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Sirtuins in atherosclerosis: guardians of healthspan and therapeutic targets

Abstract

Sirtuins are NAD+-dependent deacetylase and deacylase enzymes that control important cellular processes, including DNA damage repair, cellular metabolism, mitochondrial function and inflammation. Consequently, mammalian sirtuins are regarded as crucial regulators of cellular function and organism healthspan. Sirtuin activity and NAD+ levels decrease with age in many tissues, and reduced sirtuin expression is associated with several cardiovascular diseases. By contrast, increased sirtuin expression and activity slows disease progression and improves cardiovascular function in preclinical models and delays various features of cellular ageing. The potential cardiometabolic benefits of sirtuins have resulted in clinical trials with sirtuin-modulating agents; although expectations are high, these drugs have not yet been proven to improve healthspan. In this Review, we examine the role of sirtuins in atherosclerosis, summarize advances in the development of compounds that activate or inhibit sirtuin activity and critically evaluate the therapeutic potential of these agents.

Key points

  • Sirtuins protect against many processes associated with ageing and atherosclerosis, but only SIRT6 has been shown to extend lifespan in mice.

  • Natural compounds with sirtuin-modulating activity can delay or prevent the development of atherosclerosis in preclinical models, but have low bioavailability and off-target effects.

  • Small-molecule activators of sirtuins and NAD+ boosters have shown promising cardiometabolic effects in animal models and are well tolerated in healthy volunteers, but clinical trials showing prevention of atherosclerosis or clinical events are lacking.

  • Drug discovery has shifted from SIRT1 to SIRT6, because the lifespan-extending and chromatin-remodelling effects of SIRT6 make it an attractive therapeutic target.

  • Unravelling the multiple enzymatic activities of the sirtuins and their targets will facilitate drug discovery of specific sirtuin-activating compounds to prevent or treat atherosclerosis.

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Fig. 1: Structure and localization of human sirtuins.
Fig. 2: Biological targets and cellular processes regulated by sirtuins.
Fig. 3: The cellular roles of sirtuins.
Fig. 4: The protective role of sirtuins in atherosclerosis.

References

  1. 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  Google Scholar 

  2. 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 

  3. 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 

  4. Imai, S. I. & Guarente, L. It takes two to tango: NAD+ and sirtuins in aging/longevity control. NPJ Aging Mech. Dis. 2, 16017 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  5. Revollo, J. R., Grimm, A. A. & Imai, S. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J. Biol. Chem. 279, 50754–50763 (2004).

    CAS  PubMed  Article  Google Scholar 

  6. Guarente, L. Calorie restriction and sirtuins revisited. Genes Dev. 27, 2072–2085 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Kane, A. E. & Sinclair, D. A. Sirtuins and NAD+ in the development and treatment of metabolic and cardiovascular diseases. Circ. Res. 123, 868–885 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. You, W. et al. Structural basis of sirtuin 6 activation by synthetic small molecules. Angew. Chem. Int. Ed. Engl. 56, 1007–1011 (2017).

    CAS  PubMed  Article  Google Scholar 

  9. You, W., Zheng, W., Weiss, S., Chua, K. F. & Steegborn, C. Structural basis for the activation and inhibition of sirtuin 6 by quercetin and its derivatives. Sci. Rep. 9, 19176 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Tenhunen, J. et al. Screening of SIRT6 inhibitors and activators: a novel activator has an impact on breast cancer cells. Biomed. Pharmacother. 138, 111452 (2021).

    CAS  PubMed  Article  Google Scholar 

  11. Huang, Z. et al. Identification of a cellularly active SIRT6 allosteric activator. Nat. Chem. Biol. 14, 1118–1126 (2018).

    CAS  PubMed  Article  Google Scholar 

  12. Guo, J. et al. Endothelial SIRT6 is vital to prevent hypertension and associated cardiorenal injury through targeting Nkx3.2-GATA5 signaling. Circ. Res. 124, 1448–1461 (2019).

    CAS  PubMed  Article  Google Scholar 

  13. Grootaert, M. O. J., Finigan, A., Figg, N. L., Uryga, A. K. & Bennett, M. R. SIRT6 protects smooth muscle cells from senescence and reduces atherosclerosis. Circ. Res. 128, 474–491 (2021).

    CAS  PubMed  Article  Google Scholar 

  14. Arsiwala, T. et al. Sirt6 deletion in bone marrow-derived cells increases atherosclerosis–central role of macrophage scavenger receptor 1. J. Mol. Cell Cardiol. 139, 24–32 (2020).

    CAS  PubMed  Article  Google Scholar 

  15. Zhang, X., Ameer, F. S., Azhar, G. & Wei, J. Y. Alternative splicing increases sirtuin gene family diversity and modulates their subcellular localization and function. Int. J. Mol. Sci. 22, 473 (2021).

    CAS  PubMed Central  Article  Google Scholar 

  16. Tanno, M., Sakamoto, J., Miura, T., Shimamoto, K. & Horio, Y. Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J. Biol. Chem. 282, 6823–6832 (2007).

    CAS  PubMed  Article  Google Scholar 

  17. 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  Article  Google Scholar 

  18. Martinez-Pastor, B. & Mostoslavsky, R. Sirtuins, metabolism, and cancer. Front. Pharmacol. 3, 22 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  20. 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 

  21. 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  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Onn, L. et al. SIRT6 is a DNA double-strand break sensor. eLife 9, e51636 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Toiber, D. et al. SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling. Mol. Cell 51, 454–468 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Hou, T. et al. SIRT6 coordinates with CHD4 to promote chromatin relaxation and DNA repair. Nucleic Acids Res. 48, 2982–3000 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  27. Roichman, A. et al. Restoration of energy homeostasis by SIRT6 extends healthy lifespan. Nat. Commun. 12, 3208 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Tian, X. et al. SIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species. Cell 177, 622–638 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Meng, F. et al. Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiates the DNA damage response and repair in humans and mice. eLife 9, e55828 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  31. Chang, A. R., Ferrer, C. M. & Mostoslavsky, R. SIRT6, a mammalian deacylase with multitasking abilities. Physiol. Rev. 100, 145–169 (2020).

    CAS  PubMed  Article  Google Scholar 

  32. Sociali, G. et al. SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells. FASEB J. 33, 3704–3717 (2019).

    CAS  PubMed  Article  Google Scholar 

  33. Pan, H. et al. SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Res. 26, 190–205 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Rezazadeh, S. et al. SIRT6 promotes transcription of a subset of NRF2 targets by mono-ADP-ribosylating BAF170. Nucleic Acids Res. 47, 7914–7928 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Jiang, H. et al. SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496, 110–113 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Ford, E. et al. Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev. 20, 1075–1080 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Vazquez, B. N. et al. SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair. EMBO J. 35, 1488–1503 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Li, L. et al. SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability. Nat. Commun. 7, 12235 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Tang, M. et al. SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair. Sci. Adv. 5, eaav1118 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 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  Google Scholar 

  41. Skoge, R. H., Dolle, C. & Ziegler, M. Regulation of SIRT2-dependent α-tubulin deacetylation by cellular NAD levels. DNA Repair. 23, 33–38 (2014).

    CAS  PubMed  Article  Google Scholar 

  42. Serrano, L. et al. The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation. Genes Dev. 27, 639–653 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Zhang, H., Head, P. E. & Yu, D. S. SIRT2 orchestrates the DNA damage response. Cell Cycle 15, 2089–2090 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Wang, F., Nguyen, M., Qin, F. X. & Tong, Q. SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell 6, 505–514 (2007).

    CAS  PubMed  Article  Google Scholar 

  45. Liu, G. et al. Loss of NAD-dependent protein deacetylase sirtuin-2 alters mitochondrial protein acetylation and dysregulates mitophagy. Antioxid. Redox Signal. 26, 849–863 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Lantier, L. et al. SIRT2 knockout exacerbates insulin resistance in high fat-fed mice. PLoS ONE 13, e0208634 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  47. Chen, Y. et al. Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS. EMBO Rep. 12, 534–541 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Sundaresan, N. R. et al. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J. Clin. Invest. 119, 2758–2771 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 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 

  50. van de Ven, R. A. H., Santos, D. & Haigis, M. C. Mitochondrial sirtuins and molecular mechanisms of aging. Trends Mol. Med. 23, 320–331 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Tseng, A. H., Shieh, S. S. & Wang, D. L. SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radic. Biol. Med. 63, 222–234 (2013).

    CAS  PubMed  Article  Google Scholar 

  53. Haigis, M. C. et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic β cells. Cell 126, 941–954 (2006).

    CAS  PubMed  Article  Google Scholar 

  54. Laurent, G. et al. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol. Cell 50, 686–698 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. Anderson, K. A. et al. SIRT4 Is a lysine deacylase that controls leucine metabolism and insulin secretion. Cell Metab. 25, 838–855 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Mathias, R. A. et al. Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell 159, 1615–1625 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Jeong, S. M. et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell 23, 450–463 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Laurent, G. et al. SIRT4 represses peroxisome proliferator-activated receptor α activity to suppress hepatic fat oxidation. Mol. Cell. Biol. 33, 4552–4561 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Luo, Y. X. et al. SIRT4 accelerates Ang II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase activity. Eur. Heart J. 38, 1389–1398 (2017).

    CAS  PubMed  Article  Google Scholar 

  60. Du, J. et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334, 806–809 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Zhou, L. et al. SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense. EMBO Rep. 17, 811–822 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Balestrieri, M. L. et al. Sirtuin 6 expression and inflammatory activity in diabetic atherosclerotic plaques: effects of incretin treatment. Diabetes 64, 1395–1406 (2015).

    CAS  PubMed  Article  Google Scholar 

  63. Donato, A. J. et al. SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans. J. Physiol. 589, 4545–4554 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Gao, P. et al. Overexpression of SIRT1 in vascular smooth muscle cells attenuates angiotensin II-induced vascular remodeling and hypertension in mice. J. Mol. Med. 92, 347–357 (2014).

    CAS  PubMed  Article  Google Scholar 

  65. Gorenne, I. et al. Vascular smooth muscle cell sirtuin 1 protects against DNA damage and inhibits atherosclerosis. Circulation 127, 386–396 (2013).

    CAS  PubMed  Article  Google Scholar 

  66. Orimo, M. et al. Protective role of SIRT1 in diabetic vascular dysfunction. Arterioscler. Thromb. Vasc. Biol. 29, 889–894 (2009).

    CAS  PubMed  Article  Google Scholar 

  67. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Zhang, Q. J. et al. Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice. Cardiovasc. Res. 80, 191–199 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Guo, Y. et al. Endothelial SIRT1 prevents age-induced impairment of vasodilator responses by enhancing the expression and activity of soluble guanylyl cyclase in smooth muscle cells. Cardiovasc. Res. 115, 678–690 (2019).

    CAS  PubMed  Article  Google Scholar 

  70. 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 

  71. Stein, S. et al. SIRT1 reduces endothelial activation without affecting vascular function in ApoE-/- mice. Aging 2, 353–360 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. Zu, Y. et al. SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells. Circ. Res. 106, 1384–1393 (2010).

    CAS  PubMed  Article  Google Scholar 

  73. Breitenstein, A. et al. Sirt1 inhibition promotes in vivo arterial thrombosis and tissue factor expression in stimulated cells. Cardiovasc. Res. 89, 464–472 (2011).

    CAS  PubMed  Article  Google Scholar 

  74. Xu, S. et al. SIRT6 protects against endothelial dysfunction and atherosclerosis in mice. Aging 8, 1064–1082 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Liu, Z., Wang, J., Huang, X., Li, Z. & Liu, P. Deletion of sirtuin 6 accelerates endothelial dysfunction and atherosclerosis in apolipoprotein E-deficient mice. Transl. Res. 172, 18–29 (2016).

    CAS  PubMed  Article  Google Scholar 

  76. Lee, O. H. et al. Sirtuin 6 deficiency induces endothelial cell senescence via downregulation of forkhead box M1 expression. Aging 12, 20946–20967 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. Cardus, A., Uryga, A. K., Walters, G. & Erusalimsky, J. D. SIRT6 protects human endothelial cells from DNA damage, telomere dysfunction, and senescence. Cardiovasc. Res. 97, 571–579 (2013).

    CAS  PubMed  Article  Google Scholar 

  78. He, Y. et al. SIRT6 inhibits inflammatory response through regulation of NRF2 in vascular endothelial cells. Int. Immunopharmacol. 99, 107926 (2021).

    CAS  PubMed  Article  Google Scholar 

  79. Wang, T. et al. Sirt6 stabilizes atherosclerosis plaques by promoting macrophage autophagy and reducing contact with endothelial cells. Biochem. Cell Biol. 98, 120–129 (2020).

    PubMed  Article  CAS  Google Scholar 

  80. Yang, Z. et al. SIRT6 promotes angiogenesis and hemorrhage of carotid plaque via regulating HIF-1α and reactive oxygen species. Cell Death Dis. 12, 77 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Zhong, L. et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1α. Cell 140, 280–293 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Winnik, S. et al. Mild endothelial dysfunction in Sirt3 knockout mice fed a high-cholesterol diet: protective role of a novel C/EBP-β-dependent feedback regulation of SOD2. Basic Res. Cardiol. 111, 33 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. Winnik, S. et al. Deletion of Sirt3 does not affect atherosclerosis but accelerates weight gain and impairs rapid metabolic adaptation in LDL receptor knockout mice: implications for cardiovascular risk factor development. Basic Res. Cardiol. 109, 399 (2014).

    PubMed  Article  CAS  Google Scholar 

  84. Dikalova, A. E. et al. Mitochondrial deacetylase Sirt3 reduces vascular dysfunction and hypertension while Sirt3 depletion in essential hypertension is linked to vascular inflammation and oxidative stress. Circ. Res. 126, 439–452 (2020).

    CAS  PubMed  Article  Google Scholar 

  85. Wang, J. et al. Vascular smooth muscle cell senescence promotes atherosclerosis and features of plaque vulnerability. Circulation 132, 1909–1919 (2015).

    CAS  PubMed  Article  Google Scholar 

  86. Ho, C., van der Veer, E., Akawi, O. & Pickering, J. G. SIRT1 markedly extends replicative lifespan if the NAD+ salvage pathway is enhanced. FEBS Lett. 583, 3081–3085 (2009).

    CAS  PubMed  Article  Google Scholar 

  87. van der Veer, E. et al. Extension of human cell lifespan by nicotinamide phosphoribosyltransferase. J. Biol. Chem. 282, 10841–10845 (2007).

    PubMed  Article  CAS  Google Scholar 

  88. Li, L. et al. SIRT1 acts as a modulator of neointima formation following vascular injury in mice. Circ. Res. 108, 1180–1189 (2011).

    CAS  PubMed  Article  Google Scholar 

  89. Fry, J. L. et al. Vascular smooth muscle sirtuin-1 protects against diet-induced aortic stiffness. Hypertension 68, 775–784 (2016).

    CAS  PubMed  Article  Google Scholar 

  90. Grootaert, M. O. J. & Bennett, M. R. Vascular smooth muscle cells in atherosclerosis: time for a reassessment. Cardiovasc. Res. 117, 2326–2339 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. Ma, S. et al. Precise theranostic nanomedicines for inhibiting vulnerable atherosclerotic plaque progression through regulation of vascular smooth muscle cell phenotype switching. Theranostics 8, 3693–3706 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. Wan, W. et al. PDGFR-β modulates vascular smooth muscle cell phenotype via IRF-9/SIRT-1/NF-κB pathway in subarachnoid hemorrhage rats. J. Cereb. Blood Flow. Metab. 39, 1369–1380 (2019).

    CAS  PubMed  Article  Google Scholar 

  93. Bartoli-Leonard, F. et al. Loss of SIRT1 in diabetes accelerates DNA damage-induced vascular calcification. Cardiovasc. Res. 117, 836–849 (2021).

    CAS  PubMed  Article  Google Scholar 

  94. Qiu, L., Yi, S., Yu, T. & Hao, Y. Sirt3 protects against thoracic aortic dissection formation by reducing reactive oxygen species, vascular inflammation, and apoptosis of smooth muscle cells. Front. Cardiovasc. Med. 8, 675647 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. Yang, X. et al. SIRT1 inhibition promotes atherosclerosis through impaired autophagy. Oncotarget 8, 51447–51461 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  96. He, J. et al. SIRT6 reduces macrophage foam cell formation by inducing autophagy and cholesterol efflux under ox-LDL condition. FEBS J. 284, 1324–1337 (2017).

    CAS  PubMed  Article  Google Scholar 

  97. Lee, S. J., Baek, S. E., Jang, M. A. & Kim, C. D. SIRT1 inhibits monocyte adhesion to the vascular endothelium by suppressing Mac-1 expression on monocytes. Exp. Mol. Med. 51, 1–12 (2019).

    PubMed  PubMed Central  Google Scholar 

  98. Stein, S. et al. SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis. Eur. Heart J. 31, 2301–2309 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Schug, T. T. et al. Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Mol. Cell Biol. 30, 4712–4721 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. Lee, Y. et al. Myeloid sirtuin 6 deficiency causes insulin resistance in high-fat diet-fed mice by eliciting macrophage polarization toward an M1 phenotype. Diabetes 66, 2659–2668 (2017).

    CAS  PubMed  Article  Google Scholar 

  101. Zhang, B., Ma, Y. & Xiang, C. SIRT2 decreases atherosclerotic plaque formation in low-density lipoprotein receptor-deficient mice by modulating macrophage polarization. Biomed. Pharmacother. 97, 1238–1242 (2018).

    CAS  PubMed  Article  Google Scholar 

  102. Wei, T. et al. SIRT3 (Sirtuin-3) prevents Ang II (angiotensin II)-induced macrophage metabolic switch improving perivascular adipose tissue function. Arterioscler. Thromb. Vasc. Biol. 41, 714–730 (2021).

    CAS  PubMed  Article  Google Scholar 

  103. Ding, Y. et al. Protective role of sirtuin3 against oxidative stress and NLRP3 inflammasome in cholesterol accumulation and foam cell formation of macrophages with ox-LDL-stimulation. Biochem. Pharmacol. 192, 114665 (2021).

    CAS  PubMed  Article  Google Scholar 

  104. Liu, P. et al. Sirtuin 3-induced macrophage autophagy in regulating NLRP3 inflammasome activation. Biochim. Biophys. Acta Mol. Basis Dis. 1864, 764–777 (2018).

    CAS  PubMed  Article  Google Scholar 

  105. Legutko, A. et al. Sirtuin 1 promotes Th2 responses and airway allergy by repressing peroxisome proliferator-activated receptor-γ activity in dendritic cells. J. Immunol. 187, 4517–4529 (2011).

    CAS  PubMed  Article  Google Scholar 

  106. Audrito, V. et al. NAD-biosynthetic and consuming enzymes as central players of metabolic regulation of innate and adaptive immune responses in cancer. Front. Immunol. 10, 1720 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. Bonkowski, M. S. & Sinclair, D. A. Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat. Rev. Mol. Cell Biol. 17, 679–690 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  109. Iside, C., Scafuro, M., Nebbioso, A. & Altucci, L. SIRT1 activation by natural phytochemicals: an overview. Front. Pharmacol. 11, 1225 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. Yang, H. et al. Design and synthesis of compounds that extend yeast replicative lifespan. Aging Cell 6, 35–43 (2007).

    PubMed  Article  CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. Hubbard, B. P. et al. Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339, 1216–1219 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Sinclair, D. A. & Guarente, L. Small-molecule allosteric activators of sirtuins. Annu. Rev. Pharmacol. Toxicol. 54, 363–380 (2014).

    CAS  PubMed  Article  Google Scholar 

  114. Dai, H., Sinclair, D. A., Ellis, J. L. & Steegborn, C. Sirtuin activators and inhibitors: promises, achievements, and challenges. Pharmacol. Ther. 188, 140–154 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. Klein, M. A. & Denu, J. M. Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators. J. Biol. Chem. 295, 11021–11041 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 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  Article  Google Scholar 

  118. Minor, R. K. et al. SRT1720 improves survival and healthspan of obese mice. Sci. Rep. 1, 70 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  119. 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  Article  Google Scholar 

  120. Norata, G. D. et al. Anti-inflammatory and anti-atherogenic effects of cathechin, caffeic acid and trans-resveratrol in apolipoprotein E deficient mice. Atherosclerosis 191, 265–271 (2007).

    CAS  PubMed  Article  Google Scholar 

  121. Do, G. M. et al. Long-term effects of resveratrol supplementation on suppression of atherogenic lesion formation and cholesterol synthesis in apo E-deficient mice. Biochem. Biophys. Res. Commun. 374, 55–59 (2008).

    CAS  PubMed  Article  Google Scholar 

  122. Li, J. et al. Resveratrol improves endothelial dysfunction and attenuates atherogenesis in apolipoprotein E-deficient mice. J. Nutr. Biochem. 67, 63–71 (2019).

    CAS  PubMed  Article  Google Scholar 

  123. Seo, Y. et al. Antiatherogenic effect of resveratrol attributed to decreased expression of ICAM-1 (intercellular adhesion molecule-1). Arterioscler. Thromb. Vasc. Biol. 39, 675–684 (2019).

    CAS  PubMed  Article  Google Scholar 

  124. Berbee, J. F. et al. Resveratrol protects against atherosclerosis, but does not add to the antiatherogenic effect of atorvastatin, in APOE*3-Leiden.CETP mice. J. Nutr. Biochem. 24, 1423–1430 (2013).

    CAS  PubMed  Article  Google Scholar 

  125. Chen, Y. X., Zhang, M., Cai, Y., Zhao, Q. & Dai, W. The Sirt1 activator SRT1720 attenuates angiotensin II-induced atherosclerosis in apoE-/- mice through inhibiting vascular inflammatory response. Biochem. Biophys. Res. Commun. 465, 732–738 (2015).

    CAS  PubMed  Article  Google Scholar 

  126. Gano, L. B. et al. The SIRT1 activator SRT1720 reverses vascular endothelial dysfunction, excessive superoxide production, and inflammation with aging in mice. Am. J. Physiol. Heart Circ. Physiol. 307, H1754–H1763 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. Feng, T. et al. SIRT1 activator E1231 protects from experimental atherosclerosis and lowers plasma cholesterol and triglycerides by enhancing ABCA1 expression. Atherosclerosis 274, 172–181 (2018).

    CAS  PubMed  Article  Google Scholar 

  128. Miranda, M. X. et al. The Sirt1 activator SRT3025 provides atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression. Eur. Heart J. 36, 51–59 (2015).

    CAS  PubMed  Article  Google Scholar 

  129. Gertz, M. et al. A molecular mechanism for direct sirtuin activation by resveratrol. PLoS ONE 7, e49761 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. Baur, J. A. & Sinclair, D. A. Therapeutic potential of resveratrol: the in vivo evidence. Nat. Rev. Drug Discov. 5, 493–506 (2006).

    CAS  PubMed  Article  Google Scholar 

  131. Park, S. J. et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148, 421–433 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. Huang, P. et al. A critical role of nicotinamide phosphoribosyltransferase in human telomerase reverse transcriptase induction by resveratrol in aortic smooth muscle cells. Oncotarget 6, 10812–10824 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  133. You, W. & Steegborn, C. Binding site for activator MDL-801 on SIRT6. Nat. Chem. Biol. 17, 519–521 (2021).

    CAS  PubMed  Article  Google Scholar 

  134. Donmez, G. & Outeiro, T. F. SIRT1 and SIRT2: emerging targets in neurodegeneration. EMBO Mol. Med. 5, 344–352 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. Heltweg, B. et al. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 66, 4368–4377 (2006).

    CAS  PubMed  Article  Google Scholar 

  136. Sociali, G. et al. Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics. Eur. J. Med. Chem. 102, 530–539 (2015).

    CAS  PubMed  Article  Google Scholar 

  137. Damonte, P. et al. SIRT6 inhibitors with salicylate-like structure show immunosuppressive and chemosensitizing effects. Bioorg. Med. Chem. 25, 5849–5858 (2017).

    CAS  PubMed  Article  Google Scholar 

  138. Ferrara, G. et al. Sirt6 inhibition delays the onset of experimental autoimmune encephalomyelitis by reducing dendritic cell migration. J. Neuroinflammation 17, 228 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. Mendez-Lara, K. A. et al. Nicotinamide prevents apolipoprotein B-containing lipoprotein oxidation, inflammation and atherosclerosis in apolipoprotein E-deficient mice. Antioxidants 9, 1162 (2020).

    CAS  PubMed Central  Article  Google Scholar 

  140. de Picciotto, N. E. et al. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell 15, 522–530 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  141. Mills, K. F. et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 24, 795–806 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. Kuhnast, S. et al. Niacin reduces atherosclerosis development in APOE*3Leiden.CETP mice mainly by reducing non-HDL-cholesterol. PLoS ONE 8, e66467 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  143. Canto, 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. Gardell, S. J. et al. Boosting NAD+ with a small molecule that activates NAMPT. Nat. Commun. 10, 3241 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  145. Camacho-Pereira, J. et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 23, 1127–1139 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. Gan, L. et al. CD38 deficiency alleviates Ang II-induced vascular remodeling by inhibiting small extracellular vesicle-mediated vascular smooth muscle cell senescence in mice. Signal. Transduct. Target. Ther. 6, 223 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. Henning, R. J., Bourgeois, M. & Harbison, R. D. Poly (ADP-ribose) polymerase (PARP) and PARP inhibitors: mechanisms of action and role in cardiovascular disorders. Cardiovasc. Toxicol. 18, 493–506 (2018).

    CAS  PubMed  Article  Google Scholar 

  148. Berman, A. Y., Motechin, R. A., Wiesenfeld, M. Y. & Holz, M. K. The therapeutic potential of resveratrol: a review of clinical trials. NPJ Precis. Oncol. 1, 35 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  149. Magyar, K. et al. Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease. Clin. Hemorheol. Microcirc. 50, 179–187 (2012).

    CAS  PubMed  Article  Google Scholar 

  150. Agarwal, B. et al. Resveratrol for primary prevention of atherosclerosis: clinical trial evidence for improved gene expression in vascular endothelium. Int. J. Cardiol. 166, 246–248 (2013).

    PubMed  Article  Google Scholar 

  151. Tome-Carneiro, J. et al. One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Am. J. Cardiol. 110, 356–363 (2012).

    CAS  PubMed  Article  Google Scholar 

  152. Hoffmann, E. et al. Pharmacokinetics and tolerability of SRT2104, a first-in-class small molecule activator of SIRT1, after single and repeated oral administration in man. Br. J. Clin. Pharmacol. 75, 186–196 (2013).

    CAS  PubMed  Article  Google Scholar 

  153. Libri, V. et al. A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers. PLoS ONE 7, e51395 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. Baksi, A. et al. A phase II, randomized, placebo-controlled, double-blind, multi-dose study of SRT2104, a SIRT1 activator, in subjects with type 2 diabetes. Br. J. Clin. Pharmacol. 78, 69–77 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. Venkatasubramanian, S. et al. Effects of the small molecule SIRT1 activator, SRT2104 on arterial stiffness in otherwise healthy cigarette smokers and subjects with type 2 diabetes mellitus. Open. Heart 3, e000402 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  156. Wiewel, M. A. et al. SRT2379, a small-molecule SIRT1 activator, fails to reduce cytokine release in a human endotoxemia model. Crit. Care 17 (Suppl 4), P8 (2013).

    PubMed Central  Article  Google Scholar 

  157. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01340911 (2017).

  158. D’Andrea, E., Hey, S. P., Ramirez, C. L. & Kesselheim, A. S. Assessment of the role of niacin in managing cardiovascular disease outcomes: a systematic review and meta-analysis. JAMA Netw. Open 2, e192224 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  159. Investigators, A.-H. et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 365, 2255–2267 (2011).

    Article  CAS  Google Scholar 

  160. Martens, C. R. et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat. Commun. 9, 1286 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  161. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03821623 (2022).

  162. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04040959 (2022).

  163. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04112043 (2021).

  164. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04903210 (2022).

  165. Zwaans, B. M. & Lombard, D. B. Interplay between sirtuins, MYC and hypoxia-inducible factor in cancer-associated metabolic reprogramming. Dis. Model. Mech. 7, 1023–1032 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Yang, Y. et al. SIRT1 activation by curcumin pretreatment attenuates mitochondrial oxidative damage induced by myocardial ischemia reperfusion injury. Free Radic. Biol. Med. 65, 667–679 (2013).

    CAS  PubMed  Article  Google Scholar 

  167. Singh, L., Sharma, S., Xu, S., Tewari, D. & Fang, J. Curcumin as a natural remedy for atherosclerosis: a pharmacological review. Molecules 26, 4036 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. Zhang, F., Feng, J., Zhang, J., Kang, X. & Qian, D. Quercetin modulates AMPK/SIRT1/NF-κB signaling to inhibit inflammatory/oxidative stress responses in diabetic high fat diet-induced atherosclerosis in the rat carotid artery. Exp. Ther. Med. 20, 280 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Deng, Q., Li, X. X., Fang, Y., Chen, X. & Xue, J. Therapeutic potential of quercetin as an antiatherosclerotic agent in atherosclerotic cardiovascular disease: a review. Evid. Based Complement. Altern. Med. 2020, 5926381 (2020).

    Google Scholar 

  170. Chuengsamarn, S., Rattanamongkolgul, S., Phonrat, B., Tungtrongchitr, R. & Jirawatnotai, S. Reduction of atherogenic risk in patients with type 2 diabetes by curcuminoid extract: a randomized controlled trial. J. Nutr. Biochem. 25, 144–150 (2014).

    CAS  PubMed  Article  Google Scholar 

  171. Na, L. X. et al. Curcuminoids exert glucose-lowering effect in type 2 diabetes by decreasing serum free fatty acids: a double-blind, placebo-controlled trial. Mol. Nutr. Food Res. 57, 1569–1577 (2013).

    CAS  PubMed  Article  Google Scholar 

  172. Takahashi, M. et al. Effects of curcumin supplementation on exercise-induced oxidative stress in humans. Int. J. Sports Med. 35, 469–475 (2014).

    CAS  PubMed  Google Scholar 

  173. Zahedi, M., Ghiasvand, R., Feizi, A., Asgari, G. & Darvish, L. Does quercetin improve cardiovascular risk factors and inflammatory biomarkers in women with type 2 diabetes: a double-blind randomized controlled clinical trial. Int. J. Prev. Med. 4, 777–785 (2013).

    PubMed  PubMed Central  Google Scholar 

  174. Venkatasubramanian, S. et al. Cardiovascular effects of a novel SIRT1 activator, SRT2104, in otherwise healthy cigarette smokers. J. Am. Heart Assoc. 2, e000042 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  175. Kiss, T. et al. Nicotinamide mononucleotide (NMN) supplementation promotes anti-aging miRNA expression profile in the aorta of aged mice, predicting epigenetic rejuvenation and anti-atherogenic effects. Geroscience 41, 419–439 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. Ruparelia, N., Digby, J. E. & Choudhury, R. P. Effects of niacin on atherosclerosis and vascular function. Curr. Opin. Cardiol. 26, 66–70 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

The authors are funded by British Heart Foundation (BHF) grants RG/13/14/30314, RG/20/2/34763, PG/6/24/32090, PG/16/11/32021, PG/13/14/30314 and CH/2000003, the National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre, NIHR Senior Investigator NF-SI-0616-10036, and the BHF Centre for Research Excellence RE/18/1/34212. The authors thank A. K. Uryga (NovoNordisk) for careful reviewing of our manuscript before submission.

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M.O.J.G. researched data for the article. Both authors discussed its content and wrote the manuscript. M.R.B. reviewed and edited the manuscript before submission.

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Glossary

Apoptosis

A distinctive and important mode of ‘programmed’ cell death, characterized by cell shrinkage, chromatin condensation, DNA fragmentation and cell death.

Autophagy

A natural process in which unnecessary or damaged cellular components are removed by intrinsic mechanisms, thereby balancing energy sources at crucial times in development and in response to cellular stress.

Cell senescence

A stable cell cycle arrest that can be triggered in normal cells in response to intrinsic or extrinsic stimuli, particularly after DNA damage.

DNA damage response

(DDR). A complex network of genes and intracellular signalling pathways responsible for sensing and responding to DNA damage, regulating DNA repair, cell cycle regulation, replication stress responses and apoptosis.

Chromatin remodelling

Dynamic modification of the chromatin architecture to allow condensed genomic DNA to access the regulatory transcription machinery proteins, thereby controlling gene expression.

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Grootaert, M.O.J., Bennett, M.R. Sirtuins in atherosclerosis: guardians of healthspan and therapeutic targets. Nat Rev Cardiol 19, 668–683 (2022). https://doi.org/10.1038/s41569-022-00685-x

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