Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling
Open accessAbstract
Mitochondrial network remodeling between fused and fragmented states facilitates mitophagy, interaction with other organelles, and metabolic flexibility. Aging is associated with a loss of mitochondrial network homeostasis, but cellular processes causally linking these changes to organismal senescence remain unclear. Here, we show that AMP-activated protein kinase (AMPK) and dietary restriction (DR) promote longevity in C. elegans via maintaining mitochondrial network homeostasis and functional coordination with peroxisomes to increase fatty acid oxidation (FAO). Inhibiting fusion or fission specifically blocks AMPK- and DR-mediated longevity. Strikingly, however, preserving mitochondrial network homeostasis during aging by co-inhibition of fusion and fission is sufficient itself to increase lifespan, while dynamic network remodeling is required for intermittent fasting-mediated longevity. Finally, we show that increasing lifespan via maintaining mitochondrial network homeostasis requires FAO and peroxisomal function. Together, these data demonstrate that mechanisms that promote mitochondrial homeostasis and plasticity can be targeted to promote healthy aging.
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In C. elegans, deficient mitochondrial dynamics are sufficient to block AMPK-mediated and calorie restriction-mediated increases in longevity.
“Moreover, work on C. elegans showed that deficient mitochondrial dynamics are sufficient to block AMPK-mediated and calorie restriction-mediated increases in longevity44”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [44]
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Cites
A C. elegans mutant that lives twice as long as wild type
Kenyon, C., Chang, J., Gensch, E., Rudner, A., & Tabtiang, R. (1993) · Nature · doi:10.1038/366461a0 · Cited by 3,387 · see citing works
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 · see citing works
Mitochondrial 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 · see citing works
Mitochondrial Dynamics and Metabolic Regulation
Wai, T., & Langer, T. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.12.001 · Cited by 1,304 · see citing works
Promoting Health and Longevity through Diet: From Model Organisms to Humans
Fontana, L., & Partridge, L. (2015) · Cell · doi:10.1016/j.cell.2015.02.020 · Cited by 1,245 · see citing works
Impact of intermittent fasting on health and disease processes
Mattson, M. P., Longo, V. D., & Harvie, M. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.10.005 · Cited by 1,187 · see citing works
Rates of Behavior and Aging Specified by Mitochondrial Function During Development
Dillin, A., Hsu, A.-L., Arantes-Oliveira, N., Lehrer-Graiwer, J., Hsin, H., Fraser, A. G., Kamath, R. S., Ahringer, J., & Kenyon, C. (2002) · Science · doi:10.1126/science.1077780 · Cited by 1,121 · see citing works
AMP-activated protein kinase mediates mitochondrial fission in response to energy stress
Toyama, E. Q., Herzig, S., Courchet, J., Lewis, T. L., Losón, O. C., Hellberg, K., Young, N. P., Chen, H., Polleux, F., Chan, D. C., et al. (2016) · Science · doi:10.1126/science.aab4138 · Cited by 1,085 · see citing works
Rambold, A. S., Cohen, S., & Lippincott-Schwartz, J. (2015) · Developmental Cell · doi:10.1016/j.devcel.2015.01.029 · Cited by 1,038 · see citing works
Zong, H., Ren, J. M., Young, L. H., Pypaert, M., Mu, J., Birnbaum, M. J., & Shulman, G. I. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.252625599 · Cited by 1,036 · see citing works
Mitonuclear protein imbalance as a conserved longevity mechanism
Houtkooper, R. H., Mouchiroud, L., Ryu, D., Moullan, N., Katsyuba, E., Knott, G., Williams, R. W., & Auwerx, J. (2013) · Nature · doi:10.1038/nature12188 · Cited by 1,035 · see citing works
Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism
Cabreiro, F., Au, C., Leung, K.-Y., Vergara-Irigaray, N., Cochemé, H. M., Noori, T., Weinkove, D., Schuster, E., Greene, N. D. E., & Gems, D. (2013) · Cell · doi:10.1016/j.cell.2013.02.035 · Cited by 967 · see citing works
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 · see citing works
Cool, B. L., Zinker, B. A., Chiou, W. J. H., Kifle, L., Cao, N., Perham, M., Dickinson, R., Adler, A. L., Gagné, G. D., Iyengar, R., et al. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.05.005 · Cited by 932 · see citing works
Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans
Palikaras, K., Lionaki, E., & Tavernarakis, N. (2015) · Nature · doi:10.1038/nature14300 · Cited by 770 · see citing works
Apfeld, J., O'Connor, G., McDonagh, T., DiStefano, P. S., & Curtis, R. (2004) · Genes & Development · doi:10.1101/gad.1255404 · Cited by 643 · see citing works
Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis
Reznick, R. M., Zong, H., Li, J., Morino, K., Moore, I. K., Yu, H. J., Liu, Z.-X., Dong, J., Mustard, K. J., Hawley, S. A., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.01.008 · Cited by 555 · see citing works
Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance
Schneeberger, M., Dietrich, M. O., Sebastián, D., Imbernón, M., Castaño, C., Garcia, A., Esteban, Y., Gonzalez-Franquesa, A., Rodríguez, I. C., Bortolozzi, A., et al. (2013) · Cell · doi:10.1016/j.cell.2013.09.003 · Cited by 519 · see citing works
Mitofusins, from Mitochondria to Metabolism
Schrepfer, E., & Scorrano, L. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.02.022 · Cited by 490 · see citing works
Sebastián, D., Sorianello, E., Segalés, J., Irazoki, A., Ruiz‐Bonilla, V., Sala, D., Planet, E., Berenguer‐Llergo, A., Muñoz, J. P., Sánchez‐Feutrie, M., et al. (2016) · The EMBO Journal · doi:10.15252/embj.201593084 · Cited by 396 · see citing works
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 · see citing works
Self-citationNewly born peroxisomes are a hybrid of mitochondrial and ER-derived pre-peroxisomes
Sugiura, A., Mattie, S., Prudent, J., & McBride, H. M. (2017) · Nature · doi:10.1038/nature21375 · Cited by 386 · see citing works
Wang, Q., Zhang, M., Torres, G., Wu, S., Ouyang, C., Xie, Z., & Zou, M.-H. (2017) · Diabetes · doi:10.2337/db16-0915 · Cited by 370 · see citing works
Wanders, R. J. A., Waterham, H. R., & Ferdinandusse, S. (2016) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2015.00083 · Cited by 366 · cited 1× · see citing works
“Functional interplay exists between mitochondria and peroxisomes in the regulation of FAO, and oxidation of very long- and long-chain fatty acids takes place in peroxisomes (Wanders et al., 2016).”
Microbial Genetic Composition Tunes Host Longevity
Han, B., Sivaramakrishnan, P., Lin, C.-C., Neve, I. A. A., He, J., Tay, L. W. R., Sowa, J. N., Sizovs, A., Du, G., Wang, J., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.036 · Cited by 353 · see citing works
Scheckhuber, C. Q., Erjavec, N., Tinazli, A., Hamann, A., Nyström, T., & Osiewacz, H. D. (2007) · Nature Cell Biology · doi:10.1038/ncb1524 · Cited by 344 · see citing works
Rana, A., Rera, M., & Walker, D. W. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1216197110 · Cited by 335 · see citing works
AMPK 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 307 · see citing works
Dietrich, M. O., Liu, Z.-W., & Horvath, T. L. (2013) · Cell · doi:10.1016/j.cell.2013.09.004 · Cited by 306 · see citing works
Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice
Leduc-Gaudet, J.-P., Picard, M., Pelletier, F. S.-J., Sgarioto, N., Auger, M.-J., Vallée, J., Robitaille, R., St-Pierre, D. H., & Gouspillou, G. (2015) · Oncotarget · doi:10.18632/oncotarget.4235 · Cited by 273 · see citing works
Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans
Honjoh, S., Yamamoto, T., Uno, M., & Nishida, E. (2008) · Nature · doi:10.1038/nature07583 · Cited by 271 · see citing works
Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans
Heintz, C., Doktor, T. K., Lanjuin, A., Escoubas, C. C., Zhang, Y., Weir, H. J. M., Dutta, S., Silva-García, C. G., Bruun, G. H., Morantte, I. G., et al. (2016) · Nature · doi:10.1038/nature20789 · Cited by 218 · see citing works
Self-citationInhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone
Kennedy, J. A., Unger, S. A., & Horowitz, J. D. (1996) · Biochemical Pharmacology · doi:10.1016/0006-2952(96)00204-3 · Cited by 210 · see citing works
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 192 · see citing works
Neuronal CRTC-1 governs systemic mitochondrial metabolism and lifespan via a catecholamine signal
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. (2015) · Cell · doi:10.1016/j.cell.2015.02.004 · Cited by 186 · see citing works
Self-citationTitration of mitochondrial fusion rescues <i>Mff</i> -deficient cardiomyopathy
Chen, H., Ren, S., Clish, C., Jain, M., Mootha, V., McCaffery, J. M., & Chan, D. C. (2015) · Journal of Cell Biology · doi:10.1083/jcb.201507035 · Cited by 168 · see citing works
The C. elegans Opa1 Homologue EAT-3 Is Essential for Resistance to Free Radicals
Kanazawa, T., Zappaterra, M., Hasegawa, A., Wright, A. P., Newman-Smith, E. D., BUTTLE, K. F., McDonald, K. L., Mannella, C. A., & van der Bliek, A. M. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000022 · Cited by 164 · see citing works
Chaudhari, S. N., & Kipreos, E. T. (2017) · Nature Communications · doi:10.1038/s41467-017-00274-4 · Cited by 143 · see citing works
Wang, L., Ishihara, T., Ibayashi, Y., Tatsushima, K., Setoyama, D., Hanada, Y., Takeichi, Y., Sakamoto, S., Yokota, S., Mihara, K., et al. (2015) · Diabetologia · doi:10.1007/s00125-015-3704-7 · Cited by 139 · see citing works
Shared components of mitochondrial and peroxisomal division
Schrader, M. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.01.004 · Cited by 134 · see citing works
Deep proteome analysis identifies age-related processes in C. elegans
Narayan, V., Ly, T., Pourkarimi, E., Murillo, A. B., Gartner, A., Lamond, A. I., & Kenyon, C. (2016) · Cell Systems · doi:10.1016/j.cels.2016.06.011 · Cited by 127 · see citing works
Bernhardt, D., Müller, M., Reichert, A. S., & Osiewacz, H. D. (2015) · Scientific Reports · doi:10.1038/srep07885 · Cited by 125 · see citing works
Age-dependent changes in mitochondrial morphology and volume are not predictors of lifespan
Regmi, S. G., Rolland, S. G. M., & Conradt, B. (2014) · Aging · doi:10.18632/aging.100639 · Cited by 124 · see citing works
Kang, S. W. S., Haydar, G., Taniane, C., Farrell, G. C., Arias, I. M., Lippincott‐Schwartz, J., & Fu, D. (2016) · PLoS ONE · doi:10.1371/journal.pone.0165638 · Cited by 100 · see citing works
Regulation of Peroxisome Size and Number by Fatty Acid β-Oxidation in the Yeast Yarrowia lipolytica
Smith, J. J., Brown, T. W., Eitzen, G., & Rachubinski, R. A. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m909285199 · Cited by 78 · see citing works
Gao, A. W., Chatzispyrou, I. A., Kamble, R., Liu, Y. J., Herzog, K., Smith, R. L., van Lenthe, H., Vervaart, M. A. T., van Cruchten, A., Luyf, A. C., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-02539-w · Cited by 77 · see citing works
Jiang, H.-C., Hsu, J.-M., Yen, C.-P., Chao, C., Chen, R., & Pan, C. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1501831112 · Cited by 73 · see citing works
Yang, C. C., Chen, D., Lee, S. S., & Walter, L. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00711.x · Cited by 61 · see citing works
Unopposed mitochondrial fission leads to severe lifespan shortening
Scheckhuber, C. Q., Wanger, R. A., Mignat, C. A., & Osiewacz, H. D. (2011) · Cell Cycle · doi:10.4161/cc.10.18.17196 · Cited by 47 · see citing works
Regulation of peroxisome dynamics by phosphorylation
Oeljeklaus, S., Schummer, A., Mastalski, T., Platta, H. W., & Warscheid, B. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.12.022 · Cited by 37 · see citing works
Bonda, D., Smith, M. A., Perry, G. L., Lee, H., Wang, X., & Zhu, X. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211798072562 · Cited by 34 · see citing works
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- Authors
- Weir, H. J., Yao, P., Huynh, F. K., Escoubas, C. C., Goncalves, R. L., Burkewitz, K., Laboy, R., Hirschey, M. D., & Mair, W. B.
- Affiliations
- Harvard University (US)
- Duke University (US)
- Corresponding author
- Mair, William B.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 26
- Issue
- 6
- Pages
- 884-896.e5
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5718936
- OpenAlex
- W2766665344
- Cited by
- 372
- References
- 51
- Citations by year
- 2026: 24 · 2025: 46 · 2024: 43 · 2023: 55 · 2022: 51 · 2021: 37 · 2020: 47 · 2019: 39 · 2018: 27 · 2017: 1
- FWCI
- 13.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Lawrence Ellison Medical Foundation (U54CA155626)
- Glenn Foundation for Medical Research
- NIH (1R01AG044346, 1R01AG045351)
- American Diabetes Association/Canadian Diabetes Association (PF-3-13-4342)
- 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 › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- dietary restriction, AMPK, lifespan extension, aging, mitochondrial network, mitochondrial fusion, mitochondrial fission, mitophagy, peroxisomes, fatty acid oxidation, intermittent fasting, Caenorhabditis elegans
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Aging, Animals, Cell Line, Fatty Acids, Longevity, Mitochondria, Protein Kinases, Caenorhabditis elegans, Peroxisomes, Models, Animal, Caenorhabditis elegans Proteins, Caloric Restriction, Mice, Metabolomics, Mitochondrial Dynamics
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