热量限制对心肌细胞SIRTs表达的影响
摘要
目的:
1.研究SIRTs(SIRT1-7)在大鼠心脏组织及H9c2心肌细胞的定位;
2.初步探讨热量限制对心肌细胞SIRT1-7表达的影响。
方法:
3个月龄健康雄雌SD大鼠20只,随机分成两组:①正常对照组(ad libitum,AL)(n=10):随意进食;②热量限制组(Calorie Restriction,CR)(n=10):喂养量为对照组的60%,分别称体重。饲养3周后称体重,用质量分数2 %的戊巴比妥麻醉后处死,取出心脏,称重,沿心脏纵轴平均分为三份,心尖及心底部用于Western blot,对比两组SIRT1-7蛋白表达水平的变化;中间部分心脏用于免疫组织化学,定性检测SIRT1-7在大鼠心脏组织的定位。
大鼠心肌细胞株H9c2在含葡萄糖4.5g/L的DMEM培养基中培养48h后传代随机分为两组:①正常对照组(Control,Con):继续在含葡萄糖4.5g/L的DMEM中培养;②热量限制组(CR):弃去旧培养液,加入含葡萄糖1g/L的DMEM。两组细胞在5% CO2、37℃条件下继续培养24h后终止。免疫细胞化学法定性检测SIRT1-7在H9c2的定位; RT-PCR法检测SIRT1-7 mRNA表达水平的变化。
结果:
1.实验前两组大鼠两两体重的差别无统计学意义。心脏质量指数(HMI)=心脏重量/大鼠体重。实验后CR组大鼠体重及HMI均显著低于AL组(p<0.05)。
2.免疫组织化学法检测SIRT1-7在大鼠心肌细胞定位,结果表明:SIRT1在细胞核及细胞质均有大量表达,以细胞核表达为主;SIRT2、SIRT3、SIRT4、SIRT5主要在细胞质表达;SIRT6、SIRT7在细胞核及细胞质均有表达,主要在细胞核表达。
3.免疫细胞化学法检测SIRT1-7在H9c2细胞表达定位,结果表明:SIRT1、SIRT2、SIRT7在细胞核及细胞质均有表达,以细胞核表达为主;SIRT3、SIRT4、SIRT5、SIRT6在细胞质表达为主。
4. Western Blot法检测热量限制对大鼠心肌细胞SIRT1-7蛋白表达水平的影响,结果表明:CR组SIRT1,2,3,4,7蛋白表达水平与AL组比较显著增加(p<0.05);SIRT5,6的蛋白表达在两组中没有差异。
5. RT-PCR法检测热量限制对H9c2细胞SIRT1-7 mRNA表达水平的影响,结果表明:其变化与大鼠心脏SIRT1-7蛋白表达水平的变化一致。SIRT1,2,3,4,7 mRNA表达水平与正常对照组比较明显增加(p<0.05),SIRT5,6 mRNA的表达在两组中没有差异。
结论:
1.在心肌细胞中,SIRT1在细胞核及细胞质均有大量表达,以细胞核表达为主;SIRT2,3,4,5主要在细胞质表达;SIRT6、SIRT7主要在细胞核表达。
2.热量限制可同时激活心肌细胞SIRT1,2,3,4,7,而对SIRT5,6的表达没有影响;初步推测热量限制对心肌细胞的作用可能与SIRT1,2,3,4,7表达的上调有关。
Objective:
1. To investigate the cellular localization of SIRTs (SIRT1-7) both in rat cardiac tissues and H9c2 cells;
2. To study the effects of calorie restriction on the expression of SIRTs in cardiomyocytes.
Methods:
Twenty 3-month-old SD rats of both sexes were randomized to either control group (n=10) or CR group (n=10), with five males and five females in each group. Rats in control group were fed ad libitum (AL), while rats in CR group were fed by 60% of AL. After 3 weeks, twenty rats were weighed and killed. Hearts were flushed with 0.9% normal saline solution before taken. The hearts were then sectioned into three parts, the middle part of the heart were used for immunohistochemistry, for detecting the cellular localization of SIRTs (SIRT1-7) in rats cardiac tissues. The same area of the heart from each rat including dual atriums and dual ventricles were used for immunohistochemistry. The rest parts of hearts were used for Western blot to investigate the protein levels of SIRTs.
The H9c2 embryonic rat heart-derived cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 100ml/L fetal bovine serum (FBS) and 4.5g/L glucose. The cells were trypsinized, plated (10 000-12 000cells/cm2) in culture dishes, then were randomly divided into two groups after culturing for 48 h, (1) normal control group(Con): without any treatment; (2) calorie restriction group (CR) : cells were incubated in DMEM containing 1g/L glucose. Both groups were incubated in 5% CO2 at 37℃for 24 h. Immunohistochemistry examination was used to determine the cellular localization of SIRTs (SIRT1-7) in H9c2 cells. The expressions of SIRT1-7 mRNA were detected by RT-PCR.
Results:
1. The differences in body weight between AL group and CR group was not significant before the study protocol. However, after maintenance on a CR diet for three weeks, the body weight (BW) and the heart mass index (HMI=Heart weight/BW) were significantly lower in the CR group when compared with the AL group (p<0.05).
2. Each of the seven SIRT proteins was detected in cardiac tissues of SD rats both in AL group and CR group, evidenced by immunohistochemistry. SIRT1 is ubiquitous, as which was distributed in nucleus and cytoplasm. SIRT2, 3, 4, 5 were detected primarily in cytoplasm. SIRT6 and SIRT7 are mainly concentrated in the nucleus.
3. A similar expression pattern of SIRT1-7 was observed from immunohistological study in H9c2 cells. Our results show that SIRT1, 3, 4, 5, 7 in H9c2 cells share the same distribution characteristics as in rat heart tissues. SIRT1 is localized both in nucleus and cytoplasm. SIRT3, 4, 5 were detected mainly in cytoplasm while SIRT7 was distributed in nucleus. Intriguingly, high density of SIRT2 in nucleus was observed while SIRT6 was detected primarily in cytoplasm.
4. To explore the possible effects of CR on the expression of sirtuins in rat hearts, twenty SD 3-month-old rats were fed either AL or on a CR regimen for 3 weeks. We investigated whether protein levels of SIRT1-7 change after CR. Western blot analysis showed that CR caused SIRT1, 2, 3, 4, 7 statistically significant up-regulations (p<0.05), while the expression of SIRT5, 6 were unaffected.
5. The expression pattern of SIRT1-7 mRNA consists with the results of protein, which further support the results mentioned above. H9c2 cells were cultured either in CR group (4.5g/L glucose) or in control group (1g/L glucose) for 24h separately. RT-PCR revealed that the expression of SIRT1, 2, 3, 4, 7 mRNA significantly increased in CR group compared with control group (p<0.05), but SIRT5, 6 were unaffected.
Conclusion:
1. SIRTs are expressed in the cardiomyocytes both in vivo and in vitro; SIRT1 is distributed in nucleus and cytoplasm, mainly in nucleus. SIRT2, 3, 4, 5 were detected primarily in cytoplasm. SIRT6 and SIRT7 are mainly concentrated in the nucleus.
2. Calorie restriction has effects on cardiomyocytes by increasing the expression of SIRT1, 2, 3, 4, 7.
1.研究SIRTs(SIRT1-7)在大鼠心脏组织及H9c2心肌细胞的定位;
2.初步探讨热量限制对心肌细胞SIRT1-7表达的影响。
方法:
3个月龄健康雄雌SD大鼠20只,随机分成两组:①正常对照组(ad libitum,AL)(n=10):随意进食;②热量限制组(Calorie Restriction,CR)(n=10):喂养量为对照组的60%,分别称体重。饲养3周后称体重,用质量分数2 %的戊巴比妥麻醉后处死,取出心脏,称重,沿心脏纵轴平均分为三份,心尖及心底部用于Western blot,对比两组SIRT1-7蛋白表达水平的变化;中间部分心脏用于免疫组织化学,定性检测SIRT1-7在大鼠心脏组织的定位。
大鼠心肌细胞株H9c2在含葡萄糖4.5g/L的DMEM培养基中培养48h后传代随机分为两组:①正常对照组(Control,Con):继续在含葡萄糖4.5g/L的DMEM中培养;②热量限制组(CR):弃去旧培养液,加入含葡萄糖1g/L的DMEM。两组细胞在5% CO2、37℃条件下继续培养24h后终止。免疫细胞化学法定性检测SIRT1-7在H9c2的定位; RT-PCR法检测SIRT1-7 mRNA表达水平的变化。
结果:
1.实验前两组大鼠两两体重的差别无统计学意义。心脏质量指数(HMI)=心脏重量/大鼠体重。实验后CR组大鼠体重及HMI均显著低于AL组(p<0.05)。
2.免疫组织化学法检测SIRT1-7在大鼠心肌细胞定位,结果表明:SIRT1在细胞核及细胞质均有大量表达,以细胞核表达为主;SIRT2、SIRT3、SIRT4、SIRT5主要在细胞质表达;SIRT6、SIRT7在细胞核及细胞质均有表达,主要在细胞核表达。
3.免疫细胞化学法检测SIRT1-7在H9c2细胞表达定位,结果表明:SIRT1、SIRT2、SIRT7在细胞核及细胞质均有表达,以细胞核表达为主;SIRT3、SIRT4、SIRT5、SIRT6在细胞质表达为主。
4. Western Blot法检测热量限制对大鼠心肌细胞SIRT1-7蛋白表达水平的影响,结果表明:CR组SIRT1,2,3,4,7蛋白表达水平与AL组比较显著增加(p<0.05);SIRT5,6的蛋白表达在两组中没有差异。
5. RT-PCR法检测热量限制对H9c2细胞SIRT1-7 mRNA表达水平的影响,结果表明:其变化与大鼠心脏SIRT1-7蛋白表达水平的变化一致。SIRT1,2,3,4,7 mRNA表达水平与正常对照组比较明显增加(p<0.05),SIRT5,6 mRNA的表达在两组中没有差异。
结论:
1.在心肌细胞中,SIRT1在细胞核及细胞质均有大量表达,以细胞核表达为主;SIRT2,3,4,5主要在细胞质表达;SIRT6、SIRT7主要在细胞核表达。
2.热量限制可同时激活心肌细胞SIRT1,2,3,4,7,而对SIRT5,6的表达没有影响;初步推测热量限制对心肌细胞的作用可能与SIRT1,2,3,4,7表达的上调有关。
Objective:
1. To investigate the cellular localization of SIRTs (SIRT1-7) both in rat cardiac tissues and H9c2 cells;
2. To study the effects of calorie restriction on the expression of SIRTs in cardiomyocytes.
Methods:
Twenty 3-month-old SD rats of both sexes were randomized to either control group (n=10) or CR group (n=10), with five males and five females in each group. Rats in control group were fed ad libitum (AL), while rats in CR group were fed by 60% of AL. After 3 weeks, twenty rats were weighed and killed. Hearts were flushed with 0.9% normal saline solution before taken. The hearts were then sectioned into three parts, the middle part of the heart were used for immunohistochemistry, for detecting the cellular localization of SIRTs (SIRT1-7) in rats cardiac tissues. The same area of the heart from each rat including dual atriums and dual ventricles were used for immunohistochemistry. The rest parts of hearts were used for Western blot to investigate the protein levels of SIRTs.
The H9c2 embryonic rat heart-derived cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 100ml/L fetal bovine serum (FBS) and 4.5g/L glucose. The cells were trypsinized, plated (10 000-12 000cells/cm2) in culture dishes, then were randomly divided into two groups after culturing for 48 h, (1) normal control group(Con): without any treatment; (2) calorie restriction group (CR) : cells were incubated in DMEM containing 1g/L glucose. Both groups were incubated in 5% CO2 at 37℃for 24 h. Immunohistochemistry examination was used to determine the cellular localization of SIRTs (SIRT1-7) in H9c2 cells. The expressions of SIRT1-7 mRNA were detected by RT-PCR.
Results:
1. The differences in body weight between AL group and CR group was not significant before the study protocol. However, after maintenance on a CR diet for three weeks, the body weight (BW) and the heart mass index (HMI=Heart weight/BW) were significantly lower in the CR group when compared with the AL group (p<0.05).
2. Each of the seven SIRT proteins was detected in cardiac tissues of SD rats both in AL group and CR group, evidenced by immunohistochemistry. SIRT1 is ubiquitous, as which was distributed in nucleus and cytoplasm. SIRT2, 3, 4, 5 were detected primarily in cytoplasm. SIRT6 and SIRT7 are mainly concentrated in the nucleus.
3. A similar expression pattern of SIRT1-7 was observed from immunohistological study in H9c2 cells. Our results show that SIRT1, 3, 4, 5, 7 in H9c2 cells share the same distribution characteristics as in rat heart tissues. SIRT1 is localized both in nucleus and cytoplasm. SIRT3, 4, 5 were detected mainly in cytoplasm while SIRT7 was distributed in nucleus. Intriguingly, high density of SIRT2 in nucleus was observed while SIRT6 was detected primarily in cytoplasm.
4. To explore the possible effects of CR on the expression of sirtuins in rat hearts, twenty SD 3-month-old rats were fed either AL or on a CR regimen for 3 weeks. We investigated whether protein levels of SIRT1-7 change after CR. Western blot analysis showed that CR caused SIRT1, 2, 3, 4, 7 statistically significant up-regulations (p<0.05), while the expression of SIRT5, 6 were unaffected.
5. The expression pattern of SIRT1-7 mRNA consists with the results of protein, which further support the results mentioned above. H9c2 cells were cultured either in CR group (4.5g/L glucose) or in control group (1g/L glucose) for 24h separately. RT-PCR revealed that the expression of SIRT1, 2, 3, 4, 7 mRNA significantly increased in CR group compared with control group (p<0.05), but SIRT5, 6 were unaffected.
Conclusion:
1. SIRTs are expressed in the cardiomyocytes both in vivo and in vitro; SIRT1 is distributed in nucleus and cytoplasm, mainly in nucleus. SIRT2, 3, 4, 5 were detected primarily in cytoplasm. SIRT6 and SIRT7 are mainly concentrated in the nucleus.
2. Calorie restriction has effects on cardiomyocytes by increasing the expression of SIRT1, 2, 3, 4, 7.
引文
[1]. McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and ultimate body size, J. Nutr.1935, 10: 63–79.
[2]. Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000, 289 (5487):2126-2128.
[3]. Ingram DK, Anson RM, de Cabo R, Mamczarz J, Zhu M, Mattison J, Lane MA, Roth GS. Development of calorie restriction mimetics as a prolongevity strategy, Ann. N Y Acad. Sci. 2004, 1019:412-423.
[4]. Weindruch R, Walford RL, Fligiel S, Guthrie D. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr. 1986, 116(4):641-654.
[5]. Walford RL, Mock D, Verdery R, MacCallum T. Calorie restriction in Biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. J. Gerontol. A Biol. Sci. Med. Sci. 2002, 57, B211–B224.
[6]. Heilbronn L K, Ravussin E. Calorie restriction and aging: review of the literature and implications for studies in humans. Am. J. Clin. Nutr. 2003, 78:361–369.
[7]. Weindruch R, Kayo T, Lee CK, Prolla TA. Gene expression profiling of aging using DNA microarrays. Mech. Ageing Dev, 2002, 123:177–193.
[8]. Bordone L, Guarente L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol, 2005, 6(4):298-305.
[9]. Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, Culotta VC, Fink GR, Guarente L. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature, 2002, 418(6895):344-348.
[10]. Lin SJ, Ford E, Haigis M, Liszt G, Guarente L. Calorie restriction extends yeast life span by lowering the level of NADH. Gen Dev, 2004, 18:12-16.
[11]. Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Sinclair DA. Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature, 2003, 423(6936):181-185.
[12]. Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promotelongevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev, 1999, 13(19):2570-2580.
[13]. Hisahara S, Chiba S, Matsumoto H, et al. Transcriptional regulation of neuronal genes and its effect on neural functions: NAD-dependent histone deacetylase SIRT1 (Sir2α). J Pharmacol Sci, 2005, 98(3): 200–204.
[14]. Imai SI, Armsrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein SIR2 is an NAD-dependent histone deacetylase. Nature, 2000, 403 (6771):795-800.
[15]. Haigis MC, Guarente LP. Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev, 2006, 20:2913-2921.
[16]. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase. Science, 2004, 305(5682):390-392.
[17]. Koubova J, Guarente L How does calorie restriction work? Genes Dev, 2003, 17(3):313-321.
[18].王丽辉,金炜元,陈勇,王君晖. Sir2基因家族的功能和作用机制细胞生物学杂志. 2006, 28: 822-826.
[19]. Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J, 2007, 404:1-13.
[20]. Revollo JR, Grimm AA, Imai S. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyl transferase regulates Sir2 activity in mammalian cells. J Biol Chem, 2004, 279 (49): 50754-50763.
[21]. Motta MC, Divecha N, Lemieux M, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell, 2004, 116 (4) 551–563.
[22]. Brunet A, Sweeney LB, Sturgill JF, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science, 2004, 303 (5666) 2011–2015.
[23]. Fulco M, Schiltz RL, Iezzi S, et al. Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. Mol Cell, 2003, 12 (1) 51–62.
[24]. Luo J, Nikolaev AY, Imai S, et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell, 2001, 107 (2) 137–148.
[25]. Vaziri H, Dessain SK, Ng Eaton E, et al. hSIR2(SIRT1) functions as an NAD-dependentp53 deacetylase. Cell, 2001, 107 (2) 149–159.
[26]. Rodgers JT, Lerin C, Haas W, et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature, 2005, 434 (7029) 113–118.
[27]. Giannakou ME and Partridge L. The interaction between FOXO and SIRT1: tipping the balance towards survival. Trends Cell Biol, 2004, 14(8):408-412.
[28]. McBurney MW, Yang X, Jardine K, Hixon M, Boekelheide K, Webb JR, Lansdorp PM, Lemieux M.The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Mol Cell Biol, 2003, 23(1):38-54.
[29]. Alcendor RR, Kirshenbaum LA, Imai S, Vatner SF, Sadoshima J.Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. Circ Res, 2004, 95(10):971-890.
[30]. Pillai, JB, Isbatan A, Imai S, Gupta MP. Poly (ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2αdeacetylase activity. J Biol Chem, 2005, 280:43121–43130.
[31]. Borra MT, Smith BC, and Denu JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem, 2005, 280(17):17187–17195.
[32]. Wei Yu, Yu-Cai Fu, Xiao-Hui Zhou, Chun-Juan Chen, Xin Wang, Rui-Bo Lin, Wei Wang. Effects of resveratrol on H2O2-induced apoptosis and expression of SIRTs in H9c2 cells. J Cell Biochem, 2009, 107(4):741-747.
[33]. Verdery RB, Ingram DK, Roth GS, Lane MA. Caloric restriction increases HDL2 levels in rhesus monkeys (Macaca mulatta). Am J Physiol, 1997, 273: E714–E719.
[34]. Edwards IJ, Rudel LL, Terry JG, Kemnitz JW, Weindruch R, Zaccaro DJ, Cefalu WT. Caloric restriction lowers plasma lipoprotein (a) in male but not female rhesus monkeys. Exp Gerontol, 2001, 36:1413–1418.
[35]. Jung SH, Park HS, Kim KS, Choi WH, Ahn CW, Kim BT, Kim SM, Lee SY, Ahn SM, Kim YK, Kim HJ, Kim DJ, Lee KW. Effect of weight loss on some serum cytokines in human obesity: increase in IL-10 after weight loss. J Nutr Biochem, 2008, 19(6):371-375.
[36]. Pereira MA, Swain J, Goldfine AB, Rifai N, Ludwig DS. Effects of a low-glycemic load diet on resting energy expenditure and heart disease risk factors during weight loss. JAMA, 2004, 292: 2482–2490.
[37]. Walford RL, Harris SB, Gunion MW. The calorically restricted low-fat nutrient-dense diet in Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol, and blood pressure in humans. Proc Natl Acad Sci U S A, 1992, 89: 11533–11537.
[38]. Lefevre M, Redman LM, Heilbronn LK, Smith JV, Martin CK, Rood JC, Greenway FL, Williamson DA, Smith SR, Ravussin E; Pennington CALERIE team. Caloric restriction alone and with exercise improves CVD risk in healthy non-obese individuals. Atherosclerosis, 2009, 203(1):206-213.
[39]. Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA. Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol Cell Biol, 2003, 23(9):3173-3185.
[40]. Sundaresan NR, Samant SA, Pillai VB, Rajamohan SB, Gupta MP. SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol Cell Biol, 2008, 28(20):6384-6401.
[41]. Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell, 2005, 16(10):4623-4635.
[42]. Liszt G, Ford E, Kurtev M, Guarente L. Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem, 2005, 280(22):21313-21320.
[43]. Ford E, Voit R, Liszt G, Magin C, Grummt I, Guarente L. Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev, 2006, 20(9):1075-1080.
[44]. Vaquero A, Scher MB, Lee DH, Sutton A, Cheng HL, Alt FW, Serrano L, Sternglanz R, Reinberg D. SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev, 2006, 20(10):1256-1261.
[45]. Higami Y, Shimokawa I. Apoptosis in the aging process. Cell Tissue Res, 2000, 301(1):125-132.
[46]. Campisi J. Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes. Exp Gerontol, 2003, 38(1-2):5-11.
[47]. Ando K, Higami Y, Tsuchiya T, Kanematsu T, Shimokawa I. Impact of aging and life-long calorie restriction on expression of apoptosis-related genes in male F344 rat liver. MicroscRes Tech, 2002, 59(4):293-300.
[48]. Cohen HY, Lavu S, Bitterman KJ, Hekking B, Imahiyerobo TA, Miller C, Frye R, Ploegh H, Kessler BM, Sinclair DA. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell, 2004, 13(5):627-638.
[49]. North BJ, Marshall BL, Borra MT, Denu JM, Verdin E.The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase.Mol Cell, 2003, 11(2):437-444.
[50]. Suzuki K and Koike T. Resveratrol abolishes resistance to axonal degeneration in slow Wallerian degeneration (WldS) mice: Activation of SIRT2, an NAD-dependent tubulin deacetylase. Biochem Biophys Res Commun, 2007, 359 (3): 665–671.
[51]. Schwer B, North BJ, Frye RA, Ott M, and Verdin E. The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J Cell Biol, 2002, 158(4):647-657.
[52]. Shi T, Wang F, Stieren E, et al. SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J Biol Chem, 2005, 280 (14): 13560–13567.
[53]. Haigis MC, Mostoslavsky R, Haigis KM, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell, 2006, 126(5): 941–954.
[54]. Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L,et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell, 2006,124(2):315-329.
[55]. Vakhrusheva O, Smolka C, Gajawada P, et al. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis andinflammatory cardiomyopathy in mice. Circ Res, 2008, 102 (6): 703–710.
[1]. Fontana L, Meyer TE, Klein S, Holloszy JO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci U S A. 2004, 101: 6659–6663.
[2]. Das SK, Gilhooly CH, Golden JK, Pittas AG, Fuss PJ, Cheatham RA, Tyler S, Tsay M, McCrory MA, Lichtenstein AH, Dallal GE, Dutta C, Bhapkar MV, Delany JP, Saltzman E, Roberts SB. Long-term effects of 2 energy-restricted diets differing in glycemic load on dietary adherence, body composition, and metabolism in CALERIE: a 1-y randomized controlled trial. Am J Clin Nutr. 2007, 85: 1023–1030.
[3]. McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and ultimate body size, J. Nutr.1935, 10: 63–79.
[4]. Weindruch R, Walford RL, Fligiel S, Guthrie D. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr, 1986, 116(4):641-654.
[5]. Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science, 2000, 289(5487):2126-2128.
[6]. Ingram DK, Anson RM, de Cabo R, Mamczarz J, Zhu M, Mattison J, Lane MA, Roth GS. Development of calorie restriction mimetics as a prolongevity strategy, Ann. N Y Acad. Sci, 2004, 1019:412-423.
[7]. Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev, 1999, 13:2570–2580.
[8]. Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, Culotta VC, Fink GR, Guarente L. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature, 2002, 418(6895):344-348.
[9]. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 2003, 425(6954):191-196.
[10]. Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J, 2007, 404:1-13.
[11]. Tannenbaum A. The initiation and growth of tumors. Introduction. Effects of underfeeding. Am J Cancer, 1940, 38: 335–350.
[12]. Kritchevsky D. Caloric restriction and experimental carcinogenesis. Hybrid Hybridomics, 2002, 21: 147–151.
[13]. Verdery RB, Ingram DK, Roth GS, Lane MA. Caloric restriction increases HDL2 levels in rhesus monkeys (Macaca mulatta). Am J Physiol, 1997, 273: E714–E719.
[14]. Edwards IJ, Rudel LL, Terry JG, Kemnitz JW, Weindruch R, Zaccaro DJ, Cefalu WT. Caloric restriction lowers plasma lipoprotein (a) in male but not female rhesus monkeys. Exp Gerontol, 2001, 36: 1413–1418.
[15]. Jung SH, Park HS, Kim KS, Choi WH, Ahn CW, Kim BT, Kim SM, Lee SY, Ahn SM, Kim YK, Kim HJ, Kim DJ, Lee KW. Effect of weight loss on some serum cytokines in human obesity: increase in IL-10 after weight loss. J Nutr Biochem, 2008, 19(6):371-375.
[16]. Pereira MA, Swain J, Goldfine AB, Rifai N, Ludwig DS. Effects of a low-glycemic load diet on resting energy expenditure and heart disease risk factors during weight loss. JAMA, 2004, 292: 2482–2490.
[17]. Walford RL, Harris SB, Gunion MW. The calorically restricted low-fat nutrient-dense dietin Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol, and blood pressure in humans. Proc Natl Acad Sci U S A. 1992, 89: 11533–11537.
[18]. Lefevre M, Redman LM, Heilbronn LK, Smith JV, Martin CK, Rood JC, Greenway FL, Williamson DA, Smith SR, Ravussin E; Pennington CALERIE team. Caloric restriction alone and with exercise improves CVD risk in healthy non-obese individuals. Atherosclerosis, 2009, 203(1):206-213.
[19]. Adler A, Messina E, Sherman B, Wang Z, Huang H, Linke A, Hintze TH. NAD (P) H oxidase-generated superoxide anion accounts for reduced control of myocardial O2 consumption by NO in old Fischer 344 rats. Am J Physiol Heart Circ Physiol, 2003, 285: H1015–H1022.
[20]. Raitakari M, Ilvonen T, Ahotupa M, Lehtimaki T, Harmoinen A, Suominen P, Elo J, Hartiala J, Raitakari OT. Weight reduction with very-lowcaloric diet and endothelial function in overweight adults: role of plasma glucose. Arterioscler Thromb Vasc Biol, 2004, 24: 124–128.
[21]. Sasaki S, Higashi Y, Nakagawa K, Kimura M, Noma K, Hara K, Matsuura H, Goto C, Oshima T, Chayama K. A low-calorie diet improves endothelium-dependent vasodilation in obese patients with essential hypertension. Am J Hypertens, 2002, 15: 302–309.
[22]. Mattagajasingh I, Kim CS, Naqvi A, Yamamori T, Hoffman TA, Jung SB, DeRicco J, Kasuno K, Irani K. SIRT1 promotes endotheliumdependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci U S A, 2007, 104: 14855–14860.
[23]. Ungvari ZI, Orosz Z, Labinskyy N, Rivera A, Xiangmin Z, Smith KE, Csiszar A. Increased mitochondrial H2O2 production promotes endothelial NF-kB activation in aged rat arteries. Am J Physiol Heart Circ Physiol, 2007, 293: H37–H47.
[24]. Murdoch CE, Zhang M, Cave AC, et al. NADPH oxidase-dependent redox signaling in cardiac hypertrophy, remodeling and failure. Cardiovasc Res, 2006, 71 (2): 208–215.
[25]. Crow MT, Mani K, Nam YJ, et al. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res, 2004, 95 (10):957–970.
[26]. Kujoth GC, Hiona A, Pugh TD, et al1 Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging Science, 2005, 309 (5733) : 481-484.
[27]. Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science, 1996, 273:59–63.
[28]. Guo Z, Mitchell-Raymundo F, Yang H, Ikeno Y, Nelson J, Diaz V, Richardson A, Reddick R. Dietary restriction reduces atherosclerosis and oxidative stress in the aorta of apolipoprotein E-deficient mice. Mech Ageing Dev,2002,123: 1121–1131.
[29]. Cefalu WT, Wang ZQ, Bell-Farrow AD, Collins J, Morgan T, Wagner JD. Caloric restriction and cardiovascular aging in cynomolgus monkeys (Macaca fascicularis): metabolic, physiologic, and atherosclerotic measures from a 4-year intervention trial. J Gerontol A Biol Sci Med Sci, 2004, 59:1007–1014.
[30]. Walford RL, Mock D, Verdery R, MacCallum T. Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period.J Gerontol A Biol Sci Med Sci, 2002, 57(6):B211-224.
[31]. Alcendor RR, Kirshenbaum LA, Imai S, Vatner SF, Sadoshima J. Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. Circ Res, 2004, 95(10):971-980.
[32]. Pillai, JB, Isbatan A, Imai S and Gupta MP. Poly (ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2αdeacetylase activity. J. Biol. Chem, 2005, 280:43121–43130.
[33]. Zhou B, Wu L-J, Li L-H, Tashiro S, Onodera S, Uchiumi F, Ikejima T. Silibinin protects against isoproterenol-induced rat cardiac myocyte injury through mitochondrial pathway after up-regulation of SIRT1. J Pharmacol Sci, 2006, 102:387–395.
[34]. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, et al. Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase.Science,2004,305(5682):390-392.
[2]. Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000, 289 (5487):2126-2128.
[3]. Ingram DK, Anson RM, de Cabo R, Mamczarz J, Zhu M, Mattison J, Lane MA, Roth GS. Development of calorie restriction mimetics as a prolongevity strategy, Ann. N Y Acad. Sci. 2004, 1019:412-423.
[4]. Weindruch R, Walford RL, Fligiel S, Guthrie D. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr. 1986, 116(4):641-654.
[5]. Walford RL, Mock D, Verdery R, MacCallum T. Calorie restriction in Biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. J. Gerontol. A Biol. Sci. Med. Sci. 2002, 57, B211–B224.
[6]. Heilbronn L K, Ravussin E. Calorie restriction and aging: review of the literature and implications for studies in humans. Am. J. Clin. Nutr. 2003, 78:361–369.
[7]. Weindruch R, Kayo T, Lee CK, Prolla TA. Gene expression profiling of aging using DNA microarrays. Mech. Ageing Dev, 2002, 123:177–193.
[8]. Bordone L, Guarente L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol, 2005, 6(4):298-305.
[9]. Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, Culotta VC, Fink GR, Guarente L. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature, 2002, 418(6895):344-348.
[10]. Lin SJ, Ford E, Haigis M, Liszt G, Guarente L. Calorie restriction extends yeast life span by lowering the level of NADH. Gen Dev, 2004, 18:12-16.
[11]. Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Sinclair DA. Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature, 2003, 423(6936):181-185.
[12]. Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promotelongevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev, 1999, 13(19):2570-2580.
[13]. Hisahara S, Chiba S, Matsumoto H, et al. Transcriptional regulation of neuronal genes and its effect on neural functions: NAD-dependent histone deacetylase SIRT1 (Sir2α). J Pharmacol Sci, 2005, 98(3): 200–204.
[14]. Imai SI, Armsrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein SIR2 is an NAD-dependent histone deacetylase. Nature, 2000, 403 (6771):795-800.
[15]. Haigis MC, Guarente LP. Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev, 2006, 20:2913-2921.
[16]. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase. Science, 2004, 305(5682):390-392.
[17]. Koubova J, Guarente L How does calorie restriction work? Genes Dev, 2003, 17(3):313-321.
[18].王丽辉,金炜元,陈勇,王君晖. Sir2基因家族的功能和作用机制细胞生物学杂志. 2006, 28: 822-826.
[19]. Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J, 2007, 404:1-13.
[20]. Revollo JR, Grimm AA, Imai S. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyl transferase regulates Sir2 activity in mammalian cells. J Biol Chem, 2004, 279 (49): 50754-50763.
[21]. Motta MC, Divecha N, Lemieux M, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell, 2004, 116 (4) 551–563.
[22]. Brunet A, Sweeney LB, Sturgill JF, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science, 2004, 303 (5666) 2011–2015.
[23]. Fulco M, Schiltz RL, Iezzi S, et al. Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. Mol Cell, 2003, 12 (1) 51–62.
[24]. Luo J, Nikolaev AY, Imai S, et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell, 2001, 107 (2) 137–148.
[25]. Vaziri H, Dessain SK, Ng Eaton E, et al. hSIR2(SIRT1) functions as an NAD-dependentp53 deacetylase. Cell, 2001, 107 (2) 149–159.
[26]. Rodgers JT, Lerin C, Haas W, et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature, 2005, 434 (7029) 113–118.
[27]. Giannakou ME and Partridge L. The interaction between FOXO and SIRT1: tipping the balance towards survival. Trends Cell Biol, 2004, 14(8):408-412.
[28]. McBurney MW, Yang X, Jardine K, Hixon M, Boekelheide K, Webb JR, Lansdorp PM, Lemieux M.The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Mol Cell Biol, 2003, 23(1):38-54.
[29]. Alcendor RR, Kirshenbaum LA, Imai S, Vatner SF, Sadoshima J.Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. Circ Res, 2004, 95(10):971-890.
[30]. Pillai, JB, Isbatan A, Imai S, Gupta MP. Poly (ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2αdeacetylase activity. J Biol Chem, 2005, 280:43121–43130.
[31]. Borra MT, Smith BC, and Denu JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem, 2005, 280(17):17187–17195.
[32]. Wei Yu, Yu-Cai Fu, Xiao-Hui Zhou, Chun-Juan Chen, Xin Wang, Rui-Bo Lin, Wei Wang. Effects of resveratrol on H2O2-induced apoptosis and expression of SIRTs in H9c2 cells. J Cell Biochem, 2009, 107(4):741-747.
[33]. Verdery RB, Ingram DK, Roth GS, Lane MA. Caloric restriction increases HDL2 levels in rhesus monkeys (Macaca mulatta). Am J Physiol, 1997, 273: E714–E719.
[34]. Edwards IJ, Rudel LL, Terry JG, Kemnitz JW, Weindruch R, Zaccaro DJ, Cefalu WT. Caloric restriction lowers plasma lipoprotein (a) in male but not female rhesus monkeys. Exp Gerontol, 2001, 36:1413–1418.
[35]. Jung SH, Park HS, Kim KS, Choi WH, Ahn CW, Kim BT, Kim SM, Lee SY, Ahn SM, Kim YK, Kim HJ, Kim DJ, Lee KW. Effect of weight loss on some serum cytokines in human obesity: increase in IL-10 after weight loss. J Nutr Biochem, 2008, 19(6):371-375.
[36]. Pereira MA, Swain J, Goldfine AB, Rifai N, Ludwig DS. Effects of a low-glycemic load diet on resting energy expenditure and heart disease risk factors during weight loss. JAMA, 2004, 292: 2482–2490.
[37]. Walford RL, Harris SB, Gunion MW. The calorically restricted low-fat nutrient-dense diet in Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol, and blood pressure in humans. Proc Natl Acad Sci U S A, 1992, 89: 11533–11537.
[38]. Lefevre M, Redman LM, Heilbronn LK, Smith JV, Martin CK, Rood JC, Greenway FL, Williamson DA, Smith SR, Ravussin E; Pennington CALERIE team. Caloric restriction alone and with exercise improves CVD risk in healthy non-obese individuals. Atherosclerosis, 2009, 203(1):206-213.
[39]. Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA. Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol Cell Biol, 2003, 23(9):3173-3185.
[40]. Sundaresan NR, Samant SA, Pillai VB, Rajamohan SB, Gupta MP. SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol Cell Biol, 2008, 28(20):6384-6401.
[41]. Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell, 2005, 16(10):4623-4635.
[42]. Liszt G, Ford E, Kurtev M, Guarente L. Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem, 2005, 280(22):21313-21320.
[43]. Ford E, Voit R, Liszt G, Magin C, Grummt I, Guarente L. Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev, 2006, 20(9):1075-1080.
[44]. Vaquero A, Scher MB, Lee DH, Sutton A, Cheng HL, Alt FW, Serrano L, Sternglanz R, Reinberg D. SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev, 2006, 20(10):1256-1261.
[45]. Higami Y, Shimokawa I. Apoptosis in the aging process. Cell Tissue Res, 2000, 301(1):125-132.
[46]. Campisi J. Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes. Exp Gerontol, 2003, 38(1-2):5-11.
[47]. Ando K, Higami Y, Tsuchiya T, Kanematsu T, Shimokawa I. Impact of aging and life-long calorie restriction on expression of apoptosis-related genes in male F344 rat liver. MicroscRes Tech, 2002, 59(4):293-300.
[48]. Cohen HY, Lavu S, Bitterman KJ, Hekking B, Imahiyerobo TA, Miller C, Frye R, Ploegh H, Kessler BM, Sinclair DA. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell, 2004, 13(5):627-638.
[49]. North BJ, Marshall BL, Borra MT, Denu JM, Verdin E.The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase.Mol Cell, 2003, 11(2):437-444.
[50]. Suzuki K and Koike T. Resveratrol abolishes resistance to axonal degeneration in slow Wallerian degeneration (WldS) mice: Activation of SIRT2, an NAD-dependent tubulin deacetylase. Biochem Biophys Res Commun, 2007, 359 (3): 665–671.
[51]. Schwer B, North BJ, Frye RA, Ott M, and Verdin E. The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J Cell Biol, 2002, 158(4):647-657.
[52]. Shi T, Wang F, Stieren E, et al. SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J Biol Chem, 2005, 280 (14): 13560–13567.
[53]. Haigis MC, Mostoslavsky R, Haigis KM, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell, 2006, 126(5): 941–954.
[54]. Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L,et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell, 2006,124(2):315-329.
[55]. Vakhrusheva O, Smolka C, Gajawada P, et al. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis andinflammatory cardiomyopathy in mice. Circ Res, 2008, 102 (6): 703–710.
[1]. Fontana L, Meyer TE, Klein S, Holloszy JO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci U S A. 2004, 101: 6659–6663.
[2]. Das SK, Gilhooly CH, Golden JK, Pittas AG, Fuss PJ, Cheatham RA, Tyler S, Tsay M, McCrory MA, Lichtenstein AH, Dallal GE, Dutta C, Bhapkar MV, Delany JP, Saltzman E, Roberts SB. Long-term effects of 2 energy-restricted diets differing in glycemic load on dietary adherence, body composition, and metabolism in CALERIE: a 1-y randomized controlled trial. Am J Clin Nutr. 2007, 85: 1023–1030.
[3]. McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and ultimate body size, J. Nutr.1935, 10: 63–79.
[4]. Weindruch R, Walford RL, Fligiel S, Guthrie D. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr, 1986, 116(4):641-654.
[5]. Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science, 2000, 289(5487):2126-2128.
[6]. Ingram DK, Anson RM, de Cabo R, Mamczarz J, Zhu M, Mattison J, Lane MA, Roth GS. Development of calorie restriction mimetics as a prolongevity strategy, Ann. N Y Acad. Sci, 2004, 1019:412-423.
[7]. Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev, 1999, 13:2570–2580.
[8]. Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, Culotta VC, Fink GR, Guarente L. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature, 2002, 418(6895):344-348.
[9]. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 2003, 425(6954):191-196.
[10]. Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J, 2007, 404:1-13.
[11]. Tannenbaum A. The initiation and growth of tumors. Introduction. Effects of underfeeding. Am J Cancer, 1940, 38: 335–350.
[12]. Kritchevsky D. Caloric restriction and experimental carcinogenesis. Hybrid Hybridomics, 2002, 21: 147–151.
[13]. Verdery RB, Ingram DK, Roth GS, Lane MA. Caloric restriction increases HDL2 levels in rhesus monkeys (Macaca mulatta). Am J Physiol, 1997, 273: E714–E719.
[14]. Edwards IJ, Rudel LL, Terry JG, Kemnitz JW, Weindruch R, Zaccaro DJ, Cefalu WT. Caloric restriction lowers plasma lipoprotein (a) in male but not female rhesus monkeys. Exp Gerontol, 2001, 36: 1413–1418.
[15]. Jung SH, Park HS, Kim KS, Choi WH, Ahn CW, Kim BT, Kim SM, Lee SY, Ahn SM, Kim YK, Kim HJ, Kim DJ, Lee KW. Effect of weight loss on some serum cytokines in human obesity: increase in IL-10 after weight loss. J Nutr Biochem, 2008, 19(6):371-375.
[16]. Pereira MA, Swain J, Goldfine AB, Rifai N, Ludwig DS. Effects of a low-glycemic load diet on resting energy expenditure and heart disease risk factors during weight loss. JAMA, 2004, 292: 2482–2490.
[17]. Walford RL, Harris SB, Gunion MW. The calorically restricted low-fat nutrient-dense dietin Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol, and blood pressure in humans. Proc Natl Acad Sci U S A. 1992, 89: 11533–11537.
[18]. Lefevre M, Redman LM, Heilbronn LK, Smith JV, Martin CK, Rood JC, Greenway FL, Williamson DA, Smith SR, Ravussin E; Pennington CALERIE team. Caloric restriction alone and with exercise improves CVD risk in healthy non-obese individuals. Atherosclerosis, 2009, 203(1):206-213.
[19]. Adler A, Messina E, Sherman B, Wang Z, Huang H, Linke A, Hintze TH. NAD (P) H oxidase-generated superoxide anion accounts for reduced control of myocardial O2 consumption by NO in old Fischer 344 rats. Am J Physiol Heart Circ Physiol, 2003, 285: H1015–H1022.
[20]. Raitakari M, Ilvonen T, Ahotupa M, Lehtimaki T, Harmoinen A, Suominen P, Elo J, Hartiala J, Raitakari OT. Weight reduction with very-lowcaloric diet and endothelial function in overweight adults: role of plasma glucose. Arterioscler Thromb Vasc Biol, 2004, 24: 124–128.
[21]. Sasaki S, Higashi Y, Nakagawa K, Kimura M, Noma K, Hara K, Matsuura H, Goto C, Oshima T, Chayama K. A low-calorie diet improves endothelium-dependent vasodilation in obese patients with essential hypertension. Am J Hypertens, 2002, 15: 302–309.
[22]. Mattagajasingh I, Kim CS, Naqvi A, Yamamori T, Hoffman TA, Jung SB, DeRicco J, Kasuno K, Irani K. SIRT1 promotes endotheliumdependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci U S A, 2007, 104: 14855–14860.
[23]. Ungvari ZI, Orosz Z, Labinskyy N, Rivera A, Xiangmin Z, Smith KE, Csiszar A. Increased mitochondrial H2O2 production promotes endothelial NF-kB activation in aged rat arteries. Am J Physiol Heart Circ Physiol, 2007, 293: H37–H47.
[24]. Murdoch CE, Zhang M, Cave AC, et al. NADPH oxidase-dependent redox signaling in cardiac hypertrophy, remodeling and failure. Cardiovasc Res, 2006, 71 (2): 208–215.
[25]. Crow MT, Mani K, Nam YJ, et al. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res, 2004, 95 (10):957–970.
[26]. Kujoth GC, Hiona A, Pugh TD, et al1 Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging Science, 2005, 309 (5733) : 481-484.
[27]. Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science, 1996, 273:59–63.
[28]. Guo Z, Mitchell-Raymundo F, Yang H, Ikeno Y, Nelson J, Diaz V, Richardson A, Reddick R. Dietary restriction reduces atherosclerosis and oxidative stress in the aorta of apolipoprotein E-deficient mice. Mech Ageing Dev,2002,123: 1121–1131.
[29]. Cefalu WT, Wang ZQ, Bell-Farrow AD, Collins J, Morgan T, Wagner JD. Caloric restriction and cardiovascular aging in cynomolgus monkeys (Macaca fascicularis): metabolic, physiologic, and atherosclerotic measures from a 4-year intervention trial. J Gerontol A Biol Sci Med Sci, 2004, 59:1007–1014.
[30]. Walford RL, Mock D, Verdery R, MacCallum T. Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period.J Gerontol A Biol Sci Med Sci, 2002, 57(6):B211-224.
[31]. Alcendor RR, Kirshenbaum LA, Imai S, Vatner SF, Sadoshima J. Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. Circ Res, 2004, 95(10):971-980.
[32]. Pillai, JB, Isbatan A, Imai S and Gupta MP. Poly (ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2αdeacetylase activity. J. Biol. Chem, 2005, 280:43121–43130.
[33]. Zhou B, Wu L-J, Li L-H, Tashiro S, Onodera S, Uchiumi F, Ikejima T. Silibinin protects against isoproterenol-induced rat cardiac myocyte injury through mitochondrial pathway after up-regulation of SIRT1. J Pharmacol Sci, 2006, 102:387–395.
[34]. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, et al. Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase.Science,2004,305(5682):390-392.