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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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LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
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“Analysis of steady-state levels of LC3-II, the most commonly used marker to measure autophagic compartments (Kabeya et al., 2000), revealed that 40% CR significantly increased levels of LC3-II in B6 mice when compared to 20% CR (Figures 5E and 5F).”
BackgroundCui, C., Cui, J., Jin, F., Cui, Y., Li, R., Jiang, X., Tian, Y., Wang, R. C., Jiang, P., & Gao, J. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000479571 · Cited by 5,214
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“Indeed, recent work has shown in humans that slight overweight is associated with the lowest level of all-cause mortality (Flegal et al., 2013; Grabowski and Ellis, 2001).”
Autophagy regulates lipid metabolism
Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., Tanaka, K., Cuervo, A. M., & Czaja, M. J. (2009) · Nature · doi:10.1038/nature07976 · Cited by 3,975 · cited 3×
“Interestingly, all CR livers displayed a significant increase in lipid droplets withmorphological signatures of lipophagy (Singh et al., 2009), which was rarely observed in the AL groups (Figures S4H and S4M).”
BackgroundInfluentialSelf-citationSuppression of basal autophagy in neural cells causes neurodegenerative disease in mice
Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H., et al. (2006) · Nature · doi:10.1038/nature04724 · Cited by 3,882 · cited 1×
“Ubiquitinated proteins are amenable to degradation via macroautophagy, and blockage of this pathway leads to intracellular accumulation of K48- and K63-positive aggregates (Hara et al., 2006; Olzmann and Chin, 2008; Tan et al., 2008).”
BackgroundRapamycin fed late in life extends lifespan in genetically heterogeneous mice
Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., Nadon, N. L., Wilkinson, J. E., Frenkel, K., Carter, C. S., et al. (2009) · Nature · doi:10.1038/nature08221 · Cited by 3,766 · cited 1×
“Not surprisingly, most of these interventions have strain-, diet-, and sex-specific effects on health and survival in mice (Anisimov et al., 2008; Harrison et al., 2009, 2014; Martin-Montalvo et al., 2013; Miller et al., 2011, 2014; Pearson et al., 2008a; Strong et al., 2008, 2013).”
BackgroundFission and selective fusion govern mitochondrial segregation and elimination by autophagy
Twig, G., Elorza, A., Molina, A. J. A., Mohamed, H., Wikstrom, J. D., Walzer, G., Stiles, L., Haigh, S. E., Katz, S., Las, G., et al. (2008) · The EMBO Journal · doi:10.1038/sj.emboj.7601963 · Cited by 3,082 · cited 1×
“Whereas all CR groups showed reducedmitochondria circularity, suggestive of reducedmitophagy, only some of them displayed enhanced lipophagy (Gomes et al., 2011; Twig et al., 2008).”
BackgroundCaloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys
Colman, R. J., Anderson, R. M., Johnson, S. C., Kastman, E. K., Kosmatka, K. J., Beasley, T. M., Allison, D. B., Cruzen, C., Simmons, H. A., Kemnitz, J. W., et al. (2009) · Science · doi:10.1126/science.1173635 · Cited by 2,277 · cited 3×
“This uncoupling of lifespan/health span benefits by CR has been reported in earlier studies in mice and non-human primates (Colman et al., 2009; Mattison et al., 2012; Rikke and Johnson, 2007; Turturro and Hart, 1991).”
ResultThe Effect of Retarded Growth Upon the Length of Life Span and Upon the Ultimate Body Size
McCay, C. M., Crowell, M. F., & Maynard, L. A. (1935) · The Journal of Nutrition · doi:10.1093/jn/10.1.63 · Cited by 2,264 · cited 2×
“, 1917) and then McCay and colleagues reported the lifespan effects of calorie-restricted diet in rats (McCay et al., 1935).”
BackgroundDuring autophagy mitochondria elongate, are spared from degradation and sustain cell viability
Gomes, L. C., Benedetto, G. D., & Scorrano, L. (2011) · Nature Cell Biology · doi:10.1038/ncb2220 · Cited by 1,735 · cited 3×
“It has been shown that mitochondrial shape is closely related to mitophagy in such a way that elongated mitochondria are preserved from mitophagy (Gomes et al., 2011).”
Background
Research works printed but not linked: 1
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Items 101–200 of 452
Growth factor, energy and nutrient sensing signalling pathways in metabolic ageing
Bettedi, L., & Foukas, L. C. (2017) · Biogerontology · doi:10.1007/s10522-017-9724-6 · Cited by 55
Green, C. L., Mitchell, S. E., Derous, D., Wang, Y., Chen, L., Han, J. J., Promislow, D., Lusseau, D., Douglas, A., & Speakman, J. R. (2017) · Aging Cell · doi:10.1111/acel.12570 · Cited by 53
Yoshida, S., Yamahara, K., Kume, S., Koya, D., Yasuda‒Yamahara, M., Takeda, N., Osawa, N., Chin‒Kanasaki, M., Adachi, Y., Nagao, K., et al. (2018) · Aging Cell · doi:10.1111/acel.12796 · Cited by 54
“Based on previous reports (Bluher, Kahn, & Kahn, 2003; Forster et al., 2003; Migliaccio et al., 1999; Mitchell et al., 2016; Weindruch & Walford, 1982), the survival rate of male C57BL/6 mice is approximately 50%–60% at 24 months old.”
ResultAnti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept
Kim, D. H., Bang, E., Jung, H. J., Noh, S. G., Yu, B. P., Choi, Y. J., & Chung, H. Y. (2020) · Nutrients · doi:10.3390/nu12020422 · Cited by 53
“Similarly, reduced incidence or slower disease progression has been reported for cardiomyopathy, diabetes, chronic lung diseases, autoimmune diseases, and neurodegenerative diseases [35,36].”
BackgroundEnergy Restriction and Colorectal Cancer: A Call for Additional Research
Castejón, M., Plaza, A., Martínez-Romero, J., Fernández-Marcos, P. J., de Cabo, R., & Díaz‐Ruiz, A. (2020) · Nutrients · doi:10.3390/nu12010114 · Cited by 52
Gene-by-environment modulation of lifespan and weight gain in the murine BXD family
Roy, S., Sleiman, M. S. B., Jha, P., Ingels, J. F., Chapman, C. J., McCarty, M. S., Ziebarth, J. D., Hook, M., Sun, A., Zhao, W., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00449-w · Cited by 51
Developmental mechanisms of sex differences: from cells to organisms
Mank, J. E., & Rideout, E. J. (2021) · Development · doi:10.1242/dev.199750 · Cited by 58
Caloric Restriction Study Design Limitations in Rodent and Nonhuman Primate Studies
Vaughan, K. L., Kaiser, T. A., Peaden, R., Anson, R. M., de Cabo, R., & Mattison, J. A. (2017) · The Journals of Gerontology Series A · doi:10.1093/gerona/glx088 · Cited by 54
The effect of calorie restriction on mouse skeletal muscle is sex, strain and time-dependent
Boldrin, L., Ross, J. A., Whitmore, C. L., Doreste, B., Beaver, C., Eddaoudi, A., Pearce, D. J., & Morgan, J. E. (2017) · Scientific Reports · doi:10.1038/s41598-017-04896-y · Cited by 51
Endpoint or Kinetic Measurement of Hydrogen Sulfide Production Capacity in Tissue Extracts
Hine, C., & Mitchell, J. R. (2017) · BIO-PROTOCOL · doi:10.21769/bioprotoc.2382 · Cited by 53
“Previously, we used this method to detect changes in H2S production capacity as a function of diet or genetic background in a variety of biological samples including yeast, worms, flies, and rodent tissues/organs including liver (Hine et al., 2015; Mitchell et al., 2016; Nikonorova et al., 2017).”
MethodDíaz‐Ruiz, A., Lanasa, M., Garcia, J., Mora, H., Fan, F., Martín‐Montalvo, A., Francesco, A. D., Calvo‐Rubio, M., Salvador‐Pascual, A., Aon, M. A., et al. (2018) · Aging Cell · doi:10.1111/acel.12767 · Cited by 52
“Nonetheless, the maintenance of body weight in older RedTg mice may be due to higher fat accumulation than in Wt controls, in agreement with our recent study that showed a positive correlation between mouse longevity and conservation of body fat (Mitchell et al., 2016).”
MethodResultEpigenetic Regulation of Metabolism and Inflammation by Calorie Restriction
Hernández‐Saavedra, D., Moody, L., Xu, G. B., Chen, H., & Pan, Y. (2018) · Advances in Nutrition · doi:10.1093/advances/nmy129 · Cited by 52
“Moreover, important caveats exist in CR research, where sex-specific and strainspecific effects are observed, and higher restrictions result in improvements of neither lifespan nor health span (31).”
BackgroundDerous, D., Mitchell, S. E., Wang, L., Green, C. L., Wang, Y., Chen, L., Han, J. J., Promislow, D., Lusseau, D., Douglas, A., et al. (2017) · Aging · doi:10.18632/aging.101269 · Cited by 49
“Major urinary proteins (MUPs) are used by male mice in scent marking to attract females and their synthesis is a major cost of reproduction [31,62,63].”
Yaku, K., Okabe, K., & Nakagawa, T. (2018) · Biomedical Chromatography · doi:10.1002/bmc.4205 · Cited by 49
Dietary macronutrient content, age-specific mortality and lifespan
Senior, A. M., Solon‐Biet, S. M., Cogger, V. C., Couteur, D. G. L., Nakagawa, S., Raubenheimer, D., & Simpson, S. J. (2019) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2019.0393 · Cited by 47
Mu, W., Vanhoosier, E., Elks, C. M., & Grant, R. W. (2018) · Nutrients · doi:10.3390/nu10070918 · Cited by 48
“During caloric restriction there is also upregulation of the urea cycle, which is likely related to increased TCA cycle anapleurosis in mice [60].”
BackgroundMcKay, A. S., Costa, E. K., Chen, J., Hu, C., Chen, X., Bedbrook, C. N., Khondker, R. C., Thielvoldt, M., Singh, P. P., Wyss‐Coray, T., et al. (2022) · eLife · doi:10.7554/elife.69008 · Cited by 48
Calorie restriction effects on circadian rhythms in gene expression are sex dependent
Astaf’ev, A. A., Patel, S. A., & Kondratov, R. V. (2017) · Scientific Reports · doi:10.1038/s41598-017-09289-9 · Cited by 49
Fasting and fasting-mimicking diets for chemotherapy augmentation
Brandhorst, S. (2021) · GeroScience · doi:10.1007/s11357-020-00317-7 · Cited by 50
Caloric restriction: implications for sarcopenia and potential mechanisms
Xie, W.-Q., Xiao, W.-F., Tang, K., Wu, Y.-X., Hu, P.-W., Li, Y.-S., Duan, Y., & Lv, S. (2020) · Aging · doi:10.18632/aging.103987 · Cited by 46
“com 24447 AGING impact the overall energetic balance of the organism, which determines the outcome of the intervention on health [82].”
BackgroundBejarano, E., Murray, J. W., Wang, X., Pampliega, O., Yin, D., Patel, B., Yuste, A., Wolkoff, A. W., & Cuervo, A. M. (2018) · Aging Cell · doi:10.1111/acel.12777 · Cited by 45
Vázquez-Fonseca, L., Schäfer, J., Navas‐Enamorado, I., Santos‐Ocaña, C., Hernández‐Camacho, J. D., Guerra, I., Cascajo, M. V., Sánchez‐Cuesta, A., Horvath, Z., Siendones, E., et al. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8091374 · Cited by 42
Nicotinamide Adenine Dinucleotide in Aging Biology: Potential Applications and Many Unknowns
Bhasin, S., Seals, D. R., Migaud, M. E., Musi, N., & Baur, J. A. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnad019 · Cited by 50
Toward reconciling the roles of FGF21 in protein appetite, sweet preference, and energy expenditure
Solon‐Biet, S. M., Clark, X., Bell-Anderson, K. S., Rusu, P. M., Perks, R., Freire, T., Pulpitel, T., Senior, A. M., Hoy, A. J., Aung, O., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113536 · Cited by 43
Does diet influence aging? Evidence from animal studies
Couteur, D. G. L., Raubenheimer, D., Solon‐Biet, S. M., de Cabo, R., & Simpson, S. J. (2022) · Journal of Internal Medicine · doi:10.1111/joim.13530 · Cited by 46
“For example, in one strain of mice, 40% CR led to greater weight loss than 20% CR, yet lifespan was longer in the mice with 20% CR [86].”
BackgroundInfluentialEnergy Metabolism and Brain Aging: Strategies to Delay Neuronal Degeneration
Na, D., Zhang, Z., Meng, M., Li, M., Gao, J., Kong, J., Zhang, G., & Guo, Y. (2025) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-025-01555-z · Cited by 44
“Interestingly, gender-specific responses to CR have been identified, with female subjects exhibiting greater longevity benefits compared to males under CR conditions (Mitchell et al. 2016).”
Refeeding-associated AMPKγ1 complex activity is a hallmark of health and longevity
Ripa, R., Ballhysa, E., Steiner, J. D., Laboy, R., Annibal, A., Hochhard, N., Latza, C., Dolfi, L., Calabrese, C., Meyer, A. M., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00521-y · Cited by 44
dos Santos, C., Cambraia, A., Shrestha, S., Cutler, M., Cottam, M. A., Perkins, G. A., Lev‐Ram, V., Roy, B., Acree, C., Keun-young Kim, A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-53127-2 · Cited by 53
“Accordingly, CR increases mitochondrial bioenergetic ef fi ciency and reduces oxidative stress accumulation in several systems 21,75,76 , which may increase mitochondrial protein longevity in aged cells 77 .”
BackgroundResultInfluentialPomatto, L. C. D., Cline, M., Woodward, N. C., Pakbin, P., Sioutas, C., Morgan, T. E., Finch, C. E., Forman, H. J., & Davies, K. J. A. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.04.574 · Cited by 42
“This is important as evidence indicates sex-specific differences in lifespan [111] and healthspan [112,113].”
Metabolic remodelling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice
Cortassa, S. C., Caceres, V., Tocchetti, C. G., Bernier, M., de Cabo, R., Paolocci, N., Sollott, S. J., & Aon, M. A. (2018) · The Journal of Physiology · doi:10.1113/jp276824 · Cited by 42
Role of dietary modifications in the management of type 2 diabetic complications
Oza, M. J., Laddha, A. P., Gaikwad, A. B., Mulay, S. R., & Kulkarni, Y. A. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105602 · Cited by 42
Velingkaar, N., Mezhnina, V., Poe, A., Makwana, K., Tulsian, R., & Kondratov, R. V. (2020) · Aging Cell · doi:10.1111/acel.13138 · Cited by 40
“Caloric restriction significantly improves insulin sensitivity (Masoro et al., 1992; Mitchell et al., 2016).”
BackgroundInfluentialZeng, T., Cui, H., Tang, D., Garside, G. B., Wang, Y., Wu, J., Tao, Z., Zhang, L., & Tao, S. (2019) · Biogerontology · doi:10.1007/s10522-019-09830-5 · Cited by 41
Obesity and risk of diseases associated with hallmarks of cellular ageing: a multicohort study
Mika Kivimaki, B., Frank, P., Pentti, J., Xu, X., Vahtera, J., Ervasti, J. M., Nyberg, S. T., Lindbohm, J. V., Jokela, M. M., & Partridge, L. (2024) · The Lancet Healthy Longevity · doi:10.1016/s2666-7568(24)00087-4 · Cited by 43
“21,31 Mendelian randomisation studies support a causal association between obesity and accelerated epigenetic ageing, 32 although this relation ship might be bidirectional such that DNA methylation also contributes to fat accumulation.”
Selman, C., & Swindell, W. R. (2018) · The EMBO Journal · doi:10.15252/embj.2018100862 · Cited by 38
Is Rapamycin a Dietary Restriction Mimetic?
Unnikrishnan, A., Kurup, K., Salmon, A. B., & Richardson, A. G. (2019) · The Journals of Gerontology Series A · doi:10.1093/gerona/glz060 · Cited by 37
“(25) C57BL/6 6 mo 60% AL 19% NS Mitchell et al.”
Forney, L. A., Stone, K. P., Gibson, A. N., Vick, A. M., Sims, L. C., Fang, H., & Gettys, T. W. (2020) · Obesity · doi:10.1002/oby.22721 · Cited by 39
“The rationale for this work stems from recent studies reporting fundamentally different responses to protein dilution (15), methionine deprivation (17), and CR (37) between males and females.”
BackgroundMethodPotential Anti-Aging Substances Derived from Seaweeds
Cao, L., Lee, S. G., Lim, K. T., & Kim, H. (2020) · Marine Drugs · doi:10.3390/md18110564 · Cited by 43
Sirtuin 3 Plays a Critical Role in the Antidepressant- and Anxiolytic-like Effects of Kaempferol
Li, H., Wang, J., Liang, L., Shen, S.-Y., Li, W., Chen, X., Li, B., Zhang, Y., & Yu, J. M. (2022) · Antioxidants · doi:10.3390/antiox11101886 · Cited by 38
“Mitochondria were isolated from hippocampal tissues by mechanical homogenization and differential centrifugation using a mitochondria isolation kit for tissue (Abcam, Cambridge, UK, ab110168) with published protocols [31].”
MethodIdentifying the Critical Gaps in Research on Sex Differences in Metabolism Across the Life Span
Reusch, J. E. B., Kumar, T. R., Regensteiner, J. G., Zeitler, P. S., Participants, C., Arany, Z. P., Merz, C. N. B., Barrett-Connor, E. L., Boyle, K. E., Brown, L., et al. (2017) · Endocrinology · doi:10.1210/en.2017-03019 · Cited by 39
“In mouse strains, females do not always live longer than males; however, there are distinct differences in how females and males respond to interventions that extend life span (11).”
BackgroundImplementation of environmental enrichment after middle age promotes healthy aging
McMurphy, T. B., Huang, W., Queen, N. J., Ali, S., Widstrom, K. J., Liu, X., Xiao, R., Siu, J. J., & Cao, L. (2018) · Aging · doi:10.18632/aging.101502 · Cited by 38
“Fh1 (encoding mitochondrial fumarate hydratase) and Parp1 (encoding poly ADP-ribose polymerase 1) are associated with CRinduced metabolic adaption [49].”
BackgroundHenderson, Y. O., Bithi, N., Link, C., Yang, J., Schugar, R. C., Llarena, N. C., Brown, J. M., & Hine, C. (2021) · GeroScience · doi:10.1007/s11357-021-00330-4 · Cited by 39
Duregon, E., Fernández, M. E., Romero, J. M., Germanio, C. D., Cabassa, M., Voloshchuk, R. S., Ehrlich-Mora, M. R., Moats, J. M., Wong, S., Bosompra, O., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.05.003 · Cited by 36
Miller, B. F., Pharaoh, G. A., Hamilton, K. L., Peelor, F. F., Kirkland, J. L., Freeman, W. M., Mann, S. N., Kinter, M. T., Price, J. C., & Stout, M. B. (2019) · The Journals of Gerontology Series A · doi:10.1093/gerona/glz113 · Cited by 37
Komatsu, T., Park, S., Hayashi, H., Mori, R., Yamaza, H., & Shimokawa, I. (2019) · Nutrients · doi:10.3390/nu11123068 · Cited by 41
Cavinato, M. S., Madreiter‐Sokolowski, C. T., Büttner, S., Schosserer, M., Zwerschke, W., Wedel, S., Grillari, J., Graier, W. F., & Jansen‐Dürr, P. (2020) · FEBS Journal · doi:10.1111/febs.15631 · Cited by 38
Spurious intragenic transcription is a feature of mammalian cellular senescence and tissue aging
Sen, P., Donahue, G., Li, C. Y., Egervári, G., Yang, N., Lan, Y., Robertson, N., Shah, P. P., Kerkhoven, E., Schultz, D., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00384-3 · Cited by 39
Kritchevsky, S. B., & Cummings, S. R. (2025) · JAMA · doi:10.1001/jama.2025.11289 · Cited by 40
Green, C. L., Soltow, Q. A., Mitchell, S. E., Derous, D., Wang, Y., Chen, L., Han, J. J., Promislow, D., Lusseau, D., Douglas, A., et al. (2018) · The Journals of Gerontology Series A · doi:10.1093/gerona/gly058 · Cited by 36
“This is consistent with previous metabolic analyses in the liver, which indicated that the relationship between CR and metabolite level is not always linear (6).”
BackgroundResultInfluentialAgeing, cellular senescence and the impact of diet: an overview
Maduro, A. I., Luís, C., & Soares, R. A. (2021) · Porto Biomedical Journal · doi:10.1097/j.pbj.0000000000000120 · Cited by 37
“or slowing down of disease progression was observed for neurodegenerative disorders, cardiovascular diseases, and metabolic syndrome.(54) There is also some interesting data reporting”
BackgroundMisaligned feeding uncouples daily rhythms within brown adipose tissue and between peripheral clocks
Acosta-Rodríguez, V. A., Rijo‐Ferreira, F., van Rosmalen, L., Izumo, M., Park, N., Joseph, C., Hepler, C., Thorne, A. K., Stubblefield, J. J., Bass, J. T., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114523 · Cited by 35
Lifelong dietary intervention does not affect hematopoietic stem cell function
Lazare, S., Ausema, A., Reijne, A. C., van Dijk, G., van Os, R. P., & de Haan, G. (2017) · Experimental Hematology · doi:10.1016/j.exphem.2017.06.002 · Cited by 36
“Finally, the outcome of caloric restriction studies is dependent on many parameters, and seemingly conflicting results in this field have been reported previously [14].”
ResultBair, W.-N., Petr, M. A., Alfaras, I., Mitchell, S. J., Bernier, M., Ferrucci, L., Studenski, S. A., & de Cabo, R. (2019) · The Journals of Gerontology Series A · doi:10.1093/gerona/glz015 · Cited by 35
“To compare with humans, mouse age is scaled to an optimal life span of 37 months, which represents the typical life span for a B6 male mouse on standard diet (19).”
BackgroundMetabolic switching is impaired by aging and facilitated by ketosis independent of glycogen
Hernandez, A. R., Truckenbrod, L. M., Federico, Q. P., Campos, K. T., Moon, B., Ferekides, N., Hoppe, M., D’Agostino, D. P., & Burke, S. N. (2020) · Aging · doi:10.18632/aging.103116 · Cited by 35
“Intermittent periods of eating inevitably lead to episodes of ketogenesis, in which fat is oxidized into ketone bodies, reducing the need for glycolysis (Anson et al., 2003; Mitchell et al., 2019, 2016).”
BackgroundMetabolic adaptation to calorie restriction
Guijas, C., Montenegro-Burke, J. R., Cintrón-Colón, R., Domingo-Almenara, X., Sánchez-Alavez, M., Aguirre, C., Shankar, K., Majumder, E. L. ‐., Billings, E., Conti, B., et al. (2020) · Science Signaling · doi:10.1126/scisignal.abb2490 · Cited by 39
Understanding the aging hypothalamus, one cell at a time
Hajdarovic, K. H., Yu, D., & Webb, A. E. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2022.10.004 · Cited by 34
“4% in males compared to ad libitum fed animals [66].”
BackgroundCalorie restriction and calorie-restriction mimetics activate chaperone-mediated autophagy
Jafari, M., Macho‐González, A., Díaz, A., Lindenau, K. L., Santiago‐Fernández, O., Zeng, M., Massey, A. C., de Cabo, R., Kaushik, S., & Cuervo, A. M. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2317945121 · Cited by 40
Acyl-CoA-binding protein (ACBP): the elusive ‘hunger factor’ linking autophagy to food intake
Pedro, J. M. B., Sica, V., Madeo, F., & Kroemer, G. (2019) · Cell Stress · doi:10.15698/cst2019.10.200 · Cited by 34
“Continuous or periodic stimulation of autophagy by caloric restriction or intermittent fasting, respectively, improves the fitness of model organisms ranging from yeast to primates [24-28].”
BackgroundSREBP-1c-Dependent Metabolic Remodeling of White Adipose Tissue by Caloric Restriction
Kobayashi, M., Fujii, N., Narita, T., & Higami, Y. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113335 · Cited by 34
“Moreover, Mitchell and colleagues have demonstrated that CR-associated responses or mechanisms in mice differ according to strain and sex [9].”
BackgroundPomatto, L. C. D., Dill, T., Carboneau, L., Levan, S., Kato, J. I., Mercken, E. M., Pearson, K. J., Bernier, M., & de Cabo, R. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.01.005 · Cited by 32
“Thus, the ability to maintain fat mass may partly explain the beneficial prolongevity properties of CR (29).”
BackgroundMcCracken, A. W., Buckle, E., & Simons, M. J. P. (2020) · Journal of Experimental Biology · doi:10.1242/jeb.230185 · Cited by 33
“DR is known to reduce reproductive output and is interpreted as a response to decreased energy availability (Moatt et al., 2016).”
BackgroundSexual dimorphism of circadian liver transcriptome
Astaf’ev, A. A., Mezhnina, V., Poe, A., Jiang, P., & Kondratov, R. V. (2024) · iScience · doi:10.1016/j.isci.2024.109483 · Cited by 34
“1,2 At the same time, there is an increasing awareness of the predominantly male-favored sex-bias across the fields in biomedical research.”
BackgroundProteostasis and ageing: insights from long‐lived mutant mice
Sands, W. A., Page, M. M., & Selman, C. (2017) · The Journal of Physiology · doi:10.1113/jp274334 · Cited by 32
Changing Functional Signatures of Microglia along the Axis of Brain Aging
Brawek, B., Skok, M., & Garaschuk, O. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22031091 · Cited by 36
“, the appearance of lymphoma, without necessarily prolonging the lifespan of the animals [146].”
BackgroundRegulation of metabolic health by dietary histidine in mice
Flores, V., Spicer, A. B., Sonsalla, M. M., Richardson, N. E., Yu, D., Sheridan, G. E., Trautman, M. E., Babygirija, R., Cheng, E. P., Rojas, J. M., et al. (2022) · The Journal of Physiology · doi:10.1113/jp283261 · Cited by 29
Gibbs, V. K., Brewer, R. A., Miyasaki, N., Patki, A., & Smith, D. L. (2017) · The Journals of Gerontology Series A · doi:10.1093/gerona/glx127 · Cited by 30
The effect of different levels of dietary restriction on glucose homeostasis and metabolic memory
Matyi, S., Jackson, J. A., Garrett, K. P., Deepa, S. S., & Unnikrishnan, A. (2018) · GeroScience · doi:10.1007/s11357-018-0011-5 · Cited by 30
“The improvement in glucose tolerance after 4 months is similar for mice fed 10 to 40% DR, which is in agreement with the study by Mitchell et al. (2016), showing that glucose tolerance was similar in mice fed 20 and 40% DR for 17–18 months.”
BackgroundResultInfluentialBeyond calorie restriction: aging as a biological target for nutrient therapies
Austad, S. N., & Hoffman, J. M. (2020) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2020.11.008 · Cited by 35
Charles, K. N., Li, M., Engin, F., Arruda, A. P., Inouye, K., & Hotamışlıgil, G. S. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.051 · Cited by 30
“Recent studies suggest that calorie restriction also extends lifespan in a context-dependent manner, though it uniformly improves metabolic health (Mattison et al., 2012; Mitchell et al., 2016; Pearson et al., 2008).”
BackgroundUniversal transcriptomic hallmarks of mammalian ageing and mortality
Tyshkovskiy, A., Kholdina, D., Davitadze, M., Molière, A., Moldakozhayev, A., Tongu, Y., Kasahara, T., Glubokov, D., Eames, A., Kats, L., et al. (2026) · Nature · doi:10.1038/s41586-026-10542-3 · Cited by 39
Fate of Hematopoiesis During Aging. What Do We Really Know, and What are its Implications?
Broxmeyer, H. E., Liu, Y., Kapur, R., Orschell, C. M., Aljoufi, A., Ropa, J. P., Trinh, T. L. P., Burns, S. S., & Capitano, M. L. (2020) · Stem Cell Reviews and Reports · doi:10.1007/s12015-020-10065-y · Cited by 30
“extensively reviewed [222–224], such studies do not always take into account the sex and mouse strains utilized [225]”
BackgroundMetabolomics in aging research: aging markers from organs
Fang, W., Chen, S., Jin, X., Liu, S., Cao, X., & Liu, B. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1198794 · Cited by 30
Reduced expression of C/EBPβ-LIP extends health and lifespan in mice
Müller, C., Zidek, L. M., Ackermann, T., de Jong, T. V., Liu, P., Kliche, V., Zaini, M. A., Kortman, G., Harkema, L., Verbeek, D. S., et al. (2018) · eLife · doi:10.7554/elife.34985 · Cited by 31
Alogliptin improves survival and health of mice on a high‐fat diet
Zhu, B., Li, Y., Xiang, L., Zhang, J., Wang, L., Guo, B., Liang, M., Chen, L., Xiang, L., Dong, J., et al. (2019) · Aging Cell · doi:10.1111/acel.12883 · Cited by 29
Calorie Restriction Protects against Contrast‐Induced Nephropathy via SIRT1/GPX4 Activation
Fang, D., Wang, Y., Zhang, Z., Yang, D., Gu, D., He, B., Zhang, X., He, D., Wang, H., José, P. A., et al. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/2999296 · Cited by 28
Organ Protection by Caloric Restriction Depends on Activation of the De Novo NAD+ Synthesis Pathway
Späth, M. R., Hoyer-Allo, K. J. R., Seufert, L., Höhne, M., Lucas, C., Bock, T., Isermann, L., Brodesser, S., Lackmann, J., Kiefer, K., et al. (2023) · Journal of the American Society of Nephrology · doi:10.1681/asn.0000000000000087 · Cited by 27
Mitochondrial Aging: Is There a Mitochondrial Clock?
Zorov, D. B., Popkov, V. A., Zorova, L. D., Vorobjev, I. A., Pevzner, I. B., Silachev, D. N., Zorov, S. D., Jankauskas, S. S., Babenko, V. A., & Plotnikov, E. Y. (2016) · The Journals of Gerontology Series A · doi:10.1093/gerona/glw184 · Cited by 27
“In recent years, special attention has been paid to the process of acetylation (mostly nonenzymatic, depending on the availability of acetyl CoA) (73,74) as an aging factor and deacetylation (by deacetylases, such as Sirt3-5) as a rejuvenation factor, although the phosphorylation/dephosphorylation of mitochondrial pro…”
Cortassa, S. C., Aon, M. A., & Sollott, S. J. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00201 · Cited by 27
Tyshkovskiy, A., Kholdina, D., Ying, K., Davitadze, M., Molière, A., Tongu, Y., Kasahara, T., Kats, L., Vladimirova, A., Moldakozhayev, A., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.04.601982 · Cited by 32
Shoveller, A. K. K., McKnight, L. L., Wood, K. M., & Cant, J. P. (2018) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13546 · Cited by 26
Guo, D., Shen, Y., Li, W., Li, Q., Miao, Y., & Zhong, Y. (2020) · Aging · doi:10.18632/aging.102666 · Cited by 26
Is Sex as a Biological Variable Still Being Ignored in Preclinical Aging Research?
Carmody, C., Duesing, C., Kane, A. E., & Mitchell, S. J. (2022) · The Journals of Gerontology Series A · doi:10.1093/gerona/glac042 · Cited by 28
Liu, X., Jin, Z., Summers, S., Derous, D., Li, M., Li, B., Li, L., & Speakman, J. R. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110835 · Cited by 28
Hypothalamic Menin regulates systemic aging and cognitive decline
Leng, L., Yuan, Z., Su, X., Chen, Z., Yang, S., Chen, M., Zhuang, K., Lin, H. Z., Sun, H., Li, H., et al. (2023) · PLoS Biology · doi:10.1371/journal.pbio.3002033 · Cited by 26
Hernandez, A. R., Hernandez, C. M., Truckenbrod, L. M., Campos, K. T., McQuail, J. A., Bizon, J. L., & Burke, S. N. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00239 · Cited by 25
Almendáriz-Palacios, C., Mousseau, D. D., Eskiw, C. H., & Gillespie, Z. E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239220 · Cited by 30
Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet?
Kim, C.-K., Sachdev, P. S., & Braidy, N. (2022) · Aging and Disease · doi:10.14336/ad.2021.0705 · Cited by 27
“Indeed, CR can increase NAD+ level [162].”
Breaking the Ceiling of Human Maximal Life span
Ben-Haim, M. S., Kanfi, Y., Mitchell, S. J., Maoz, N., Vaughan, K. L., Amariglio, N., Lerrer, B., de Cabo, R., Rechavi, G., & Cohen, H. Y. (2017) · The Journals of Gerontology Series A · doi:10.1093/gerona/glx219 · Cited by 27
“Once on a DR diet, mice were identified as having better metabolic measurements and increased life spans compared to ad libitum fed controls (15).”
BackgroundGinkgolide B increases healthspan and lifespan of female mice
Lee, C., Wang, B. Y., Wong, S. H., Chen, Y., Cao, Q., Hsiao, A. W., Fung, S.-H., Chen, Y.-F., Wu, H.-H., Cheng, P.-Y., et al. (2025) · Nature Aging · doi:10.1038/s43587-024-00802-0 · Cited by 26
“However, early increases in mortality have been observed in calorie-restricted 112 and protein-restricted 113,114 mouse models, which might be due to severe metabolic stress or lean loss caused by the diet switch.”
Unnikrishnan, A., Matyi, S., Garrett, K. P., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., Chen, X., Dickinson, S., & Richardson, A. G. (2021) · Aging Cell · doi:10.1111/acel.13500 · Cited by 22
Chow diet in mouse aging studies: nothing regular about it
Lee, J., Purello, C. T., Booth, S. L., Bennett, B. J., Wiley, C. D., & Korstanje, R. (2023) · GeroScience · doi:10.1007/s11357-023-00775-9 · Cited by 24
“Rodent models of aging are critical for advancing the field of geroscience but biological heterogeneity has long hampered the reproducibility of aging rodent studies [1, 2].”
Metabolic regulation of aging and age-related disease
Hamrick, M. W., & Stranahan, A. M. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101175 · Cited by 27
Aon, M. A., Cortassa, S. C., Juhaszova, M., González-Reyes, J. A., Calvo‐Rubio, M., Villalba, J. M., Lachance, A. D., Ziman, B. D., Mitchell, S. J., Murt, K. N., et al. (2021) · npj Aging and Mechanisms of Disease · doi:10.1038/s41514-020-00054-3 · Cited by 23
Schumann, T., König, J., von Loeffelholz, C., Vatner, D. F., Zhang, D., Perry, R. J., Bernier, M., Chami, J., Henke, C., Kurzbach, A., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02279-8 · Cited by 23
Diet composition influences the metabolic benefits of short cycles of very low caloric intake
Díaz‐Ruiz, A., Rhinesmith, T., Pomatto, L. C. D., Price, N. L., Eshaghi, F., Ehrlich, M. R., Moats, J. M., Carpenter, M., Rudderow, A., Brandhorst, S., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26654-5 · Cited by 23
Goedeke, L., Murt, K. N., Di Francesco, A., Camporez, J. P., Nasiri, A. R., Wang, Y., Zhang, X., Cline, G. W., de Cabo, R., & Shulman, G. I. (2022) · Aging Cell · doi:10.1111/acel.13539 · Cited by 22
Hoyer-Allo, K. J. R., Späth, M. R., Brodesser, S., Zhu, Y., Binz-Lotter, J., Höhne, M., Brönneke, H. S., Bohl, K., Johnsen, M., Kubacki, T., et al. (2022) · Kidney International · doi:10.1016/j.kint.2022.04.033 · Cited by 23
Long-term Dietary Macronutrients and Hepatic Gene Expression in Aging Mice
Gokarn, R., Solon‐Biet, S. M., Cogger, V. C., Cooney, G. J., Wahl, D., McMahon, A. C., Mitchell, J. R., Mitchell, S. J., Hine, C., de Cabo, R., et al. (2018) · The Journals of Gerontology Series A · doi:10.1093/gerona/gly065 · Cited by 23
Derous, D., Mitchell, S. E., Green, C. L., Wang, Y., Han, J. D. J., Chen, L., Promislow, D., Lusseau, D., Douglas, A., & Speakman, J. R. (2017) · The Journals of Gerontology Series A · doi:10.1093/gerona/glx101 · Cited by 24
“The responses of these strains to CR elucidated a clear role of sex, strain and the level of CR with decreased lifespan at 40% CR for some strains (84).”
BackgroundMalcomson, F. C., & Mathers, J. C. (2018) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-981-13-2835-0_13 · Cited by 21
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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