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.

  • Review Article
  • Published:

The metabolic regulation of aging

Nature Medicine volume 21, pages 1416–1423 (2015)Cite this article

Subjects

Abstract

Here we review the environmental and genetic manipulations that link cellular and organismal metabolism to aging. In particular, we explore how nutrients are sensed and how various intracellular energy nodes seem to coordinate distinct metabolic alterations linked to extended longevity. In addition, the role of mitochondria as both a metabolic and signaling organelle is discussed. Finally, we review a host of new targeted pharmacological approaches that attempt to exploit the connection between aging and metabolism to treat a wide range of age-related diseases. Together, these insights are beginning to reveal answers to century-old mysteries and are providing a future road map for the rational extension of lifespan.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The myriad effects of caloric restriction (CR).

Debbie Maizels/Nature Publishing Group

Figure 2: Interaction between various nutrient-sensing and longevity pathways.
Figure 3: Interaction between the mitochondria and nucleus.
Figure 4: Energy partition and lifespan.

Debbie Maizels/Nature Publishing Group

Similar content being viewed by others

References

  1. Schäfer, D. Aging, longevity, and diet: historical remarks on calorie intake reduction. Gerontology 51, 126–130 (2005).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Dillin, A. et al. Rates of behavior and aging specified by mitochondrial function during development. Science 298, 2398–2401 (2002).

    CAS  PubMed  Google Scholar 

  4. Lee, S.S. et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat. Genet. 33, 40–48 (2003).

    CAS  PubMed  Google Scholar 

  5. Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).

    CAS  PubMed  Google Scholar 

  6. Kujoth, G.C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005).

    CAS  PubMed  Google Scholar 

  7. Riera, C.E. & Dillin, A. Tipping the metabolic scales towards increased longevity in mammals. Nat. Cell Biol. 17, 196–203 (2015).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  9. Brown-Borg, H.M., Borg, K.E., Meliska, C.J. & Bartke, A. Dwarf mice and the ageing process. Nature 384, 33 (1996).

    CAS  PubMed  Google Scholar 

  10. Mattison, J.A. et al. Studies of aging in Ames dwarf mice: Effects of caloric restriction. J. Am. Aging Assoc. 23, 9–16 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  12. Heilbronn, L.K. et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. J. Am. Med. Assoc. 295, 1539–1548 (2006).

    CAS  Google Scholar 

  13. Ravussin, E. et al. A 2-year randomized controlled trial of human caloric restriction: feasibility and effects on predictors of health span and longevity. J. Gerontol. A Biol. Sci. Med. Sci. 70, 1097–1104 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bertrand, H.A., Lynd, F.T., Masoro, E.J. & Yu, B.P. Changes in adipose mass and cellularity through the adult life of rats fed ad libitum or a life-prolonging restricted diet. J. Gerontol. 35, 827–835 (1980).

    CAS  PubMed  Google Scholar 

  15. Barzilai, N., Banerjee, S., Hawkins, M., Chen, W. & Rossetti, L. Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat. J. Clin. Invest. 101, 1353–1361 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 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  Google Scholar 

  17. Liao, C.Y. et al. Fat maintenance is a predictor of the murine lifespan response to dietary restriction. Aging Cell 10, 629–639 (2011).

    CAS  PubMed  Google Scholar 

  18. Greenberg, J.A. & Boozer, C.N. Metabolic mass, metabolic rate, caloric restriction, and aging in male Fischer 344 rats. Mech. Ageing Dev. 113, 37–48 (2000).

    CAS  PubMed  Google Scholar 

  19. Selman, C. et al. Energy expenditure of calorically restricted rats is higher than predicted from their altered body composition. Mech. Ageing Dev. 126, 783–793 (2005).

    PubMed  Google Scholar 

  20. Bartke, A. & Westbrook, R. Metabolic characteristics of long-lived mice. Front. Genet. 3, 288 (2012).

    PubMed  PubMed Central  Google Scholar 

  21. Petersen, K.F. et al. Effect of aging on muscle mitochondrial substrate utilization in humans. Proc. Natl. Acad. Sci. USA 112, 11330–11334 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Huffman, K.M. et al. Caloric restriction alters the metabolic response to a mixed-meal: results from a randomized, controlled trial. PLoS ONE 7, e28190 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Willette, A.A. et al. Interleukin-8 and interleukin-10, brain volume and microstructure, and the influence of calorie restriction in old rhesus macaques. Age (Dordr.) 35, 2215–2227 (2013).

    CAS  Google Scholar 

  24. Youm, Y.H. et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease. Nat. Med. 21, 263–269 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Yang, H., Youm, Y.H. & Dixit, V.D. Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution. J. Immunol. 183, 3040–3052 (2009).

    CAS  PubMed  Google Scholar 

  26. Masoro, E.J. Overview of caloric restriction and ageing. Mech. Ageing Dev. 126, 913–922 (2005).

    CAS  PubMed  Google Scholar 

  27. Colman, R.J. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Mattison, J.A. et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489, 318–321 (2012).

    CAS  PubMed  Google Scholar 

  29. Albert, V. & Hall, M.N. mTOR signaling in cellular and organismal energetics. Curr. Opin. Cell Biol. 33, 55–66 (2015).

    CAS  PubMed  Google Scholar 

  30. Vellai, T. et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426, 620 (2003).

    CAS  PubMed  Google Scholar 

  31. Kapahi, P. et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885–890 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Lamming, D.W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 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  Google Scholar 

  34. 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  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  36. 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  Google Scholar 

  37. Desai, B.N., Myers, B.R. & Schreiber, S.L. FKBP12-rapamycin–associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction. Proc. Natl. Acad. Sci. USA 99, 4319–4324 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Schieke, S.M. et al. The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J. Biol. Chem. 281, 27643–27652 (2006).

    CAS  PubMed  Google Scholar 

  39. Ramanathan, A. & Schreiber, S.L. Direct control of mitochondrial function by mTOR. Proc. Natl. Acad. Sci. USA 106, 22229–22232 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Bonawitz, N.D., Chatenay-Lapointe, M., Pan, Y. & Shadel, G.S. Reduced TOR signaling extends chronological life span via increased respiration and upregulation of mitochondrial gene expression. Cell Metab. 5, 265–277 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Bentzinger, C.F. et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 8, 411–424 (2008).

    CAS  PubMed  Google Scholar 

  42. Polak, P. et al. Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab. 8, 399–410 (2008).

    CAS  PubMed  Google Scholar 

  43. Yilmaz, Ö.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  Google Scholar 

  44. Hirschey, M.D. & Zhao, Y. Metabolic regulation by lysine malonylation, succinylation and glutarylation. Mol. Cell. Proteomics 14, 2308–2315 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 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  Google Scholar 

  46. Rogina, B. & Helfand, S.L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl. Acad. Sci. USA 101, 15998–16003 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Kaeberlein, M., Kirkland, K.T., Fields, S. & Kennedy, B.K. Sir2-independent life span extension by calorie restriction in yeast. PLoS Biol. 2, e296 (2004).

    PubMed  PubMed Central  Google Scholar 

  48. Nemoto, S., Fergusson, M.M. & Finkel, T. Nutrient availability regulates SIRT1 through a Forkhead-dependent pathway. Science 306, 2105–2108 (2004).

    CAS  PubMed  Google Scholar 

  49. Cohen, H.Y. et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305, 390–392 (2004).

    CAS  PubMed  Google Scholar 

  50. Chen, D. et al. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev. 22, 1753–1757 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Mercken, E.M. et al. SIRT1 but not its increased expression is essential for lifespan extension in caloric-restricted mice. Aging Cell 13, 193–196 (2014).

    CAS  PubMed  Google Scholar 

  52. 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  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  54. Ahn, B.H. et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc. Natl. Acad. Sci. USA 105, 14447–14452 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Hirschey, M.D. et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121–125 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Qiu, X., Brown, K., Hirschey, M.D., Verdin, E. & Chen, D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 12, 662–667 (2010).

    CAS  PubMed  Google Scholar 

  57. Tao, R. et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol. Cell 40, 893–904 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 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  Google Scholar 

  59. 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  Google Scholar 

  60. Barger, J.L. et al. A conserved transcriptional signature of delayed aging and reduced disease vulnerability is partially mediated by SIRT3. PLoS ONE 10, e0120738 (2015).

    PubMed  PubMed Central  Google Scholar 

  61. Hardie, D.G. AMPK: positive and negative regulation, and its role in whole-body energy homeostasis. Curr. Opin. Cell Biol. 33, 1–7 (2015).

    CAS  PubMed  Google Scholar 

  62. Greer, E.L. et al. An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr. Biol. 17, 1646–1656 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 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  Google Scholar 

  64. Stenesen, D. et al. Adenosine nucleotide biosynthesis and AMPK regulate adult life span and mediate the longevity benefit of caloric restriction in flies. Cell Metab. 17, 101–112 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Burkewitz, K., Zhang, Y. & Mair, W.B. AMPK at the nexus of energetics and aging. Cell Metab. 20, 10–25 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Cantó, C. & Auwerx, J. Calorie restriction: is AMPK a key sensor and effector? Physiology (Bethesda) 26, 214–224 (2011).

    Google Scholar 

  67. Ulgherait, M., Rana, A., Rera, M., Graniel, J. & Walker, D.W. AMPK modulates tissue and organismal aging in a non-cell-autonomous manner. Cell Rep. 8, 1767–1780 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Meléndez, A. et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 1387–1391 (2003).

    PubMed  Google Scholar 

  69. Morselli, E. et al. Caloric restriction and resveratrol promote longevity through the Sirtuin-1–dependent induction of autophagy. Cell Death Dis. 1, e10 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Ruckenstuhl, C. et al. Lifespan extension by methionine restriction requires autophagy-dependent vacuolar acidification. PLoS Genet. 10, e1004347 (2014).

    PubMed  PubMed Central  Google Scholar 

  71. Pyo, J.O. et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat. Commun. 4, 2300 (2013).

    PubMed  Google Scholar 

  72. Lapierre, L.R. et al. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat. Commun. 4, 2267 (2013).

    PubMed  Google Scholar 

  73. Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R.A. C. elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993).

    CAS  PubMed  Google Scholar 

  74. 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  Google Scholar 

  75. Murphy, C.T. et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424, 277–283 (2003).

    CAS  PubMed  Google Scholar 

  76. 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  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  78. Xu, J. et al. Longevity effect of IGF-1R+/− mutation depends on genetic background-specific receptor activation. Aging Cell 13, 19–28 (2014).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  80. 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  Google Scholar 

  81. Suh, Y. et al. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc. Natl. Acad. Sci. USA 105, 3438–3442 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Wheeler, H.E. & Kim, S.K. Genetics and genomics of human ageing. Phil. Trans. R. Soc. Lond. B 366, 43–50 (2011).

    CAS  Google Scholar 

  83. Brown-Borg, H.M. The somatotropic axis and longevity in mice. Am. J. Physiol. Endocrinol. Metab. 309, E503–E510 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhang, G. et al. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 497, 211–216 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Madeo, F., Zimmermann, A., Maiuri, M.C. & Kroemer, G. Essential role for autophagy in lifespan extension. J. Clin. Invest. 125, 85–93 (2015).

    PubMed  PubMed Central  Google Scholar 

  86. Lee, I.H. et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc. Natl. Acad. Sci. USA 105, 3374–3379 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Short, K.R. et al. Decline in skeletal muscle mitochondrial function with aging in humans. Proc. Natl. Acad. Sci. USA 102, 5618–5623 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Rea, S.L., Ventura, N. & Johnson, T.E. Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in Caenorhabditis elegans. PLoS Biol. 5, e259 (2007).

    PubMed  PubMed Central  Google Scholar 

  89. Liu, X. et al. Evolutionary conservation of the clk-1–dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice. Genes Dev. 19, 2424–2434 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Dell′Agnello, C. et al. Increased longevity and refractoriness to Ca2+-dependent neurodegeneration in Surf1 knockout mice. Hum. Mol. Genet. 16, 431–444 (2007).

    PubMed  Google Scholar 

  91. Chang, H.W., Shtessel, L. & Lee, S.S. Collaboration between mitochondria and the nucleus is key to long life in Caenorhabditis elegans. Free Radic. Biol. Med. 78, 168–178 (2015).

    CAS  PubMed  Google Scholar 

  92. Lee, S.J., Hwang, A.B. & Kenyon, C. Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr. Biol. 20, 2131–2136 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Hwang, A.B. et al. Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 111, E4458–E4467 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Ventura, N. et al. p53/CEP-1 increases or decreases lifespan, depending on level of mitochondrial bioenergetic stress. Aging Cell 8, 380–393 (2009).

    CAS  PubMed  Google Scholar 

  95. Walter, L., Baruah, A., Chang, H.W., Pace, H.M. & Lee, S.S. The homeobox protein CEH-23 mediates prolonged longevity in response to impaired mitochondrial electron transport chain in C. elegans. PLoS Biol. 9, e1001084 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Yee, C., Yang, W. & Hekimi, S. The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans. Cell 157, 897–909 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Schmeisser, S. et al. Neuronal ROS signaling rather than AMPK/sirtuin–mediated energy sensing links dietary restriction to lifespan extension. Mol. Metab. 2, 92–102 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Zhang, H., Davies, K.J. & Forman, H.J. Oxidative stress response and Nrf2 signaling in aging. Free Radic. Biol. Med. 88, 314–336 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Paek, J. et al. Mitochondrial SKN-1/Nrf mediates a conserved starvation response. Cell Metab. 16, 526–537 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Schmeisser, S. et al. Mitochondrial hormesis links low-dose arsenite exposure to lifespan extension. Aging Cell 12, 508–517 (2013).

    CAS  PubMed  Google Scholar 

  101. Pearson, K.J. et al. Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction. Proc. Natl. Acad. Sci. USA 105, 2325–2330 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Harman, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298–300 (1956).

    CAS  PubMed  Google Scholar 

  103. Barja, G. The mitochondrial free radical theory of aging. Prog. Mol. Biol. Transl. Sci. 127, 1–27 (2014).

    CAS  PubMed  Google Scholar 

  104. Yun, J. & Finkel, T. Mitohormesis. Cell Metab. 19, 757–766 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Ristow, M. Unraveling the truth about antioxidants: mitohormesis explains ROS-induced health benefits. Nat. Med. 20, 709–711 (2014).

    CAS  PubMed  Google Scholar 

  106. Ristow, M. & Schmeisser, K. Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS). Dose Response 12, 288–341 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Durieux, J., Wolff, S. & Dillin, A. The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144, 79–91 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Owusu-Ansah, E., Song, W. & Perrimon, N. Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 155, 699–712 (2013).

    CAS  PubMed  Google Scholar 

  109. Jovaisaite, V. & Auwerx, J. The mitochondrial unfolded protein response-synchronizing genomes. Curr. Opin. Cell Biol. 33, 74–81 (2015).

    CAS  PubMed  Google Scholar 

  110. Nargund, A.M., Pellegrino, M.W., Fiorese, C.J., Baker, B.M. & Haynes, C.M. Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337, 587–590 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Liu, Y., Samuel, B.S., Breen, P.C. & Ruvkun, G. Caenorhabditis elegans pathways that surveil and defend mitochondria. Nature 508, 406–410 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Pellegrino, M.W. et al. Mitochondrial UPR–regulated innate immunity provides resistance to pathogen infection. Nature 516, 414–417 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Houtkooper, R.H. et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497, 451–457 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  115. Finley, L.W. et al. Skeletal muscle transcriptional coactivator PGC-1α mediates mitochondrial, but not metabolic, changes during calorie restriction. Proc. Natl. Acad. Sci. USA 109, 2931–2936 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Gomes, A.P. et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Cuervo, A.M. et al. Autophagy and aging: the importance of maintaining “clean” cells. Autophagy 1, 131–140 (2005).

    PubMed  Google Scholar 

  118. Palikaras, K., Lionaki, E. & Tavernarakis, N. Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521, 525–528 (2015).

    CAS  PubMed  Google Scholar 

  119. Rana, A., Rera, M. & Walker, D.W. Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan. Proc. Natl. Acad. Sci. USA 110, 8638–8643 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Howitz, K.T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003).

    CAS  PubMed  Google Scholar 

  121. Dang, W. The controversial world of sirtuins. Drug Discov. Today. Technol. 12, e9–e17 (2014).

    PubMed  PubMed Central  Google Scholar 

  122. Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).

    CAS  PubMed  Google Scholar 

  123. Pearson, K.J. et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 8, 157–168 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Jimenez-Gomez, Y. et al. Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metab. 18, 533–545 (2013).

    CAS  PubMed  Google Scholar 

  125. Mattison, J.A. et al. Resveratrol prevents high fat/sucrose diet–induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metab. 20, 183–190 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Timmers, S. et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 14, 612–622 (2011).

    CAS  PubMed  Google Scholar 

  127. Mitchell, S.J. et al. The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell Rep. 6, 836–843 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Harrison, D.E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. De Haes, W. et al. Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. Proc. Natl. Acad. Sci. USA 111, E2501–E2509 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Martin-Montalvo, A. et al. Metformin improves healthspan and lifespan in mice. Nat. Commun. 4, 2192 (2013).

    PubMed  Google Scholar 

  131. Kasznicki, J., Sliwinska, A. & Drzewoski, J. Metformin in cancer prevention and therapy. Ann. Transl. Med. 2, 57 (2014).

    PubMed  PubMed Central  Google Scholar 

  132. Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009).

    CAS  PubMed  Google Scholar 

  133. Gupta, V.K. et al. Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat. Neurosci. 16, 1453–1460 (2013).

    CAS  PubMed  Google Scholar 

  134. Cantó, C., Menzies, K.J. & Auwerx, J. NAD+ metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab. 22, 31–53 (2015).

    PubMed  PubMed Central  Google Scholar 

  135. Mouchiroud, L. et al. The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Yoshino, J., Mills, K.F., Yoon, M.J. & Imai, S. Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528–536 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Cantó, C. et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 15, 838–847 (2012).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Austad, S.N. Methusaleh's zoo: how nature provides us with clues for extending human health span. J. Comp. Pathol. 142 (suppl. 1), S10–S21 (2010).

    PubMed  Google Scholar 

  140. Wall, C.E. et al. High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice. Proc. Natl. Acad. Sci. USA 112, 8714–8719 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I am grateful to members of my laboratory for their helpful suggestions, and in particular to I. Rovira for help with the manuscript. This work is supported by funds from the US National Institutes of Health Intramural Program and from The Leducq Foundation.

Author information

Authors and Affiliations

  1. Center for Molecular Medicine, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA

    Toren Finkel

Authors
  1. Toren Finkel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toren Finkel.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Finkel, T. The metabolic regulation of aging. Nat Med 21, 1416–1423 (2015). https://doi.org/10.1038/nm.3998

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3998

This article is cited by

Search

Advanced 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