Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Molecular mechanisms of dietary restriction promoting health and longevity

Abstract

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.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: The hallmarks of dietary restriction.
Fig. 2: Multiple molecular pathways engaged by dietary restriction.
Fig. 3: Species-specific effects of fasting on ketone body production and survival.

References

  1. 1.

    Fontana, L., Partridge, L. & Longo, V. D. Extending healthy life span — from yeast to humans. Science 328, 321–326 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010).

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Speakman, J. R. & Mitchell, S. E. Caloric restriction. Mol. Asp. Med. 32, 159–221 (2011).

    CAS  Article  Google Scholar 

  4. 4.

    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).

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Maegawa, S. et al. Caloric restriction delays age-related methylation drift. Nat. Commun. 8, 539 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. 9.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Austad, S. N. Mixed results for dieting monkeys. Nature 489, 210–211 (2012).

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    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).

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    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).

    CAS  Article  Google Scholar 

  13. 13.

    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).

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Stein, P. K. et al. Caloric restriction may reverse age-related autonomic decline in humans. Aging Cell 11, 644–650 (2012).

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Wang, M. et al. Calorie restriction curbs proinflammation that accompanies arterial aging, preserving a youthful phenotype. J. Am. Heart Assoc. 7, e009112 (2018).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    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).

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    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.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  18. 18.

    Nisoli, E. et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310, 314–317 (2005).

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Lopez-Lluch, G. et al. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc. Natl Acad. Sci. USA 103, 1768–1773 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Cuervo, A. M. Calorie restriction and aging: the ultimate “cleansing diet”. J. Gerontol. A Biol. Sci. Med. Sci 63, 547–549 (2008).

    PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    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.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    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).

    PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Mana, M. D., Kuo, E. Y. & Yilmaz, Ö. H. Dietary regulation of adult stem cells. Curr. stem Cell Rep. 3, 1–8 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Yilmaz, O. H. et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Tatar, M. et al. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292, 107–110 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Clancy, D. J. et al. Extension of life-span by loss of CHICO, a drosophila insulin receptor substrate protein. Science 292, 104–106 (2001).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    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.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    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).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    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.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Bonkowski, M. S. et al. Disruption of growth hormone receptor prevents calorie restriction from improving insulin action and longevity. PLoS ONE 4, e4567 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. 41.

    Bartke, A., Sun, L. Y. & Longo, V. Somatotropic signaling: trade-offs between growth, reproductive development, and longevity. Physiol. Rev. 93,571–598 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Lamming, D. W. & Anderson, R. M. in eLS (John Wiley & Sons, 2014).

  43. 43.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45.

    Spadaro, O. et al. Growth hormone receptor deficiency protects against age-related NLRP3 inflammasome activation and immune senescence. Cell Rep. 14, 1571–1580 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Lamming, D. W. Diminished mTOR signaling: a common mode of action for endocrine longevity factors. SpringerPlus 3, 735 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Holzenberger, M. et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Bokov, A. F. et al. Does reduced IGF-1R signaling in Igf1r+/- mice alter aging? PLoS ONE 6, e26891 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Bluher, M., Kahn, B. B. & Kahn, C. R. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572–574 (2003).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  50. 50.

    Taguchi, A., Wartschow, L. M. & White, M. F. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 317, 369–372 (2007).

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    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).

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Conover, C. A. & Bale, L. K. Loss of pregnancy-associated plasma protein A extends lifespan in mice. Aging Cell 6, 727–729 (2007).

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Mao, K. et al. Late-life targeting of the IGF-1 receptor improves healthspan and lifespan in female mice. Nat. Commun. 9, 2394 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. 56.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Chen, X. et al. Cryo-EM structure of human mTOR complex 2. Cell Res. 28, 518–528 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Scaiola, A. et al. The 3.2-A resolution structure of human mTORC2. Sci. Adv. 6, eabc1251 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006).

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Dominick, G. et al. Regulation of mTOR activity in Snell dwarf and GH receptor gene-disrupted mice. Endocrinology 156, 565–575 (2015).

    PubMed  Article  CAS  Google Scholar 

  63. 63.

    Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–144 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Johnson, S. C., Rabinovitch, P. S. & Kaeberlein, M. mTOR is a key modulator of ageing and age-related disease. Nature 493, 338–345 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. 68.

    Bitto, A. et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife 5, e16351 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. 70.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    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).

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Schreiber, K. H. et al. A novel rapamycin analog is highly selective for mTORC1 in vivo. Nat. Commun. 10, 3194 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  73. 73.

    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).

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Chellappa, K. et al. Hypothalamic mTORC2 is essential for metabolic health and longevity. Aging Cell 18, e13014 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Lamming, D. W. et al. Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan. Aging Cell 13, 911–917 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Chang, K. et al. TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2. Autophagy 16, 1807–1822 (2020).

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Strong, R. et al. Rapamycin-mediated mouse lifespan extension: late-life dosage regimes with sex-specific effects. Aging Cel 19, e13269 (2020).

    CAS  Google Scholar 

  83. 83.

    Mahoney, S. J. et al. A small molecule inhibitor of Rheb selectively targets mTORC1 signaling. Nat. Commun. 9, 548 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. 84.

    Kaeberlein, M. et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193–1196 (2005).

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Hansen, M. et al. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6, 95–110 (2007).

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Heintz, C. et al. Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans. Nature 541, 102–106 (2017).

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    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).

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Wu, Z. et al. Dietary restriction extends lifespan through metabolic regulation of innate immunity. Cell Metab. 29, 1192–1205 e1198 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    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).

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  92. 92.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    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).

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    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).

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Ravindran, R. et al. The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation. Nature 531, 523–527 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    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).

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Harding, H. P. et al. The ribosomal P-stalk couples amino acid starvation to GCN2 activation in mammalian cells. eLife 8, e50149 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    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).

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Harding, H. P. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell 6, 1099–1108 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  103. 103.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  105. 105.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Averous, J. et al. GCN2 contributes to mTORC1 inhibition by leucine deprivation through an ATF4 independent mechanism. Sci. Rep. 6, 27698 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    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).

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. 109.

    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.

    PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115, 1627–1635 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  114. 114.

    Zhang, Y. et al. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife 1, e00065 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  115. 115.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  116. 116.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Ruhlmann, C. et al. Neuroprotective effects of the FGF21 analogue LY2405319. J. Alzheimers Dis. 80, 357–369 (2021).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  118. 118.

    Imai, S. & Guarente, L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24, 464–471 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  120. 120.

    Lamming, D. W. et al. HST2 mediates SIR2-independent life-span extension by calorie restriction. Science 309, 1861–1864 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  121. 121.

    Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13, 225–238 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Burnett, C. et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477, 482–485 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Haigis, M. C. & Sinclair, D. A. Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 5, 253–295 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    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).

    CAS  PubMed  Article  Google Scholar 

  127. 127.

    Mao, Z. et al. SIRT6 promotes DNA repair under stress by activating PARP1. Science 332, 1443–1446 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128.

    Du, J. et al. Sirt5 Is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334, 806 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Peng, C. et al. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol. Cell Proteom. 10, M111 012658 (2011).

    Article  CAS  Google Scholar 

  130. 130.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  133. 133.

    Moroz, N. et al. Dietary restriction involves NAD+-dependent mechanisms and a shift toward oxidative metabolism. Aging Cell 13, 1075–1085 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Yoshida, M. et al. Extracellular vesicle-contained eNAMPT delays aging and extends lifespan in mice. Cell Metab. 30, 329–342 e325 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  136. 136.

    Cohen, H. Y. et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305, 390 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  137. 137.

    Civitarese, A. E. et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med. 4, e76 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  138. 138.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  139. 139.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. 140.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    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).

    CAS  Article  Google Scholar 

  142. 142.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  143. 143.

    Boily, G. et al. SirT1 regulates energy metabolism and response to caloric restriction in mice. PLoS ONE 3, e1759 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  144. 144.

    Bordone, L. et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 6, 759–767 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  145. 145.

    Herranz, D. et al. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat. Commun. 1, 3 (2010).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  146. 146.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    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).

    PubMed  PubMed Central  Google Scholar 

  148. 148.

    North, B. J. et al. SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. EMBO J. 33, 1438–1453 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. 149.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  150. 150.

    Brown, K. et al. SIRT3 reverses aging-associated degeneration. Cell Rep. 3, 319–327 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Vakhrusheva, O. et al. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ. Res. 102, 703–710 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  153. 153.

    Kanfi, Y. et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483, 218–221 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  154. 154.

    Roichman, A. et al. SIRT6 overexpression improves various aspects of mouse healthspan. J. Gerontol. A Biol. Sci. Med. Sci 72, 603–615 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. 156.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  157. 157.

    Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434, 113–118 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  158. 158.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. 159.

    Menghini, R. et al. MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1. Circulation 120, 1524–1532 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  160. 160.

    Ota, H. et al. Sirt1 modulates premature senescence-like phenotype in human endothelial cells. J. Mol. Cell Cardiol. 43, 571–579 (2007).

    CAS  PubMed  Article  Google Scholar 

  161. 161.

    Hebert, A. S. et al. Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol. Cell 49, 186–199 (2013).

    CAS  PubMed  Article  Google Scholar 

  162. 162.

    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).

    CAS  PubMed  Article  Google Scholar 

  163. 163.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  164. 164.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  165. 165.

    Simon, M. et al. LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell Metab. 29, 871–885 e875 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. 166.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  167. 167.

    Schriner, S. E. et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Elchuri, S. et al. CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24, 367–380 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. 169.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  170. 170.

    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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  171. 171.

    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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  172. 172.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. 173.

    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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  174. 174.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  175. 175.

    Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. 176.

    Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).

    CAS  Article  Google Scholar 

  177. 177.

    Weimer, S. et al. D-Glucosamine supplementation extends life span of nematodes and of ageing mice. Nat. Commun. 5, 3563 (2014).

    PubMed  Article  CAS  Google Scholar 

  178. 178.

    Ristow, M. et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc. Natl Acad. Sci. USA 106, 8665–8670 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. 179.

    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).

    CAS  PubMed  Article  Google Scholar 

  180. 180.

    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).

    Google Scholar 

  181. 181.

    Fontana, L. & Partridge, L. Promoting health and longevity through diet: from model organisms to humans. Cell 161, 106–118 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. 182.

    Green, C. L. & Lamming, D. W. Regulation of metabolic health by essential dietary amino acids. Mech. Ageing Dev. 177, 186–200 (2019).

    CAS  PubMed  Article  Google Scholar 

  183. 183.

    Soultoukis, G. A. & Partridge, L. Dietary protein, metabolism, and aging. Annu. Rev. Biochem. 85, 5–34 (2016).

    CAS  PubMed  Article  Google Scholar 

  184. 184.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  185. 185.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. 186.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  187. 187.

    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.

    PubMed  PubMed Central  Article  Google Scholar 

  188. 188.

    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).

    CAS  PubMed  Article  Google Scholar 

  189. 189.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  190. 190.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  191. 191.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  192. 192.

    Mittendorfer, B., Klein, S. & Fontana, L. A word of caution against excessive protein intake. Nat. Rev. Endocrinol. 16, 59–66 (2020).

    PubMed  Article  Google Scholar 

  193. 193.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. 194.

    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).

    CAS  PubMed  Article  Google Scholar 

  195. 195.

    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).

  196. 196.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  197. 197.

    Hill, C. M. et al. Low protein-induced increases in FGF21 drive UCP1-dependent metabolic but not thermoregulatory endpoints. Sci. Rep. 7, 8209 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  198. 198.

    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.

    CAS  PubMed  Google Scholar 

  199. 199.

    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).

    CAS  PubMed  Article  Google Scholar 

  200. 200.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  201. 201.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  202. 202.

    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).

    CAS  PubMed  Article  Google Scholar 

  203. 203.

    Yu, D. et al. Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms. FASEB J. 32, 3471–3482 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  204. 204.

    Douris, N. et al. Central fibroblast growth factor 21 browns white fat via sympathetic action in male mice. Endocrinology 156, 2470–2481 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  205. 205.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  206. 206.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  207. 207.

    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).

    CAS  PubMed  Article  Google Scholar 

  208. 208.

    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).

    CAS  PubMed  Article  Google Scholar 

  209. 209.

    Haws, S. A., Leech, C. M. & Denu, J. M. Metabolism and the epigenome: a dynamic relationship. Trends Biochem. Sci. 45, 731–747 (2020).

    CAS  PubMed  Article  Google Scholar 

  210. 210.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  211. 211.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  212. 212.

    Das, A. et al. Impairment of an endothelial NAD+-H2S signaling network is a reversible cause of vascular aging. Cell 176, 944–945 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  213. 213.

    Hine, C. et al. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell 160, 132–144 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  214. 214.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  215. 215.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  216. 216.

    Gu, X. et al. SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science 358, 813–818 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  217. 217.

    Cummings, N. E. et al. Restoration of metabolic health by decreased consumption of branched-chain amino acids. J. Physiol. 596, 623–645 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  218. 218.

    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.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  219. 219.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  220. 220.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  221. 221.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  222. 222.

    Wijeyesekera, A. et al. Metabotyping of long-lived mice using 1H NMR spectroscopy. J. Proteome Res. 11, 2224–2235 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  223. 223.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  224. 224.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  225. 225.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  226. 226.

    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).

    PubMed  Article  PubMed Central  Google Scholar 

  227. 227.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  228. 228.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  229. 229.

    Chen, T. et al. Tryptophan predicts the risk for future type 2 diabetes. PLoS ONE 11, e0162192 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  230. 230.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. 231.

    Yap, Y. W. et al. Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution. Nat. Commun. 11, 2894 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  232. 232.

    Ravichandran, M. et al. Impairing L-threonine catabolism promotes healthspan through methylglyoxal-mediated proteohormesis. Cell Metab. 27, 914–925 e915 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  233. 233.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  234. 234.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  235. 235.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  236. 236.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  237. 237.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  238. 238.

    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.

  239. 239.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  240. 240.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  241. 241.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  242. 242.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  243. 243.

    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).

    CAS  PubMed  Article  Google Scholar 

  244. 244.

    Mattson, M. P., Longo, V. D. & Harvie, M. Impact of intermittent fasting on health and disease processes. Ageing Res. Rev. 39, 46–58 (2017).

    PubMed  Article  Google Scholar 

  245. 245.

    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).

    CAS  PubMed  Article  Google Scholar 

  246. 246.

    Tomasi, C. et al. Effect of fasting/refeeding on the incidence of chemically induced hepatocellular carcinoma in the rat. Carcinogenesis 20, 1979–1983 (1999).

    CAS  PubMed  Article  Google Scholar 

  247. 247.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  248. 248.

    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).

    CAS  PubMed  Article  Google Scholar 

  249. 249.

    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).

    PubMed  Article  Google Scholar 

  250. 250.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  251. 251.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  252. 252.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  253. 253.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  254. 254.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  255. 255.

    Shimazu, T. et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  256. 256.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  257. 257.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  258. 258.

    Cahill, G. F. Jr et al. Hormone-fuel interrelationships during fasting. J. Clin. Invest. 45, 1751–1769 (1966).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  259. 259.

    Mattson, M. P. & Arumugam, T. V. Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab. 27, 1176–1199 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  260. 260.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  261. 261.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  262. 262.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  263. 263.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  264. 264.

    Choi, I. Y. et al. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Rep. 15, 2136–2146 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  265. 265.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  266. 266.

    Cheng, C.-W. et al. Fasting-mimicking diet promotes Ngn3-driven β-cell regeneration to reverse diabetes. Cell 168, 775–788.e712 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  267. 267.

    Raffaghello, L. et al. Fasting and differential chemotherapy protection in patients. Cell Cycle 9, 4474–4476 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  268. 268.

    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).

    Article  Google Scholar 

  269. 269.

    Caffa, I. et al. Fasting-mimicking diet and hormone therapy induce breast cancer regression. Nature 583, 620–624 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  270. 270.

    Di Biase, S. et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 30, 136–146 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  271. 271.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  272. 272.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  273. 273.

    Safdie, F. M. et al. Fasting and cancer treatment in humans: a case series report. Aging 1, 988 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  274. 274.

    Mattson, M. P. et al. Meal frequency and timing in health and disease. Proc. Natl Acad. Sci. USA 111, 16647–16653 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  275. 275.

    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).

    PubMed Central  Article  Google Scholar 

  276. 276.

    Turek, F. W. et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308, 1043–1045 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  277. 277.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  278. 278.

    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).

    PubMed  Article  PubMed Central  Google Scholar 

  279. 279.

    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).

    CAS  Article  Google Scholar 

  280. 280.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  281. 281.

    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).

    PubMed  Article  Google Scholar 

  282. 282.

    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).

    PubMed  Article  Google Scholar 

  283. 283.

    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).

    CAS  Article  Google Scholar 

  284. 284.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  285. 285.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  286. 286.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  287. 287.

    Bartke, A. et al. Extending the lifespan of long-lived mice. Nature 414, 412 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  288. 288.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  289. 289.

    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).

    PubMed  Article  PubMed Central  Google Scholar 

  290. 290.

    Bartke, A., Chandrashekar, V., Bailey, B., Zaczek, D. & Turyn, D. Consequences of growth hormone (GH) overexpression and GH resistance. Neuropeptides 36, 201–208 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  291. 291.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  292. 292.

    Yan, L. et al. Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 130, 247–258 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  293. 293.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  294. 294.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  295. 295.

    Nojima, A. et al. Haploinsufficiency of akt1 prolongs the lifespan of mice. PLoS ONE 8, e69178 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  296. 296.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  297. 297.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  298. 298.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  299. 299.

    Wu, X. et al. FLCN maintains the leucine level in lysosome to stimulate mTORC1. PLoS ONE 11, e0157100 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  300. 300.

    Martinez-Carreres, L. et al. CDK4 regulates lysosomal function and mTORC1 activation to promote cancer cell survival. Cancer Res. 79, 5245–5259 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  301. 301.

    Hesketh, G. G. et al. The GATOR-Rag GTPase pathway inhibits mTORC1 activation by lysosome-derived amino acids. Science 370, 351–356 (2020).

    CAS  PubMed  Article  Google Scholar 

  302. 302.

    Efeyan, A. et al. Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature 493, 679–683 (2013).

    CAS  PubMed  Article  Google Scholar 

  303. 303.

    Wolfson, R. L. et al. KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature 543, 438–442 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  304. 304.

    Orozco, J. M. et al. Dihydroxyacetone phosphate signals glucose availability to mTORC1. Nat. Metab. 2, 893–901 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  305. 305.

    Yang, H. et al. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature 552, 368–373 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  306. 306.

    Dibble, C. C. et al. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol. Cell 47, 535–546 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  307. 307.

    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).

    CAS  PubMed  Article  Google Scholar 

  308. 308.

    Budanov, A. V. & Karin, M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134, 451–460 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

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.

Author information

Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Luigi Fontana.

Ethics declarations

Competing interests

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.

Additional information

Peer review information

Nature Reviews Molecular Cell Biology thanks the anonymous reviewers for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

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.

Presbycusis

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.

Sarcopenia

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.

Metalloproteinase

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.

BubR1

A mitotic checkpoint serine/threonine protein kinase, an enzyme that is an essential component of the mitotic checkpoint, required for normal mitosis progression.

Hyperinsulinaemia

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.

HER2-negative

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Green, C.L., Lamming, D.W. & Fontana, L. Molecular mechanisms of dietary restriction promoting health and longevity. Nat Rev Mol Cell Biol (2021). https://doi.org/10.1038/s41580-021-00411-4

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing