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Mechanisms underlying caloric restriction and lifespan regulation: implications for vascular aging. In a postmortem study, the levels of SIRT1 showed a slight increase in the dementia patients with Lewy bodies (16, 83). Sir2 mediates longevity in the fly through a pathway related to calorie restriction. doi: 10.1523/JNEUROSCI.3308-07.2007, 45. The decline in the activity of SIRT1 may not be related directly with SIRT1 protein but also its downstream or upstream molecules such as a decline in NAD+ levels with aging (65). (2011) 29:5115. doi: 10.1002/art.37807, 100. Cornelius C, Trovato Salinaro A, Scuto M, Fronte V, Cambria MT, Pennisi M, et al. (2018) 105:17580. Furthermore, in the patients with Huntington's disease (HD), Baldo and his colleagues found higher expression of SIRT1 protein level in the most affected brain regions, especially hypothalamic regions important for metabolic regulation, compared to brain regions which were less affected from the mutant huntingtin protein (28). doi: 10.1371/journal.pone.0008322, 33. Insulin sensitivity is increased in the pancreatic beta cells which have insulin resistance due to overexpression of SIRT1 (30, 33). Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, et al. EMBO J. SIRT1 gene variants are related to risk of childhood obesity. Rev Neurosci. Res. doi: 10.1016/j.jhep.2016.10.023, 49. (2008) 177:86170. Am J Physiol Lung Cell Mol Physiol. Neuropeptides (2018) 71:5460 doi: 10.1016/j.npep.2018.07.001, 72. In addition, the regulation of metabolism and longevity by SIRT1 occurs through controlling the maturation of hypothalamic peptide hormones (25, 26). (2011) 10:2759. 41. Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschp MH. As shown in previous studies, SIRT1 epigenetically reprograms inflammation taking about AD formation at the earlier stages by altering transcription factors (24, 75, 76). Specificity for SIRT1 increases in the relevant metabolic pathways in the hypothalamic circuitries which is also associated with altered downstream factors of SIRT1 such as FoxO transcription factors (27, 28). J Biol Chem. Bedalov A, Simon JA. (2010) 20:6339. doi: 10.1038/ncb1468, 14. doi: 10.1038/ijo.2008.78, 30. doi: 10.1101/gad.13.19.2570, 6. SIRT1 inhibition causes oxidative stress and inflammation in patients with coronary artery disease. doi: 10.1007/s00431-014-2424-1, 51. Endocrinol. (2018) 111:2039. Genes Dev. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. doi: 10.1002/jor.21284, 52. Effect of resveratrol on cartilage protection and apoptosis inhibition in experimental osteoarthritis of rabbit. The activity of PPAR which have a role in the storage of glucose and fatty acid in adipose tissue is repressed by SIRT1 (34). A remarkable age-related increase in SIRT1 protein expression against oxidative stress in elderly: SIRT1 gene variants and longevity in human. (1999) 68:194953. In one of our previous studies (61), we found a positive correlation between total antioxidant level and SIRT1 level in CVD patients. Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S, et al. SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease. Specific alterations in the circulating levels of the SIRT1, TLR4, and IL7 proteins in patients with dementia. (2018) 119:24954. Cell (2006) 126:25768. Previous reports also showed the protective role of SIRT1 on the development of osteoarthritis by upregulation of cartilage extracellular matrix genes and downregulation of matrix-degrading enzymes (51, 52). Mudo G, Makela J, Di Liberto V, Tselykh TV, Olivieri M, Piepponen P, et al. (2007) 100:144251. Nillni EA. Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. Cant C, Auwerx J. Caloric restriction, SIRT1 and longevity. NF-kappaB signaling in neurite growth and neuronal survival. Indeed, the dysregulation of energy sensing may cause inflammation and insulin resistance. Cell Mol Life Sci. J Neurosci (2012) 32:1263040. (2013) 14:383459. doi: 10.1523/JNEUROSCI.0277-12.2012. doi: 10.1073/pnas.0802917105, 42. doi: 10.1016/j.ijbiomac.2018.07.099, 22. Contrary to some previous studies (98, 99), the SIRT1 level significantly decreased approaching to control values in the CVD patients receiving statin therapy (100). In addition to the obesity, SIRT1 has a role in the hepatic energy metabolism by modulating it nutritionally and hormonally. (2013) 67:607. Xie J, Zhang X, Zhang L. Negative regulation of inflammation by SIRT1. (2008) 105:97938. Wang J, Gao JS, Chen JW Li F, Tian J. (2018) 19:E911. doi: 10.1007/s12035-017-0646-8, 73. doi: 10.1016/j.neuroscience.2008.04.065, 84. (2007) 26:316979. Received: 31 July 2018; Accepted: 27 September 2018; Published: 15 October 2018. The overarching aim of this paper is to provide a basis for hypothesizing that the level of SIRT1 are mechanistically increased to overcome the dysfunction of SIRT1 activity in the diseased conditions. Li W, Cai L, Zhang Y, Cui L, Shen G. Intra-articular resveratrol injection prevents osteoarthritis progression in a mouse model by activating SIRT1 and thereby silencing HIF-2. doi: 10.1016/j.mad.2009.11.002, 65. (2016) 438:7788 doi: 10.1016/j.mce.2016.09.002, 27. Froy O, Sherman H, Bhargava G, Chapnik N, Cohen R, Gutman R, et al. doi: 10.1093/abbs/gms108, 32. Nucleic Acids Res. J Neuropathol Exp Neurol. This study explained clearly the relation between oxidative stress and overexpression of SIRT1 to the pathological levels in CVD patients. Nat Cell Biol. doi: 10.1038/nature03354, 38. The editor and reviewer's affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. Lancet Neurol. doi: 10.1007/s00018-011-0850-z, 83. doi: 10.2174/1381612823666170125153334, 19. doi: 10.1016/j.drup.2010.12.001, 12. doi: 10.1074/jbc.M602909200, 78. Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. 19 Articles, This article is part of the Research Topic, SIRT1 and Age-Related Neurodegenerative Diseases, Creative Commons Attribution License (CC BY). In one of the recent study, after feeding with high dietary fructose, the liver of rats were investigated in response to SIRT1 expression as a main energy sensing protein (40). Song JH, Yu JT, Liu M, Yan CZ, Tan L. Genetic association between ADAM10 gene polymorphism and Alzheimer's disease in a Northern Han Chinese population. In addition, increase in the SIRT1 activity had a protective effect against osteoarthritis in animal models (53, 54). The most studied targets of SIRT1 in the metabolic diseases, age-related diseases and cardiovascular diseases. Rodgers JT, Lerin C, Haas W. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Exp Mol Pathol. Nawaz A, Mehmood A, Kanatani Y, Kado T, Igarashi Y, Takikawa A, et al. Neurochem. The decline in the SIRT1 level by statins can be explained by the statins' inducement effect on PPAR activity to protect patients against the progression of atherosclerosis (101). BMC Neurosci. doi: 10.1161/CIRCULATIONAHA.110.958033, 93. doi: 10.1016/j.pnpbp.2018.05.017. Fujita N, Matsushita T, Ishida K, Topark-Ngarm A, Senawong T, Machado De Oliveira R, et al. Olmos Y, Brosens JJ, Lam EW. Costa Cdos S, Hammes TO, Rohden F, Margis R, Bortolotto JW, Padoin AV, et al. Salminen A, Kaarniranta K, Kauppinen A. Crosstalk between oxidative stress and SIRT1: impact on the aging process. No use, distribution or reproduction is permitted which does not comply with these terms. In the in vitro PD model, it was observed that an overexpression of SIRT1 due to application of toxin (rotenone or MPTP) which causes neurodegeneration was rescued cells from oxidative stress (16, 83). doi: 10.1515/REVNEURO.2010.21.4.299, 94. On the other hand, SIRT1 behaves as a double edged sword in response to inflammation which is a cause of neurodegeneration. Drug Resist Update (2011) 14:3544. Circ Res. It is also thought that transcriptional activity of NF-B protein, a preconditioner in cardiac ischemia, is inhibited by SIRT1 protein to promote cell protection (93, 94). In addition, it was observed that brains of AD patients have consistently reduced NAD+ levels and SIRT1 transcription and/or protein levels involved in chronic inflammation that can also be altered by increased levels of the activated proinflammatory transcription factor NF-B (7779). (2004) 136:2615. BE wrote the draft of the manuscript and UK finalized the manuscript. Silent information regulator 1 protects the heart from ischemia/reperfusion. doi: 10.1016/j.redox.2017.05.027, 18. In PD, SIRT1 inhibits -synuclein aggregation by deacetylating proteins such as heat shock proteins and PGC-1 and, therefore, it protects dopaminergic neurons against cell death which occur due to the formation of insoluble fibrils called Lewy bodies (81, 82). The relationships between SIRT1 and age were investigated in the previous studies related to interaction of lifespan elongation and calorie restriction which is thought as an enhancer for SIRT1 activity (56, 57). (2007) 27:1426574. In cardiomyocytes, myoblast gains resistance against to oxidative stress by increasing expression of nuclear SIRT1 protein. doi: 10.1074/jbc.M501485200, 36. It was thought that increased protein level of SIRT1 in older people may be a compensatory mechanism due to accumulation of oxidative stress-related products and elimination of antioxidant enzyme level in elderly (62). Nature (2005) 434:1138. These favorable effects of SIRT1 may be related with the activation of the antioxidant enzymes and stimulation of PGC1 to decrease the level of pro-inflammatory cytokines (41). Pedersen SB, lholm J, Paulsen SK, Bennetzen MF, Richelsen B. Sirtuins in cognitive ageing and Alzheimer's disease. Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I. SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease. doi: 10.1016/j.brainres.2011.09.008, 75. 29. Sirt1 extends lifespan and delays aging in mice through the regulation of nk2 homeobox1 in the dmh and lh. Low Sirt1 expression, which is upregulated by fasting, in human adipose tissue from obese women. Aging Cell (2014) 13:1936. (91) noted that the rate of SIRT1 overexpression had two-sided action in the cardiovascular system. Jeko H, Wencel P, Strosznajder RP, Strosznajder JB. Teng FY, Tang BL. In addition, SIRT1 also regulates the expression of BDNF in the brain. Alageel A, Tomasi J, Tersigni C, Brietzke E, Zuckerman H, Subramaniapillai M, et al. SIRT1 transcription is decreased in visceral adipose tissue of morbidly obese patients with severe hepatic steatosis. Cell (2005) 120:64961. Unger TJ, Calderon GA, Bradley LC, Sena-Esteves M, Rios M. Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity. doi: 10.1101/gad.1052903, 9. Singh P, Hanson PS, Morris CM. Longo VD, Kennedy BK. Immun Ageing (2013) 10:41. doi: 10.1186/1742-4933-10-41, 67. However, they demonstrated a significant increase in the SIRT1 expression in the fructose-induced inflammation suggesting compensatory rise in the level of SIRT1 to decline the inflammation-related metabolic reactions (40). J Biol Chem. Cell Metab. Aging Cell (2008) 7:7888. Therefore, the role of SIRT1 protein and its downstream molecules also gains importance in the experimental studies related with CVD development. Sirt1 regulates aging and resistance to oxidative stress in the heart. Serrano-Marco L, Chacn MR, Maym-Masip E, Barroso E, Salvad L, Wabitsch M, et al. J Biol Chem. Copyright 2018 Elibol and Kilic. Transgenic expression and activation of PGC-1alpha protect dopaminergic neurons in the MPTP mouse model of Parkinson's disease. (2005) 66:56273. doi: 10.1152/ajplung.00308.2006, 23. doi: 10.1016/j.cmet.2009.02.006, 37. In this previous study, we also found a significant increase in the oxidative stress parameters which may be an inducer for SIRT1 expression. Alcendor et al. (2005) 280:1645660. In this context, the current approaches to enhancing the expression of SIRT1 points the importance of epigenetics in several age-related diseases to provide a healthy aging by developing novel therapies which can prevent or damp the progression of some diseases. Sirtuin 1 (SIRT1) which is encoded by the SIRT1 gene is the most conserved mammalian nicotinamide adenine dinucleotide (NAD+) dependent histone deacetylase (1). This modulation is mostly occurred through the deacetylation of metabolic regulators (46). The sirtuin pathway in ageing and Alzheimer disease: mechanistic and therapeutic considerations. doi: 10.1093/nar/gkq609, Keywords: SIRT1 expression, oxidative stress, metabolic diseases, cardiovascular diseases, neurodegenerative diseases, Citation: Elibol B and Kilic U (2018) High Levels of SIRT1 Expression as a Protective Mechanism Against Disease-Related Conditions. Int J Mol Sci. PLoS ONE (2009) 4:e8414. Nowadays, the sirtuin protein family is thought as one of the important target for cardiovascular diseases (CVD). Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X, et al. Distinct patterns of sirtuin expression during progression of Alzheimer's disease. Proc Natl Acad Sci USA. In addition, SIRT1 deacetlylates sterol regulatory element binding protein (SREBP), farnesoid X receptor (FXR), as well as liver X receptor (LXR) to increase bile acid production and to reverse cholesterol transport (30, 38). (2012) 287:2575869. [Epub ahead of print]. 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