Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis
Abstract
Reduced insulin-like signaling extends the life span of Caenorhabditis elegans and Drosophila . Here, we show that, in mice, less insulin receptor substrate–2 (Irs2) signaling throughout the body or just in the brain extended life span up to 18%. At 22 months of age, brain-specific Irs2 knockout mice were overweight, hyperinsulinemic, and glucose intolerant; however, compared with control mice, they were more active and displayed greater glucose oxidation, and during meals they displayed stable superoxide dismutase–2 concentrations in the hypothalamus. Thus, less Irs2 signaling in aging brains can promote healthy metabolism, attenuate meal-induced oxidative stress, and extend the life span of overweight and insulin-resistant mice.
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Reduction of IIS by neuron-specific knockout of the insulin receptor substrate Irs2 is sufficient to extend mouse lifespan.
“By contrast, reduction of IIS by neuron-specific knockout of the insulin receptor substrate Irs2 is sufficient to extend mouse lifespan (69).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [69]
Cites
Disruption of IRS-2 causes type 2 diabetes in mice
Withers, D., Gutiérrez, J., Towery, H., Burks, D., Ren, J.-M., Previs, S., Zhang, Y., Bernal, D., Pons, S., Shulman, G., et al. (1998) · Nature · doi:10.1038/36116 · Cited by 1,850 · see citing works
Self-citationExtension of Life-Span by Loss of CHICO, a Drosophila Insulin Receptor Substrate Protein
Clancy, D. J., Gems, D., Harshman, L. G., Oldham, S., Stocker, H., Hafen, E., Leevers, S. J., & Partridge, L. (2001) · Science · doi:10.1126/science.1057991 · Cited by 1,436 · see citing works
The plasticity of aging: insights from long-lived mutants
Kenyon, C. (2005) · Cell · doi:10.1016/j.cell.2005.02.002 · Cited by 1,338 · see citing works
Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body
Hwangbo, D., Gersham, B., Tu, M., Palmer, M., & Tatar, M. (2004) · Nature · doi:10.1038/nature02549 · Cited by 954 · see citing works
Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons
Parkes, T. L., Elia, A., Dickinson, D., Hilliker, A. J., Phillips, J. P., & Boulianne, G. L. (1998) · Nature Genetics · doi:10.1038/534 · Cited by 862 · see citing works
Insulin signaling in health and disease
White, M. F. (2003) · Science · doi:10.1126/science.1092952 · Cited by 733 · see citing works
Regulation of C. elegans Life-Span by Insulinlike Signaling in the Nervous System
Wolkow, C. A., Kimura, K. D., Lee, M. S., & Ruvkun, G. (2000) · Science · doi:10.1126/science.290.5489.147 · Cited by 681 · see citing works
Irs-2 coordinates Igf-1 receptor-mediated β-cell development and peripheral insulin signalling
Withers, D. J., Burks, D. J., Towery, H. H., Altamuro, S. L., Flint, C. L., & White, M. F. (1999) · Nature Genetics · doi:10.1038/12631 · Cited by 530 · see citing works
Self-citationInsulin Receptor Substrate-2 Deficiency Impairs Brain Growth and Promotes Tau Phosphorylation
Schubert, M., Brazil, D. P., Burks, D. J., Kushner, J. A., Ye, J., Flint, C. L., Farhang-Fallah, J., Dikkes, P., Warot, X. M., Rio, C., et al. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-18-07084.2003 · Cited by 488 · see citing works
Self-citationIRS-2 pathways integrate female reproduction and energy homeostasis
Burks, D. J., de Mora, J. F., Schubert, M., Withers, D. J., Myers, M. G., Towery, H. H., Altamuro, S. L., Flint, C. L., & White, M. F. (2000) · Nature · doi:10.1038/35030105 · Cited by 455 · see citing works
Self-citationEVOLUTIONARY AND MECHANISTIC THEORIES OF AGING
Hughes, K. A., & Reynolds, R. M. (2004) · Annual Review of Entomology · doi:10.1146/annurev.ento.50.071803.130409 · Cited by 328 · see citing works
Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes
Lin, X., Taguchi, A., Park, S., Kushner, J. A., Li, F., Li, Y., & White, M. F. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22217 · Cited by 313 · see citing works
Self-citationBonkowski, M. S., Rocha, J. S., Masternak, M. M., Al-Regaiey, K., & Bartke, A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600161103 · Cited by 311 · see citing works
The role of insulin receptor substrate 2 in hypothalamic and β cell function
Choudhury, A. I., Heffron, H., Smith, M. A., Al‐Qassab, H., Xu, A. W., Selman, C., Simmgen, M., Clements, M., Claret, M., MacColl, G., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24445 · Cited by 241 · see citing works
Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice
Miller, R. A., Harper, J. M., Gałecki, A. T., & Burke, D. (2002) · Aging Cell · doi:10.1046/j.1474-9728.2002.00006.x · Cited by 229 · see citing works
Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes
Gelling, R. W., Morton, G. J., Morrison, C. D., Niswender, K. D., Myers, M. G., Rhodes, C. J., & Schwartz, M. W. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2005.11.013 · Cited by 169 · see citing works
Glucose regulation and oxidative stress in healthy centenarians
Barbieri, M. (2003) · Experimental Gerontology · doi:10.1016/s0531-5565(02)00153-5 · Cited by 83 · see citing works
Resting Metabolic Rate and Respiratory Quotient in Human Longevity
Rizzo, M. R., Mari, D., Barbieri, M., Ragno, E., Grella, R., Provenzano, R., Villa, I., Esposito, K., Giugliano, D., & Paolisso, G. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0390 · Cited by 47 · see citing works
Defective carbohydrate metabolism in mice homozygous for the tubby mutation
Wang, Y., Seburn, K. L., Bechtel, L. J., Lee, B. Y., Szatkiewicz, J. P., Nishina, P. M., & Naggert, J. Κ. (2006) · Physiological Genomics · doi:10.1152/physiolgenomics.00239.2005 · Cited by 41 · see citing works
Kabil, H., Partridge, L., & Harshman, L. G. (2006) · Biogerontology · doi:10.1007/s10522-006-9065-3 · Cited by 32 · see citing works
Intrigue at the Immune Synapse
Davis, D. M. (2006) · Scientific American · doi:10.1038/scientificamerican0206-48 · Cited by 30 · see citing works
Genetic Approaches to the Study of Aging
Miller, R. A. (2005) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2005.53490.x · Cited by 13 · see citing works
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Neural mechanisms of ageing and cognitive decline
Bishop, N. A., Lu, T., & Yankner, B. A. (2010) · Nature · doi:10.1038/nature08983 · Cited by 1,323 · see citing works
Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation
Qiu, X., Brown, K., Hirschey, M. D., Verdin, E., & Chen, D. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.11.015 · Cited by 1,310 · see citing works
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Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., Davis, J. G., Salmon, A. B., Richardson, A., Ahima, R. S., et al. (2012) · Science · doi:10.1126/science.1215135 · Cited by 1,199 · see citing works
Schulz, T. J., Zarse, K., Voigt, A., Urban, N., Birringer, M., & Ristow, M. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.08.011 · Cited by 1,209 · see citing works
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Durieux, J., Wolff, S., & Dillin, A. (2011) · Cell · doi:10.1016/j.cell.2010.12.016 · Cited by 1,059 · see citing works
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Zhang, G., Li, J., Purkayastha, S., Tang, Y., Zhang, H., Yin, Y., Li, B., Liu, G., & Cai, D. (2013) · Nature · doi:10.1038/nature12143 · Cited by 834 · see citing works
Ristow, M., & Zarse, K. (2010) · Experimental Gerontology · doi:10.1016/j.exger.2010.03.014 · Cited by 789 · see citing works
Moloney, A. M., Griffin, R. J., Timmons, S., O’Connor, R., Ravid, R., & O’Neill, C. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.04.002 · Cited by 764 · see citing works
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Green, C. L., Lamming, D. W., & Fontana, L. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00411-4 · Cited by 714 · see citing works
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Junnila, R. K., List, E. O., Berryman, D. E., Murrey, J. W., & Kopchick, J. J. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.67 · Cited by 574 · see citing works
Kell, D. B. (2009) · BMC Medical Genomics · doi:10.1186/1755-8794-2-2 · Cited by 554 · see citing works
Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)
Ristow, M., & Schmeisser, K. (2014) · Dose-Response · doi:10.2203/dose-response.13-035.ristow · Cited by 534 · see citing works
Reduced IGF-1 signaling delays age-associated proteotoxicity in mice
Cohen, E., Paulsson, J. F., Blinder, P., Burstyn-Cohen, T., Du, D., Estepa, G., Adame, A., Pham, H. M., Holzenberger, M., Kelly, J. W., et al. (2009) · Cell · doi:10.1016/j.cell.2009.11.014 · Cited by 488 · see citing works
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Myers, M. G., & Olson, D. P. (2012) · Nature · doi:10.1038/nature11705 · Cited by 399 · see citing works
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Broughton, S., & Partridge, L. (2009) · Biochemical Journal · doi:10.1042/bj20082102 · Cited by 228 · see citing works
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Toth, M. L., Melentijevic, I., Shah, L., Bhatia, A., Lu, K., Talwar, A., Naji, H., Ibanez-Ventoso, C., Ghose, P., Jevince, A., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1494-11.2012 · Cited by 205 · see citing works
Freude, S., Hettich, M. M., Schumann, C., Stöhr, O., Koch, L., Köhler, C., Udelhoven, M., Leeser, U., Müller, M., Kubota, N., et al. (2009) · The FASEB Journal · doi:10.1096/fj.09-132043 · Cited by 218 · see citing works
Uchiki, T., Weikel, K. A., Jiao, W., Shang, F., Caceres, A., Pawlak, D., Handa, J. T., Brownlee, M., Nagaraj, R., & Taylor, A. (2012) · Aging Cell · doi:10.1111/j.1474-9726.2011.00752.x · Cited by 200 · see citing works
“Importantly, fasting insulin and fasting glucose were within normal ranges for aged mice, albeit that HOMA-IR levels were higher for the high GI-fed mice than the low GI-fed mice (Weikel, unpublished data) (Taguchi et al., 2007; Yau et al., 2007; Cai et al., 2008).”
BackgroundVitale, G., Pellegrino, G., Vollery, M., & Hofland, L. J. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00027 · Cited by 166 · see citing works
Effect of Intranasal Insulin on Cognitive Function: A Systematic Review
Shemesh, E., Rudich, A., Harman-Boehm, I., & Cukierman-Yaffe, T. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1802 · Cited by 162 · see citing works
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Sadagurski, M., Cheng, Z., Rozzo, A., Palazzolo, I., Kelley, G. R., Dong, X., Krainc, D., & White, M. F. (2011) · Journal of Clinical Investigation · doi:10.1172/jci46305 · Cited by 107 · see citing works
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Fox, A. S., Oler, J. A., Shelton, S. E., Nanda, S. A., Davidson, R. J., Roseboom, P. H., & Kalin, N. H. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206723109 · Cited by 57 · see citing works
Liu, C., Carvalho, A., & McIntyre, R. (2015) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527313666141130204031 · Cited by 61 · see citing works
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Hennige, A. M., Sartorius, T., Lutz, S. Z., Tschritter, O., Preissl, H., Hopp, S., Fritsche, A., Rammensee, H.-G., Ruth, P., & Häring, H.-U. (2009) · Diabetologia · doi:10.1007/s00125-009-1522-5 · Cited by 41 · see citing works
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- Authors
- Taguchi, A., Wartschow, L. M., & White, M. F.
- Affiliations
- Boston Children's Hospital (US)
- Corresponding author
- White, Morris F.
- Venue
- Science
- Published
- 2007-07-20
- Volume
- 317
- Issue
- 5836
- Pages
- 369-372
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2055708395
- Cited by
- 523
- References
- 22
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 15 · 2023: 15 · 2022: 16 · 2021: 18 · 2020: 19 · 2019: 18 · 2018: 22 · 2017: 22 · 2016: 27 · 2015: 29 · 2014: 34 · 2013: 36 · 2012: 37
- FWCI
- 14.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK55326, R01DK055326, DK 38712)
- 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 › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- insulin receptor substrate 2, lifespan extension, aging, nutrient homeostasis, insulin resistance, impaired glucose tolerance, hyperinsulinemia, obesity, glucose oxidation, oxidative stress, manganese superoxide dismutase, hypothalamus, insulin-like signaling
- MeSH terms
- Superoxide Dismutase 2, Aging, Animals, Brain, Circadian Rhythm, Crosses, Genetic, Diet, Female, Glucose, Homeostasis, Insulin Resistance, Longevity, Male, Mice, Transgenic, Oxidation-Reduction, Oxygen Consumption, Phosphoproteins, Respiration, Superoxide Dismutase, Signal Transduction, Mice, Knockout, Intracellular Signaling Peptides and Proteins, Overweight, Mice, Insulin Receptor Substrate Proteins
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