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Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice
Open accessAbstract
Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions.
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“However, dietary restriction regimens do not extend lifespan in all mouse strains, supporting the contention that they must be adapted to the genetic makeup of each individual 151 .”
From Hallmarks of aging: An expanding universe (2023) · cites this paper as [151]
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InfluentialDietary restriction impacts health and lifespan of genetically diverse mice
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InfluentialIdentification and Application of Gene Expression Signatures Associated with Lifespan Extension
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ResultA toolbox for the longitudinal assessment of healthspan in aging mice
Bellantuono, I., de Cabo, R., Ehninger, D., Di Germanio, C., Lawrie, A., Miller, J., Mitchell, S. J., Navas-Enamorado, I., Potter, P. K., Tchkonia, T., et al. (2020) · Nature Protocols · doi:10.1038/s41596-019-0256-1 · Cited by 145
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MethodIntermittent fasting: from calories to time restriction
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“…incidence of cancer, the leading cause of death in rodents, is drastically reduced in CR animals; similar reductions or slowing down of disease progression have been observed for nephropathy, cardiomyopathy, diabetes, chronic lung diseases, autoimmune diseases and neurodegenerative disease 36,37 .”
BackgroundDistinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle
Ham, D. J., Börsch, A., Chojnowska, K., Lin, S., Leuchtmann, A. B., Ham, A. S., Thürkauf, M., Delezie, J., Furrer, R., Bürri, D., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-29714-6 · Cited by 110
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Bronikowski, A. M., Meisel, R. P., Biga, P. R., Walters, J. R., Mank, J. E., Larschan, E., Wilkinson, G. S., Valenzuela, N., Conard, A. M., de Magalhães, J. P., et al. (2022) · Aging Cell · doi:10.1111/acel.13542 · Cited by 105
Current nutritional and pharmacological anti-aging interventions
Ros, M., & Carrascosa, J. M. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.165612 · Cited by 86
Andreadou, I., Schulz, R., Papapetropoulos, A., Turan, B., Ytrehus, K., Ferdinandy, P., Daiber, A., & Lisa, F. D. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.15279 · Cited by 92
Mihaylova, M. M., Chaix, A., Delibegović, M., Ramsey, J. J., Bass, J. T., Melkani, G. C., Singh, R., Chen, Z., Ja, W. W., Shirasu-Hiza, M., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.06.008 · Cited by 97
Energy Metabolism and Ageing in the Mouse: A Mini-Review
Azzu, V., & Valencak, T. G. (2017) · Gerontology · doi:10.1159/000454924 · Cited by 90
Neocortex saves energy by reducing coding precision during food scarcity
Padamsey, Z., Katsanevaki, D., Dupuy, N., & Rochefort, N. L. (2021) · Neuron · doi:10.1016/j.neuron.2021.10.024 · Cited by 97
“Thus, it is possible thatmoremodest forms of food restriction may have a beneficial impact on information processing (Fu et al., 2017; Ingram and deCabo, 2017;Mitchell et al., 2016).”
Gong, H., Sun, L., Chen, B., Han, Y., Pang, J., Wu, W., Qi, R., & Zhang, T. (2016) · Scientific Reports · doi:10.1038/srep38513 · Cited by 88
“Thus, we checked Leptin expression in Leptin-expressing tissues iWAT and Sk.”
InfluentialPetr, M. A., Alfaras, I., Krawcyzk, M., Bair, W.-N., Mitchell, S. J., Morrell, C. H., Studenski, S. A., Price, N. L., Fishbein, K. W., Spencer, R. G. S., et al. (2021) · eLife · doi:10.7554/elife.62952 · Cited by 87
“Interestingly, a positive association was observed between fasting glucose levels and percent body fat, which, in turn, correlates with extended lifespan in mice (Mitchell et al., 2016).”
BackgroundMethodInfluentialImpact of dietary carbohydrate type and protein–carbohydrate interaction on metabolic health
Wali, J. A., Milner, A. J., Luk, A. W. S., Pulpitel, T., Dodgson, T., Facey, H. J. W., Wahl, D., Kebede, M. A., Senior, A. M., Sullivan, M. A., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00393-9 · Cited by 91
Sex differences in the response to dietary restriction in rodents
Kane, A. E., Sinclair, D. A., Mitchell, J. R., & Mitchell, S. J. (2018) · Current Opinion in Physiology · doi:10.1016/j.cophys.2018.03.008 · Cited by 86
Fasting blood glucose as a predictor of mortality: Lost in translation
Palliyaguru, D. L., Shiroma, E. J., Nam, J. K., Duregon, E., Teixeira, C. V. L., Price, N. L., Bernier, M., Camandola, S., Vaughan, K. L., Colman, R. J., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.08.013 · Cited by 81
Nutrition and Inflammation: Are Centenarians Similar to Individuals on Calorie-Restricted Diets?
Franceschi, C., Ostan, R., & Santoro, A. (2018) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-082117-051637 · Cited by 84
Amoedo, N. D., Obre, E., & Rossignol, R. (2017) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2017.02.005 · Cited by 76
Regulation of metabolic health and aging by nutrient-sensitive signaling pathways
Richardson, N. E., & Lamming, D. W. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.11.014 · Cited by 73
“of recombinant inbred mice found a range of responses including strains with decreased lifespan, and it has been proposed that the response to CR and/or the optimal degree of restriction to promote longevity may vary according to genotype (Liao et al., 2010; Mitchell et al., 2016).”
BackgroundTrautman, M. E., Richardson, N. E., & Lamming, D. W. (2022) · Aging Cell · doi:10.1111/acel.13626 · Cited by 68
“Modern longevity studies have found substantial effects of sex on lifespan and disease burden (Le Couteur et al., 2018; Mitchell et al., 2016), so it is perhaps unsurprising that sexually dimorphic effects have also been found in mice subject to protein and BCAA restriction.”
BackgroundThe effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent
Suchacki, K. J., Thomas, B. J., Ikushima, Y. M., Chen, K.-C., Fyfe, C., Tavares, A., Sulston, R. J., Lovdel, A., Woodward, H. J., Han, X., et al. (2023) · eLife · doi:10.7554/elife.88080 · Cited by 75
Health benefits of late-onset metformin treatment every other week in mice
Alfaras, I., Mitchell, S. J., Mora, H., Lugo, D. R., Warren, A., Navas-Enamorado, I., Hoffmann, V., Hine, C., Mitchell, J. R., Le Couteur, D. G., et al. (2017) · npj Aging and Mechanisms of Disease · doi:10.1038/s41514-017-0018-7 · Cited by 68
“Metformin is a calorie restriction (CR) mimetic, with several of its metabolic actions, particularly those related to glucose metabolism, resembling to some extent those of CR.2,3,20,21 Our previous study showed that diet supplementation with a low dose of metformin (0.1% w/w) improves healthspan and extends lifespan…”
InfluentialSelf-citationAn isocaloric moderately high-fat diet extends lifespan in male rats and Drosophila
Shi, D., Han, T., Chu, X., Lu, H., Yang, X. Y., Zi, T., Zhao, Y., Wang, X., Liu, Z., Ruan, J., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2020.12.017 · Cited by 66
Sex differences in the intergenerational inheritance of metabolic traits
Sandovici, I., Fernandez‐Twinn, D. S., Hufnagel, A., Constância, M., & Ozanne, S. E. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00570-4 · Cited by 69
Corrales, P., Vivas, Y., Izquierdo‐Lahuerta, A., Horrillo, D., Seoane‐Collazo, P., Velasco, I., Torres, L., López, Y., Martı́nez, C., López, M., et al. (2019) · Aging Cell · doi:10.1111/acel.12948 · Cited by 68
“Reduction in body temperature has been described consistently in the literature as one of the consequences of CR in several animal models, including humans (Barger et al., 2017; Duffy et al., 1989; Mattison et al., 2017; Mitchell et al., 2016; Soare, Cangemi, Omodei, Holloszy, & Fontana, 2011).”
BackgroundFlorian, M. C., Leins, H., Gobs, M., Han, Y., Marka, G., Soller, K., Vollmer, A., Sakk, V., Nattamai, K., Rayes, A., et al. (2020) · Aging Cell · doi:10.1111/acel.13208 · Cited by 66
“…reproducible approaches to extend lifespan and healthspan by non-genetic means like dietary restriction (Longo et al., 2015; Mercken et al., 2013; Mitchell et al., 2016) or pharmacological compounds (https://www.nia.nih.gov/resea rch/dab/inter venti ons-testi ng-progr am-itp) (Campisi et al.,…”
BackgroundSpecies comparison of liver proteomes reveals links to naked mole-rat longevity and human aging
Heinze, I., Bens, M., Calzia, E., Holtze, S., Dakhovnik, O., Sahm, A., Kirkpatrick, J. M., Szafranski, K., Romanov, N., Sama, S. N., et al. (2018) · BMC Biology · doi:10.1186/s12915-018-0547-y · Cited by 65
Protective effects of short-term dietary restriction in surgical stress and chemotherapy
Brandhorst, S., Harputlugil, E., Mitchell, J. R., & Longo, V. D. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.02.001 · Cited by 67
The hidden costs of dietary restriction: Implications for its evolutionary and mechanistic origins
McCracken, A. W., Adams, G., Hartshorne, L., Tatar, M., & Simons, M. J. P. (2020) · Science Advances · doi:10.1126/sciadv.aay3047 · Cited by 68
“Genetic variation in the response to DR, reported in rodents ( 40 ) and flies ( 41 ), might therefore not necessarily, or wholly, constitute variation in the physiological mechanisms that connect DR to ageing.”
Animal models of frailty: current applications in clinical research
Kane, A. E., Hilmer, S. N., Mach, J., Mitchell, S. J., de Cabo, R., & Howlett, S. E. (2016) · Clinical Interventions in Aging · doi:10.2147/cia.s105714 · Cited by 63
Metabolic and molecular framework for the enhancement of endurance by intermittent food deprivation
Marosi, K., Moehl, K., Navas‐Enamorado, I., Mitchell, S. J., Zhang, Y., Lehrmann, E., Aon, M. A., Cortassa, S. C., Becker, K. G., & Mattson, M. P. (2018) · The FASEB Journal · doi:10.1096/fj.201701378rr · Cited by 62
“Analyses were performed using GC-MSmethods previously described (26, 27).”
MethodShirasuna, K., Karasawa, T., & Takahashi, M. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27475 · Cited by 62
“…metabolic interventions (such as caloric restriction) induce fatty acid oxidation and ketone body production, and caloric restriction and BHB reduce inflammation and extend lifespan in animals (Dessein, Shipton, Stanwix, Joffe, & Ramokgadi, 2000; Edwards et al., 2014; Mitchell et al., 2016).”
BackgroundLoos, B., Klionsky, D. J., & Wong, E. S. P. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.05.001 · Cited by 64
Aging, Metabolism, and Cancer Development: from Peto’s Paradox to the Warburg Effect
Tidwell, T., Søreide, K., & Hagland, H. R. (2017) · Aging and Disease · doi:10.14336/ad.2017.0713 · Cited by 64
“The consumption of reduced calories, but not below nutritional levels, has been shown to reduce resting metabolic rate [136], and depends on mitochondrial function for its beneficial outcomes [137].”
BackgroundHine, C., Zhu, Y., Hollenberg, A. N., & Mitchell, J. R. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7434 · Cited by 63
“Twenty to forty percent CR results in a dose-dependent increase in hepatic H2S production in both male and female mice of different strain backgrounds, correlating with improved health, although intriguingly, not always with extended longevity (116).”
BackgroundAman, Y., Frank, J., Lautrup, S., Matysek, A., Niu, Z., Yang, G., Shi, L., Bergersen, L. H., Storm‐Mathisen, J., Rasmussen, L. J., et al. (2019) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2019.111194 · Cited by 63
“In fact, AMPK activation and dietary restriction, which also increases NAD + levels, has been shown to increase lifespan in C. elegans via maintenance of mitochondrial network homeostasis (Mitchell et al., 2016; Weir et al., 2017).”
BackgroundWilson, K. A., Beck, J. N., Nelson, C. S., Hilsabeck, T. A. U., Promislow, D., Brem, R. B., & Kapahi, P. (2020) · Current Biology · doi:10.1016/j.cub.2020.05.020 · Cited by 63
“To determine the effects of genetic variation under DR-mediated changes in lifespan, we reared ~200 mated females in eight vials from 161 DGRP lines under AL conditions or a DR protocol previously demonstrated to consistently extend lifespan [5, 28].”
BackgroundMethodStudy of Longitudinal Aging in Mice: Presentation of Experimental Techniques
Palliyaguru, D. L., Teixeira, C. V. L., Duregon, E., Germanio, C. D., Alfaras, I., Mitchell, S. J., Navas‐Enamorado, I., Shiroma, E. J., Studenski, S. A., Bernier, M., et al. (2020) · The Journals of Gerontology Series A · doi:10.1093/gerona/glaa285 · Cited by 62
The impact of age and frailty on ventricular structure and function in C57BL/6J mice
Feridooni, H. A., Kane, A. E., Ayaz, O., Boroumandi, A., Polidovitch, N., Tsushima, R. G., Rose, R. A., & Howlett, S. E. (2017) · The Journal of Physiology · doi:10.1113/jp274134 · Cited by 56
Hypothalamic gene transfer of BDNF promotes healthy aging in mice
McMurphy, T. B., Huang, W., Liu, X., Siu, J. J., Queen, N. J., Xiao, R., & Cao, L. (2018) · Aging Cell · doi:10.1111/acel.12846 · Cited by 55
Wilson, K. A., Chamoli, M., Hilsabeck, T. A. U., Pandey, M., Bansal, S., Chawla, G., & Kapahi, P. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.08.018 · Cited by 57
“Overall, the outcomes and optimal dosage of DR differ by sex and by strain (Mitchell et al., 2016), which necessitates study into the best means to treat different sexes with DR-based treatments.”
BackgroundThe translation of age-related body composition findings from rodents to humans
Pappas, L. E., & Nagy, T. R. (2018) · European Journal of Clinical Nutrition · doi:10.1038/s41430-018-0324-6 · Cited by 55
Sex as a Biological Variable in Nutrition Research: From Human Studies to Animal Models
Chen, Y., Kim, M., Paye, S. M., & Benayoun, B. A. (2022) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-062220-105852 · Cited by 59
Biomarkers of aging: from molecules and surrogates to physiology and function
Furrer, R., & Handschin, C. (2025) · Physiological Reviews · doi:10.1152/physrev.00045.2024 · Cited by 68
Metadata
- Authors
- Mitchell, S. J., Madrigal-Matute, J., Scheibye-Knudsen, M., Fang, E., Aon, M., González-Reyes, J. A., Cortassa, S., Kaushik, S., Gonzalez-Freire, M., Patel, B., Wahl, D., Ali, A., Calvo-Rubio, M., Burón, M. I., Guiterrez, V., Ward, T. M., Palacios, H. H., Cai, H., Frederick, D. W., Hine, C., Broeskamp, F., Habering, L., Dawson, J., Beasley, T. M., Wan, J., Ikeno, Y., Hubbard, G., Becker, K. G., Zhang, Y., Bohr, V. A., Longo, D. L., Navas, P., Ferrucci, L., Sinclair, D. A., Cohen, P., Egan, J. M., Mitchell, J. R., Baur, J. A., Allison, D. B., Anson, R. M., Villalba, J. M., Madeo, F., Cuervo, A. M., Pearson, K. J., Ingram, D. K., Bernier, M., & de Cabo, R.
- Affiliations
- National Institutes of Health (US)
- University of Córdoba (ES)
- Albert Einstein College of Medicine (US)
- University of Pennsylvania (US)
- Harvard University (US)
- University of Graz (AT)
- University of Alabama (US)
- University of Southern California (US)
- The University of Texas at San Antonio Health Science Center (US)
- Pennington Biomedical Research Center (US)
- ORCID
- Mitchell, Sarah J.
- Fang, Evandro
- Aon, Miguel
- González-Reyes, José A.
- Cortassa, Sonia
- Kaushik, Susmita
- Wahl, Devin
- Burón, María I.
- Palacios, Hector H.
- Cai, Huan
- Hine, Christopher
- Broeskamp, Filomena
- Dawson, John
- Beasley, T. Mark
- Wan, Junxiang
- Ikeno, Yuji
- Becker, Kevin G.
- Zhang, Yongqing
- Bohr, Vilhelm A.
- Ferrucci, Luigi
- Sinclair, David A.
- Cohen, Pinchas
- Egan, Josephine M.
- Mitchell, James R.
- Baur, Joseph A.
- Allison, David B.
- Anson, R. Michael
- Villalba, José M.
- Madeo, Frank
- Pearson, Kevin J.
- Ingram, Donald K.
- Bernier, Michel
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 23
- Issue
- 6
- Pages
- 1093-1112
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4911707
- OpenAlex
- W2421296032
- Cited by
- 451
- References
- 117
- Citations by year
- 2026: 28 · 2025: 37 · 2024: 45 · 2023: 51 · 2022: 56 · 2021: 57 · 2020: 44 · 2019: 38 · 2018: 50 · 2017: 37 · 2016: 8
- FWCI
- 23.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Deposito Digital UFV (Francisco de Vitoria University) (submittedVersion, cc-by-nc-nd)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Repository of Digital Objects for Teaching Research and Culture (University of Valencia) (submittedVersion, other-oa)
- Funders
- American Diabetes Association (1-15-MI-03)
- Austrian Science Fund (P 24381, P 27893, I1000, P29203)
- Bundesministerium für Wissenschaft, Forschung und Wirtschaft
- National Institutes of Health (AG031782, AG038072)
- National Institute on Aging (AG-04-3483, P01AG034906, R01AG043483, P01AG031782, AG031782, P30AG038072, AG038072, P30AG013319, ZIAAG000368)
- National Institute of General Medical Sciences (R01GM090311)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK041296, P30DK020541, R01DK098656, P30DK079626)
- National Institute of Environmental Health Sciences (R01ES020812, P30ES013508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology (medical) › Dietary Effects on Health
- Keywords
- caloric restriction, aging, sex differences, mouse strains, lifespan extension, healthspan, mitochondrial function, fatty acid metabolism, mitochondrial ultrastructure, metabolomics, gene expression changes
- MeSH terms
- Aging, Animals, Autophagy, Energy Intake, Female, Gene Expression Regulation, Glucose, Homeostasis, Hydrogen Sulfide, Islets of Langerhans, Liver, Longevity, Male, Mice, Inbred Strains, Mitochondria, Phenotype, Sex Characteristics, Biomarkers, Cluster Analysis, Gene Expression Profiling, Ubiquitin, Caloric Restriction, Proteasome Endopeptidase Complex, Mice, Metabolomics, Metabolome
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