Sirtuins: Guardians of mammalian healthspan

Trends in Genetics

Volumn 30, Issue 7, 2014, Pages 271-286

  Giblin, William ^a   Skinner, Mary E ^b   Lombard, David B ^b,c  

^a UNIVERSITY OF MICHIGAN   (United States)

^b UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^c UNIVERSITY OF MICHIGAN HEALTH SYSTEM   (United States)

Author keywords

Age associated disease; Aging; Longevity; Mitochondria; SIRT1; SIRT3; SIRT6

Indexed keywords

SIRTUIN 1; SIRTUIN 3; SIRTUIN 6; SIRTUIN;

AGING; CARDIOVASCULAR DISEASE; DEGENERATIVE DISEASE; GENE EXPRESSION; INFLAMMATION; LIFE EXTENSION; LIFESPAN; LONGEVITY; MAMMAL; NEOPLASM; NONHUMAN; OBSERVATIONAL STUDY; PHENOTYPE; PRIORITY JOURNAL; REVIEW; ANIMAL; GENETIC ASSOCIATION; GENETICS; HUMAN; METABOLISM; MOUSE;

AGING; ANIMALS; GENETIC ASSOCIATION STUDIES; HUMANS; LONGEVITY; MAMMALS; MICE; PHENOTYPE; SIRTUINS;

EID: 84903451392     PISSN: 01689525     EISSN: 13624555     Source Type: Journal    
DOI: 10.1016/j.tig.2014.04.007     Document Type: Review

References (223)

1. Finch C.E. Evolution in health and medicine Sackler colloquium: evolution of the human lifespan and diseases of aging: roles of infection, inflammation, and nutrition. Proc. Natl. Acad. Sci. U.S.A. 2010, 107(Suppl. 1):1718-1724.
2. Hoyert D.L., Xu J. Deaths: preliminary data for 2011. Natl. Vital Stat. Rep. 2012, 61:1-52.
3. Thies W., et al. 2013 Alzheimer's disease facts and figures. Alzheimers Dement. 2013, 9:208-245.
4. Lopez-Otin C., et al. The hallmarks of aging. Cell 2013, 153:1194-1217.
5. Gems D. Tragedy and delight: the ethics of decelerated ageing. Philos. Trans. R. Soc. Lond. B: Biol. Sci. 2011, 366:108-112.
6. Lombard D.B., Miller R.A. Aging, disease, and longevity in mice. Annu. Rev. Gerontol. Geriatr. 2014, 34:93-138.
7. Mortimer R.K., Johnston J.R. Life span of individual yeast cells. Nature 1959, 183:1751-1752.
8. Kaeberlein M., Kennedy B.K. Large-scale identification in yeast of conserved ageing genes. Mech. Ageing Dev. 2005, 126:17-21.
9. Imai S., et al. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000, 403:795-800.
10. Kaeberlein M., et al. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999, 13:2570-2580.
11. Sinclair D.A., Guarente L. Extrachromosomal rDNA circles: a cause of aging in yeast. Cell 1997, 91:1033-1042.
12. Defossez P.A., et al. Elimination of replication block protein Fob1 extends the life span of yeast mother cells. Mol. Cell 1999, 3:447-455.
13. Liu B., et al. The polarisome is required for segregation and retrograde transport of protein aggregates. Cell 2010, 140:257-267.
14. Higuchi R., et al. Actin dynamics affect mitochondrial quality control and aging in budding yeast. Curr. Biol. 2013, 23:2417-2422.
15. Suka N., et al. Sir2p and Sas2p opposingly regulate acetylation of yeast histone H4 lysine16 and spreading of heterochromatin. Nat. Genet. 2002, 32:378-383.
16. Dang W., et al. Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 2009, 459:802-807.
17. Frye R.A. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 2000, 273:793-798.
18. Jiang H., et al. SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine. Nature 2013, 496:110-113.
19. Du J., et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 2011, 334:806-809.
20. Tan M., et al. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab. 2014, 19:605-617.
21. Peng C., et al. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol. Cell. Proteomics 2011, 10. M111.012658.
22. Tanner K.G., et al. Silent information regulator 2 family of NAD- dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose. Proc. Natl. Acad. Sci. U.S.A. 2000, 97:14178-14182.
23. Canto C., et al. Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes. Mol. Aspects Med. 2013, 34:1168-1201.
24. Bordone L., Guarente L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat. Rev. Mol. Cell Biol. 2005, 6:298-305.
25. Rahman S., Islam R. Mammalian Sirt1: insights on its biological functions. Cell Commun. Signal. 2011, 9:11.
26. Feldman J.L., et al. Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. J. Biol. Chem. 2013, 288:31350-31356.
27. Jin Q., et al. Cytoplasm-localized SIRT1 enhances apoptosis. J. Cell. Physiol. 2007, 213:88-97.
28. Byles V., et al. Aberrant cytoplasm localization and protein stability of SIRT1 is regulated by PI3K/IGF-1R signaling in human cancer cells. Int. J. Biol. Sci. 2010, 6:599-612.
29. Tanno M., et al. Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J. Biol. Chem. 2007, 282:6823-6832.
30. Hisahara S., et al. Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation. Proc. Natl. Acad. Sci. U.S.A. 2008, 105:15599-15604.
31. Li Y., et al. SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab. 2008, 8:38-48.
32. Jeong H., et al. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat. Med. 2012, 18:159-165.
33. Herranz D., et al. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat. Commun. 2010, 1:3.
34. 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. 2013, 18:416-430.
35. Alcendor R.R., et al. Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ. Res. 2007, 100:1512-1521.
36. Whitaker R., et al. Increased expression of Drosophila Sir2 extends life span in a dose-dependent manner. Aging 2013, 5:682-691.
37. McBurney M.W., et al. The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Mol. Cell. Biol. 2003, 23:38-54.
38. Satoh A., et al. SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus. J. Neurosci. 2010, 30:10220-10232.
39. Mercken E.M., et al. SIRT1 but not its increased expression is essential for lifespan extension in caloric-restricted mice. Aging Cell 2014, 13:193-196.
40. Boily G., et al. SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol. Oncogene 2009, 28:2882-2893.
41. Lombard D.B., Zwaans B.M. SIRT3: as simple as it seems?. Gerontology 2014, 60:56-64.
42. Brown K., et al. SIRT3 reverses aging-associated degeneration. Cell Rep. 2013, 3:319-327.
43. Yang B., et al. The sirtuin SIRT6 deacetylates H3 K56Ac in vivo to promote genomic stability. Cell Cycle 2009, 8:2662-2663.
44. Michishita E., et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 2008, 452:492-496.
45. Michishita E., et al. Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6. Cell Cycle 2009, 8:2664-2666.
46. Kaidi A., et al. Human SIRT6 promotes DNA end resection through CtIP deacetylation. Science 2010, 329:1348-1353.
47. Dominy J.E., et al. The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Mol. Cell 2012, 48:900-913.
48. Mao Z., et al. SIRT6 promotes DNA repair under stress by activating PARP1. Science 2011, 332:1443-1446.
49. Jedrusik-Bode M., et al. The sirtuin SIRT6 regulates stress granule formation in C. elegans and mammals. J. Cell Sci. 2013, 126:5166-5177.
50. Miteva Y., Cristea M. A proteomic perspective of Sirtuin 6 (SIRT6) phosphorylation and interactions and their dependence on catalytic activity. Mol. Cell. Proteomics 2014, 13:168-183.
51. Simeoni F., et al. Proteomic analysis of the SIRT6 interactome: novel links to genome maintenance and cellular stress signaling. Sci. Rep. 2013, 3:3085.
52. Beauharnois J.M., et al. Sirtuin 6: a review of biological effects and potential therapeutic properties. Mol. Biosyst. 2013, 9:1789-1806.
53. Kanfi Y., et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 2012, 483:218-221.
54. Rincon M., et al. The paradox of the insulin/IGF-1 signaling pathway in longevity. Mech. Ageing Dev. 2004, 125:397-403.
55. Mostoslavsky R., et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 2006, 124:315-329.
56. Xiao C., et al. SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice. J. Biol. Chem. 2010, 285:36776-36784.
57. Sundaresan N.R., et al. The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat. Med. 2012, 18:1643-1650.
58. Miller R.A., et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J. Gerontol. A: Biol. Sci. Med. Sci. 2011, 66:191-201.
59. Neff F., et al. Rapamycin extends murine lifespan but has limited effects on aging. J. Clin. Invest. 2013, 123:3272-3291.
60. Richardson A. Rapamycin, anti-aging, and avoiding the fate of Tithonus. J. Clin. Invest. 2013, 123:3204-3206.
61. Hall J.A., et al. The sirtuin family's role in aging and age-associated pathologies. J. Clin. Invest. 2013, 123:973-979.
62. Brown R.C., et al. Neurodegenerative diseases: an overview of environmental risk factors. Environ. Health Perspect. 2005, 113:1250-1256.
63. Herskovits A.Z., Guarente L. SIRT1 in neurodevelopment and brain senescence. Neuron 2014, 81:471-483.
64. Donmez G., et al. SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. Cell 2010, 142:320-332.
65. Min S.W., et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 2010, 67:953-966.
66. Cohen T.J., et al. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat. Commun. 2011, 2:252.
67. Donmez G., et al. SIRT1 protects against alpha-synuclein aggregation by activating molecular chaperones. J. Neurosci. 2012, 32:124-132.
68. Pallos J., et al. Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington's disease. Hum. Mol. Genet. 2008, 17:3767-3775.
69. Parker J.A., et al. Integration of beta-catenin, sirtuin, and FOXO signaling protects from mutant huntingtin toxicity. J. Neurosci. 2012, 32:12630-12640.
70. Jiang M., et al. Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets. Nat. Med. 2012, 18:153-158.
71. Fu J., et al. trans-(-)-epsilon-Viniferin increases mitochondrial sirtuin 3 (SIRT3), activates AMP-activated protein kinase (AMPK), and protects cells in models of Huntington Disease. J. Biol. Chem. 2012, 287:24460-24472.
72. Song W., et al. Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat. Med. 2011, 17:377-382.
73. Fukagawa N.K., et al. Effect of age on body composition and resting metabolic rate. Am. J. Physiol. 1990, 259:E233-E238.
74. St-Onge M.P., Gallagher D. Body composition changes with aging: the cause or the result of alterations in metabolic rate and macronutrient oxidation?. Nutrition 2010, 26:152-155.
75. Basen-Engquist K., Chang M. Obesity and cancer risk: recent review and evidence. Curr. Oncol. Rep. 2011, 13:71-76.
76. Morley J.E. The metabolic syndrome and aging. J. Gerontol. A: Biol. Sci. Med. Sci. 2004, 59:139-142.
77. Polednak A.P. Estimating the number of U.S. incident cancers attributable to obesity and the impact on temporal trends in incidence rates for obesity-related cancers. Cancer Detect. Prev. 2008, 32:190-199.
78. Roberts D.L., et al. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu. Rev. Med. 2010, 61:301-316.
79. Li X. SIRT1 and energy metabolism. Acta Biochim. Biophys. Sin. 2013, 45:51-60.
80. Chang H.C., Guarente L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol. Metab. 2014, 25:138-145.
81. Purushotham A., et al. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 2009, 9:327-338.
82. Wang R.H., et al. Liver steatosis and increased ChREBP expression in mice carrying a liver specific SIRT1 null mutation under a normal feeding condition. Int. J. Biol. Sci. 2010, 6:682-690.
83. Cakir I., et al. Hypothalamic Sirt1 regulates food intake in a rodent model system. PLoS ONE 2009, 4:e8322.
84. Ramadori G., et al. SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab. 2010, 12:78-87.
85. Gerhart-Hines Z., et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J. 2007, 26:1913-1923.
86. Gomes A.P., et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 2013, 155:1624-1638.
87. Qiang L., et al. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of PPARgamma. Cell 2012, 150:620-632.
88. Picard F., et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 2004, 429:771-776.
89. Ramsey K.M., et al. Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell 2008, 7:78-88.
90. Moynihan K.A., et al. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metab. 2005, 2:105-117.
91. Yoshino J., et al. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011, 14:528-536.
92. Hirschey M.D., et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 2010, 464:121-125.
93. Fan J., et al. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol. Cell 2014, 53:534-548.
94. Shimazu T., et al. SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab. 2010, 12:654-661.
95. Jing E., et al. Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc. Natl. Acad. Sci. U.S.A. 2011, 108:14608-14613.
96. Hirschey M.D., et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol. Cell 2011, 44:177-190.
97. Fernandez-Marcos P.J., et al. Muscle or liver-specific Sirt3 deficiency induces hyperacetylation of mitochondrial proteins without affecting global metabolic homeostasis. Sci. Rep. 2012, 2:425.
98. Zhong L., et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 2010, 140:280-293.
99. Kim H.S., et al. Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab. 2010, 12:224-236.
100. Elhanati S., et al. Multiple regulatory layers of SREBP1/2 by SIRT6. Cell Rep. 2013, 4:905-912.
101. Tao R., et al. Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6. J. Lipid Res. 2013, 54:2745-2753.
102. Kanfi Y., et al. SIRT6 protects against pathological damage caused by diet-induced obesity. Aging Cell 2010, 9:162-173.
103. Barbaresko J., et al. Dietary pattern analysis and biomarkers of low-grade inflammation: a systematic literature review. Nutr. Rev. 2013, 71:511-527.
104. Tilstra J.S., et al. NF-kappaB in aging and disease. Aging Dis. 2011, 2:449-465.
105. Haigis M.C., Sinclair D.A. Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 2010, 5:253-295.
106. Kawahara T.L., et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 2009, 136:62-74.
107. Jung K.J., et al. Effect of short term calorie restriction on pro-inflammatory NF-kB and AP-1 in aged rat kidney. Inflamm. Res. 2009, 58:143-150.
108. Gabay O., Gabay C. Hand osteoarthritis: new insights. Joint Bone Spine 2013, 80:130-134.
109. Biason-Lauber A., et al. Identification of a SIRT1 mutation in a family with type 1 diabetes. Cell Metab. 2013, 17:448-455.
110. Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell 2011, 144:646-674.
111. Yuan H., et al. The emerging and diverse roles of sirtuins in cancer: a clinical perspective. Onco Targets Ther. 2013, 6:1399-1416.
112. Yuan J., et al. A c-Myc-SIRT1 feedback loop regulates cell growth and transformation. J. Cell Biol. 2009, 185:203-211.
113. Lim J.H., et al. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol. Cell 2010, 38:864-878.
114. Srisuttee R., et al. Hepatitis B virus X (HBX) protein upregulates beta-catenin in a human hepatic cell line by sequestering SIRT1 deacetylase. Oncol. Rep. 2012, 28:276-282.
115. Firestein R., et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS ONE 2008, 3:e2020.
116. Leko V., et al. Enterocyte-specific inactivation of SIRT1 reduces tumor load in the APC(+/min) mouse model. PLoS ONE 2013, 8:e66283.
117. Laemmle A., et al. Inhibition of SIRT1 impairs the accumulation and transcriptional activity of HIF-1alpha protein under hypoxic conditions. PLoS ONE 2012, 7:e33433.
118. Menssen A., et al. The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop. Proc. Natl. Acad. Sci. U.S.A. 2012, 109:E187-E196.
119. Mao B., et al. Sirt1 deacetylates c-Myc and promotes c-Myc/Max association. Int. J. Biochem. Cell Biol. 2011, 43:1573-1581.
120. Finley L.W., et al. SIRT3 Opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell 2011, 19:416-428.
121. Kim H.S., et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 2010, 17:41-52.
122. Liou G.Y., Storz P. Reactive oxygen species in cancer. Free Radic. Res. 2010, 44:479-496.
123. Finley L.W., Haigis M.C. Metabolic regulation by SIRT3: implications for tumorigenesis. Trends Mol. Med. 2012, 18:516-523.
124. Bell E.L., et al. SirT3 suppresses hypoxia inducible factor 1alpha and tumor growth by inhibiting mitochondrial ROS production. Oncogene 2011, 30:2986-2996.
125. Kaplon J., et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 2013, 498:109-112.
126. Li S., et al. p53-induced growth arrest is regulated by the mitochondrial SirT3 deacetylase. PLoS ONE 2010, 5:e10486.
127. Aury-Landas J., et al. Germline copy number variation of genes involved in chromatin remodelling in families suggestive of Li-Fraumeni syndrome with brain tumours. Eur. J. Hum. Genet. 2013, 21:1369-1376.
128. Ashraf N., et al. Altered sirtuin expression is associated with node-positive breast cancer. Br. J. Cancer 2006, 95:1056-1061.
129. Alhazzazi T.Y., et al. Sirtuin-3 (SIRT3), a novel potential therapeutic target for oral cancer. Cancer 2011, 117:1670-1678.
130. Khongkow M., et al. SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer. Carcinogenesis 2013, 34:1476-1486.
131. Liu Y., et al. Inhibition of SIRT6 in prostate cancer reduces cell viability and increases sensitivity to chemotherapeutics. Protein Cell 2013, 4:702-710.
132. Sebastian C., et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 2012, 151:1185-1199.
133. Min L., et al. Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin. Nat. Cell Biol. 2012, 14:1203-1211.
134. Van Meter M., et al. SIRT6 overexpression induces massive apoptosis in cancer cells but not in normal cells. Cell Cycle 2011, 10:3153-3158.
135. 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 2013, 23:450-463.
136. Csibi A., et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 2013, 153:840-854.
137. Jeong S.M., et al. SIRT4 protein suppresses tumor formation in genetic models of Myc-induced B cell lymphoma. J. Biol. Chem. 2014, 289:4135-4144.
138. Barber M.F., et al. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 2012, 487:114-118.
139. Go A.S., et al. Heart disease and stroke statistics 2014 update: a report from the American Heart Association. Circulation 2014, 129:e28-e292.
140. Lakatta E.G., Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation 2003, 107:346-354.
141. Mattagajasingh I., et al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. U.S.A. 2007, 104:14855-14860.
142. Csiszar A., et al. Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations. Am. J. Physiol. Heart Circ. Physiol. 2008, 294:H2721-H2735.
143. Potente M., Dimmeler S. Emerging roles of SIRT1 in vascular endothelial homeostasis. Cell Cycle 2008, 7:2117-2122.
144. Potente M., et al. SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev. 2007, 21:2644-2658.
145. Guarani V., et al. Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase. Nature 2011, 473:234-238.
146. Oellerich M.F., Potente M. FOXOs and sirtuins in vascular growth, maintenance, and aging. Circ. Res. 2012, 110:1238-1251.
147. Paik J.H. FOXOs in the maintenance of vascular homoeostasis. Biochem. Soc. Trans. 2006, 34:731-734.
148. Paik J.H., et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 2007, 128:309-323.
149. Potente M., et al. Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J. Clin. Invest. 2005, 115:2382-2392.
150. Phng L.K., Gerhardt H. Angiogenesis: a team effort coordinated by notch. Dev. Cell 2009, 16:196-208.
151. 2+/calmodulin-dependent protein kinase kinase beta phosphorylation of Sirtuin 1 in endothelium is atheroprotective. Proc. Natl. Acad. Sci. U.S.A. 2013, 110:E2420-E2427.
152. Kolwicz S.C., Tian R. Glucose metabolism and cardiac hypertrophy. Cardiovasc. Res. 2011, 90:194-201.
153. Planavila A., et al. Sirt1 acts in association with PPARalpha to protect the heart from hypertrophy, metabolic dysregulation, and inflammation. Cardiovasc. Res. 2011, 90:276-284.
154. Oka S., et al. PPARalpha-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway. Cell Metab. 2011, 14:598-611.
155. Sundaresan N.R., et al. The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy. Sci. Signal. 2011, 4:ra46.
156. Manning B.D., Cantley L.C. AKT/PKB signaling: navigating downstream. Cell 2007, 129:1261-1274.
157. Condorelli G., et al. Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 2002, 99:12333-12338.
158. Shiojima I., et al. Akt signaling mediates postnatal heart growth in response to insulin and nutritional status. J. Biol. Chem. 2002, 277:37670-37677.
159. Sundaresan N.R., et al. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J. Clin. Invest. 2009, 119:2758-2771.
160. Pillai V.B., et al. Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. J. Biol. Chem. 2010, 285:3133-3144.
161. Mouchiroud L., et al. The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 2013, 154:430-441.
162. Braidy N., et al. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats. PLoS ONE 2011, 6:e19194.
163. Braidy N., et al. Mapping NAD(+) metabolism in the brain of ageing Wistar rats: potential targets for influencing brain senescence. Biogerontology 2014, 15:177-198.
164. Massudi H., et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS ONE 2012, 7:e42357.
165. Canto C., et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012, 15:838-847.
166. Barbosa M.T., et al. The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity. FASEB J. 2007, 21:3629-3639.
167. Sharma A., et al. The role of SIRT6 protein in aging and reprogramming of human induced pluripotent stem cells. J. Biol. Chem. 2013, 288:18439-18447.
168. Kennedy B.K., Pennypacker J.K. Drugs that modulate aging: the promising yet difficult path ahead. Transl. Res. 2013, 163:456-465.
169. Kim H.J., et al. Metabolomic analysis of livers and serum from high-fat diet induced obese mice. J. Proteome Res. 2011, 10:722-731.
170. Bai P., Canto C. The role of PARP-1 and PARP-2 enzymes in metabolic regulation and disease. Cell Metab. 2012, 16:290-295.
171. Tissenbaum H.A., Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 2001, 410:227-230.
172. Tissenbaum H.A., Guarente L. Model organisms as a guide to mammalian aging. Dev. Cell 2002, 2:9-19.
173. Viswanathan M., Guarente L. Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. Nature 2011, 477:E1-E2.
174. Rizki G., et al. The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS Genet. 2011, 7:e1002235.
175. Berdichevsky A., et al. C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell 2006, 125:1165-1177.
176. Ludewig A.H., et al. Pheromone sensing regulates Caenorhabditis elegans lifespan and stress resistance via the deacetylase SIR-2.1. Proc. Natl. Acad. Sci. U.S.A. 2013, 110:5522-5527.
177. Rogina B., Helfand S.L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl. Acad. Sci. U.S.A. 2004, 101:15998-16003.
178. Banerjee K.K., et al. dSir2 in the adult fat body, but not in muscles, regulates life span in a diet-dependent manner. Cell Rep. 2012, 2:1485-1491.
179. Hoffmann J., et al. Overexpression of Sir2 in the adult fat body is sufficient to extend lifespan of male and female Drosophila. Aging 2013, 5:315-327.
180. Burnett C., et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 2011, 477:482-485.
181. Rose G., et al. Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly. Exp. Gerontol. 2003, 38:1065-1070.
182. Bellizzi D., et al. A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. Genomics 2005, 85:258-263.
183. Lescai F., et al. Human longevity and 11p15.5: a study in 1321 centenarians. Eur. J. Hum. Genet. 2009, 17:1515-1519.
184. Gallucci M., et al. The Treviso Longeva (Trelong) study: a biomedical, demographic, economic and social investigation on people 70 years and over in a typical town of North-East of Italy. Arch. Gerontol. Geriatr. 2007, 44(Suppl. 1):173-192.
185. Halaschek-Wiener J., et al. Genetic variation in healthy oldest-old. PLoS ONE 2009, 4:e6641.
186. Albani D., et al. Modulation of human longevity by SIRT3 single nucleotide polymorphisms in the prospective study 'Treviso Longeva (TRELONG)'. Age 2014, 36:469-478.
187. Speakman J.R., Mitchell S.E. Caloric restriction. Mol. Aspects Med. 2011, 32:159-221.
188. Guarente L. Calorie restriction and sirtuins revisited. Genes Dev. 2013, 27:2072-2085.
189. Lamming D.W., et al. HST2 mediates SIR2-independent life-span extension by calorie restriction. Science 2005, 309:1861-1864.
190. Lin S.J., et al. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 2000, 289:2126-2128.
191. Kaeberlein M., Powers R.W. Sir2 and calorie restriction in yeast: a skeptical perspective. Ageing Res. Rev. 2007, 6:128-140.
192. Longo V.D., et al. Replicative and chronological aging in Saccharomyces cerevisiae. Cell Metab. 2012, 16:18-31.
193. Hansen M., et al. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 2007, 6:95-110.
194. Wang Y., Tissenbaum H.A. Overlapping and distinct functions for a Caenorhabditis elegans SIR2 and DAF-16/FOXO. Mech. Ageing Dev. 2006, 127:48-56.
195. Mair W., et al. Optimizing dietary restriction for genetic epistasis analysis and gene discovery in C. elegans. PLoS ONE 2009, 4:e4535.
196. Lee G.D., et al. Dietary deprivation extends lifespan in Caenorhabditis elegans. Aging Cell 2006, 5:515-524.
197. Kaeberlein T.L., et al. Lifespan extension in Caenorhabditis elegans by complete removal of food. Aging Cell 2006, 5:487-494.
198. Greer E.L., Brunet A. Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans. Aging Cell 2009, 8:113-127.
199. Bauer J.H., et al. dSir2 and Dmp53 interact to mediate aspects of CR-dependent lifespan extension in D. melanogaster. Aging 2009, 1:38-48.
200. Chen D., et al. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev. 2008, 22:1753-1757.
201. Schenk S., et al. Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction. J. Clin. Invest. 2011, 121:4281-4288.
202. Cohen D.E., et al. Neuronal SIRT1 regulates endocrine and behavioral responses to calorie restriction. Genes Dev. 2009, 23:2812-2817.
203. Lu M., et al. Neuronal Sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues. J. Biol. Chem. 2013, 288:10722-10735.
204. Kume S., et al. Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J. Clin. Invest. 2010, 120:1043-1055.
205. Boily G., et al. SirT1 regulates energy metabolism and response to caloric restriction in mice. PLoS ONE 2008, 3:e1759.
206. Palacios O.M., et al. Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle. Aging 2009, 1:771-783.
207. Shi T., et al. SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J. Biol. Chem. 2005, 280:13560-13567.
208. Schwer B., et al. Calorie restriction alters mitochondrial protein acetylation. Aging Cell 2009, 8:604-606.
209. Hallows W.C., et al. Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol. Cell 2011, 41:139-149.
210. Someya S., et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 2010, 143:802-812.
211. Nakagawa T., et al. SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 2009, 137:560-570.
212. Qiu X., et al. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 2010, 12:662-667.
213. Tao R., et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol. Cell 2010, 40:893-904.
214. Hebert A.S., et al. Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol. Cell 2012, 49:186-199.
215. Baur J.A. Resveratrol, sirtuins, and the promise of a DR mimetic. Mech. Ageing Dev. 2010, 131:261-269.
216. Baur J.A., et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006, 444:337-342.
217. Pearson K.J., et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 2008, 8:157-168.
218. Pacholec M., et al. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J. Biol. Chem. 2010, 285:8340-8351.
219. Price N.L., et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012, 15:675-690.
220. Chachay V.S., et al. Resveratrol does not benefit patients with non-alcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 2014, 10.1016/j.cgh.2014.02.024.
221. Minor R.K., et al. SRT1720 improves survival and healthspan of obese mice. Sci. Rep. 2011, 1:70.
222. Mitchell S.J., et al. The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell Rep. 2014, 6:836-843.
223. Hubbard B.P., et al. Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 2013, 339:1216-1219.