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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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The road ahead of dietary restriction on anti-aging: focusing on personalized nutrition
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“Many factors would cause these contradictory results, such as the differences in the host, DR degree, and DR duration in different studies (Maegawa et al. 2017; Mitchell et al. 2016; Flanagan et al. 2020; Fontana, Partridge, and Longo 2010).”
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“The extension of human lifespan does not always guarantee an extension of healthspan (defined as the period free from disease), as the two are not necessarily linked (Prince et al., 2015; Fischer et al., 2016; Hansen and Kennedy, 2016; Mitchell et al., 2016; Atella et al., 2019; GBD Ageing Collaborators, 2022; GBD Age…”
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“It is known that female rats and mice had lower body fat deposition compared to males (20, 21).”
BackgroundContextual modifiers of healthspan, lifespan, and epigenome in mice under chronic social stress
Razzoli, M., Nyuyki, K. D., Chen, B. H., & Bartolomucci, A. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2211755120 · Cited by 19
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“CR increases healthspan and lifespan through many mechanisms, including improved glucose homeostasis and mitochondrial health, and by inhibiting all molecular hallmarks of aging (24).”
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“However, if such genes follow the AP model, they should harm old animals and shorten lifespan, as is the normal case in high-stress conditions when organisms exhibit distinct gene expression profiles.(26,39) There-”
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Spankovich, C., & Prell, C. G. L. (2019) · The Journal of the Acoustical Society of America · doi:10.1121/1.5132707 · Cited by 18
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Increased alcohol dehydrogenase 1 activity promotes longevity
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“In addition, influence of sex on aging has also been implicated (78).”
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Targeting mitochondrial autophagy for anti-aging
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Live Longer, but How? Nutrition and Aging
Güzeldere, H. K. B., & Aksoy, M. (2021) · Geriatrik Bilimler Dergisi · doi:10.47141/geriatrik.905089 · Cited by 16
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Pharmacological interventions in human aging
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“These pathways have previously been implicated as having important roles in aging and longevity primarily at the level of gene expression, and our results identify them at the protein level [8, 40, 41, 45].”
Quantification of healthspan in aging mice: introducing FAMY and GRAIL
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“However, the level of CR that optimally extends lifespan may vary by sex and genetic background, and it has been reported that in some strains 40% CR shortens lifespan [19, 20].”
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“Dietary restriction can extend lifespan in some animals, but its effectiveness diminishes with age [149].”
BackgroundLongevity, Metabolic Disease, and Community Health
Spann, S. J., & Ottinger, M. A. (2018) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2017.11.015 · Cited by 14
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“…(MPST) activity was determined in liver by measuring thiocyanate production capacity as described previously for thiosulfate sulfurtransferase (TST) rhodanese activity (Morton et al. 2016), except that sodium 3- mercaptopyruvate (3-MP) was used as a substrate instead of sodium thiosulfate.”
MethodGlucose Metabolism and Aging of Hematopoietic Stem and Progenitor Cells
Poisa-Beiro, L., Landry, J. J. M., Raffel, S., Tanaka, M., Zaugg, J. B., Gavin, A., & Ho, A. D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063028 · Cited by 14
“Multiple studies have demonstrated that caloric restriction can retard the aging decline [83].”
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Sex Specific Differences in Response to Calorie Restriction in Skeletal Muscle of Young Rats
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“Mitochondrial dysfunction, including alterations in the OXPHOS complexes and in mitochondrial dynamics, is as a key hallmark of aging [2,20,21].”
BackgroundThe importance of reaction norms in dietary restriction and ageing research
Simons, M. J. P., & Dobson, A. J. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101926 · Cited by 13
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“The C57BL/6 strain, for example, appears to retain fat mass with aging better than DBA/2 mice [26], and along the same lines recombinant inbred strains responding favorably to CR are better able to maintain adiposity compared to those strains with lifespan shortening due to CR [25].”
BackgroundModulation of frailty syndrome by diet: A review of evidence from mouse studies
Mitchell, S. J., Mitchell, G. J., & Mitchell, J. R. (2019) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2019.04.003 · Cited by 11
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“In contrast, reduced food intake alone (pair-feeding) does not induce alterations or expansion of liver ER membranes or lipid accumulation in the liver [25,26].”
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Obesity and lifespan, a complex tango
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The Geometric Framework for Nutrition and Its Application to Rodent Models
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“…effects on glucose homeostasis, including improvements in glucose tolerance, a lowering of fed and fasting blood glucose levels and increased insulin sensitivity (Mitchell et al., 2016; Hempenstall et al., 2010; Selman and Hempenstall, 2012; Weindruch and Walford, 1988; Velingkaar et al., 2020).”
BackgroundInfluentialSexual dimorphism in Caenorhabditis elegans stress resistance
Piloto, J., Rodriguez, M. J., & Choe, K. P. (2022) · PLoS ONE · doi:10.1371/journal.pone.0272452 · Cited by 9
Grundler, F., Viallon, M., Mesnage, R., Ruscica, M., von Schacky, C., Madeo, F., Hofer, S. J., Mitchell, S. J., Croisille, P., & de Toledo, F. W. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.951000 · Cited by 11
“Another aspect of LF-induced metabolic effects is increased endogenous hydrogen sulfide (H2S) production, a physiological gasotransmitter (37, 38) via sulfhydration/persulfidation (39) with health-promoting properties (REF).”
BackgroundAdult neural stem cells and neurogenesis are resilient to intermittent fasting
Gabarró‐Solanas, R., Davaatseren, A., Kleifeld, J., Kepčija, T., Köcher, T., Giralt, A., Crespo‐Enríquez, I., & Urbán, N. (2023) · EMBO Reports · doi:10.15252/embr.202357268 · Cited by 10
“…can occur even within the C57BL/6J strain and the response to dietary interventions is strain and even substrain-specific (Hwang et al , 2008; Mitchell et al , 2016; Siersbæk et al , 2020; Bachmann et al , 2022), we cannot rule out that small differences in the animals’ background could have…”
BackgroundLate-life shift in caloric intake affects fly metabolism and longevity
Li, M., Macro, J., Meadows, K., Mishra, D., Martin, D., Olson, S., Huggins, B., Graveley, B. R., Li, J. Y. H., & Rogina, B. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2311019120 · Cited by 12
“This is consistent with the work showing that best survival in mice subjected to CR was observed in mice that preserved their fat mass longer under CR suggesting that preservation of fat could have a protective role (49, 50).”
ResultMacronutrient interactions and models of obesity: Insights from nutritional geometry
Wali, J. A., Ni, D., Raubenheimer, D., & Simpson, S. J. (2024) · BioEssays · doi:10.1002/bies.202400071 · Cited by 11
Litichevskiy, L., Considine, M., Gill, J., Shandar, V., Cox, T. O., Descamps, H. C., Wright, K. M., Amses, K. R., Dohnalová, L., Liou, M. J., et al. (2025) · Nature Microbiology · doi:10.1038/s41564-025-01963-3 · Cited by 19
Alfaras, I., Ejima, K., Teixeira, C. V. L., Germanio, C. D., Mitchell, S. J., Hamilton, S., Ferrucci, L., Price, N. L., Allison, D. B., Bernier, M., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109560 · Cited by 11
Perinatal diet influences health and survival in a mouse model of leukemia
Palliyaguru, D. L., Rudderow, A., Sossong, A. M., Lewis, K. N., Younts, C. M., Pearson, K. J., Bernier, M., & de Cabo, R. (2020) · GeroScience · doi:10.1007/s11357-020-00199-9 · Cited by 12
Phosphoproteome profiling of mouse liver during normal aging
Liu, J.-F., Wu, Y., Yang, Y.-H., Wu, S., Liu, S., Xu, P., & Yang, J. (2022) · Proteome Science · doi:10.1186/s12953-022-00194-2 · Cited by 11
Zádor, E. (2025) · Cells · doi:10.3390/cells14060431 · Cited by 9
“CR is a method of deliberate reduction in food intake with 10–50% with careful avoidance of malnutrition, that is, providing a sufficient amount of macro-and microelements, vitamins, and dietary fibres [77].”
Effects of calorie, protein, and branched chain amino acid restriction on ovarian aging in mice
Veiga, G. B., Zanini, B. M., Garcia, D. N., Hense, J. D., Barreto, M. M., Isola, J. V. V., Mondadori, R. G., Masternak, M. M., Stout, M. B., & Schneider, A. (2024) · Reproductive Biology · doi:10.1016/j.repbio.2024.100856 · Cited by 10
Ivimey‐Cook, E. R., Sultanova, Z., & Maklakov, A. A. (2025) · Aging Cell · doi:10.1111/acel.70131 · Cited by 12
Dietary restriction reveals sex-specific expression of the mTOR pathway genes in Japanese quails
Reda, G. K., Ndunguru, S. F., Csernus, B., Knop, R., Lugata, J. K., Szabó, C., Czeglédi, L., & Lendvai, Á. Z. (2024) · Scientific Reports · doi:10.1038/s41598-024-58487-9 · Cited by 13
Jablonsky, J., Lasher, A. T., Patki, A., Nagarajan, A., & Sun, L. Y. (2024) · Aging Cell · doi:10.1111/acel.14238 · Cited by 10
“Previous work has shown that female mice display greater increases in lifespan from mild calorie restriction (Mitchell et al., 2016), which may suggest that female mouse lifespan is susceptible to dietary intervention.”
BackgroundPhysiological basis for sex-specific differences in longevity
Cheng, C. J. A., & Nelson, J. F. (2018) · Current Opinion in Physiology · doi:10.1016/j.cophys.2018.04.003 · Cited by 10
Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity
Hahn, O., Stubbs, T. M., Reik, W., Grönke, S., Beyer, A., & Partridge, L. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007766 · Cited by 10
Aging: a New Perspective on an Old Issue
Mori, M. A. (2020) · Anais da Academia Brasileira de Ciências · doi:10.1590/0001-3765202020200437 · Cited by 10
Komine, R., Sugasawa, T., Manevich, L., Tamai, S., Takekoshi, K., & Kanki, Y. (2022) · Nutrients · doi:10.3390/nu14112239 · Cited by 12
“The effect of dietary restrictions on murine lifespan depends on species, strain, and age at the start of an experiment, with both negative and positive effects reported [45,46].”
BackgroundThe cold truth: torpor as a confound in studies of caloric restriction
Wheatley, W. S. R., Marshall, C. J., Taddei, L., Hitrec, T., Pickering, A. E., & Ambler, M. T. (2025) · Journal of Comparative Physiology B · doi:10.1007/s00360-025-01616-1 · Cited by 13
“…the effects of long term caloric restriction and/or periods of fasting in mice, including: delayed aging-related physiological deterioration (Mitchell et al. 2016; Xie et al. 2020; Green et al. 2022) and extended longevity (Weindruch et al. 1986; Mitchell et al. 2019; Green et al. 2022),…”
Molecular hydrogen therapy: A “democratic” emerging strategy against aging and age-related diseases
Brandi, G., Delbaldo, C., Deserti, M., Relli, V., Rimedio, S., Palloni, A., Deiana, C., Saccoccio, G., Ingenito, R., & Tavolari, S. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102802 · Cited by 9
Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice
Trautman, M. E., Green, C. L., MacArthur, M. R., Chaiyakul, K., Alam, Y. H., Yeh, C., Babygirija, R., James, I., Gilpin, M., Zelenovskiy, E., et al. (2025) · Molecular Metabolism · doi:10.1016/j.molmet.2025.102248 · Cited by 10
Calorie Restriction Rescues Mitochondrial Dysfunction in Adck2-Deficient Skeletal Muscle
Hernández‐Camacho, J. D., Fernández‐Ayala, D. J. M., Vicente‐García, C., Navas‐Enamorado, I., López‐Lluch, G., Oliva, C., Artuch, R., García‐Villoria, J., Ribes, A., de Cabo, R., et al. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.898792 · Cited by 10
Pomatto, L. C. D., Bodogai, M., Carpenter, M., Chowdhury, D., Krishna, P., Ng, S., Bosompra, O., Kato, J. I., Wong, S., Reyes-Sepúlveda, C. J., et al. (2022) · GeroScience · doi:10.1007/s11357-022-00635-y · Cited by 10
Tao, S., Wang, Y., Yu, C., Qiu, R., Jiang, Y., Jia, J., Tao, Z., Zhang, L., Zou, B., & Tang, D. (2022) · Gut Microbes · doi:10.1080/19490976.2022.2117509 · Cited by 9
Cell Senescence and Mesenchymal Stromal Cells
Ratushnyy, A. Y., & Buravkova, L. B. (2020) · Human Physiology · doi:10.1134/s0362119720010132 · Cited by 9
“Caloric restriction leads to a significant reduction in the manifestation aging-associated signs [23].”
BackgroundVitiello, D., Dakhovnik, A., Statzer, C., & Ewald, C. Y. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.694033 · Cited by 10
Emiliano, A. B., Lopatinsky, N. R., Kraljević, M., Higuchi, S., He, Y., Haeusler, R. A., & Schwartz, G. J. (2022) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00017.2022 · Cited by 9
Biology of Stress Responses in Aging
Calubag, M. F., Ademi, I., Yeh, C., Babygirija, R., Bhoopat, A. M., Kasza, I., Sonsalla, M. M., Green, C. L., Pak, H. H., & Lamming, D. W. (2023) · doi:10.59368/agingbio.20230002 · Cited by 10
Is Aging as Inevitable as Death and Taxes?
Granger, A., Mott, R. E., & Emambokus, N. R. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.06.003 · Cited by 9
McLean, S., Lee, M. B., Liu, W., Hameed, R., Gujjala, V. A., Zhou, X., Kaeberlein, M. R., & Kaya, A. (2024) · Frontiers in Aging · doi:10.3389/fragi.2024.1408160 · Cited by 10
“…may have a different optimal (for longevity) level of nutrient availability, or the activity of metabolic pathways might differ signi fi cantly depending on genetic background under CR condition, as it was shown in mice previously (Mitchell et al., 2016; Wilkie et al., 2020; Mulvey et al., 2021”
Calubag, M. F., Ademi, I., Grunow, I., Breuer, L., Babygirija, R., Lialios, P., Le, S. M., Minton, D. M., Sonsalla, M. M., Illiano, J., et al. (2025) · Aging Cell · doi:10.1111/acel.70176 · Cited by 9
“Studies of calorie restriction, protein restriction, and geroprotective drugs like rapamycin have shown that different levels of restriction or drugs can yield different responses (Green, Pak, et al. 2022; Miller et al. 2014; Mitchell et al. 2016; Solon-Biet et al. 2014; Weindruch et al. 1986).”
Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice
Calubag, M. F., Ademi, I., Green, C. L., Manchanayake, D. N. H., Jayarathne, H. S. M., Marshall, R. N., Le, S. M., Lialios, P., Breuer, L. E., Yakar, S., et al. (2026) · Nature Aging · doi:10.1038/s43587-026-01169-0 · Cited by 9
“As different strains of mice have distinct responses to lifespan interventions 84,87 , and interventions that begin later in life are more likely to be translatable, future studies of Val-R should be conducted in other strains of mice, including genetically heterogeneous UM-HET3 mice, and test…”
Lipid metabolic alterations in cancer: Common pathophysiology with cardiovascular disease
Llena-Meler, M., Canfrán‐Duque, A., Madrigal‐Matute, J., & Rotllán, N. (2026) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2026.01.003 · Cited by 12
Vatashchuk, M., Hurza, V., Stefanyshyn, N., Bayliak, M. M., Gospodaryov, D. V., Garaschuk, O., & Lushchak, V. I. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.109859 · Cited by 8
Predicting longevity responses to dietary restriction: A stepping stone toward precision geroscience
Pérez-Matos, M. C., & Mair, W. B. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1008833 · Cited by 8
Nonaka, Y., Takeda, R., Kano, Y., & Hoshino, D. (2021) · Nutrients · doi:10.3390/nu13041190 · Cited by 8
“Furthermore, we need to examine sex differences in effects of CR in late-stage of the disease because we used only male mice and there are differences between male and female mice in health and longevity benefits with CR [39].”
Background
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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