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Neuronal CRTC-1 Governs Systemic Mitochondrial Metabolism and Lifespan via a Catecholamine Signal
Open accessAbstract
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.
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“knockdown of CRTC-1 in C. elegans extends lifespan (Burkewitz et al., 2015).”
From The Aging Epigenome (2016) · cites this paper as Burkewitz et al., 2015
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Cites
Gene Ontology: tool for the unification of biology
Ashburner, M., Ball, C. A., Blake, J. A., Botstein, D., Butler, H., Cherry, J. M., Davis, A. P., Dolinski, K., Dwight, S. S., Eppig, J. T., et al. (2000) · Nature Genetics · doi:10.1038/75556 · Cited by 43,206
Robinson, M. D., McCarthy, D. J., & Smyth, G. K. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btp616 · Cited by 41,364
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.211 · Cited by 35,890
Heinz, S., Benner, C., Spann, N., Bertolino, E., Lin, Y. C., Laslo, P., Cheng, J. X., Murre, C., Singh, H., & Glass, C. K. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.05.004 · Cited by 13,382
Kim, D., Pertea, G., Trapnell, C., Pimentel, H., Kelley, R., & Salzberg, S. L. (2013) · Genome Biology · doi:10.1186/gb-2013-14-4-r36 · Cited by 12,668
REVIGO summarizes and visualizes long lists of gene ontology terms
Supek, F., Bošnjak, M., Škunca, N., & Šmuc, T. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021800 · Cited by 6,264
AMPK: a nutrient and energy sensor that maintains energy homeostasis
Hardie, D. G., Ross, F. A., & Hawley, S. A. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3311 · Cited by 4,602
Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy
Egan, D. F., Shackelford, D. B., Mihaylova, M. M., Gelino, S., Kohnz, R. A., Mair, W., Vasquez, D. S., Joshi, A., Gwinn, D. M., Taylor, R., et al. (2011) · Science · doi:10.1126/science.1196371 · Cited by 2,600
Self-citationAMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus
Minokoshi, Y., Alquier, T., Furukawa, N., Kim, Y.-B., Lee, A., Xue, B., Mu, J., Foufelle, F., Ferré, P., Birnbaum, M. J., et al. (2004) · Nature · doi:10.1038/nature02440 · Cited by 1,637
Metformin improves healthspan and lifespan in mice
Martin-Montalvo, A., Mercken, E. M., Mitchell, S. J., Palacios, H. H., Mote, P. L., Scheibye-Knudsen, M., Gomes, A. P., Ward, T. M., Minor, R. K., Blouin, M.-J., et al. (2013) · Nature Communications · doi:10.1038/ncomms3192 · Cited by 1,445
Self-citationMitochondrial Dynamics in the Regulation of Nutrient Utilization and Energy Expenditure
Liesa, M., & Shirihai, O. S. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.03.002 · Cited by 1,341
CREB and the CRTC co-activators: sensors for hormonal and metabolic signals
Altarejos, J. Y., & Montminy, M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3072 · Cited by 1,061
Dagda, R. K., Cherra, S. J., Kulich, S. M., Tandon, A., Park, D., & Chu, C. T. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808515200 · Cited by 954
Greer, E. L., Dowlatshahi, D., Banko, M. R., Villen, J., Hoang, K., Blanchard, D., Gygi, S. P., & Brunet, A. (2007) · Current Biology · doi:10.1016/j.cub.2007.08.047 · Cited by 801
PPARs at the crossroads of lipid signaling and inflammation
Wahli, W., & Michalik, L. (2012) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2012.05.001 · Cited by 692
Onken, B., & Driscoll, M. (2010) · PLoS ONE · doi:10.1371/journal.pone.0008758 · Cited by 671
Apfeld, J., O'Connor, G., McDonagh, T., DiStefano, P. S., & Curtis, R. (2004) · Genes & Development · doi:10.1101/gad.1255404 · Cited by 643
The AMP-activated protein kinase α2 catalytic subunit controls whole-body insulin sensitivity
Viollet, B., Andreelli, F., Jørgensen, S. B., Perrin, C., Geloen, A., Flamez, D., Mu, J., Lenzner, C., Baud, O., Bennoun, M., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci16567 · Cited by 499
AMPK at the Nexus of Energetics and Aging
Burkewitz, K., Zhang, Y., & Mair, W. B. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.03.002 · Cited by 483
Self-citationAn, J., Muoio, D. M., Shiota, M., Fujimoto, Y., Cline, G. W., Shulman, G. I., Koves, T. R., Stevens, R., Millington, D., & Newgard, C. B. (2004) · Nature Medicine · doi:10.1038/nm995 · Cited by 450
Transcriptional regulation of autophagy by an FXR–CREB axis
Seok, S., Fu, T., Choi, S., Yang, L., Zhu, R., Kumar, S., Sun, X., Yoon, G., KANG, Y. Y., Zhong, W., et al. (2014) · Nature · doi:10.1038/nature13949 · Cited by 432
Nuclear Hormone Receptor NHR-49 Controls Fat Consumption and Fatty Acid Composition in C. elegans
Gilst, M. R. V., Hadjivassiliou, H., Jolly, A. L., & Yamamoto, K. R. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030053 · Cited by 431
Tyramine Functions Independently of Octopamine in the Caenorhabditis elegans Nervous System
Alkema, M. J., Hunter-Ensor, M., Ringstad, N., & Horvitz, H. R. (2005) · Neuron · doi:10.1016/j.neuron.2005.02.024 · Cited by 402
Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB
Mair, W., Morantte, I., Rodrigues, A. P. C., Manning, G., Montminy, M., Shaw, R. J., & Dillin, A. (2011) · Nature · doi:10.1038/nature09706 · Cited by 393
Self-citationAMPK Modulates Tissue and Organismal Aging in a Non-Cell-Autonomous Manner
Ulgherait, M., Rana, A., Rera, M., Graniel, J. V., & Walker, D. W. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.006 · Cited by 320
Tepper, R. G., Ashraf, J. M., Kaletsky, R. L., Kleemann, G. A., Murphy, C. T., & Bussemaker, H. J. (2013) · Cell · doi:10.1016/j.cell.2013.07.006 · Cited by 313
p70S6 Kinase Phosphorylates AMPK on Serine 491 to Mediate Leptin's Effect on Food Intake
Dagon, Y., Hur, E. E., Zheng, B., Wellenstein, K., Cantley, L. C., & Kahn, B. B. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.05.010 · Cited by 297
An antidepressant that extends lifespan in adult Caenorhabditis elegans
Petrascheck, M., Ye, X., & Buck, L. B. (2007) · Nature · doi:10.1038/nature05991 · Cited by 290
Lu, M. M., Sarruf, D. A., Talukdar, S., Sharma, S., Li, P., Bandyopadhyay, G. K., Nalbandian, S., Fan, W., Gayen, J. R., Mahata, S. K., et al. (2011) · Nature Medicine · doi:10.1038/nm.2332 · Cited by 227
TRPV1 Pain Receptors Regulate Longevity and Metabolism by Neuropeptide Signaling
Riera, C. E., Huising, M. O., Follett, P., Leblanc, M., Halloran, J. J., Andel, R. V., Filho, C. D. D. M., Merkwirth, C., & Dillin, A. G. (2014) · Cell · doi:10.1016/j.cell.2014.03.051 · Cited by 223
A role for central nervous system PPAR-γ in the regulation of energy balance
Ryan, K. K., Li, B., Grayson, B. E., Matter, E. K., Woods, S. C., & Seeley, R. J. (2011) · Nature Medicine · doi:10.1038/nm.2349 · Cited by 214
Obesity and the regulation of fat metabolism
Ashrafi, K. (2007) · WormBook · doi:10.1895/wormbook.1.130.1 · Cited by 211
Stenesen, D., Suh, J. M., Seo, J. H., Yu, K., Lee, K., Kim, J.-S., Min, K., & Graff, J. M. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2012.12.006 · Cited by 210
The Creb1 coactivator Crtc1 is required for energy balance and fertility
Altarejos, J. Y., Goebel, N., Conkright, M. D., Inoue, H., Xie, J., Arias, C. M., Sawchenko, P. E., & Montminy, M. (2008) · Nature Medicine · doi:10.1038/nm.1866 · Cited by 199
CAPS Acts at a Prefusion Step in Dense-Core Vesicle Exocytosis as a PIP2 Binding Protein
Grishanin, R. N., Kowalchyk, J. A., Klenchin, V. A., Ann, K., Earles, C. A., Chapman, E. R., Gerona, R. R. L., & Martin, T. F. J. (2004) · Neuron · doi:10.1016/j.neuron.2004.07.028 · Cited by 182
Compensatory Responses to Pyruvate Carboxylase Suppression in Islet β-Cells
Jensen, M. V., Joseph, J. W., Ilkayeva, O., Burgess, S. C., Lu, D., Ronnebaum, S. M., Odegaard, M. L., Becker, T. C., Sherry, A. D., & Newgard, C. B. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604350200 · Cited by 144
Self-citationWu, J.-Y., Kao, H., Li, S., Stevens, R., Hillman, S. L., Millington, D. S., & Chen, Y.-T. (2004) · Journal of Clinical Investigation · doi:10.1172/jci19574 · Cited by 104
Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships
Pathare, P., Lin, A., Bornfeldt, K., Taubert, S., & Gilst, M. R. V. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002645 · Cited by 102
Noble, T., Stieglitz, J., & Srinivasan, S. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.09.007 · Cited by 93
Knauf, C., Rieusset, J., Foretz, M., Cani, P. D., Uldry, M., Hosokawa, M., Martinez, E., Bringart, M., Waget, A., Kersten, S., et al. (2006) · Endocrinology · doi:10.1210/en.2005-1536 · Cited by 75
Li, T., Xie, Q., Ding, Y., Li, S., Peng, S., Zhang, Y., Tan, D., Yuan, Z., & Dong, M. (2013) · eLife · doi:10.7554/elife.00518 · Cited by 60
Self-citationAutophagy genes mediate the effect of calcineurin on life span in C. elegans
Dwivedi, M., Song, H.-O., & Ahnn, J. (2009) · Autophagy · doi:10.4161/auto.5.5.8157 · Cited by 55
Cunningham, K. A., Bouagnon, A. D., Barros, A. G. D. A., Lin, L., Malard, L. M., Romano‐Silva, M. A., & Ashrafi, K. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004394 · Cited by 45
Mouse fertility is not dependent on the CREB coactivator Crtc1
Breuillaud, L., Halfon, O., Magistretti, P. J., Pralong, F. P., & Cardinaux, J. (2009) · Nature Medicine · doi:10.1038/nm0909-989 · Cited by 42
Lerner, R. G., Depatie, C., Rutter, G. A., Screaton, R. A., & Balthasar, N. (2009) · EMBO Reports · doi:10.1038/embor.2009.177 · Cited by 41
Kocalis, H. E., Turney, M. K., Printz, R. L., Laryea, G. N., Muglia, L. J., Davies, S. S., Stanwood, G. D., McGuinness, O. P., & Niswender, K. D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042981 · Cited by 35
Control of metabolism by nutrient-regulated nuclear receptors acting in the brain
Bantubungi, K., Prawitt, J., & Staels, B. (2011) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2011.10.002 · Cited by 20
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Metadata
- Authors
- Burkewitz, K., Morantte, I., Weir, H. J. M., Yeo, R., Zhang, Y., Huynh, F. K., Ilkayeva, O. R., Hirschey, M. D., Grant, A. R., & Mair, W. B.
- Affiliations
- Harvard University (US)
- Duke University (US)
- University of Michigan (US)
- Corresponding author
- Mair, William B.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 160
- Issue
- 5
- Pages
- 842-855
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4392909
- OpenAlex
- W2064550415
- Cited by
- 186
- References
- 47
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 14 · 2023: 14 · 2022: 24 · 2021: 19 · 2020: 23 · 2019: 17 · 2018: 15 · 2017: 21 · 2016: 20 · 2015: 6
- FWCI
- 8.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Diabetes Association
- Ellison Medical Foundation
- National Institutes of Health
- National Institute on Aging (R01AG045351, R01AG044346, F32AG044944)
- National Cancer Institute (U54CA155626)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- lifespan, aging, mitochondrial metabolism, AMPK, calcineurin, CREB, catecholamine signaling, neuronal regulation, PPARα, NHR-49, mitochondrial fragmentation, Caenorhabditis elegans, energy sensing
- MeSH terms
- Animals, Catecholamines, Longevity, Mitochondria, Neurons, Signal Transduction, Trans-Activators, Caenorhabditis elegans, Cyclic AMP Response Element-Binding Protein, Receptors, Cytoplasmic and Nuclear, Caenorhabditis elegans Proteins, AMP-Activated Protein Kinases
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