Neuronal CRTC-1 Governs Systemic Mitochondrial Metabolism and Lifespan via a Catecholamine Signal

Abstract

SUMMARY 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.

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

“…NHR‐49 is a critical regulator of lipid metabolism and longevity (Burkewitz et al., 2015; Chamoli, Singh, Malik & Mukhopadhyay, 2014; Folick et al., 2015; Khan et al., 2013; Ratnappan et al., 2014; Seah et al., 2016), while related nuclear receptors, HNF4 and PPARα, are therapeutic targets that share at least some of these functions in mammals. Here, we show that NHR‐49 is also vital for an adaptive transcriptional response to the organic peroxide tBOOH.…”

Macronutrients and caloric intake in health and longevity

“…Recently, Mair and colleagues showed that cyclic AMP-responsive element binding protein (CREB)-regulated transcriptional co-activator (CRTC-1) is an essential target for AMPK-mediated lifespan extension in C. elegans (Mair, et al 2011). Longevity via transcriptional regulation of AMPK occurred through CRTC-1 downregulation, with neuronal CRTC-1 playing a primary role in regulating longevity and mitochondrial metabolism in peripheral tissues (Burkewitz, et al 2015; Mair et al 2011). In mammals, hepatic AMPK activation acts to slow gluconeogenesis and down-regulate key genes such as G6Pase and PEPCK, while in the muscle, it stimulates glucose uptake by increasing expression of glucose transporters such as GLUT-4 (McCarty 2004).…”

Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling

“…Activating AMPK increases lifespan in C. elegans and Drosophila , while pharmacological activation via metformin treatment promotes healthy aging in mice (Apfeld et al, 2004; Mair et al, 2011; Martin-Montalvo et al, 2013; Stenesen et al, 2013). Considerable interplay exists between AMPK and mitochondrial function; AMPK induces mitochondrial biogenesis (Reznick et al, 2007; Zong et al, 2002), and has emerging roles in the regulation of both mitochondrial metabolism and dynamics (Burkewitz et al, 2015; Kang et al, 2016; Toyama et al, 2016). We previously reported that AMPK increases lifespan in C. elegans via remodeling of systemic mitochondrial metabolism, which correlates with altered mitochondrial morphology in peripheral tissues (Burkewitz et al, 2015).…”