Abstract
Intermittent fasting (IF) and ketogenic diets (KDs) have recently attracted much attention in the scientific literature and in popular culture and follow a longer history of exercise and caloric restriction (CR) research. Whereas IF involves cyclic metabolic switching (CMS) between ketogenic and non-ketogenic states, KDs and CR may not. In this Perspective, I postulate that the beneficial effects of IF result from alternating between activation of adaptive cellular stress response pathways during the fasting period, followed by cell growth and plasticity pathways during the feeding period. Thereby, I establish the cyclic metabolic switching (CMS) theory of IF. The health benefits of IF may go beyond those seen with continuous CR or KDs without CMS owing to the unique interplay between the signalling functions of the ketone β-hydroxybutyrate, mitochondrial adaptations, reciprocal activation of autophagy and mTOR pathways, endocrine and paracrine signalling, gut microbiota, and circadian biology. The CMS theory may have important implications for future basic research, clinical trials, development of pharmacological interventions, and healthy lifestyle practices.
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Fig. 1: Mechanisms by which the cycles of switching between a ketogenic fasted state and a non-ketogenic fed state (IF) could enhance cellular resilience and plasticity, promote health, and prevent or reverse disease processes.
Fig. 2: Model for the time courses of cell, tissue, organ system, and organismal adaptations to CMS (TRE).
Fig. 3: Mechanisms through which the ketone BHB might affect gene expression, protein function, and inflammation.
References
Mattson, M. P. The Intermittent Fasting Revolution(MIT Press, 2022).
BookGoogle Scholar
Longo, V. D., Di Tano, M., Mattson, M. P. & Guidi, N. Intermittent and periodic fasting, longevity and disease. Nat. Aging 1, 47–59 (2021).
ArticlePubMedPubMed CentralGoogle Scholar
Varady, K. A., Cienfuegos, S., Ezpeleta, M. & Gabel, K. Clinical application of intermittent fasting for weight loss: progress and future directions. Nat. Rev. Endocrinol. 18, 309–321 (2022).
ArticlePubMedGoogle Scholar
Manoogian, E. N. C., Chow, L. S., Taub, P. R., Laferrère, B. & Panda, S. Time-restricted eating for the prevention and management of metabolic diseases. Endocrine Rev. 43, 405–436 (2022).
ArticleGoogle Scholar
de Cabo, R. & Mattson, M. P. Effects of intermittent fasting on health, aging, and disease. N. Engl. J. Med. 381, 2541–2551 (2019).
ArticlePubMedGoogle Scholar
Harvie, M. N. et al. The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women. Int. J. Obes. 35, 714–727 (2011).
ArticleCASGoogle Scholar
Mohr, A. E. et al. Gut microbiome remodeling and metabolic profile improves in response to protein pacing with intermittent fasting versus continuous caloric restriction. Nat. Commun. 15, 4155 (2024).
ArticlePubMedPubMed CentralCASGoogle Scholar
Teong, X. T. et al. Intermittent fasting plus early time-restricted eating versus calorie restriction and standard care in adults at risk of type 2 diabetes: a randomized controlled trial. Nat. Med. 29, 963–972 (2023).
ArticlePubMedCASGoogle Scholar
Guo, L. et al. A 5:2 intermittent fasting meal replacement diet and glycemic control for adults with diabetes: the EARLY randomized clinical trial. JAMA Netw. Open. 7, e2416786 (2024).
ArticlePubMedPubMed CentralGoogle Scholar
Johnson, J. B. et al. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radic. Biol. Med. 42, 665–674 (2007).
ArticlePubMedCASGoogle Scholar
Vernieri, C. et al. Fasting-mimicking diet is safe and reshapes metabolism and antitumor immunity in patients with cancer. Cancer Discov. 12, 90–107 (2022).
ArticlePubMedCASGoogle Scholar
Dutzmann, J. et al. Intermittent fasting after ST-segment-elevation myocardial infarction improves left ventricular function: the randomized controlled INTERFAST-MI trial. Circ. Heart. Fail. 17, e010936 (2024).
ArticlePubMedCASGoogle Scholar
Vernieri C., Ligorio F., Tripathy D. & Longo V. D. Cyclic fasting-mimicking diet in cancer treatment: preclinical and clinical evidence. Cell Metab. 23, S1550-S413100270-5 (2024).
Ezpeleta, M. et al. Effect of alternate day fasting combined with aerobic exercise on non-alcoholic fatty liver disease: a randomized controlled trial. Cell Metab. 35, 56–70 (2023).
ArticlePubMedCASGoogle Scholar
Rangan, P. et al. Fasting-mimicking diet modulates microbiota and promotes intestinal regeneration to reduce inflammatory bowel disease pathology. Cell Rep. 26, 2704–2719 (2019).
ArticlePubMedPubMed CentralCASGoogle Scholar
Fitzgerald, K. C. et al. Effect of intermittent vs. daily calorie restriction on changes in weight and patient-reported outcomes in people with multiple sclerosis. Mult. Scler. Relat. Disord. 23, 33–39 (2018).
ArticlePubMedPubMed CentralGoogle Scholar
Dewey, E. H. The No Breakfast Plan and the Fasting Cure. pp. 207 (L. N. Fowler and Company, 1900).
Google Scholar
Hatori, M. et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab. 15, 848–860 (2012).
ArticlePubMedPubMed CentralCASGoogle Scholar
Weindruch, R. & Walford, R. L. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science 215, 1415–1418 (1982).
ArticlePubMedCASGoogle Scholar
Goodrick, C. L., Ingram, D. K., Reynolds, M. A., Freeman, J. R. & Cider, N. L. Effects of intermittent feeding upon growth and life span in rats. Gerontology 28, 233–241 (1982).
ArticlePubMedCASGoogle Scholar
Goodrick, C. L., Ingram, D. K., Reynolds, M. A., Freeman, J. R. & Cider, N. Effects of intermittent feeding upon body weight and lifespan in inbred mice: interaction of genotype and age. Mech. Ageing Dev. 55, 69–87 (1990).
ArticlePubMedCASGoogle Scholar
Bruce-Keller, A. J., Umberger, G., McFall, R. & Mattson, M. P. Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults. Ann. Neurol. 45, 8–15 (1999).
3.0.CO;2-V" data-track-item_id="10.1002/1531-8249(199901)45:1<8::AID-ART4>3.0.CO;2-V" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2F1531-8249%28199901%2945%3A1%3C8%3A%3AAID-ART4%3E3.0.CO%3B2-V" aria-label="Article reference 22" data-doi="10.1002/1531-8249(199901)45:1<8::AID-ART4>3.0.CO;2-V">ArticlePubMedCASGoogle Scholar
Halagappa, V. K. et al. Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer’s disease. Neurobiol. Dis. 26, 212–220 (2007).
ArticlePubMedCASGoogle Scholar
Ahmet, I., Wan, R., Mattson, M. P., Lakatta, E. G. & Talan, M. Cardioprotection by intermittent fasting in rats. Circulation 112, 3115–3121 (2005).
ArticlePubMedGoogle Scholar
Chaix, A., Zarrinpar, A., Miu, P. & Panda, S. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab. 20, 991–1005 (2014).
ArticlePubMedPubMed CentralCASGoogle Scholar
Blaževitš, O., Di Tano, M. & Longo, V. D. Fasting and fasting mimicking diets in cancer prevention and therapy. Trends Cancer 9, 212–222 (2023).
ArticlePubMedGoogle Scholar
Duffy, P. H., Feuers, R., Nakamura, K. D., Leakey, J. & Hart, R. W. Effect of chronic caloric restriction on the synchronization of various physiological measures in old female Fischer 344 rats. Chronobiol. Int. 7, 113–124 (1990).
ArticlePubMedCASGoogle Scholar
Acosta-Rodríguez, V. A., de Groot, M. H. M., Rijo-Ferreira, F., Green, C. B. & Takahashi, J. S. Mice under caloric restriction self-impose a temporal restriction of food intake as revealed by an automated feeder system. Cell Metab. 26, 267–277 (2017).
ArticlePubMedPubMed CentralGoogle Scholar
Bruss, M. D., Khambatta, C. F., Ruby, M. A., Aggarwal, I. & Hellerstein, M. K. Calorie restriction increases fatty acid synthesis and whole body fat oxidation rates. Am. J. Physiol. Endocrinol. Metab. 298, E108–E116 (2010).
ArticlePubMedCASGoogle Scholar
Nakamura, S., Hisamura, R., Shimoda, S., Shibuya, I. & Tsubota, K. Fasting mitigates immediate hypersensitivity: a pivotal role of endogenous d-β-hydroxybutyrate. Nutr. Metab. 11, 40 (2014).
ArticleGoogle Scholar
Schupp, M. et al. Metabolite and transcriptome analysis during fasting suggest a role for the p53–Ddit4 axis in major metabolic tissues. BMC Genomics. 14, 758 (2013).
ArticlePubMedPubMed CentralGoogle Scholar
Zauner, C. et al. Resting energy expenditure in short- term starvation is increased as a result of an increase in serum norepinephrine. Am. J. Clin. Nutr. 71, 1511–1515 (2000).
ArticlePubMedCASGoogle Scholar
Gibbons, T. D. et al. Fasting for 20 h does not affect exercise-induced increases in circulating BDNF in humans. J. Physiol. 601, 2121–2137 (2023).
ArticlePubMedCASGoogle Scholar
Buga, A. et al. Fasting and diurnal blood ketonemia and glycemia responses to a six-week, energy-controlled ketogenic diet, supplemented with racemic R/S-BHB salts. Clin. Nutr. Espen. 54, 277–287 (2023).
ArticlePubMedGoogle Scholar
Anson, R. M. et al. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proc. Natl Acad. Sci. USA 100, 6216–6220 (2003).
ArticlePubMedPubMed CentralCASGoogle Scholar
Jeong, M. A. et al. Intermittent fasting improves functional recovery after rat thoracic contusion spinal cord injury. J. Neurotrauma 28, 479–492 (2011).
ArticlePubMedPubMed CentralGoogle Scholar
Pak, H. H. et al. Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice. Nat Metab. 3, 1327–1341 (2021).
ArticlePubMedPubMed CentralCASGoogle Scholar
Gallage S. et al. A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARalpha and PCK1. Cell Metab. 36, 1371–1393 (2024).
Sutton, E. F. et al. Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes. Cell Metab. 27, 1212–1221 (2018).
ArticlePubMedPubMed CentralCASGoogle Scholar
Jamshed, H. et al. Effectiveness of early time-restricted eating for weight loss, fat loss, and cardiometabolic health in adults with obesity: a randomized clinical trial. JAMA Intern Med. 182, 953–962 (2022).
ArticlePubMedPubMed CentralGoogle Scholar
Manoogian, E. N. C. et al. Feasibility of time-restricted eating and impacts on cardiometabolic health in 24-h shift workers: The Healthy Heroes randomized control trial. Cell Metab. 34, 1442–1456 (2022).
ArticlePubMedPubMed CentralCASGoogle Scholar
Tinsley, G. M. et al. Time-restricted feeding in young men performing resistance training: a randomized controlled trial. Eur. J. Sport. Sci. 17, 200–207 (2017).
ArticlePubMedGoogle Scholar
Tinsley, G. M. et al. Time-restricted feeding plus resistance training in active females: a randomized trial. Am. J. Clin. Nutr. 110, 628–640 (2019).
ArticlePubMedPubMed CentralGoogle Scholar
Keenan, S. J. et al. Intermittent fasting and continuous energy restriction result in similar changes in body composition and muscle strength when combined with a 12 week resistance training program. Eur. J. Nutr. 61, 2183–2199 (2022).
ArticlePubMedPubMed CentralCASGoogle Scholar
Stratton, M. T. et al. Four weeks of time-restricted feeding combined with resistance training does not differentially influence measures of body composition, muscle performance, resting energy expenditure, and blood biomarkers. Nutrients 12, 1126 (2020).
ArticlePubMedPubMed CentralCASGoogle Scholar
Moro, T. et al. Time-restricted eating effects on performance, immune function, and body composition in elite cyclists: a randomized controlled trial. J. Int. Soc. Sports Nutr. 17, 65 (2020).
ArticlePubMedPubMed CentralCASGoogle Scholar
Tovar, A. P. et al. Four weeks of 16/8 time restrictive feeding in endurance trained male runners decreases fat mass, without affecting exercise performance. Nutrients 13, 2941 (2021).
ArticlePubMedPubMed CentralCASGoogle Scholar
Richardson, C. E. et al. An intervention of four weeks of time-restricted eating (16/8) in male long-distance runners does not affect cardiometabolic risk factors. Nutrients 15, 985 (2023).
ArticlePubMedPubMed CentralCASGoogle Scholar
Čermáková, E., Forejt, M. & Čermák, M. The influence of intermittent fasting on selected human anthropometric parameters. Int. J. Med. Sci. 21, 2630–2639 (2024).
ArticlePubMedPubMed CentralGoogle Scholar
Almeida, L. G., Dera, A., Murphy, J. & Santosa, S. Improvements in cardiorespiratory fitness, muscle strength and body composition to modest weight loss are similar in those with adult- versus childhood-onset obesity. Clin. Obes. 14, e12623 (2024).
ArticlePubMedGoogle Scholar
Pinto, A. M. et al. Intermittent energy restriction is comparable to continuous energy restriction for cardiometabolic health in adults with central obesity: a randomized controlled trial; the Met-IER study. Clin. Nutr. 39, 1753–1763 (2020).
ArticlePubMedCASGoogle Scholar
Steger, F. L. et al. Intermittent and continuous energy restriction result in similar weight loss, weight loss maintenance, and body composition changes in a 6 month randomized pilot study. Clin. Obes. 11, e12430 (2021).
ArticlePubMedGoogle Scholar
Templeman, I. et al. A randomized controlled trial to isolate the effects of fasting and energy restriction on weight loss and metabolic health in lean adults. Sci. Transl. Med. 13, eabd8034 (2021).
ArticlePubMedGoogle Scholar
Castela, I. et al. Intermittent energy restriction ameliorates adipose tissue-associated inflammation in adults with obesity: a randomised controlled trial. Clin. Nutr. 41, 1660–1666 (2022).
ArticlePubMedCASGoogle Scholar
Sun, X. et al. Intermittent compared with continuous calorie restriction for treatment of metabolic dysfunction-associated steatotic liver disease: a randomized clinical trial. Am. J. Clin. Nutr. 22, S0002-9165(24)00819-0 (2024).
Thomas, A. C. Q., Stead, C. A., Burniston, J. G. & Phillips, S. M. Exercise-specific adaptations in human skeletal muscle: molecular mechanism of making muscles fit and mighty. Free Radic. Biol. Med. 223, 341–356 (2024).
ArticlePubMedCASGoogle Scholar
Heydari, A. R., Wu, B., Takahashi, R., Strong, R. & Richardson, A. Expression of heat shock protein 70 is altered by age and diet at the level of transcription. Mol. Cell. Biol. 13, 2909–2918 (1993).
PubMedPubMed CentralCASGoogle Scholar
Guo, Z., Ersoz, A., Butterfield, D. A. & Mattson, M. P. Beneficial effects of dietary restriction on cerebral cortical synaptic terminals: preservation of glucose and glutamate transport and mitochondrial function after exposure to amyloid beta-peptide, iron, and 3-nitropropionic acid. J. Neurochem. 75, 314–320 (2000).
ArticlePubMedCASGoogle Scholar
Yang, L. et al. Long-term calorie restriction enhances cellular quality-control processes in human skeletal muscle. Cell Rep. 14, 422–428 (2016).
ArticlePubMedCASGoogle Scholar
Gredilla, R. & Barja, G. Minireview: the role of oxidative stress in relation to caloric restriction and longevity. Endocrinology 146, 3713–3717 (2005).
ArticlePubMedCASGoogle Scholar
Qiu, X., Brown, K., Hirschey, M. D., Verdin, E. & Chen, D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 12, 662–667 (2010).
ArticlePubMedCASGoogle Scholar
Arumugam, T. V. et al. Age and energy intake interact to modify cell stress pathways and stroke outcome. Ann. Neurol. 67, 41–52 (2010).
ArticlePubMedPubMed CentralCASGoogle Scholar
Cabelof, D. C. et al. Caloric restriction promotes genomic stability by induction of base excision repair and reversal of its age-related decline. DNA Repair 2, 295–307 (2003).
ArticlePubMedCASGoogle Scholar
Escobar, K. A., Cole, N. H., Mermier, C. M. & VanDusseldorp, T. A. Autophagy and aging: maintaining the proteome through exercise and caloric restriction. Aging Cell. 18, e12876 (2019).
ArticlePubMedGoogle Scholar
Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183–203 (2020).
ArticlePubMedPubMed CentralCASGoogle Scholar
Godar, R. J. et al. Repetitive stimulation of autophagy–lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury. Autophagy 11, 1537–1560 (2015).
ArticlePubMedPubMed CentralCASGoogle Scholar
Liu, H. et al. Intermittent fasting preserves beta-cell mass in obesity-induced diabetes via the autophagy–lysosome pathway. Autophagy 13, 1952–1968 (2017).
ArticlePubMedPubMed CentralCASGoogle Scholar
Ehrnhoefer, D. E. et al. Preventing mutant huntingtin proteolysis and intermittent fasting promote autophagy in models of Huntington disease. Acta Neuropathol. Commun. 6, 16 (2018).
ArticlePubMedPubMed CentralGoogle Scholar
Cruces-Sande, M. et al. Autophagy mediates hepatic GRK2 degradation to facilitate glucagon-induced metabolic adaptation to fasting. FASEB J. 34, 399–409 (2020).
ArticlePubMedCASGoogle Scholar
Wohlgemuth, S. E., Seo, A. Y., Marzetti, E., Lees, H. A. & Leeuwenburgh, C. Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise. Exp. Gerontol. 45, 138–148 (2010).
ArticlePubMedCASGoogle Scholar
Chaudhary, R. et al. Intermittent fasting activates markers of autophagy in mouse liver, but not muscle from mouse or humans. Nutrition 101, 111662 (2022).
ArticlePubMedCASGoogle Scholar
Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 12, 1–222 (2016).
ArticlePubMedPubMed CentralGoogle Scholar
Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).
ArticlePubMedPubMed CentralCASGoogle Scholar
Hofer, S. J. et al. Spermidine is essential for fasting-mediated autophagy and longevity. Nat. Cell Biol. 26, 1571–1584 (2024).
ArticlePubMedPubMed CentralCASGoogle Scholar
Chalkiadaki, A. & Guarente, L. Sirtuins mediate mammalian metabolic responses to nutrient availability. Nat. Rev. Endocrinol. 8, 287–296 (2012).
ArticlePubMedCASGoogle Scholar
Palacios, O. M. et al. Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1α in skeletal muscle. Aging 1, 771–783 (2009).
ArticlePubMedPubMed CentralCASGoogle Scholar
Someya, S. et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143, 802–812 (2010).
ArticlePubMedPubMed CentralCASGoogle Scholar
Liu, Y. et al. SIRT3 mediates hippocampal synaptic adaptations to intermittent fasting and ameliorates deficits in APP mutant mice. Nat. Commun. 10, 1886 (2019).
ArticlePubMedPubMed CentralGoogle Scholar
Hebert, A. S. et al. Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol. Cell 49, 186–199 (2013).
ArticlePubMedCASGoogle Scholar
Cheng, A. et al. Mitochondrial SIRT3 mediates adaptive responses of neurons to exercise and metabolic and excitatory challenges. Cell Metab. 23, 128–142 (2016).
ArticlePubMedCASGoogle Scholar
Kang, C. & Li Ji, L. Role of PGC-1α signaling in skeletal muscle health and disease. Ann. NY Acad. Sci. 1271, 110–117 (2012).
ArticlePubMedCASGoogle Scholar
Martin-Montalvo, A. & de Cabo, R. Mitochondrial metabolic reprogramming induced by calorie restriction. Antioxid. Redox. Signal 19, 310–320 (2013).
ArticlePubMedPubMed CentralCASGoogle Scholar
Picca, A. et al. Aging and calorie restriction oppositely affect mitochondrial biogenesis through TFAM binding at both origins of mitochondrial DNA replication in rat liver. PLoS ONE 8, e74644 (2013).
ArticlePubMedPubMed CentralCASGoogle Scholar
Storoschuk, K. L. et al. Impact of fasting on the AMPK and PGC-1α axis in rodent and human skeletal muscle: a systematic review. Metabolism 152, 155768 (2024).
ArticlePubMedCASGoogle Scholar
Camara, A. et al. The daytime feeding frequency affects appetite-regulating hormones, amino acids, physical activity, and respiratory quotient, but not energy expenditure, in adult cats fed regimens for 21 days. PLoS ONE 15, e0238522 (2020).
ArticlePubMedPubMed CentralCASGoogle Scholar
Briatore, L., Andraghetti, G. & Cordera, R. Effect of two fasting periods of different duration on ghrelin response to a mixed meal. Nutr. Metab. Cardiovasc. Dis. 16, 471–476 (2006).
ArticlePubMedCASGoogle Scholar
Moon, M., Kim, S., Hwang, L. & Park, S. Ghrelin regulates hippocampal neurogenesis in adult mice. Endocr. J. 56, 525–531 (2009).
ArticlePubMedCASGoogle Scholar
Hornsby, A. K. et al. Short-term calorie restriction enhances adult hippocampal neurogenesis and remote fear memory in a Ghsr-dependent manner. Psychoneuroendocrinology 63, 198–207 (2016).
ArticlePubMedPubMed CentralCASGoogle Scholar
Santos, V. V. et al. Acyl ghrelin improves cognition, synaptic plasticity deficits and neuroinflammation following amyloid beta (Aβ1–40) administration in mice. https://doi.org/10.1111/jne.12476 (2017).
Dixit, V. D. et al. Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J. Clin. Invest. 114, 57–66 (2004).
ArticlePubMedPubMed CentralCASGoogle Scholar
Dixit, V. D. et al. Ghrelin promotes thymopoiesis during aging. J. Clin. Invest. 117, 2778–2790 (2007).
ArticlePubMedPubMed CentralCASGoogle Scholar
Tilg, H. & Wolf, A. M. Adiponectin: a key fat-derived molecule regulating inflammation. Expert Opin. Ther. Targets 9, 245–251 (2005).
ArticlePubMedCASGoogle Scholar
Wan, R. et al. Cardioprotective effect of intermittent fasting is associated with an elevation of adiponectin levels in rats. J. Nutr. Biochem. 21, 413–417 (2010).
ArticlePubMedCASGoogle Scholar
Moro, T. et al. Effects of eight weeks of time-restricted feeding (16/8) on basal metabolism, maximal strength, body composition, inflammation, and cardiovascular risk factors in resistance-trained males. J. Transl. Med. 14, 290 (2016).
ArticlePubMedPubMed CentralGoogle Scholar
Li, N. et al. Adiponectin preserves metabolic fitness during aging. eLife 10, e65108 (2021).
ArticlePubMedPubMed CentralCASGoogle Scholar
Balasubramanian, P. et al. Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice. eLife 11, e71282 (2022).
ArticlePubMedPubMed CentralCASGoogle Scholar
Gonon, A. T. et al. Adiponectin protects against myocardial ischaemia-reperfusion injury via AMP-activated protein kinase, Akt, and nitric oxide. Cardiovasc. Res. 78, 116–122 (2008).
ArticlePubMedCASGoogle Scholar
Formolo, D. A., Cheng, T., Yu, J., Kranz, G. S. & Yau, S. Y. Central adiponectin signaling—a metabolic regulator in support of brain plasticity. Brain Plast. 8, 79–96 (2022).
ArticlePubMedPubMed CentralGoogle Scholar
Michenthaler, H. et al. Systemic and transcriptional response to intermittent fasting and fasting-mimicking diet in mice. BMC Biol. 22, 268 (2024).
ArticlePubMedPubMed CentralCASGoogle Scholar
Zhang, Y. et al. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife 1, e00065 (2012).
ArticlePubMedPubMed CentralGoogle Scholar
Hill, C. M. et al. FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice. Nat. Commun. 13, 1897 (2022).
ArticlePubMedPubMed CentralCASGoogle Scholar
Youm, Y. H., Horvath, T. L., Mangelsdorf, D. J., Kliewer, S. A. & Dixit, V. D. Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proc. Natl Acad. Sci. USA 113, 1026–1031 (2016).
ArticlePubMedPubMed CentralCASGoogle Scholar
Yamashita, T., Nifuji, A., Furuya, K., Nabeshima, Y. & Noda, M. Elongation of the epiphyseal trabecular bone in transgenic mice carrying a klotho gene locus mutation that leads to a syndrome resembling aging. J. Endocrinol. 159, 1–8 (1998).
ArticlePubMedCASGoogle Scholar
Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51 (1997).
ArticlePubMedCASGoogle Scholar
Kurosu, H. et al. Suppression of aging in mice by the hormone Klotho. Science 309, 1829–1833 (2005).
ArticlePubMedPubMed CentralCASGoogle Scholar
Dubal, D. B. et al. Life extension factor klotho enhances cognition. Cell Rep. 7, 1065–1076 (2014).
ArticlePubMedPubMed CentralCASGoogle Scholar
Dias, G. P. et al. Intermittent fasting enhances long-term memory consolidation, adult hippocampal neurogenesis, and expression of longevity gene Klotho. Mol. Psychiatry 26, 6365–6379 (2021).
ArticlePubMedPubMed CentralCASGoogle Scholar
Tripathi S. J., Chakraborty S., Miller E., Pieper A. A., Paul B. D. Hydrogen sulfide signalling in neurodegenerative diseases. https://doi.org/10.1111/bph.16170 (2023).
Hine, C. et al. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell 160, 132–144 (2015).
ArticlePubMedCASGoogle Scholar
Sasaki, S. et al. A low-calorie diet improves endothelium-dependent vasodilation in obese patients with essential hypertension. Am. J. Hypertens. 15, 302–309 (2002).
ArticlePubMedCASGoogle Scholar
Shinmura, K., Tamaki, K. & Bolli, R. Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear Sirt1. Am. J. Physiol. Heart Circ. Physiol. 295, H2348–H2355 (2008).
ArticlePubMedPubMed CentralCASGoogle Scholar
Nisoli, E. et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310, 314–317 (2005).
ArticlePubMedCASGoogle Scholar
Mager, D. E. et al. Caloric restriction and intermittent fasting alter spectral measures of heart rate and blood pressure variability in rats. FASEB J. 20, 631–637 (2006).
ArticlePubMedCASGoogle Scholar
Shimazu, T. et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).
ArticlePubMedCASGoogle Scholar
Spigoni, V. et al. Activation of G protein-coupled receptors by ketone bodies: clinical implication of the ketogenic diet in metabolic disorders. Front. Endocrinol. 13, 972890 (2022).
ArticleGoogle Scholar
Marosi, K. et al. 3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons. J. Neurochem. 139, 769–781 (2016).
ArticlePubMedPubMed CentralCASGoogle Scholar
Luda, K. M. et al. Ketolysis drives CD8+ effector function through effects on histone acetylation. Immunity 56, 2021–2035 (2023).
ArticlePubMedPubMed CentralCASGoogle Scholar
Youm, Y. H. et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 21, 263–269 (2015).
ArticlePubMedPubMed CentralCASGoogle Scholar
Voss, M. W., Soto, C., Yoo, S., Sodoma, M., Vivar, C. & van Praag, H. Exercise and hippocampal memory systems. Trends Cogn Sci 23, 318–333 (2019).
ArticlePubMedPubMed CentralGoogle Scholar
Lee, J., Duan, W. & Mattson, M. P. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J. Neurochem. 82, 1367–1375 (2002).
ArticlePubMedCASGoogle Scholar
Stranahan, A. M. et al. Voluntary exercise and caloric restriction enhance hippocampal dendritic spine density and BDNF levels in diabetic mice. Hippocampus 19, 951–961 (2009).
ArticlePubMedPubMed CentralCASGoogle Scholar
Kashiwaya, Y. et al. A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer’s disease. Neurobiol. Aging 34, 1530–1539 (2013).
ArticlePubMedCASGoogle Scholar
Cox, P. J. et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 24, 256–268 (2016).
ArticlePubMedCASGoogle Scholar
Murray, A. J. et al. Novel ketone diet enhances physical and cognitive performance. FASEB J. 30, 4021–4032 (2016).
ArticlePubMedPubMed CentralCASGoogle Scholar
Soni, S. et al. Exogenous ketone ester administration attenuates systemic inflammation and reduces organ damage in a lipopolysaccharide model of sepsis. Biochim. Biophys. Acta Mol. Basis Dis. 1868, 166507 (2022).
ArticlePubMedCASGoogle Scholar
Cheng, A. et al. SIRT3 haploinsufficiency aggravates loss of GABAergic interneurons and neuronal network hyperexcitability in an Alzheimer’s disease model. J. Neurosci. 40, 694–709 (2020).
ArticlePubMedPubMed CentralCASGoogle Scholar
Yurista, S. R. et al. Ketone ester supplementation suppresses cardiac inflammation and improves cardiac energetics in a swine model of acute myocardial infarction. Metabolism 145, 155608 (2023).
ArticlePubMedPubMed CentralCASGoogle Scholar
Poff, A. M., Ari, C., Arnold, P., Seyfried, T. N. & D’Agostino, D. P. Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer. Int. J. Cancer 135, 1711–1720 (2014).
ArticlePubMedPubMed CentralCASGoogle Scholar
Wang, S. P. et al. 3-Hydroxy-3-methylglutaryl-CoA lyase (HL): gene targeting causes prenatal lethality in HL-deficient mice. Hum. Mol. Genet. 7, 2057–2062 (1998).
ArticlePubMedCASGoogle Scholar
Stagg, D. B. et al. Diminished ketone interconversion, hepatic TCA cycle flux, and glucose production in d-β-hydroxybutyrate dehydrogenase hepatocyte-deficient mice. Mol. Metab. 53, 101269 (2021).
ArticlePubMedPubMed CentralCASGoogle Scholar
Horton, J. L. et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight 4, e124079 (2019).
ArticlePubMedPubMed CentralGoogle Scholar
Ducarmon, Q. R. et al. Remodelling of the intestinal ecosystem during caloric restriction and fasting. Trends Microbiol. 31, 832–844 (2023).
ArticlePubMedCASGoogle Scholar
Li, G. et al. Intermittent fasting promotes white adipose browning and decreases obesity by shaping the gut microbiota. Cell Metab. 26, 672–685 (2017).
ArticlePubMedPubMed CentralCASGoogle Scholar
Cignarella, F. et al. Intermittent fasting confers protection in CNS autoimmunity by altering the gut microbiota. Cell Metab. 27, 1222–1235 (2018).
ArticlePubMedPubMed CentralCASGoogle Scholar
Alexander, M. et al. A diet-dependent host metabolite shapes the gut microbiota to protect from autoimmunity. Cell Rep. 43, 114891 (2024).
ArticlePubMedPubMed CentralCASGoogle Scholar
Beli, E. et al. Restructuring of the gut microbiome by intermittent fasting prevents retinopathy and prolongs survival in db/db mice. Diabetes 67, 1867–1879 (2018).
ArticlePubMedPubMed CentralCASGoogle Scholar
Pan, R. Y. et al. Intermittent fasting protects against Alzheimer’s disease in mice by altering metabolism through remodeling of the gut microbiota. Nat. Aging 2, 1024–1039 (2022).
ArticlePubMedCASGoogle Scholar
Serger, E. et al. The gut metabolite indole-3 propionate promotes nerve regeneration and repair. Nature 607, 585–592 (2022).
ArticlePubMedCASGoogle Scholar
Guo, Y. et al. Intermittent fasting improves cardiometabolic risk factors and alters gut microbiota in metabolic syndrome patients. J. Clin. Endocrinol. Metab. 106, 64–79 (2021).
ArticlePubMedGoogle Scholar
Maifeld, A. et al. Fasting alters the gut microbiome reducing blood pressure and body weight in metabolic syndrome patients. Nat. Commun. 12, 1970 (2021).
ArticlePubMedPubMed CentralCASGoogle Scholar
Gabel, K. et al. Effect of time restricted feeding on the gut microbiome in adults with obesity: a pilot study. Nutr. Health 26, 79–85 (2020).
ArticlePubMedGoogle Scholar
Batitucci, G. et al. Intermittent fasting and high-intensity interval training do not alter gut microbiota composition in adult women with obesity. Am. J. Physiol. Endocrinol. Metab. 327, E241–E257 (2024).
ArticlePubMedCASGoogle Scholar
Li, L. et al. Effects of healthy low-carbohydrate diet and time-restricted eating on weight and gut microbiome in adults with overweight or obesity: Feeding RCT. Cell Rep. Med. 5, 101801 (2024).
ArticlePubMedPubMed CentralCASGoogle Scholar
Mao, Y. Q. et al. The antitumour effects of caloric restriction are mediated by the gut microbiome. Nat. Metab. 5, 96–110 (2023).
ArticlePubMedCASGoogle Scholar
Yu, Z. F. & Mattson, M. P. Dietary restriction and 2-deoxyglucose administration reduce focal ischemic brain damage and improve behavioral outcome: evidence for a preconditioning mechanism. J. Neurosci. Res. 57, 830–839 (1999).
3.0.CO;2-2" data-track-item_id="10.1002/(SICI)1097-4547(19990915)57:6<830::AID-JNR8>3.0.CO;2-2" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2F%28SICI%291097-4547%2819990915%2957%3A6%3C830%3A%3AAID-JNR8%3E3.0.CO%3B2-2" aria-label="Article reference 145" data-doi="10.1002/(SICI)1097-4547(19990915)57:6<830::AID-JNR8>3.0.CO;2-2">ArticlePubMedCASGoogle Scholar
Duan, W. & Mattson, M. P. Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson’s disease. J. Neurosci. Res. 57, 195–206 (1999).
3.0.CO;2-P" data-track-item_id="10.1002/(SICI)1097-4547(19990715)57:2<195::AID-JNR5>3.0.CO;2-P" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2F%28SICI%291097-4547%2819990715%2957%3A2%3C195%3A%3AAID-JNR5%3E3.0.CO%3B2-P" aria-label="Article reference 146" data-doi="10.1002/(SICI)1097-4547(19990715)57:2<195::AID-JNR5>3.0.CO;2-P">ArticlePubMedCASGoogle Scholar
Kumar, A. et al. 2-Deoxyglucose drives plasticity via an adaptive ER stress–ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience. Neuron 111, 2831–2846 (2023).
ArticlePubMedPubMed CentralCASGoogle Scholar
Stafstrom, C. E. et al. Anticonvulsant and antiepileptic actions of 2-deoxy-d-glucose in epilepsy models. Ann. Neurol. 65, 435–447 (2009).
ArticlePubMedPubMed CentralCASGoogle Scholar
Wan, R., Camandola, S. & Mattson, M. P. Intermittent fasting and dietary supplementation with 2-deoxy-d-glucose improve functional and metabolic cardiovascular risk factors in rats. FASEB J. 17, 1133–1144 (2003).
ArticlePubMedCASGoogle Scholar
Zhang, D. et al. 2-Deoxy-d-glucose targeting of glucose metabolism in cancer cells as a potential therapy. Cancer Lett 355, 176–183 (2014).
ArticlePubMedCASGoogle Scholar
Minor, R. K. et al. Chronic ingestion of 2-deoxy-d-glucose induces cardiac vacuolization and increases mortality in rats. Toxicol. Appl. Pharmacol. 243, 332–339 (2010).
ArticlePubMedCASGoogle Scholar
Spilman, P. et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS ONE 5, e9979 (2010).
ArticlePubMedPubMed CentralGoogle Scholar
Khan, M. R. et al. Enhanced mTORC1 signaling and protein synthesis in pathologic alpha-synuclein cellular and animal models of Parkinson’s disease. Sci. Transl. Med. 15, eadd0499 (2023).
ArticlePubMedCASGoogle Scholar
Hofmann, C. et al. Transient inhibition of translation improves cardiac function after ischemia/reperfusion by attenuating the inflammatory response. Circulation 150, 1248–1267 (2024).
ArticlePubMedPubMed CentralGoogle Scholar
Dancey, J. mTOR signaling and drug development in cancer. Nat. Rev. Clin. Oncol. 7, 209–219 (2010).
ArticlePubMedCASGoogle Scholar
Schrauwen, P., Walder, K. & Ravussin, E. Human uncoupling proteins and obesity. Obes. Res. 7, 97–105 (1999).
ArticlePubMedCASGoogle Scholar
Andrews, Z. B., Diano, S. & Horvath, T. L. Mitochondrial uncoupling proteins in the CNS: in support of function and survival. Nat. Rev. Neurosci. 6, 829–840 (2005).
ArticlePubMedCASGoogle Scholar
Geisler, J. G., Marosi, K., Halpern, J. & Mattson, M. P. DNP mitochondrial uncoupling, and neuroprotection: a little dab’ll do ya. Alzheimers Dement. 13, 582–591 (2017).
ArticlePubMedGoogle Scholar
Chu, A. C. et al. Mitochondrial UCP4 attenuates MPP+- and dopamine-induced oxidative stress, mitochondrial depolarization, and ATP deficiency in neurons and is interlinked with UCP2 expression. Free Radic. Biol. Med. 46, 810–820 (2009).
ArticlePubMedCASGoogle Scholar
Kishimoto, Y. et al. A mitochondrial uncoupler prodrug protects dopaminergic neurons and improves functional outcome in a mouse model of Parkinson’s disease. Neurobiol. Aging. 85, 123–130 (2020).
ArticlePubMedCASGoogle Scholar
Zhong, R. et al. Micro-doses of DNP preserve motor and muscle function with a period of functional recovery in amyotrophic lateral sclerosis mice. Ann. Neurol. 97, 542–557 (2024).
Liu, D. et al. The mitochondrial uncoupler DNP triggers brain cell mTOR signaling network reprogramming and CREB pathway up-regulation. J. Neurochem. 134, 677–692 (2015).
ArticlePubMedPubMed CentralCASGoogle Scholar
Madeo, F., Carmona-Gutierrez, D., Hofer, S. J. & Kroemer, G. Caloric restriction mimetics against age-associated disease: targets, mechanisms, and therapeutic potential. Cell Metab. 29, 592–610 (2019).
ArticlePubMedCASGoogle Scholar
Lee, J., Jo, D. G., Park, D., Chung, H. Y. & Mattson, M. P. Adaptive cellular stress pathways as therapeutic targets of dietary phytochemicals: focus on the nervous system. Pharmacol. Rev. 66, 815–868 (2014).
ArticlePubMedPubMed CentralGoogle Scholar
Koppel, S. J. & Swerdlow, R. H. Neuroketotherapeutics: a modern review of a century-old therapy. Neurochem. Int. 117, 114–125 (2018).
ArticlePubMedCASGoogle Scholar
Paoli, A. et al. Common and divergent molecular mechanisms of fasting and ketogenic diets. Trends Endocrinol. Metab. 35, 125–141 (2024).
ArticlePubMedCASGoogle Scholar
Minor, R. K. et al. The arcuate nucleus and neuropeptide Y contribute to the antitumorigenic effect of calorie restriction. Aging Cell 10, 483–492 (2011).
ArticlePubMedCASGoogle Scholar
Suwa, G. et al. Paleobiological implications of the Ardipithecus ramidus dentition. Science 326, 94–99 (2009).
ArticlePubMedCASGoogle Scholar
Murugaiyah, V. & Mattson, M. P. Neurohormetic phytochemicals: an evolutionary-bioenergetic perspective. Neurochem. Int. 89, 271–280 (2015).
ArticlePubMedPubMed CentralCASGoogle Scholar
Hu, F. B. Diet strategies for promoting healthy aging and longevity: An epidemiological perspective. J. Intern. Med. 295, 508–531 (2024).
ArticlePubMedGoogle Scholar
Buettner, D. & Skemp, S. Blue zones: lessons from the world’s longest lived. Am. J. Lifestyle Med. 10, 318–321 (2016).
ArticlePubMedPubMed CentralGoogle Scholar
Crosby, L. et al. Ketogenic diets and chronic disease: weighing the benefits against the risks. Front Nutr. 8, 702802 (2021).
ArticlePubMedPubMed CentralGoogle Scholar
Sharma, S. High fat diet and its effects on cognitive health: alterations of neuronal and vascular components of brain. Physiol. Behav. 240, 113528 (2021).
ArticlePubMedCASGoogle Scholar
Feingold K. R. The effect of diet on cardiovascular disease and lipid and lipoprotein levels. In Endotext (eds. Feingold, K. R. et al.) (MDText.com, 2024).
De Caterina, R. N. n-3 fatty acids in cardiovascular disease. N. Engl. J. Med. 364, 2439–24350 (2011).
ArticlePubMedGoogle Scholar
Marosi, K. et al. Metabolic and molecular framework for the enhancement of endurance by intermittent food deprivation. FASEB J. 32, 3844–3858 (2018).
ArticlePubMedPubMed CentralCASGoogle Scholar
Vieira, R. F. L. et al. Time-restricted feeding combined with aerobic exercise training can prevent weight gain and improve metabolic disorders in mice fed a high-fat diet. J. Physiol. 600, 797–813 (2022).
ArticlePubMedCASGoogle Scholar
Beresford-Jones, B. S. et al. The mouse gastrointestinal bacteria catalogue enables translation between the mouse and human gut microbiotas via functional mapping. Cell Host Microbe. 30, 124–138 (2022).
ArticlePubMedPubMed CentralCASGoogle Scholar
Patikorn, C. et al. Intermittent fasting and obesity-related health outcomes: an umbrella review of meta-analyses of randomized clinical trials. JAMA Netw. Open. 4, e2139558 (2021).
ArticlePubMedPubMed CentralGoogle Scholar
Schroor, M. M., Joris, P. J., Plat, J. & Mensink, R. P. Effects of intermittent energy restriction compared with those of continuous energy restriction on body composition and cardiometabolic risk markers — a systematic review and meta-analysis of randomized controlled trials in adults. Adv. Nutr. 15, 100130 (2024).
ArticlePubMedCASGoogle Scholar
Fitzgerald, K. C. et al. Intermittent calorie restriction alters T cell subsets and metabolic markers in people with multiple sclerosis. EBioMedicine 82, 104124 (2022).
ArticlePubMedPubMed CentralCASGoogle Scholar
Kapogiannis, D. et al. Brain responses to intermittent fasting and the healthy living diet in older adults. Cell Metab. 36, 1668–1678 (2024).
ArticlePubMedCASGoogle Scholar
Lugtenberg, R. T. et al. Quality of life and illness perceptions in patients with breast cancer using a fasting mimicking diet as an adjunct to neoadjuvant chemotherapy in the phase 2 DIRECT (BOOG 2013-14) trial. Breast Cancer Res. Treat. 185, 741–758 (2021).
ArticlePubMedCASGoogle Scholar
Harvie, M. et al. Randomised controlled trial of intermittent vs continuous energy restriction during chemotherapy for early breast cancer. Br. J. Cancer 126, 1157–1167 (2022).
ArticlePubMedCASGoogle Scholar
Kleckner, A. S. et al. Time-restricted eating to address cancer-related fatigue among cancer survivors: a single-arm pilot study. J. Integr. Oncol. 11, 379 (2022).
PubMedPubMed CentralGoogle Scholar
Hastings, M. H., Maywood, E. S. & Brancaccio, M. Generation of circadian rhythms in the suprachiasmatic nucleus. Nat. Rev. Neurosci. 19, 453–469 (2018).
ArticlePubMedCASGoogle Scholar
Panda, S. Circadian physiology of metabolism. Science 354, 1008–1015 (2016).
ArticlePubMedPubMed CentralCASGoogle Scholar
Chaix, A., Lin, T., Le, H. D., Chang, M. W. & Panda, S. Time-restricted feeding prevents obesity and metabolic syndrome in mice lacking a circadian clock. Cell Metab. 29, 303–319 (2019).
ArticlePubMedCASGoogle Scholar
Deota, S. et al. Diurnal transcriptome landscape of a multi-tissue response to time-restricted feeding in mammals. Cell Metab. 35, 150–165 (2023).
ArticlePubMedPubMed CentralCASGoogle Scholar
Jamshed, H. et al. Early time-restricted eating improves 24-hour glucose levels and affects markers of the circadian clock, aging, and autophagy in humans. Nutrients 11, 1234 (2019).
ArticlePubMedPubMed CentralCASGoogle Scholar
Zhao, L. et al. Time-restricted eating alters the 24-hour profile of adipose tissue transcriptome in men with obesity. Obesity 31, 63–74 (2023).
ArticlePubMedCASGoogle Scholar
Hawley, J. A., Sassone-Corsi, P. & Zierath, J. R. Chrono-nutrition for the prevention and treatment of obesity and type 2 diabetes: from mice to men. Diabetologia 63, 2253–2259 (2020).
ArticlePubMedGoogle Scholar
Harris, S. B., Weindruch, R., Smith, G. S., Mickey, M. R. & Walford, R. L. Dietary restriction alone and in combination with oral ethoxyquin/2-mercaptoethylamine in mice. J. Gerontol. 45, B141–B147 (1990).
ArticlePubMedCASGoogle Scholar
Jeong, S. et al. Circadian-dependent intermittent fasting influences ischemic tolerance and dendritic spine remodeling. Stroke 55, 2139–2150 (2024).
ArticlePubMedCASGoogle Scholar
Whittaker, D. S. et al. Circadian modulation by time-restricted feeding rescues brain pathology and improves memory in mouse models of Alzheimer’s disease. Cell Metab. 35, 1704–1721 (2003).
ArticleGoogle Scholar
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I thank all lab members and collaborators who worked with me on IF studies in rodent models and RCTs in humans over the past four decades.
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Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Mark P. Mattson
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Mattson, M.P. The cyclic metabolic switching theory of intermittent fasting. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01254-5
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Received:25 September 2024
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DOI:https://doi.org/10.1038/s42255-025-01254-5
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