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.

Recent progress in the biology and physiology of sirtuins

Abstract

The sirtuins are a highly conserved family of NAD+-dependent enzymes that regulate lifespan in lower organisms. Recently, the mammalian sirtuins have been connected to an ever widening circle of activities that encompass cellular stress resistance, genomic stability, tumorigenesis and energy metabolism. Here we review the recent progress in sirtuin biology, the role these proteins have in various age-related diseases and the tantalizing notion that the activity of this family of enzymes somehow regulates how long we live.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Mouse knockout models as tools for exploring sirtuin function.
Figure 2: The diverse physiological roles of the sirtuins.
Figure 3: Complex regulation of SIRT1 activity.

References

  1. 1

    Rine, J., Strathern, J. N., Hicks, J. B. & Herskowitz, I. A suppressor of mating-type locus mutations in Saccharomyces cerevisiae: evidence for and identification of cryptic mating-type loci. Genetics 93, 877–901 (1979)

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Kennedy, B. K., Austriaco, N. R., Zhang, J. & Guarente, L. Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae . Cell 80, 485–496 (1995)

    CAS  PubMed  Google Scholar 

  3. 3

    Kaeberlein, M., McVey, M. & Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 13, 2570–2580 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    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)

    Article  ADS  CAS  Google Scholar 

  5. 5

    Guarente, L. & Picard, F. Calorie restriction—the SIR2 connection. Cell 120, 473–482 (2005)

    CAS  PubMed  Google Scholar 

  6. 6

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

    ADS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Bass, T. M., Weinkove, D., Houthoofd, K., Gems, D. & Partridge, L. Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans . Mech. Ageing Dev. 128, 546–552 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    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 

  9. 9

    Haigis, M. C. & Guarente, L. P. Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev. 20, 2913–2921 (2006)

    CAS  Google Scholar 

  10. 10

    Denu, J. M. Linking chromatin function with metabolic networks: Sir2 family of NAD+-dependent deacetylases. Trends Biochem. Sci. 28, 41–48 (2003)

    CAS  PubMed  Google Scholar 

  11. 11

    Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006)

    CAS  Google Scholar 

  12. 12

    Michishita, E. et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492–496 (2008)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Yuan, Z., Zhang, X., Sengupta, N., Lane, W. S. & Seto, E. SIRT1 regulates the function of the Nijmegen breakage syndrome protein. Mol. Cell 27, 149–162 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Wang, R. H. et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 14, 312–323 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Oberdoerffer, P. et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135, 907–918 (2008)Refs 14 and 15 describe a role for SIRT1 in genomic stability and how disruption of this activity might contribute to cancer and ageing.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Murayama, A. et al. Epigenetic control of rDNA loci in response to intracellular energy status. Cell 133, 627–639 (2008)

    CAS  Google Scholar 

  17. 17

    Vaquero, A. et al. SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation. Nature 450, 440–444 (2007)

    ADS  CAS  PubMed  Google Scholar 

  18. 18

    Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011–2015 (2004)

    ADS  CAS  Google Scholar 

  19. 19

    Motta, M. C. et al. Mammalian SIRT1 represses forkhead transcription factors. Cell 116, 551–563 (2004)

    CAS  Google Scholar 

  20. 20

    Westerheide, S. D., Anckar, J., Stevens, S. M., Sistonen, L. & Morimoto, R. I. Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 323, 1063–1066 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Luo, J. et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137–148 (2001)

    CAS  Google Scholar 

  22. 22

    Vaziri, H. et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149–159 (2001)

    CAS  Google Scholar 

  23. 23

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

    ADS  CAS  Google Scholar 

  24. 24

    Chen, W. Y. et al. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123, 437–448 (2005)

    CAS  Google Scholar 

  25. 25

    Yamakuchi, M., Ferlito, M. & Lowenstein, C. J. miR-34a repression of SIRT1 regulates apoptosis. Proc. Natl Acad. Sci. USA 105, 13421–13426 (2008)

    ADS  CAS  PubMed  Google Scholar 

  26. 26

    Michan, S. & Sinclair, D. Sirtuins in mammals: insights into their biological function. Biochem. J. 404, 1–13 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Yang, H. et al. Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130, 1095–1107 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Yeung, F. et al. Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23, 2369–2380 (2004)

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Langley, E. et al. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J. 21, 2383–2396 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Kawahara, T. L. et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-κB-dependent gene expression and organismal life span. Cell 136, 62–74 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Chua, K. F. et al. Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metab. 2, 67–76 (2005)

    CAS  PubMed  Google Scholar 

  32. 32

    Feige, J. N. & Auwerx, J. Transcriptional targets of sirtuins in the coordination of mammalian physiology. Curr. Opin. Cell Biol. 20, 303–309 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Prozorovski, T. et al. Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nature Cell Biol. 10, 385–394 (2008)

    CAS  PubMed  Google Scholar 

  34. 34

    Han, M. K. et al. SIRT1 regulates apoptosis and Nanog expression in mouse embryonic stem cells by controlling p53 subcellular localization. Cell Stem Cell 2, 241–251 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Kuzmichev, A. et al. Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation. Proc. Natl Acad. Sci. USA 102, 1859–1864 (2005)

    ADS  CAS  PubMed  Google Scholar 

  36. 36

    Nemoto, S., Fergusson, M. M. & Finkel, T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J. Biol. Chem. 280, 16456–16460 (2005)

    CAS  Google Scholar 

  37. 37

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Rodgers, J. T. & Puigserver, P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc. Natl Acad. Sci. USA 104, 12861–12866 (2007)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Liu, Y. et al. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456, 269–273 (2008)A detailed look at the role of protein acetylation and SIRT1-dependent deacetylation in the hepatic response to starvation.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Moynihan, K. A. et al. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metab. 2, 105–117 (2005)

    CAS  PubMed  Google Scholar 

  41. 41

    Bordone, L. et al. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol. 4, e31 (2006)

    PubMed  Google Scholar 

  42. 42

    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  Google Scholar 

  43. 43

    Ahuja, N. et al. Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J. Biol. Chem. 282, 33583–33592 (2007)

    CAS  PubMed  Google Scholar 

  44. 44

    Rodgers, J. T., Lerin, C., Gerhart-Hines, Z. & Puigserver, P. Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways. FEBS Lett. 582, 46–53 (2008)

    CAS  PubMed  Google Scholar 

  45. 45

    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)

    ADS  CAS  Google Scholar 

  46. 46

    Schwer, B., Bunkenborg, J., Verdin, R. O., Andersen, J. S. & Verdin, E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc. Natl Acad. Sci. USA 103, 10224–10229 (2006)

    ADS  CAS  PubMed  Google Scholar 

  47. 47

    Hallows, W. C., Lee, S. & Denu, J. M. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc. Natl Acad. Sci. USA 103, 10230–10235 (2006)

    ADS  CAS  PubMed  Google Scholar 

  48. 48

    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)

    ADS  CAS  PubMed  Google Scholar 

  49. 49

    Lombard, D. B. et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol. Cell. Biol. 27, 8807–8814 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    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)A recent demonstration of the expanding connection between sirtuin family members and metabolic regulation.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Crujeiras, A. B., Parra, D., Goyenechea, E. & Martinez, J. A. Sirtuin gene expression in human mononuclear cells is modulated by caloric restriction. Eur. J. Clin. Invest. 38, 672–678 (2008)

    CAS  PubMed  Google Scholar 

  52. 52

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

    PubMed  PubMed Central  Google Scholar 

  53. 53

    Asher, G. et al. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134, 317–328 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Nakahata, Y. et al. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134, 329–340 (2008)Refs 53 and 54 provide the first link between sirtuins and circadian rhythms.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Banks, A. S. et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab. 8, 333–341 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Pfluger, P. T., Herranz, D., Velasco-Miguel, S., Serrano, M. & Tschop, M. H. Sirt1 protects against high-fat diet-induced metabolic damage. Proc. Natl Acad. Sci. USA 105, 9793–9798 (2008)

    ADS  CAS  PubMed  Google Scholar 

  57. 57

    Sun, C. et al. SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab. 6, 307–319 (2007)

    CAS  PubMed  Google Scholar 

  58. 58

    Weyrich, P. et al. SIRT1 genetic variants associate with the metabolic response of Caucasians to a controlled lifestyle intervention — the TULIP Study. BMC Med. Genet. 9 10.1186/1471-2350-9-100 (2008)

  59. 59

    Peeters, A. V. et al. Association of SIRT1 gene variation with visceral obesity. Hum. Genet. 124, 431–436 (2008)

    CAS  PubMed  Google Scholar 

  60. 60

    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  Google Scholar 

  61. 61

    Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Canto, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 458, 1056–1060 (2009)Provides a link between sirtuins and other energy sensing pathways in the cell.

  63. 63

    Feige, J. N. et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab. 8, 347–358 (2008)

    CAS  PubMed  Google Scholar 

  64. 64

    Milne, J. C. et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712–716 (2007)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Deng, C. X. SIRT1, is it a tumor promoter or tumor suppressor? Int. J. Biol. Sci. 5, 147–152 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Wang, R. H. et al. Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol. Cell 32, 11–20 (2008)

    PubMed  PubMed Central  Google Scholar 

  67. 67

    Firestein, R. et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One 3, e2020 (2008)

    ADS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Li, X. et al. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol. Cell 28, 91–106 (2007)

    PubMed  Google Scholar 

  69. 69

    Potente, M. et al. SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev. 21, 2644–2658 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Mattagajasingh, I. et al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc. Natl Acad. Sci. USA 104, 14855–14860 (2007)

    ADS  CAS  PubMed  Google Scholar 

  71. 71

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    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  Google Scholar 

  73. 73

    Benigni, A. et al. Disruption of the Ang II type 1 receptor promotes longevity in mice. J. Clin. Invest. 119, 524–530 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Araki, T., Sasaki, Y. & Milbrandt, J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 305, 1010–1013 (2004)

    ADS  CAS  PubMed  Google Scholar 

  75. 75

    Fainzilber, M. & Twiss, J. L. Tracking in the Wlds—the hunting of the SIRT and the luring of the Draper. Neuron 50, 819–821 (2006)

    CAS  PubMed  Google Scholar 

  76. 76

    Li, Y., Xu, W., McBurney, M. W. & Longo, V. D. SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab. 8, 38–48 (2008)

    PubMed  PubMed Central  Google Scholar 

  77. 77

    van Ham, T. J. et al. C. elegans model identifies genetic modifiers of α-synuclein inclusion formation during aging. PLoS Genet. 4, e1000027 (2008)

    PubMed  PubMed Central  Google Scholar 

  78. 78

    Kim, D. et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 26, 3169–3179 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Outeiro, T. F. et al. Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson's disease. Science 317, 516–519 (2007)

    ADS  CAS  PubMed  Google Scholar 

  80. 80

    Zhao, W. et al. Negative regulation of the deacetylase SIRT1 by DBC1. Nature 451, 587–590 (2008)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Kim, J. E., Chen, J. & Lou, Z. DBC1 is a negative regulator of SIRT1. Nature 451, 583–586 (2008)Refs 80 and 81 demonstrate the role of protein–protein interactions in modulating SIRT1 function and suggest that this mode of regulation probably exists for other sirtuins.

    ADS  CAS  Google Scholar 

  82. 82

    Kim, E. J., Kho, J. H., Kang, M. R. & Um, S. J. Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. Mol. Cell 28, 277–290 (2007)

    CAS  Google Scholar 

  83. 83

    Elliott, P. J. & Jirousek, M. Sirtuins: novel targets for metabolic disease. Curr. Opin. Investig. Drugs 9, 371–378 (2008)

    CAS  PubMed  Google Scholar 

  84. 84

    Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We apologize to our colleagues for being unable to cite all appropriate references owing to space limitations. Highlighted references are a subjective appraisal of some of the most interesting manuscripts published in the last year. We are grateful to I. Rovira for help with figures. This work was supported by NIH Intramural funds (T.F, C.-X.D.), The Ellison Medical Foundation (T.F.), The Sidney Kimmel Cancer Research Foundation (R.M.) and the V Foundation (R.M.).

Author Contributions All authors contributed to the writing of this Review.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Chu-Xia Deng.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Finkel, T., Deng, CX. & Mostoslavsky, R. Recent progress in the biology and physiology of sirtuins. Nature 460, 587–591 (2009). https://doi.org/10.1038/nature08197

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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