Dietary restriction with adequate nutrition is the gold standard for delaying ageing and extending healthspan and lifespan in diverse species, including rodents and non-human primates. In this Review, we discuss the effects of dietary restriction in these mammalian model organisms and discuss accumulating data that suggest that dietary restriction results in many of the same physiological, metabolic and molecular changes responsible for the prevention of multiple ageing-associated diseases in humans. We further discuss how different forms of fasting, protein restriction and specific reductions in the levels of essential amino acids such as methionine and the branched-chain amino acids selectively impact the activity of AKT, FOXO, mTOR, nicotinamide adenine dinucleotide (NAD+), AMP-activated protein kinase (AMPK) and fibroblast growth factor 21 (FGF21), which are key components of some of the most important nutrient-sensing geroprotective signalling pathways that promote healthy longevity.
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Fontana, L., Partridge, L. & Longo, V. D. Extending healthy life span — from yeast to humans. Science 328, 321–326 (2010).
Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010).
Speakman, J. R. & Mitchell, S. E. Caloric restriction. Mol. Asp. Med. 32, 159–221 (2011).
Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V. & Nelson, J. F. Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. Aging Cell 9, 92–95 (2010).
Mitchell, S. J. et al. Effects of sex, strain, and energy intake on hallmarks of aging in mice. Cell Metab. 23, 1093–1112 (2016). This study by Mitchell et al. shows that sex, genetic background and the degree of restriction determine the impact of DR on the lifespan of mice.
Weindruch, R. & Sohal, R. S. Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging. N. Engl. J. Med. 337, 986–994 (1997).
Mattison, J. A. et al. Caloric restriction improves health and survival of rhesus monkeys. Nat. Commun. 8, 14063 (2017). Mattison et al. report that calorie restriction increases healthspan and lifespan of rhesus monkeys.
Maegawa, S. et al. Caloric restriction delays age-related methylation drift. Nat. Commun. 8, 539 (2017).
Stonebarger, G. A. et al. Amyloidosis increase is not attenuated by long-term calorie restriction or related to neuron density in the prefrontal cortex of extremely aged rhesus macaques. Geroscience 42, 1733–1749 (2020).
Austad, S. N. Mixed results for dieting monkeys. Nature 489, 210–211 (2012).
Shimokawa, I. et al. Diet and the suitability of the male Fischer 344 rat as a model for aging research. J. Gerontol. 48, B27–B32 (1993).
Ikeno, Y. et al. Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J. Gerontol. A 64A, 522–529 (2009).
Meyer, T. E. et al. Long-term caloric restriction ameliorates the decline in diastolic function in humans. J. Am. Coll. Cardiol. 47, 398–402 (2006).
Stein, P. K. et al. Caloric restriction may reverse age-related autonomic decline in humans. Aging Cell 11, 644–650 (2012).
Wang, M. et al. Calorie restriction curbs proinflammation that accompanies arterial aging, preserving a youthful phenotype. J. Am. Heart Assoc. 7, e009112 (2018).
Ristow, M. & Zarse, K. How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Exp. Gerontol. 45, 410–418 (2010).
Il’yasova, D. et al. Effects of 2 years of caloric restriction on oxidative status assessed by urinary F2-isoprostanes: the CALERIE 2 randomized clinical trial. Aging Cell 17, e12719 (2018). This randomized clinical trial by Il’yasova et al. shows for the first time that moderate calorie restriction reduces oxidative stress in humans.
Nisoli, E. et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310, 314–317 (2005).
Lopez-Lluch, G. et al. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc. Natl Acad. Sci. USA 103, 1768–1773 (2006).
Hansen, M., Rubinsztein, D. C. & Walker, D. W. Autophagy as a promoter of longevity: insights from model organisms. Nat. Rev. Mol. Cell Biol. 19, 579–593 (2018).
Cuervo, A. M. Calorie restriction and aging: the ultimate “cleansing diet”. J. Gerontol. A Biol. Sci. Med. Sci 63, 547–549 (2008).
Yang, L. et al. Long-term calorie restriction enhances cellular quality-control processes in human skeletal muscle. Cell Rep. 14, 422–428 (2016). This study by Yang et al. finds that long-term calorie restriction increases HSP70, LC3 and beclin 1 levels in human skeletal muscle.
Hetz, C., Zhang, K. & Kaufman, R. J. Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell Biol. 21, 421–438 (2020).
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).
Marzetti, E., Lees, H. A., Wohlgemuth, S. E. & Leeuwenburgh, C. Sarcopenia of aging: underlying cellular mechanisms and protection by calorie restriction. BioFactors 35, 28–35 (2009).
Yamada, Y. et al. Caloric restriction and healthy life span: frail phenotype of nonhuman primates in the Wisconsin National Primate Research Center caloric restriction study. J. Gerontol. A Biol. Sci. Med. Sci 73, 273–278 (2018).
Rhoads, T. W. et al. Molecular and functional networks linked to sarcopenia prevention by caloric restriction in rhesus monkeys. Cell Syst. 10, 156–168 e155 (2020).
Mercken, E. M. et al. Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile. Aging Cell 12, 645–651 (2013).
Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
Mana, M. D., Kuo, E. Y. & Yilmaz, Ö. H. Dietary regulation of adult stem cells. Curr. stem Cell Rep. 3, 1–8 (2017).
Yilmaz, O. H. et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012).
Friedman, D. B. & Johnson, T. E. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118, 75–86 (1988).
Kimura, K. D., Tissenbaum, H. A., Liu, Y. & Ruvkun, G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277, 942–946 (1997).
Tatar, M. et al. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292, 107–110 (2001).
Clancy, D. J. et al. Extension of life-span by loss of CHICO, a drosophila insulin receptor substrate protein. Science 292, 104–106 (2001).
Tu, M.-P., Epstein, D. & Tatar, M. The demography of slow aging in male and female Drosophila mutant for the insulin-receptor substrate homologue chico. Aging Cell 1, 75–80 (2002).
Brown-Borg, H. M., Borg, K. E., Meliska, C. J. & Bartke, A. Dwarf mice and the ageing process. Nature 384, 33 (1996). This study by Brown-Borg et al. shows that Ames dwarf mice are long-lived.
Gesing, A., Al-Regaiey, K. A., Bartke, A. & Masternak, M. M. Growth hormone abolishes beneficial effects of calorie restriction in long-lived Ames dwarf mice. Exp. Gerontol. 58, 219–229 (2014).
Coschigano, K. T., Clemmons, D., Bellush, L. L. & Kopchick, J. J. Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 141, 2608–2613 (2000). This study by Coschigano et al shows that Ghr-knockout mice are long-lived.
Bonkowski, M. S. et al. Disruption of growth hormone receptor prevents calorie restriction from improving insulin action and longevity. PLoS ONE 4, e4567 (2009).
Bartke, A., Sun, L. Y. & Longo, V. Somatotropic signaling: trade-offs between growth, reproductive development, and longevity. Physiol. Rev. 93,571–598 (2013).
Lamming, D. W. & Anderson, R. M. in eLS (John Wiley & Sons, 2014).
Yu, D. et al. Calorie-restriction-induced insulin sensitivity is mediated by adipose mTORC2 and not required for lifespan extension. Cell Rep. 29, 236–248 e233 (2019).
Endicott, S. J., Boynton, D. N. Jr, Beckmann, L. J. & Miller, R. A. Long-lived mice with reduced growth hormone signaling have a constitutive upregulation of hepatic chaperone-mediated autophagy. Autophagy 17, 612–625 (2020).
Spadaro, O. et al. Growth hormone receptor deficiency protects against age-related NLRP3 inflammasome activation and immune senescence. Cell Rep. 14, 1571–1580 (2016).
Lamming, D. W. Diminished mTOR signaling: a common mode of action for endocrine longevity factors. SpringerPlus 3, 735 (2014).
Holzenberger, M. et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187 (2003).
Bokov, A. F. et al. Does reduced IGF-1R signaling in Igf1r+/- mice alter aging? PLoS ONE 6, e26891 (2011).
Bluher, M., Kahn, B. B. & Kahn, C. R. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572–574 (2003).
Taguchi, A., Wartschow, L. M. & White, M. F. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 317, 369–372 (2007).
Selman, C. et al. Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J. 22, 807–818 (2008).
Selman, C., Partridge, L. & Withers, D. J. Replication of extended lifespan phenotype in mice with deletion of insulin receptor substrate 1. PLoS ONE 6, e16144 (2011).
Conover, C. A. & Bale, L. K. Loss of pregnancy-associated plasma protein A extends lifespan in mice. Aging Cell 6, 727–729 (2007).
Bale, L. K., West, S. A. & Conover, C. A. Inducible knockdown of pregnancy-associated plasma protein-A gene expression in adult female mice extends life span. Aging Cell 16, 895–897 (2017).
Mao, K. et al. Late-life targeting of the IGF-1 receptor improves healthspan and lifespan in female mice. Nat. Commun. 9, 2394 (2018).
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).
Chen, X. et al. Cryo-EM structure of human mTOR complex 2. Cell Res. 28, 518–528 (2018).
Scaiola, A. et al. The 3.2-A resolution structure of human mTORC2. Sci. Adv. 6, eabc1251 (2020).
Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012). In this study, Lamming et al. find that chronic rapamycin treatment inhibits mTORC2 in vivo, resulting in hepatic insulin resistance.
Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006).
Schreiber, K. H. et al. Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins. Aging Cell 14, 265–273 (2015).
Dominick, G. et al. Regulation of mTOR activity in Snell dwarf and GH receptor gene-disrupted mice. Endocrinology 156, 565–575 (2015).
Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–144 (2009).
Wu, J. J. et al. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep. 4, 913–920 (2013).
Johnson, S. C., Rabinovitch, P. S. & Kaeberlein, M. mTOR is a key modulator of ageing and age-related disease. Nature 493, 338–345 (2013).
Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009). Harrison et al. demonstrate that rapamycin can extend the lifespan of mice.
Arriola Apelo, S. I., Pumper, C. P., Baar, E. L., Cummings, N. E. & Lamming, D. W. Intermittent administration of rapamycin extends the life span of female C57BL/6J mice. J. Gerontol. A Biol. Sci. Med. Sci 71, 876–881 (2016).
Bitto, A. et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife 5, e16351 (2016).
Arriola Apelo, S. I. & Lamming, D. W. Rapamycin: an inhibitor of aging emerges from the soil of Easter Island. J. Gerontol. A Biol. Sci. Med. Sci 71, 841–849 (2016).
Urfer, S. R. et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience 39, 117–127 (2017).
Powell, J. D., Pollizzi, K. N., Heikamp, E. B. & Horton, M. R. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39–68 (2012).
Schreiber, K. H. et al. A novel rapamycin analog is highly selective for mTORC1 in vivo. Nat. Commun. 10, 3194 (2019).
Arriola Apelo, S. I. et al. Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging Cell 15, 28–38 (2016).
Arriola Apelo, S. I. et al. Ovariectomy uncouples lifespan from metabolic health and reveals a sex-hormone-dependent role of hepatic mTORC2 in aging. eLife 9, e56177 (2020).
Chellappa, K. et al. Hypothalamic mTORC2 is essential for metabolic health and longevity. Aging Cell 18, e13014 (2019).
Lamming, D. W. et al. Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan. Aging Cell 13, 911–917 (2014).
Soukas, A. A., Kane, E. A., Carr, C. E., Melo, J. A. & Ruvkun, G. Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev. 23, 496–511 (2009).
Chang, K. et al. TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2. Autophagy 16, 1807–1822 (2020).
Robida-Stubbs, S. et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 15, 713–724 (2012).
Mizunuma, M., Neumann-Haefelin, E., Moroz, N., Li, Y. & Blackwell, T. K. mTORC2-SGK-1 acts in two environmentally responsive pathways with opposing effects on longevity. Aging Cell 13, 869–878 (2014).
Garratt, M., Bower, B., Garcia, G. G. & Miller, R. A. Sex differences in lifespan extension with acarbose and 17-alpha estradiol: gonadal hormones underlie male-specific improvements in glucose tolerance and mTORC2 signaling. Aging Cell 16, 1256–1266 (2017).
Strong, R. et al. Rapamycin-mediated mouse lifespan extension: late-life dosage regimes with sex-specific effects. Aging Cel 19, e13269 (2020).
Mahoney, S. J. et al. A small molecule inhibitor of Rheb selectively targets mTORC1 signaling. Nat. Commun. 9, 548 (2018).
Kaeberlein, M. et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193–1196 (2005).
Hansen, M. et al. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6, 95–110 (2007).
Heintz, C. et al. Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans. Nature 541, 102–106 (2017).
Greer, E. L. & Brunet, A. Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans. Aging Cell 8, 113–127 (2009).
Wu, Z. et al. Dietary restriction extends lifespan through metabolic regulation of innate immunity. Cell Metab. 29, 1192–1205 e1198 (2019).
Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010).
Fok, W. C. et al. Combined treatment of rapamycin and dietary restriction has a larger effect on the transcriptome and metabolome of liver. Aging Cell 13, 311–319 (2014).
Fok, W. C. et al. Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome. PLoS ONE 9, e83988 (2014).
Fok, W. C. et al. Short-term rapamycin treatment in mice has few effects on the transcriptome of white adipose tissue compared to dietary restriction. Mech. Ageing Dev. 140, 23–29 (2014).
Fok, W. C. et al. Short-term treatment with rapamycin and dietary restriction have overlapping and distinctive effects in young mice. J. Gerontol. A Biol. Sci. Med. Sci 68, 108–116 (2013).
Yu, Z. et al. Rapamycin and dietary restriction induce metabolically distinctive changes in mouse liver. J. Gerontol. A Biol. Sci. Med. Sci 70, 410–420 (2015).
Bunpo, P. et al. The eIF2 kinase GCN2 is essential for the murine immune system to adapt to amino acid deprivation by asparaginase. J. Nutr. 140, 2020–2027 (2010).
Ye, J. et al. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J. 29, 2082–2096 (2010).
Ravindran, R. et al. The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation. Nature 531, 523–527 (2016).
Wek, S. A., Zhu, S. & Wek, R. C. The histidyl-tRNA synthetase-related sequence in the eIF-2 alpha protein kinase GCN2 interacts with tRNA and is required for activation in response to starvation for different amino acids. Mol. Cell. Biol. 15, 4497–4506 (1995).
Dong, J., Qiu, H., Garcia-Barrio, M., Anderson, J. & Hinnebusch, A. G. Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain. Mol. Cell 6, 269–279 (2000).
Harding, H. P. et al. The ribosomal P-stalk couples amino acid starvation to GCN2 activation in mammalian cells. eLife 8, e50149 (2019).
Dever, T. E. et al. Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Cell 68, 585–596 (1992).
Harding, H. P. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell 6, 1099–1108 (2000).
Vattem, K. M. & Wek, R. C. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc. Natl Acad. Sci. USA 101, 11269 (2004).
De Sousa-Coelho, A. L., Marrero, P. F. & Haro, D. Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation. Biochem. J. 443, 165–171 (2012).
Laeger, T. et al. Metabolic responses to dietary protein restriction require an increase in FGF21 that is delayed by the absence of GCN2. Cell Rep. 16, 707–716 (2016).
Averous, J. et al. GCN2 contributes to mTORC1 inhibition by leucine deprivation through an ATF4 independent mechanism. Sci. Rep. 6, 27698 (2016).
Rousakis, A. et al. The general control nonderepressible-2 kinase mediates stress response and longevity induced by target of rapamycin inactivation in Caenorhabditis elegans. Aging Cell 12, 742–751 (2013).
Nishimura, T., Nakatake, Y., Konishi, M. & Itoh, N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim. Biophys. Acta 1492, 203–206 (2000).
Laeger, T. et al. FGF21 is an endocrine signal of protein restriction. J. Clin. Invest. 124, 3913–3922 (2014). This study by Laeger et al. shows that many of the metabolic effects of protein restriction are mediated by the hormone FGF21.
Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115, 1627–1635 (2005).
Hill, C. M. et al. FGF21 signals protein status to the brain and adaptively regulates food choice and metabolism. Cell Rep. 27, 2934–2947 e2933 (2019).
Fontana, L. et al. Decreased consumption of branched-chain amino acids improves metabolic health. Cell Rep. 16, 520–530 (2016). Fontana et al. report that short-term protein restriction improves the metabolic health of humans and mice, and that in mice the benefits of protein restriction can be recapitulated by specifically restricting BCAAs.
Thompson, A. C. et al. Fibroblast growth factor 21 is not required for the reductions in circulating insulin-like growth factor-1 or global cell proliferation rates in response to moderate calorie restriction in adult mice. PLoS ONE 9, e111418 (2014).
Zhang, Y. et al. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife 1, e00065 (2012).
Gaich, G. et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 18, 333–340 (2013).
Lee, J. H. et al. An engineered FGF21 variant, LY2405319, can prevent non-alcoholic steatohepatitis by enhancing hepatic mitochondrial function. Am. J. Transl. Res. 8, 4750–4763 (2016).
Ruhlmann, C. et al. Neuroprotective effects of the FGF21 analogue LY2405319. J. Alzheimers Dis. 80, 357–369 (2021).
Imai, S. & Guarente, L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24, 464–471 (2014).
Lin, S. J., Defossez, P. A. & Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126–2128 (2000).
Lamming, D. W. et al. HST2 mediates SIR2-independent life-span extension by calorie restriction. Science 309, 1861–1864 (2005).
Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13, 225–238 (2012).
Wood, J. G. et al. Sirt4 is a mitochondrial regulator of metabolism and lifespan in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 115, 1564–1569 (2018).
Burnett, C. et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477, 482–485 (2011).
Haigis, M. C. & Sinclair, D. A. Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 5, 253–295 (2010).
Eldridge, M. J. G., Pereira, J. M., Impens, F. & Hamon, M. A. Active nuclear import of the deacetylase sirtuin-2 is controlled by its C-terminus and importins. Sci. Rep. 10, 2034 (2020).
Haigis, M. C. et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126, 941–954 (2006).
Mao, Z. et al. SIRT6 promotes DNA repair under stress by activating PARP1. Science 332, 1443–1446 (2011).
Du, J. et al. Sirt5 Is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334, 806 (2011).
Peng, C. et al. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol. Cell Proteom. 10, M111 012658 (2011).
Feldman, J. L., Baeza, J. & Denu, J. M. Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. J. Biol. Chem. 288, 31350–31356 (2013).
Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O. & Sinclair, D. A. Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423, 181–185 (2003).
Medvedik, O., Lamming, D. W., Kim, K. D. & Sinclair, D. A. MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae. PLoS Biol. 5, e261 (2007).
Moroz, N. et al. Dietary restriction involves NAD+-dependent mechanisms and a shift toward oxidative metabolism. Aging Cell 13, 1075–1085 (2014).
Yoshida, M. et al. Extracellular vesicle-contained eNAMPT delays aging and extends lifespan in mice. Cell Metab. 30, 329–342 e325 (2019).
Covarrubias, A. J., Perrone, R., Grozio, A. & Verdin, E. NAD+ metabolism and its roles in cellular processes during ageing. Nat. Rev. Mol. Cell Biol. 22, 119–141 (2021).
Cohen, H. Y. et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305, 390 (2004).
Civitarese, A. E. et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med. 4, e76 (2007).
Shi, T., Wang, F., Stieren, E. & Tong, Q. SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J. Biol. Chem. 280, 13560–13567 (2005).
Nakagawa, T., Lomb, D. J., Haigis, M. C. & Guarente, L. SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 137, 560–570 (2009).
Chalkiadaki, A. & Guarente, L. High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction. Cell Metab. 16, 180–188 (2012).
Pedersen, S. B., Ølholm, J., Paulsen, S. K., Bennetzen, M. F. & Richelsen, B. Low Sirt1 expression, which is upregulated by fasting, in human adipose tissue from obese women. Int. J. Obes. 32, 1250–1255 (2008).
Lutz, M. I., Milenkovic, I., Regelsberger, G. & Kovacs, G. G. Distinct patterns of sirtuin expression during progression of Alzheimer’s disease. Neuromolecular Med. 16, 405–414 (2014).
Boily, G. et al. SirT1 regulates energy metabolism and response to caloric restriction in mice. PLoS ONE 3, e1759 (2008).
Bordone, L. et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 6, 759–767 (2007).
Herranz, D. et al. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat. Commun. 1, 3 (2010).
Satoh, A. et al. Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab. 18, 416–430 (2013).
Park, S. H. et al. SIRT2 is a tumor suppressor that connects aging, acetylome, cell cycle signaling, and carcinogenesis. Transl. Cancer Res. 1, 15–21 (2012).
North, B. J. et al. SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. EMBO J. 33, 1438–1453 (2014).
Benigni, A. et al. Sirt3 deficiency shortens life span and impairs cardiac mitochondrial function rescued by Opa1 gene transfer. Antioxid. Redox Signal. 31, 1255–1271 (2019).
Brown, K. et al. SIRT3 reverses aging-associated degeneration. Cell Rep. 3, 319–327 (2013).
Kawahara, T. L. et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136, 62–74 (2009).
Vakhrusheva, O. et al. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ. Res. 102, 703–710 (2008).
Kanfi, Y. et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483, 218–221 (2012).
Roichman, A. et al. SIRT6 overexpression improves various aspects of mouse healthspan. J. Gerontol. A Biol. Sci. Med. Sci 72, 603–615 (2017).
Sun, S. et al. Vascular endothelium-targeted Sirt7 gene therapy rejuvenates blood vessels and extends life span in a Hutchinson-Gilford progeria model. Sci. Adv. 6, eaay5556 (2020).
Anderson, R. M. et al. Dynamic regulation of PGC-1alpha localization and turnover implicates mitochondrial adaptation in calorie restriction and the stress response. Aging Cell 7, 101–111 (2008).
Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434, 113–118 (2005).
Wang, R. H. et al. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J. Clin. Invest. 121, 4477–4490 (2011).
Menghini, R. et al. MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1. Circulation 120, 1524–1532 (2009).
Ota, H. et al. Sirt1 modulates premature senescence-like phenotype in human endothelial cells. J. Mol. Cell Cardiol. 43, 571–579 (2007).
Hebert, A. S. et al. Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol. Cell 49, 186–199 (2013).
Rose, G. et al. Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly. Exp. Gerontol. 38, 1065–1070 (2003).
Van Meter, M. et al. JNK phosphorylates SIRT6 to stimulate DNA double-strand break repair in response to oxidative stress by recruiting PARP1 to DNA breaks. Cell Rep. 16, 2641–2650 (2016).
Chen, J. et al. Sirt6 overexpression suppresses senescence and apoptosis of nucleus pulposus cells by inducing autophagy in a model of intervertebral disc degeneration. Cell Death Dis. 9, 56 (2018).
Simon, M. et al. LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell Metab. 29, 871–885 e875 (2019).
Salmon, A. B., Richardson, A. & Perez, V. I. Update on the oxidative stress theory of aging: does oxidative stress play a role in aging or healthy aging? Free Radic. Biol. Med. 48, 642–655 (2010).
Schriner, S. E. et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911 (2005).
Elchuri, S. et al. CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24, 367–380 (2005).
Sentman, M. L. et al. Phenotypes of mice lacking extracellular superoxide dismutase and copper- and zinc-containing superoxide dismutase. J. Biol. Chem. 281, 6904–6909 (2006).
Van Remmen, H. et al. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol. Genomics 16, 29–37 (2003).
Zhang, Y. et al. Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity. J. Gerontol. A Biol. Sci. Med. Sci 64, 1212–1220 (2009).
Salmon, A. B. et al. Lack of methionine sulfoxide reductase A in mice increases sensitivity to oxidative stress but does not diminish life span. FASEB J. 23, 3601–3608 (2009).
Van Remmen, H. et al. Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress. Free Radic. Biol. Med. 36, 1625–1634 (2004).
Schulz, T. J. et al. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 6, 280–293 (2007).
Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008).
Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).
Weimer, S. et al. D-Glucosamine supplementation extends life span of nematodes and of ageing mice. Nat. Commun. 5, 3563 (2014).
Ristow, M. et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc. Natl Acad. Sci. USA 106, 8665–8670 (2009).
Bjornsen, T. et al. Vitamin C and E supplementation blunts increases in total lean body mass in elderly men after strength training. Scand. J. Med. Sci. Sports 26, 755–763 (2016).
Bjelakovic, G., Nikolova, D., Gluud, L. L., Simonetti, R. G. & Gluud, C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst. Rev. 14, Cd007176 (2012).
Fontana, L. & Partridge, L. Promoting health and longevity through diet: from model organisms to humans. Cell 161, 106–118 (2015).
Green, C. L. & Lamming, D. W. Regulation of metabolic health by essential dietary amino acids. Mech. Ageing Dev. 177, 186–200 (2019).
Soultoukis, G. A. & Partridge, L. Dietary protein, metabolism, and aging. Annu. Rev. Biochem. 85, 5–34 (2016).
Mair, W., Piper, M. D. & Partridge, L. Calories do not explain extension of life span by dietary restriction in Drosophila. PLoS Biol. 3, e223 (2005).
Grandison, R. C., Piper, M. D. & Partridge, L. Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila. Nature 462, 1061–1064 (2009).
Solon-Biet, S. M. et al. The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metab. 19, 418–430 (2014).
Richardson, N. E. et al. Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and life span in mice. Nat. Aging 1, 73–86 (2021). The study by Richardson et al. shows that lifelong restriction of BCAAs reduces frailty and increases lifespan in male mice.
Speakman, J. R., Mitchell, S. E. & Mazidi, M. Calories or protein? The effect of dietary restriction on lifespan in rodents is explained by calories alone. Exp. Gerontol. 86, 28–38 (2016).
Mitchell, S. E. et al. The effects of graded levels of calorie restriction: I. Impact of short term calorie and protein restriction on body composition in the C57BL/6 mouse. Oncotarget 6, 15902–15930 (2015).
Mitchell, S. E. et al. The effects of graded levels of calorie restriction: II. Impact of short term calorie and protein restriction on circulating hormone levels, glucose homeostasis and oxidative stress in male C57BL/6 mice. Oncotarget 6, 23213–23237 (2015).
Gardner, C. D., Hartle, J. C., Garrett, R. D., Offringa, L. C. & Wasserman, A. S. Maximizing the intersection of human health and the health of the environment with regard to the amount and type of protein produced and consumed in the United States. Nutr. Rev. 77, 197–215 (2019).
Mittendorfer, B., Klein, S. & Fontana, L. A word of caution against excessive protein intake. Nat. Rev. Endocrinol. 16, 59–66 (2020).
Smith, G. I. et al. High-protein intake during weight loss therapy eliminates the weight-loss-induced improvement in insulin action in obese postmenopausal women. Cell Rep. 17, 849–861 (2016).
Weber, M. et al. Lower protein content in infant formula reduces BMI and obesity risk at school age: follow-up of a randomized trial. Am. J. Clin. Nutr. 99, 1041–1051 (2014).
Willcox, B. J. et al. in Healthy Aging and Longevity. Annals of the New York Academy of Sciences Vol. 1114 (eds Weller, N. J. & Rattan, S. I. S.) 434-455 (Springer, 2007).
Lamming, D. W. et al. Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model. Oncotarget 6, 31233–31240 (2015).
Hill, C. M. et al. Low protein-induced increases in FGF21 drive UCP1-dependent metabolic but not thermoregulatory endpoints. Sci. Rep. 7, 8209 (2017).
Orentreich, N., Matias, J. R., DeFelice, A. & Zimmerman, J. A. Low methionine ingestion by rats extends life span. J. Nutr. 123, 269–274 (1993). The study by Orentreich et al. shows that specific restriction of dietary methionine extends the lifespan of rats.
Miller, R. A. et al. Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell 4, 119–125 (2005).
Mazor, K. M. et al. Effects of single amino acid deficiency on mRNA translation are markedly different for methionine versus leucine. Sci. Rep. 8, 8076 (2018).
Lees, E. K. et al. Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21. Aging Cell 13, 817–827 (2014).
Perrone, C. E. et al. Genomic and metabolic responses to methionine-restricted and methionine-restricted, cysteine-supplemented diets in Fischer 344 rat inguinal adipose tissue, liver and quadriceps muscle. J. Nutrigenet Nutrigenomics 5, 132–157 (2012).
Yu, D. et al. Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms. FASEB J. 32, 3471–3482 (2018).
Douris, N. et al. Central fibroblast growth factor 21 browns white fat via sympathetic action in male mice. Endocrinology 156, 2470–2481 (2015).
Wanders, D. et al. Role of GCN2-independent signaling through a noncanonical PERK/NRF2 pathway in the physiological responses to dietary methionine restriction. Diabetes 65, 1499–1510 (2016).
Elshorbagy, A. K. et al. Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase. J. Lipid Res. 52, 104–112 (2011).
Hine, C. & Mitchell, J. R. Calorie restriction and methionine restriction in control of endogenous hydrogen sulfide production by the transsulfuration pathway. Exp. Gerontol. 68, 26–32 (2015).
Mattocks, D. A. et al. Short term methionine restriction increases hepatic global DNA methylation in adult but not young male C57BL/6J mice. Exp. Gerontol. 88, 1–8 (2017).
Haws, S. A., Leech, C. M. & Denu, J. M. Metabolism and the epigenome: a dynamic relationship. Trends Biochem. Sci. 45, 731–747 (2020).
Haws, S. A. et al. Methyl-metabolite depletion elicits adaptive responses to support heterochromatin stability and epigenetic persistence. Mol. Cell 78, 210–223 e218 (2020).
Lees, E. K. et al. Direct comparison of methionine restriction with leucine restriction on the metabolic health of C57BL/6J mice. Sci. Rep. 7, 9977 (2017).
Das, A. et al. Impairment of an endothelial NAD+-H2S signaling network is a reversible cause of vascular aging. Cell 176, 944–945 (2019).
Hine, C. et al. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell 160, 132–144 (2015).
Wang, S. Y. et al. Methionine restriction delays senescence and suppresses the senescence-associated secretory phenotype in the kidney through endogenous hydrogen sulfide. Cell Cycle 18, 1573–1587 (2019).
Ogawa, T. et al. Stimulating S-adenosyl-l-methionine synthesis extends lifespan via activation of AMPK. Proc. Natl Acad. Sci. USA 113, 11913–11918 (2016).
Gu, X. et al. SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science 358, 813–818 (2017).
Cummings, N. E. et al. Restoration of metabolic health by decreased consumption of branched-chain amino acids. J. Physiol. 596, 623–645 (2018).
Yu, D. et al. The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. Cell Metab. 33, 905–922 e906 (2021). This study by Yu et al. shows that restriction of isoleucine is necessary and sufficient for the metabolic benefits of protein restriction.
Solon-Biet, S. M. et al. Branched chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control. Nat. Metab. 1, 532–545 (2019). The study by Solon-Biet et al. shows that dietary supplementation with BCAAs results in hyperphagia, obesity and shorter lifespan of mice.
Newgard, C. B. et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 9, 311–326 (2009).
Maida, A. et al. Repletion of branched chain amino acids reverses mTORC1 signaling but not improved metabolism during dietary protein dilution. Mol. Metab. 6, 873–881 (2017).
Wijeyesekera, A. et al. Metabotyping of long-lived mice using 1H NMR spectroscopy. J. Proteome Res. 11, 2224–2235 (2012).
Juricic, P., Gronke, S. & Partridge, L. Branched-chain amino acids have equivalent effects to other essential amino acids on lifespan and aging-related traits in Drosophila. J. Gerontol. A Biol. Sci. Med. Sci 75, 24–31 (2020).
Ooka, H., Segall, P. E. & Timiras, P. S. Histology and survival in age-delayed low-tryptophan-fed rats. Mech. Ageing Dev. 43, 79–98 (1988).
Segall, P. E. & Timiras, P. S. Patho-physiologic findings after chronic tryptophan deficiency in rats: a model for delayed growth and aging. Mech. Ageing Dev. 5, 109–124 (1976).
De Marte, M. L. & Enesco, H. E. Influence of low tryptophan diet on survival and organ growth in mice. Mech. Ageing Dev. 36, 161–171 (1986).
He, C. et al. Enhanced longevity by ibuprofen, conserved in multiple species, occurs in yeast through inhibition of tryptophan import. PLoS Genet. 10, e1004860 (2014).
Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000).
Chen, T. et al. Tryptophan predicts the risk for future type 2 diabetes. PLoS ONE 11, e0162192 (2016).
Ramos-Chavez, L. A. et al. Low serum tryptophan levels as an indicator of global cognitive performance in nondemented women over 50 years of age. Oxid. Med. Cell Longev. 2018, 8604718 (2018).
Yap, Y. W. et al. Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution. Nat. Commun. 11, 2894 (2020).
Ravichandran, M. et al. Impairing L-threonine catabolism promotes healthspan through methylglyoxal-mediated proteohormesis. Cell Metab. 27, 914–925 e915 (2018).
Acosta-Rodriguez, 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 e262 (2017).
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).
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).
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).
Mitchell, S. J. et al. Daily fasting improves health and survival in male mice independent of diet composition and calories. Cell Metab. 29, 221–228 e223 (2019).
Pak, H. H. et al. Distinct roles of fasting and calories in the metabolic, molecular, and geroprotective effects of a calorie restricted diet. Nat. Metab. (2021) in press.
Trepanowski, J. F. et al. Effect of alternate-day fasting on weight loss, weight maintenance, and cardioprotection among metabolically healthy obese adults: a randomized clinical trial. JAMA Intern. Med. 177, 930–938 (2017).
Griffin, N. W. et al. Prior dietary practices and connections to a human gut microbial metacommunity alter responses to diet interventions. Cell Host Microbe 21, 84–96 (2017).
Dey, N. et al. Regulators of gut motility revealed by a gnotobiotic model of diet-microbiome interactions related to travel. Cell 163, 95–107 (2015).
Carter, S., Clifton, P. M. & Keogh, J. B. The effects of intermittent compared to continuous energy restriction on glycaemic control in type 2 diabetes; a pragmatic pilot trial. Diabetes Res. Clin. Pract. 122, 106–112 (2016).
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).
Mattson, M. P., Longo, V. D. & Harvie, M. Impact of intermittent fasting on health and disease processes. Ageing Res. Rev. 39, 46–58 (2017).
Caderni, G., Perrelli, M. G., Cecchini, F. & Tessitore, L. Enhanced growth of colorectal aberrant crypt foci in fasted/refed rats involves changes in TGFbeta1 and p21CIP expressions. Carcinogenesis 23, 323–327 (2002).
Tomasi, C. et al. Effect of fasting/refeeding on the incidence of chemically induced hepatocellular carcinoma in the rat. Carcinogenesis 20, 1979–1983 (1999).
Tessitore, L. & Bollito, E. Early induction of TGF-beta1 through a fasting-re-feeding regimen promotes liver carcinogenesis by a sub-initiating dose of diethylnitrosamine. Cell Prolif. 39, 105–116 (2006).
Yang, W. et al. Alternate-day fasting protects the livers of mice against high-fat diet-induced inflammation associated with the suppression of Toll-like receptor 4/nuclear factor kappaB signaling. Nutr. Res. 36, 586–593 (2016).
Bagherniya, M., Butler, A. E., Barreto, G. E. & Sahebkar, A. The effect of fasting or calorie restriction on autophagy induction: a review of the literature. Ageing Res. Rev. 47, 183–197 (2018).
Mihaylova, M. M. et al. Fasting activates fatty acid oxidation to enhance intestinal stem cell function during homeostasis and aging. Cell Stem Cell 22, 769–778 e764 (2018).
Li, G. et al. Intermittent fasting promotes white adipose browning and decreases obesity by shaping the gut microbiota. Cell Metab. 26, 672–685.e674 (2017).
Liu, B., Page, A. J., Hutchison, A. T., Wittert, G. A. & Heilbronn, L. K. Intermittent fasting increases energy expenditure and promotes adipose tissue browning in mice. Nutrition 66, 38–43 (2019).
Kimura, I. et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl Acad. Sci. USA 108, 8030–8035 (2011).
Taggart, A. K. et al. (d)-β-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J. Biol. Chem. 280, 26649–26652 (2005).
Shimazu, T. et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).
Schreiber, R. A. & Yeh, Y. Y. Temporal changes in plasma levels and metabolism of ketone bodies by liver and brain after ethanol and/or starvation in C57BL/6J mice. Drug Alcohol. Depend. 13, 151–160 (1984).
Haymond, M. W., Karl, I. E., Clarke, W. L., Pagliara, A. S. & Santiago, J. V. Differences in circulating gluconeogenic substrates during short-term fasting in men, women, and children. Metabolism 31, 33–42 (1982).
Cahill, G. F. Jr et al. Hormone-fuel interrelationships during fasting. J. Clin. Invest. 45, 1751–1769 (1966).
Mattson, M. P. & Arumugam, T. V. Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab. 27, 1176–1199 (2018).
Schübel, R. et al. Effects of intermittent and continuous calorie restriction on body weight and metabolism over 50 wk: a randomized controlled trial. Am. J. Clin. Nutr. 108, 933–945 (2018).
Catenacci, V. A. et al. A randomized pilot study comparing zero-calorie alternate-day fasting to daily caloric restriction in adults with obesity. Obesity 24, 1874–1883 (2016).
Hutchison, A. T. et al. Effects of intermittent versus continuous energy intakes on insulin sensitivity and metabolic risk in women with overweight. Obesity 27, 50–58 (2019).
Brandhorst, S. et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab. 22, 86–99 (2015).
Choi, I. Y. et al. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Rep. 15, 2136–2146 (2016).
Cheng, C. W. et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell 14, 810–823 (2014).
Cheng, C.-W. et al. Fasting-mimicking diet promotes Ngn3-driven β-cell regeneration to reverse diabetes. Cell 168, 775–788.e712 (2017).
Raffaghello, L. et al. Fasting and differential chemotherapy protection in patients. Cell Cycle 9, 4474–4476 (2010).
Lee, C. et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci. Transl. Med. 4, 124ra127 (2012).
Caffa, I. et al. Fasting-mimicking diet and hormone therapy induce breast cancer regression. Nature 583, 620–624 (2020).
Di Biase, S. et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 30, 136–146 (2016).
de Groot, S. et al. Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial. Nat. Commun. 11, 3083 (2020).
Bauersfeld, S. P. et al. The effects of short-term fasting on quality of life and tolerance to chemotherapy in patients with breast and ovarian cancer: a randomized cross-over pilot study. BMC Cancer 18, 476 (2018).
Safdie, F. M. et al. Fasting and cancer treatment in humans: a case series report. Aging 1, 988 (2009).
Mattson, M. P. et al. Meal frequency and timing in health and disease. Proc. Natl Acad. Sci. USA 111, 16647–16653 (2014).
Kavanagh, K., Bashore, A. C., Davis, M., Sherrill, C. & Parks, J. Early time restricted feeding improves high density lipoprotein function in geriatric monkeys. Innov. Aging 3, S104–S104 (2019).
Turek, F. W. et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308, 1043–1045 (2005).
Rudic, R. D. et al. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol. 2, e377 (2004).
Arble, D. M., Bass, J., Laposky, A. D., Vitaterna, M. H. & Turek, F. W. Circadian timing of food intake contributes to weight gain. Obesity 17, 2100–2102 (2009).
Jakubowicz, D., Barnea, M., Wainstein, J. & Froy, O. Effects of caloric intake timing on insulin resistance and hyperandrogenism in lean women with polycystic ovary syndrome. Clin. Sci. 125, 423–432 (2013).
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.e1213 (2018).
St-Onge, M. P. et al. Meal timing and frequency: implications for cardiovascular disease prevention: a scientific statement from the american heart association. Circulation 135, e96–e121 (2017).
Lowe, D. A. et al. Effects of time-restricted eating on weight loss and other metabolic parameters in women and men with overweight and obesity: the TREAT randomized clinical trial. JAMA Intern. Med. 180, 1491–1499 (2020).
Mindikoglu, A. L. et al. Intermittent fasting from dawn to sunset for 30 consecutive days is associated with anticancer proteomic signature and upregulates key regulatory proteins of glucose and lipid metabolism, circadian clock, DNA repair, cytoskeleton remodeling, immune system and cognitive function in healthy subjects. J. Proteom. 217, 103645 (2020).
Fontana, L., Fasano, A., Chong, Y. S., Vineis, P. & Willett, W. C. Transdisciplinary research and clinical priorities for better health. PLoS Med. 18, e1003699 (2021).
Flurkey, K., Papaconstantinou, J., Miller, R. A. & Harrison, D. E. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc. Natl Acad. Sci. USA 98, 6736 (2001).
Flurkey, K., Papaconstantinou, J. & Harrison, D. E. The Snell dwarf mutation Pit1dw can increase life span in mice. Mech. Ageing Dev. 123, 121–130 (2002).
Bartke, A. et al. Extending the lifespan of long-lived mice. Nature 414, 412 (2001).
Bartke, A. et al. Effects of Soy-derived diets on plasma and liver lipids, glucose tolerance, and longevity in normal, long-lived and short-lived mice. Horm. Metab. Res. 36, 550–558 (2004).
Ikeno, Y., Bronson, R. T., Hubbard, G. B., Lee, S. & Bartke, A. Delayed occurrence of fatal neoplastic diseases in Ames dwarf mice: correlation to extended longevity. J. Gerontol. A Biol. Sci. Med. Sci 58, 291–296 (2003).
Bartke, A., Chandrashekar, V., Bailey, B., Zaczek, D. & Turyn, D. Consequences of growth hormone (GH) overexpression and GH resistance. Neuropeptides 36, 201–208 (2002).
Coschigano, K. T. et al. Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology 144, 3799–3810 (2003).
Yan, L. et al. Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 130, 247–258 (2007).
Zhang, H. M., Diaz, V., Walsh, M. E. & Zhang, Y. Moderate lifelong overexpression of tuberous sclerosis complex 1 (TSC1) improves health and survival in mice. Sci. Rep. 7, 834 (2017).
Miskin, R. & Masos, T. Transgenic mice overexpressing urokinase-type plasminogen activator in the brain exhibit reduced food consumption, body weight and size, and increased longevity. J. Gerontol. A Biol. Sci. Med. Sci 52, B118–B124 (1997).
Nojima, A. et al. Haploinsufficiency of akt1 prolongs the lifespan of mice. PLoS ONE 8, e69178 (2013).
Uneda, K. et al. Angiotensin II type 1 receptor-associated protein regulates kidney aging and lifespan independent of angiotensin. J. Am. Heart Assoc. 6, e006120 (2017).
Meng, J. & Ferguson, S. M. GATOR1-dependent recruitment of FLCN-FNIP to lysosomes coordinates Rag GTPase heterodimer nucleotide status in response to amino acids. J. Cell Biol. 217, 2765–2776 (2018).
Petit, C. S., Roczniak-Ferguson, A. & Ferguson, S. M. Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. J. Cell Biol. 202, 1107–1122 (2013).
Wu, X. et al. FLCN maintains the leucine level in lysosome to stimulate mTORC1. PLoS ONE 11, e0157100 (2016).
Martinez-Carreres, L. et al. CDK4 regulates lysosomal function and mTORC1 activation to promote cancer cell survival. Cancer Res. 79, 5245–5259 (2019).
Hesketh, G. G. et al. The GATOR-Rag GTPase pathway inhibits mTORC1 activation by lysosome-derived amino acids. Science 370, 351–356 (2020).
Efeyan, A. et al. Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature 493, 679–683 (2013).
Wolfson, R. L. et al. KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature 543, 438–442 (2017).
Orozco, J. M. et al. Dihydroxyacetone phosphate signals glucose availability to mTORC1. Nat. Metab. 2, 893–901 (2020).
Yang, H. et al. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature 552, 368–373 (2017).
Dibble, C. C. et al. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol. Cell 47, 535–546 (2012).
Yang, S. et al. The Rag GTPase regulates the dynamic behavior of TSC downstream of both amino acid and growth factor restriction. Dev. Cell 55, 272–288.e5 (2020).
Budanov, A. V. & Karin, M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134, 451–460 (2008).
The authors specially thank A.Y.X. Dai for helping with the creation of figures. The Lamming laboratory is supported by the US National Institute on Aging (AG056771, AG061635 and AG062328 to D.W.L.), the US National Institute of Diabetes and Digestive and Kidney Diseases (DK125859 to D.W.L.), and by funding from the University of Wisconsin-Madison School of Medicine and Public Health and Department of Medicine to D.W.L. C.L.G. is a Glenn Foundation for Medical Research Postdoctoral Fellow. The Lamming laboratory and C.L.G. were supported in part by a generous gift from Dalio Philanthropies. The Lamming laboratory is also supported by the US Department of Veterans Affairs (I01-BX004031), and this work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. The Fontana laboratory is supported by grants from the Australian National Health and Medical Research Council Investigator Grants programme (APP1177797), the Australian Youth and Health Foundation and the Bakewell Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health, the US Department of Veterans Affairs or the US Government. The authors apologize for the omission of relevant work owing to space constraints.
D.W.L. has received funding from and is a scientific advisory board member of Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases. The University of Wisconsin-Madison has applied for a patent for the use of amino acid-restricted diets to promote metabolic health, for which D.W.L. is an inventor. The remaining authors declare no competing interests.
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- Hazard ratio
A comparison between the probability of events in a treatment group and the probability of events in a control group.
- Kaplan–Meier estimated survival
Kaplan–Meier estimated survival or the Kaplan–Meier estimator, also known as the product limit estimator, is a non-parametric statistic used to estimate the survival function from lifetime data. It measures and generates statistics for the fraction of a designated population that is alive at a certain time point.
Age-related hearing loss.
- Cochlear ganglion cells
A group of neurons in the conical central axis of the cochlea. These bipolar neurons innervate the hair cells of the organ of Corti.
Age-related skeletal muscle loss.
- NLRP3 inflammasome
A critical component of the innate immune system that mediates caspase 1 activation and the secretion of the proinflammatory cytokines IL-1β and IL-18 in response to infections or cellular damage.
An enzyme that can break down proteins that are normally found in the spaces between cells in tissues and that is involved in wound healing, angiogenesis and tumour cell metastasis.
A mitotic checkpoint serine/threonine protein kinase, an enzyme that is an essential component of the mitotic checkpoint, required for normal mitosis progression.
A condition in which there are excess levels of insulin circulating in the blood relative to the level of glucose, usually associated with insulin resistance.
When a breast cancer is human epidermal growth factor receptor 2 (HER2)-negative, it means that the cancerous cells do not contain high levels of HER2.
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Green, C.L., Lamming, D.W. & Fontana, L. Molecular mechanisms of dietary restriction promoting health and longevity. Nat Rev Mol Cell Biol 23, 56–73 (2022). https://doi.org/10.1038/s41580-021-00411-4
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