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

Mair, William; Morantte, Ianessa; Rodrigues, Ana Paula; Manning, Gerard; Montminy, Marc; Shaw, Reuben J.; Dillin, Andrew

doi:10.1038/nature09706

Cited by 358 publications

(385 citation statements)

References 39 publications

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“…When activated, AMPK negatively regulates mTOR activation (Mihaylova and Shaw 2011). AMPK activation slows aging in C. elegans (Apfeld et al 2004;Mair et al 2011) and is being considered as a calorie restriction mimetic (Ingram et al 2006). Therefore, metformin has been used for life extension in mammals and, in some studies although not all, has demonstrated gerosuppressive effects (Smith et al 2010;Anisimov et al 2011;Berstein 2012).…”

Section: Introductionmentioning

confidence: 99%

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

Kusne

Goldberg

Parker

et al. 2013

AGE

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The chronic and systemic administration of rapamycin extends life span in mammals. Rapamycin is a pharmacological inhibitor of mTOR. Metformin also inhibits mTOR signaling but by activating the upstream kinase AMPK. Here we report the effects of chronic and systemic administration of the two mTOR inhibitors, rapamycin and metformin, on adult neural stem cells of the subventricular region and the dendate gyrus of the mouse hippocampus. While rapamycin decreased the number of neural progenitors, metforminmediated inhibition of mTOR had no such effect. Adult-born neurons are considered important for cognitive and behavioral health, and may contribute to improved health span. Our results demonstrate that distinct approaches of inhibiting mTOR signaling can have significantly different effects on organ function. These results underscore the importance of screening individual mTOR inhibitors on different organs and physiological AGE

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Section: Introductionmentioning

confidence: 99%

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

Kusne

Goldberg

Parker

et al. 2013

AGE

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“…Generally, decreased CREB activity was associated with learning impairments in healthy aged animals [31,32] and with cognitive deficits in animal models of neurodegenerative disorders [33][34][35]. Importantly, the level of phosphorylated CREB and the activity-induced increase in CREB phosphorylation is diminished in ageing [36,37], and this itself may influence the ageing process [38,39]. Altered calcium signalling in ageing neurons significantly contributes to diminished CREB activity.…”

Section: Functional Histological and Molecular Changes In The Ageingmentioning

confidence: 99%

“…These changes may lead to an enhanced calcium signal after activation and elevated activity of calcium-dependent signalling pathways. Agedependent alterations in the intracellular signalling system have a huge impact on the transcriptional activity of the cells [30,38,45].…”

Section: Functional Histological and Molecular Changes In The Ageingmentioning

confidence: 99%

The endocannabinoid system in normal and pathological brain ageing

Bilkei-Gorzó

2012

Phil. Trans. R. Soc. B

121

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The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, proageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brainderived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing.

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“…Deletion of TORC, the single CRTC homolog in Drosophila, reduces fat stores and increases sensitivity to starvation (11). CRTCs also seem to be important in aging: RNAi-mediated depletion of CRTC1 in Caenorhabditis elegans extends lifespan, in part through down-regulation of the CREB pathway (12).…”

mentioning

confidence: 99%

Mechanism of CREB recognition and coactivation by the CREB-regulated transcriptional coactivator CRTC2

Luo

Viste

Urday-Zaa

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Basic leucine zipper (bZip) transcription factors regulate cellular gene expression in response to a variety of extracellular signals and nutrient cues. Although the bZip domain is widely known to play significant roles in DNA binding and dimerization, recent studies point to an additional role for this motif in the recruitment of the transcriptional apparatus. For example, the cAMP response element binding protein (CREB)-regulated transcriptional coactivator (CRTC) family of transcriptional coactivators has been proposed to promote the expression of calcium and cAMP responsive genes, by binding to the CREB bZip in response to extracellular signals. Here we show that the CREB-binding domain (CBD) of CRTC2 folds into a single isolated 28-residue helix that seems to be critical for its interaction with the CREB bZip. The interaction is of micromolar affinity on palindromic and variant half-site cAMP response elements (CREs). The CBD and CREB assemble on the CRE with 2:2:1 stoichiometry, consistent with the presence of one CRTC binding site on each CREB monomer. Indeed, the CBD helix and the solvent-exposed residues in the dimeric CREB bZip coiled-coil form an extended protein-protein interface. Because mutation of relevant bZip residues in this interface disrupts the CRTC interaction without affecting DNA binding, our results illustrate that distinct DNA binding and transactivation functions are encoded within the structural constraints of a canonical bZip domain.transcription regulation | cellular signaling | protein-protein interaction

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

Cited by 358 publications

References 39 publications

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

The endocannabinoid system in normal and pathological brain ageing

Mechanism of CREB recognition and coactivation by the CREB-regulated transcriptional coactivator CRTC2

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