346, F32AG044944)
- National Cancer Institute (U54CA155626)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- lifespan, aging, mitochondrial metabolism, AMPK, calcineurin, CREB, catecholamine signaling, neuronal regulation, PPARα, NHR-49, mitochondrial fragmentation, Caenorhabditis elegans, energy sensing
- MeSH terms
- Animals, Catecholamines, Longevity, Mitochondria, Neurons, Signal Transduction, Trans-Activators, Caenorhabditis elegans, Cyclic AMP Response Element-Binding Protein, Receptors, Cytoplasmic and Nuclear, Caenorhabditis elegans Proteins, AMP-Activated Protein Kinases
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