Presentation/Session Information

Session Information

Session Title: Physiology: Aging and Stress II Session Type: Parallel
Session Location: Carnesale Palisades Ballroom Session Time: Fri, Jun 26 8:30AM - 11:30AM

Presentation Information

Program Number: 78 Presentation Time: 9:30AM - 9:42AM

Presentation Content

Neuronal CRTC-1 governs systemic mitochondrial metabolism and lifespan via a catecholamine signal.Kristopher Burkewitz 1, Ianessa Morantte 1, Heather Weir 1, Robin Yeo 1, Yue Zhang 1, Frank Huynh 2, Olga Ilkayeva 2, Matthew Hirschey 2, Ana Grant 3, William Mair 1. 1)Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA; 2)Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA; 3)Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA

Low energy status delays aging in multiple species, yet the mechanisms coordinating energetics and longevity remain poorly defined. One established and highly conserved link to both energetics and aging is AMP-activated protein kinase (AMPK). AMPK mediates metabolic adaptation to low energy both at the cellular and organismal levels, and mutations conferring constitutive activation to AMPK extend lifespan in multiple animal models. Previously, we established that AMPK and the phosphatase calcineurin antagonistically regulate CREB-regulated transcriptional coactivator (CRTC)-1 to modulate longevity in C. elegans. We now show that AMPK- and calcineurin-mediated effects on lifespan can be uncoupled from associated pleiotropic side effects through CRTC-1, and exploit this observation to demonstrate that the mechanisms specific to AMPK longevity involve reprogramming of mitochondrial and metabolic function. Strikingly, this pro-longevity metabolic state is regulated cell-nonautonomously by CRTC-1 and its partner transcription factor CREB in the nervous system. Neuronal CRTC-1 drives mitochondrial fragmentation in distal tissues and suppresses the effect of AMPK on systemic mitochondrial metabolism and longevity via a cell-nonautonomous catecholamine signal. These results demonstrate that transcriptional control of neuronal signals can override enzymatic regulation of metabolism across the organism. Neuronal perception of energetic state therefore represents a target to promote healthy aging.




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