Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB

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Abstract
Ageing is slowed, and lifespan extended, in the nematode Caenorhabditis elegans by the activation of the enzyme AMPK (5′ adenosine monophosphate-activated protein kinase) or by inactivation of the protein phosphatase calcineurin. The nature of the related molecular pathways involved has remained unclear, but here it is shown that inhibition of CRTC-1, the sole CREB-regulated transcriptional activator in C. elegans, is required for these life-extending effects. Eliminating the crtc-1 gene increases lifespan in a crh-1 dependent manner, as does elimination of crh-1 (the gene for CREB homologue 1) alone. Downregulation of components in the CRTC/CREB pathway has been shown to confer health benefits to mice, complementing their lifespan effects in worms, and it will be interesting to discover whether CTRCs act as ageing modulators more generally in mammals. Activating AMPK or inactivating calcineurin slows ageing in worms and increases their lifespan. Here it is shown that inhibition of CRTC-1 is required for these life-extending effects. CRTC-1 is the only worm member in the family of CREB-regulated transcriptional co-activators, or CRTCs, and, like the mammalian family members, CRTC-1 interacts with a worm homologue of the CREB transcription factor (CRH-1). Eliminating crtc-1 increases lifespan in a crh-1-dependent manner, as does elimination of crh-1 alone. Downregulation of components in the CRTC/CREB pathway has previously been shown to confer health benefits to mice, complementing their lifespan effects in worms. Activating AMPK or inactivating calcineurin slows ageing in Caenorhabditis elegans1,2 and both have been implicated as therapeutic targets for age-related pathology in mammals3,4,5. However, the direct targets that mediate their effects on longevity remain unclear. In mammals, CREB-regulated transcriptional coactivators (CRTCs)6 are a family of cofactors involved in diverse physiological processes including energy homeostasis7,8,9, cancer10 and endoplasmic reticulum stress11. Here we show that both AMPK and calcineurin modulate longevity exclusively through post-translational modification of CRTC-1, the sole C. elegans CRTC. We demonstrate that CRTC-1 is a direct AMPK target, and interacts with the CREB homologue-1 (CRH-1) transcription factor in vivo. The pro-longevity effects of activating AMPK or deactivating calcineurin decrease CRTC-1 and CRH-1 activity and induce transcriptional responses similar to those of CRH-1 null worms. Downregulation of crtc-1 increases lifespan in a crh-1-dependent manner and directly reducing crh-1 expression increases longevity, substantiating a role for CRTCs and CREB in ageing. Together, these findings indicate a novel role for CRTCs and CREB in determining lifespan downstream of AMPK and calcineurin, and illustrate the molecular mechanisms by which an evolutionarily conserved pathway responds to low energy to increase longevity.