Sirt1 regulates aging and resistance to oxidative stress in the heart. Han L, Zhou R, Niu J, McNutt MA, Wang P, Tong T. SIRT1 is regulated by a PPAR-SIRT1 negative feedback loop associated with senescence. doi: 10.1038/ijo.2010.125, 43. In cardiomyocytes, myoblast gains resistance against to oxidative stress by increasing expression of nuclear SIRT1 protein. Because of prevention of pro-inflammatory responses, SIRT1 behaves as a positive regulator of insulin in the adipose tissue (39). 9:614. doi: 10.3389/fendo.2018.00614. During long term fasting, SIRT1 expression deacetylates and activates the PGC-1 to decrease adiposity and lipogenesis and to increase fatty acid oxidation (3537). Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, et al. Hypothalamic dysfunction of the thrombospondin receptor alpha2delta-1 underlies the overeating and obesity triggered by brain-derived neurotrophic factor deficiency. In addition, increase in the SIRT1 activity had a protective effect against osteoarthritis in animal models (53, 54). doi: 10.1016/j.neuroscience.2011.09.007, 87. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. In cardiomyocytes, during prenatal period, SIRT1 is found in the nucleus, however, it is mostly located in the cytoplasm of myocytes of adult heart of rodents (90). doi: 10.1097/YCO.0b013e32835112c1, 21. 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). Drug Resist Update (2011) 14:3544. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Curr Pharm Des. 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). In addition, we found a polymorphism in the promoter region of SIRT1 gene in obese children drawing attention to the association between altered SIRT1 activity and the risk of obesity (50). doi: 10.1101/gad.13.19.2570, 6. Prog Neuropsychopharmacol Biol Psychiatry (2018) 86:95101. 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). In one of our studies, we found a significant increase in the SIRT1 level of dementia patients (80). 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. Rev Neurosci. (2018) doi: 10.1111/nan.12514. doi: 10.1016/j.cell.2006.07.002, 8. The activity of PPAR which have a role in the storage of glucose and fatty acid in adipose tissue is repressed by SIRT1 (34). (2012) 287:2575869. doi: 10.1016/j.cell.2004.12.041, 96. doi: 10.3109/07853890.2010.547211, 31. (2017) 18:46. doi: 10.1186/s12868-017-0364-1, 17. In a postmortem study, the levels of SIRT1 showed a slight increase in the dementia patients with Lewy bodies (16, 83). Mol Endocrinol. doi: 10.1016/j.cmet.2009.02.006, 37. Science (2004) 305:95455. Huang PS, Son JH, Abbott LC, Winzer-Serhan UH. A remarkable age-related increase in SIRT1 protein expression against oxidative stress in elderly: SIRT1 gene variants and longevity in human. Herskovits AZ, Guarente L. Sirtuin deacetylases in neurodegenerative diseases of aging. doi: 10.1016/S0003-4975(99)01033-4, 95. PLoS ONE (2009) 4:e8414. Longo VD, Kennedy BK. Pharmacol Res. (2011) 364:223544. Front. J Neurosci. NAD to the rescue. For example, 2.5- to 7.5-fold increase in the SIRT1 expression attenuated apoptosis, the symptoms of cardiac dysfunction, age-related cardiac hypertrophy and expression of senescence markers. (2011) 10:2759. doi: 10.1038/ijo.2008.78, 30. (2013) 67:607. Disruption of Sirt1 in chondrocytes causes accelerated progression of osteoarthritis under mechanical stress and during ageing in mice. Cordeira JW, Felsted JA, Teillon S, Daftary S, Panessiti M, Wirth J, et al. doi: 10.1007/s00431-014-2424-1, 51. Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. During short term fasting, the CRTC2 is also depressed by SIRT1 and thus gluconeogenesis is declined in the liver tissue. Here, we provide an overview of the association of the increasing level of SIRT1 protein for regulating some disease related conditions such as obesity, cardiovascular diseases and neurodegeneration. 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). (2003) 17:31321. (2011) 29:5115. Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, et al. Mudo G, Makela J, Di Liberto V, Tselykh TV, Olivieri M, Piepponen P, et al. On the other hand, SIRT1 behaves as a double edged sword in response to inflammation which is a cause of neurodegeneration. However, as seen in the AD, the activity of the SIRT1 protein also decreased in the PD patients producing neurodegeneration in correlation with possible higher oxidative stress, synaptic and cell loss, and neuroinflammation (16). doi: 10.1002/jor.22859, 55. (2011) 1421:7881. Kilic U, Gok O, Bacaksiz A, Izmirli M, Elibol-Can B, Uysal O. SIRT1 gene polymorphisms affect the protein expression in cardiovascular diseases. Insulin sensitivity is increased in the pancreatic beta cells which have insulin resistance due to overexpression of SIRT1 (30, 33). Cell Res. Circulation (2010) 122:217082. Biochim Biophys Acta (2012) 1821:117785. Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Distinct patterns of sirtuin expression during progression of Alzheimer's disease. (2010) 21:299313. Cant C, Auwerx J. Caloric restriction, SIRT1 and longevity. Cakir I, Perello M, Lansari O, Messier NJ, Vaslet CA, Nillni EA. doi: 10.1302/2046-3758.73.BJR-2017-0227.R1, 56. doi: 10.1007/s12035-017-0646-8, 73. Yamamoto H, Schoonjans K, Auwerx J. Sirtuin functions in health and disease. doi: 10.1074/jbc.M501485200, 36. Copyright 2018 Elibol and Kilic. Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschp MH. Science (2004) 305:10103. Genes Dev. Endocrinol. As shown in previous studies, SIRT1 epigenetically reprograms inflammation taking about AD formation at the earlier stages by altering transcription factors (24, 75, 76). doi: 10.1210/me.2007-0079, 3. doi: 10.3390/ijms19030911, 47. (2013) 18:41630. doi: 10.1016/j.cmet.2008.08.014, 34. 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). (2017) 13:3019. doi: 10.1038/sj.emboj.7600244, 25. doi: 10.1136/annrheumdis-2012-202620, 53. Nature (2004) 429:7716. This review also provides a detailed molecular understanding of the interaction of the some basic molecules with increasing SIRT1 levels rather than reduction of the SIRT1 expression. Patel NV, Gordon MN, Connor KE, Good RA, Engelman RW, Mason J, et al. Clin Sci (Lond.) doi: 10.1161/01.RES.0000267723.65696.4a, 92. J Hepatol. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Mol Cell (2007) 28:91106. doi: 10.1016/j.cardiores.2005.01.026, 11. Previous studies also showed that obese patients with non-alcoholic fatty-liver disease (NAFLD), which is the most common liver disease caused by elevated hepatic lipids, inflammation and oxidative stress, had high plasma levels of SIRT1 producing a potential against the physiological mechanisms related to NAFLD (47). Koubova J, Guarente L. How does calorie restriction work? 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: 10.1038/nature03354, 38. Figure 1. doi: 10.1038/ncb1468, 14. doi: 10.1007/s12020-014-0465-x, 48. Evidence supporting a mechanistic role of sirtuins in mood and metabolic disorders. Froy O, Sherman H, Bhargava G, Chapnik N, Cohen R, Gutman R, et al. Cellular stress response, sirtuins and UCP proteins in Alzheimer disease: role of vitagenes. To do produce this antioxidative activity, SIRT1 protein enhances the level of MnSOD expression through p53 deacetylation (90). (2016) 438:7788 doi: 10.1016/j.mce.2016.09.002, 27. Sirtuin 1 (SIRT1) which is encoded by the SIRT1 gene is the most conserved mammalian nicotinamide adenine dinucleotide (NAD+) dependent histone deacetylase (1). Whereas an increase in the expression of the SIRT1 protein was observed in cancer (12, 13), reductions in the SIRT1 level was more common in other diseases such as Alzheimer's Diseases (AD), Parkinson Disease (PD), obesity, diabetes, and cardiovascular diseases (1418). Mech Ageing Dev. Braidy N, Jayasena T, Poljak A, Sachdev PS. On the other hand, it was found that increase in the SIRT1 activity upregulates genes-related metabolic functions, promotes insulin sensitivity and reduces inflammatory gene expressions in the adipose tissue of diet-induced obese animals (49). Alcendor et al. Sirt1 extends lifespan and delays aging in mice through the regulation of nk2 homeobox1 in the dmh and lh. Nasrin N, Kaushik VK, Fortier E, Wall D, Pearson KJ, de Cabo R, et al. doi: 10.1016/j.yexmp.2018.07.008, 89. The common underlying mechanisms of neurodegeneration are increase in the neuroinflammation, mitochondrial damages and oxidative stress (66, 67). 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). (2004) 101:159986003. J Biol Chem. BE wrote the draft of the manuscript and UK finalized the manuscript. Aging Cell (2014) 13:1936. doi: 10.1016/S1474-4422(11)70013-8, 71. 285:837582. 29. 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Molecular studies showed that SIRT1 activation prevents the accumulation of A plaques and tau pathology through the NF-B signaling pathway by upregulation of the ADAM10 gene, induction of the Notch pathway, and inhibition of the mTOR pathway (20, 73, 74). (2017) 23:2299307. J Neurosci Off J Soc Neurosci. By the help of this pathway, cardiac infarct volume is reduced to ameliorate and recover cardiac function after ischemia/reperfusion in mice (92). Tabuchi T, Satoh M, Itoh T, Nakamura M. MicroRNA-34a regulates the longevity-associated protein SIRT1 in coronary artery disease: effect of statins on SIRT1 and microRNA-34a expression. That means, low levels of SIRT1 cause early acute inflammation-related damages to tissues by increasing NF-kB, and high levels of SIRT1 during late inflammation cause immunosuppression and increased the rate of death (87). For example, SIRT1 upregulates the level of orexin receptor specifically in the lateral hypothalamic area and the ventromedial nucleus of the hypothalamus, whereas the expression of orexin and melanin-concentrating hormone is reduced in the hypothalamus due to inhibition of the active state of orexin neurons (25, 42, 43). (2014) 73:1397404. doi: 10.1371/journal.pone.0008322, 33. In addition to the obesity, SIRT1 has a role in the hepatic energy metabolism by modulating it nutritionally and hormonally. doi: 10.1111/1440-1681.12362, 101. For example, Ciriello and his colleagues observed a significant decrease in the level of phosphorylated SIRT1, the active form of SIRT1, in the patients with multiple sclerosis (88). Exp Mol Pathol. Plasma levels of SIRT1 associate with non-alcoholic fatty liver disease in obese patients. Endocrine (2015) 49:7116. Statins activate peroxisome proliferator-activated receptor gamma through extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages. Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X, et al. Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice. Inhibition of Poly(ADP-ribose) polymerase-1 enhances gene expression of selected sirtuins and app cleaving enzymes in amyloid beta cytotoxicity. (2018) 19:E911. Rheumatol Int. Neuroscience (2008) 154:138897. Therefore, we can conclude that the increase in the SIRT1 level may be a compensatory mechanism to increase the antioxidants against oxidative stress in CVD patients. Lutz MI, Milenkovic I, Regelsberger G, Kovacs GG. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. SIRT1 ameliorates oxidative stress induced neural cell death and is down-regulated in Parkinson's disease. Mercken EM, Hu J, Krzysik-Walker S, Wei M, Li Y, McBurney MW, et al. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Nishida K, Matsushita T, Takayama K, Tanaka T, Miyaji N, Ibaraki K, et al. Koltai E, Szabo Z, Atalay M, Bolodogh I, Naito H, Goto S, et al. Int J Biol Macromol. Braidy N, Guillemin GJ, Mansour H, Chan-Ling T, Poljak A, Grant R. Age related changes in NAD+metabolism oxidative stress and Sirt1 activity in wistar rats. Nawaz A, Mehmood A, Kanatani Y, Kado T, Igarashi Y, Takikawa A, et al. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. NAD+-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response. Through its deacetylation activity, SIRT1 modulates functions of these critical molecules and shows its critical and multifaceted roles in cellular physiology (Figure 1). doi: 10.1161/01.RES.0000268411.49545.9c, 102. SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. (2013) 14:383459. Low Sirt1 expression, which is upregulated by fasting, in human adipose tissue from obese women. On the other hand, PPAR inhibits SIRT1 expression at the transcriptional level which interrupting compensatory action of increased SIRT1 expression (102). PLoS ONE (2009) 4:e8322. doi: 10.3390/ijms14023834, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. (2008) 105:97938. Banks AS, Kon N, Knight C, Matsumoto M, Gutirrez-Jurez R, Rossetti L, et al. 1. That means, altered SIRT1 expression and activity is thought to be a potent way to keep the cells and organs properly functioning for longer times. doi: 10.1016/j.cell.2005.08.011, 13. doi: 10.1126/science.1098014, 85. (2013) 288:17099110. Kilic U, Gok O, Elibol-Can B, Uysal O, Bacaksiz A. Efficacy of statins on sirtuin 1 and endothelial nitric oxide synthase expression: the role of sirtuin 1 gene variants in human coronary atherosclerosis. Epigenetic switching by the metabolism-sensing factors in the generation of orexin neurons from mouse embryonic stem cells. (2005) 280:4036474. 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). Schug TT, Li X. Sirtuin 1 in lipid metabolism and obesity. (2007) 26:316979. SIRT1 inhibition causes oxidative stress and inflammation in patients with coronary artery disease. Interestingly, a significant negative correlation between phosphorylated and non-phosphorylated forms of SIRT1 was observed explaining both the SIRT1 overexpression and inactivity of SIRT1 in diseased state. SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus. The neuroprotection against to PD occurred by the mechanism of decreasing in the expression of NF-B and cleaved PARP-1. 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). Li K, Lv G, Pan L. Sirt1 alleviates LPS induced inflammation of periodontal ligament fibroblasts via downregulation of TLR4. doi: 10.1016/j.phrs.2012.10.010, 76. Neuroscience. doi: 10.1523/JNEUROSCI.3442-11.2012, 82. Science (2004) 305:3902. 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Most of these studies showed that calorie intake restriction innervates the extension of life by the inducement of defense of cells against to free radicals and toxins for attenuation of apoptosis or amelioration of cell repair which are desired factors in aging (5860). doi: 10.1038/cr.2013.70, 68. Wang J, Gao JS, Chen JW Li F, Tian J. doi: 10.1042/CS20110563, 99. (2012) 32:15418. (2007) 100:144251. 28. [Epub ahead of print]. Neurobiol Aging (2005) 26:9951000. Eur J Pediatr. Nat Cell Biol. Ungvari Z, Parrado-Fernandez C, Csiszar A, de Cabo R. Mechanisms underlying caloric restriction and lifespan regulation: implications for vascular aging. Hsu CP, Zhai P, Yamamoto T, Maejima Y, Matsushima S, Hariharan N, et al. Potential involvement of SIRT1 in the pathogenesis of osteoarthritis through the modulation of chondrocyte gene expressions. (2004) 23:236980. (2017) 66:589600. doi: 10.1016/j.tem.2009.03.008, 59. Brain Res. Jeko H, Wencel P, Strosznajder RP, Strosznajder JB. EMBO J. Cell (2005) 123:43748. Wencel PL, Lukiw WJ, Strosznajder JB, Strosznajder RP. SIRT1 but not its increased expression is essential for lifespan extension in caloric-restricted mice. Sci Rep. (2018) 8:11370. doi: 10.1038/s41598-018-29773-0, 50. doi: 10.1111/j.1474-9726.2007.00355.x, 66. Cell Mol Life Sci. Neuroscience (2011) 196:189202. Changes in sirtuin expression are critical in several diseases, including metabolic syndrome, cardiovascular diseases, cancer and neurodegeneration. Furthermore, this phosphorylation increased the activity of SIRT1 resulting its translocation into the nuclei (97). (2018) 105:17580. doi: 10.1126/science.1072994, 77. Am J Physiol Lung Cell Mol Physiol. (2008) 177:86170. Obes Surg. Matsuzaki T, Matsushita T, Takayama K, Matsumoto T, Nishida K, Kuroda R, et al. (2012). Kok SH, Lin LD, Hou KL, Hong CY, Chang CC, Hsiao M, et al. Cardiovasc Res. (2008) 102:51928. Rodgers JT, Lerin C, Haas W. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Science (2002) 297:3536. doi: 10.1161/CIRCRESAHA.107.168369, 61. Guarente L, Franklin H. Epstein lecture: sirtuins, aging, and medicine. 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. No use, distribution or reproduction is permitted which does not comply with these terms. In literature, it was reported that the activity of SIRT1 protein is directly or indirectly controlled via the JNK1-SIRT1 link by accumulated oxidative stress which is caused by an increase in the ROS level due to aging or age-related diseases enzyme (1). (2013) 65:63949. Circ Res. PLoS ONE (2014) 9:e90428. This study explained clearly the relation between oxidative stress and overexpression of SIRT1 to the pathological levels in CVD patients. In this previous study, we also found a significant increase in the oxidative stress parameters which may be an inducer for SIRT1 expression. 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). doi: 10.1371/journal.pone.0008414, 98. In addition to the key role on extending life by regulating the response to some conditions such as fasting, caloric restriction and exercise, SIRT1 regulates many endocrine functions, protects organism from oxidative stress-related cellular events, promotes DNA stability, and decreases various age-related disorders, such as neurodegenerative disease, metabolic abnormalities, and cancer (69). Res. The metabolic sensor Sirt1 and the hypothalamus: interplay between peptide hormones and pro-hormone convertases. Hypothalamic Sirt1 regulates food intake in a rodent model system. SIRT1 protein protects the functions of adipose tissue and liver in several aspects (29, 30) such as glucose homeostasis and fat metabolism against severe obesity (31, 32). Xie J, Zhang X, Zhang L. Negative regulation of inflammation by SIRT1. In addition, activation of FoxO1-dependent oxidative pathway by overexpression of SIRT1 protein is another regulatory way of protection of cardiomyocytes from oxidative stress (91). N Engl J Med. PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis. Exp Geront. SIRT1 protein is expressed in most of the body parts including brain, heart, kidney, liver, pancreas, spleen, skeletal muscle, endothelial tissue and white adipose tissue. Singh P, Hanson PS, Morris CM. J Biol Chem. 40. doi: 10.1074/jbc.M109.090266, 91. J Biol Chem. Circ Res. doi: 10.1073/pnas.0404184101, 4. (2018) 7:25262. Guarente L. Mitochondriaa nexus for aging, calorie restriction, and sirtuins? In literature, it was shown that sirtuins' hyperactivity could reduce these negative outcomes both in vivo and in vitro due to its neuroprotective role (6871). J Biol Chem. Modulation of SIRT1 expression in different neurodegenerative models and human pathologies. In addition, SIRT1 also regulates the expression of BDNF in the brain. Kilic U, Gok O, Elibol-Can B, Ozgen IT, Erenberk U, Uysal O, et al. 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. doi: 10.1038/nature02583, 35. doi: 10.1016/j.pnpbp.2018.05.017. Mukhopadhyay P, Horvth B, Rajesh M, Varga ZV, Gariani K, Ryu D, et al. Cell (2008) 132:1716. doi: 10.1093/jb/mvh134, 97. Chan SH, Hung CH, Shih JY, Chu PM, Cheng YH, Lin HC, et al. Parker JA, Vazquez-Manrique RP, Tourette C, Farina F, Offner N, Mukhopadhyay A, et al. Sirtuins and their roles in brain aging and neurodegenerative disorders. J Biochem. (2012) 32:12432. Spontaneous caloric restriction associated with increased leptin levels in obesity-resistant alphaMUPA mice. (2010) 131:218. Eur J Nutr. doi: 10.1016/j.molcel.2007.07.032, 39. TNF- inhibits PPAR/ activity and SIRT1 expression through NF-kB in human adipocytes. It is also involved in energy balance and stress. Salminen A, Kaarniranta K, Kauppinen A. Crosstalk between oxidative stress and SIRT1: impact on the aging process.
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