Neuronal CRTC-1 governs systemic mitochondrial metabolism and lifespan via a catecholamine signal.
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.
Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
Kristopher
K
Burkewitz
Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
Ianessa
I
Morantte
Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
Heather J M
HJM
Weir
Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
Robin
R
Yeo
Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
Yue
Y
Zhang
Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC 27701, USA.
Frank K
FK
Huynh
Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC 27701, USA.
Olga R
OR
Ilkayeva
Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC 27701, USA.
Matthew D
MD
Hirschey
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, 100 Washtenah Avenue, Ann Arbor, MI 48109, USA.
Ana R
AR
Grant
Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA. Electronic address: wmair@hsph.harvard.edu.
William B
WB
Mair
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D008136:Longevity; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
C556192:CRTC-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002395:Catecholamines; D017362:Cyclic AMP Response Element-Binding Protein; C505159:NHR-49 protein, C elegans; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D055372:AMP-Activated Protein Kinases