雌激素上调SIRT1抗衰老机制研究进展

沉默信息调节因子2(silent information regulator 2,Sir2)及其蛋白家族,是一种高度保守的依赖于烟酰胺腺嘌呤二核苷酸(NAD+)的去乙酰化酶,最先在酵母中发现。哺乳动物中Sir2相关酶1(SIRT1)与其同源性最高,被认为是长寿蛋白,通过能量限制来发挥抗衰老作用。在多种组织器官中SIRT1通过与组蛋白或非组蛋白的相互作用调控多种生理过程,如调节能量代谢、脂质氧化及延缓心脑血管疾病等老年疾病的发生发展,进而延缓衰老。既往研究表明雌激素在抗衰老方面发挥重要作用,传统观点认为雌激素通过直接或间接地与雌激素受体结合激活目的基因而发挥抗衰老作用。而近期研究表明雌激素可以通过多条旁路途径上调SIRT1的表达而延缓细胞衰老。综述雌激素上调SIRT1的表达途径以探讨雌激素抗衰老机制。     

Sirtuins与脓毒症的研究进展

脓毒症是一种由微生物感染引起,导致宿主调节功能异常,包括炎性因子级联释放,内皮功能障碍,细胞凋亡,免疫抑制,最终导致多器官功能障碍的疾病综合征。现今脓毒症患者的死亡率仍居高不下,这与其复杂的病理生理学机制密切相关。Sirtuins家族作为一类依赖NAD 的高度保守的蛋白脱酰化酶,其可以通过催化组蛋白和非组蛋白底物的赖氨酸侧链发生去酰化反应,减少促炎因子的释放,影响线粒体功能,改变线粒体活性氧生成,能量代谢及免疫反应等,对于控制炎症反应,维持基因组稳定等有着重要作用。本篇就Sirtuins可能在脓毒症急性炎症、免疫和代谢中的作用,及其对脓毒症治疗的应用前景作一综述。     

The yin and yang faces of the mitochondrial deacetylase sirtuin 3 in age-related disorders

Aging, the most important risk factor for many of the chronic diseases affecting Western society, is associated with a decline in mitochondrial function and dynamics. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase that has emerged as a key regulator of fundamental processes which are frequently dysregulated in aging and related disorders. This review highlights recent advances and controversies regarding the yin and yang functions of SIRT3 in metabolic, cardiovascular and neurodegenerative diseases, as well as the use of SIRT3 modulators as a therapeutic strategy against those disorders. Although most studies point to a protective role upon SIRT3 activation, there are conflicting findings that need a better elucidation. The discovery of novel SIRT3 modulators with higher selectivity together with the assessment of the relative importance of different SIRT3 enzymatic activities and the relevance of crosstalk between distinct sirtuin isoforms will be pivotal to validate SIRT3 as a useful drug target for the prevention and treatment of age-related diseases.     

Differential effects of binge methamphetamine injections on the mRNA expression of histone deacetylases (HDACs) in the rat striatum

Methamphetamine use disorder is characterized by recurrent binge episodes. Humans addicted to methamphetamine experience various degrees of cognitive deficits and show evidence of neurodegenerative processes in the brain. Binge injections of METH to rodents also cause significant toxic changes in the brain. In addition, this pattern of METH injections can alter gene expression in the dorsal striatum. Gene expression is regulated, in part, by histone deacetylation. We thus tested the possibility that METH toxic doses might cause changes in the mRNA levels of histone deacetylases (HDACs). We found that METH did produce significant decreases in the mRNA expression of HDAC8, which is a class I HDAC. METH also decreased expression of HDAC6, HDAC9, and HDAC10 that are class II HDACs. The expression of the class IV HDAC, HDAC11, was also suppressed by METH. The expression of Sirt2, Sirt5, and Sirt6 that are members of class III HDACs was also downregulated by METH injections. Our findings implicate changes in HDAC expression may be an early indicator of impending METH-induced neurotoxicity in the striatum. This idea is consistent with the accumulated evidence that some HDACs are involved in neurodegenerative processes in the brain.     

Functional characterization of NAD dependent de-acetylases SIRT1 and SIRT2 in B-Cell Chronic Lymphocytic Leukemia (CLL)

Sirtuins (SIRT) are nicotinamide adenine dinucleotide (NAD+) dependent deacetylases or ADP- ribosyl transferases (ARTs) that deacetylate lysine residues on various proteins regulating a variety of cellular and metabolic processes. These enzymes regulate metabolism, cell survival, differentiation and DNA repair. SIRT proteins play an important role in the survival and drug resistance of cancer cells. The purpose of the present study was to investigate the expression and role of SIRT in chronic lymphocytic leukemia (CLL). We analyzed the expression of SIRT1 and SIRT2 in CLL and normal B cells using the Oncomine database as well as by Western blotting of fresh CLL cells from patients and pro-lymphocytic leukemia (PLL) cell lines, JVM-3 and MEC-2. We showed that both primary CLL cells and JVM-3 and MEC-2 cell lines overexpress high levels of functional SIRT1 and SIRT2. SIRT inhibitors EX-527 and sirtinol impair cell growth, induce ROS production, loss of mitochondrial membrane potential and apoptosis in primary CLL cells and cell lines. Using shRNA knock down of SIRT1 and SIRT2 in JVM-3 and MEC-2 cell lines, we showed that expression of both proteins is crucial for the survival of these cells. Furthermore, studies in nutrient deprived conditions suggest a role of SIRT in metabolism in CLL. These results demonstrate that the inhibition of SIRT1 and SIRT2 activity may be a new therapeutic approach for CLL.     

Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging

Innate and adaptive immunity are the major defence mechanisms of higher organisms against inherent and environmental threats. Innate immunity is present already in unicellular organisms but evolution has added novel adaptive immune mechanisms to the defence armament. Interestingly, during aging, adaptive immunity significantly declines, a phenomenon called immunosenescence, whereas innate immunity seems to be activated which induces a characteristic pro-inflammatory profile. This process is called inflamm-aging. The recognition and signaling mechanisms involved in innate immunity have been conserved during evolution. The master regulator of the innate immunity is the NF-kB system, an ancient signaling pathway found in both insects and vertebrates. The NF-kB system is in the nodal point linking together the pathogenic assault signals and cellular danger signals and then organizing the cellular resistance. Recent studies have revealed that SIRT1 (Sir2 homolog) and FoxO (DAF-16), the key regulators of aging in budding yeast and Caenorhabditis elegans models, regulate the efficiency of NF-kB signaling and the level of inflammatory responses. We will review the role of innate immunity signaling in the aging process and examine the function of NF-kB system in the organization of defence mechanisms and in addition, its interactions with the protein products of several gerontogenes. Our conclusion is that NF-kB signaling seems to be the culprit of inflamm-aging, since this signaling system integrates the intracellular regulation of immune responses in both aging and age-related diseases.     

Effects of Sirt1 gene knockout on chronic kidney disease induced by 5/6 nephrectomy in mice and VEGF/Flk?1 signaling pathway

Objective To investigate the effect of Sirt1 gene knockout on chronic kidney disease induced by 5/6 nephrectomy in mice and vascular endothelial growth factor (VEGF)/fetal liver kinase-1 (Flk-1) signaling pathway. Methods Twenty four male Sirt1+/+ and Sirt1+/- mice were randomly divided into four groups: Sirt1+/+ mice with sham-operation (WT-Sham, n=6), Sirt1+/- mice with sham-operation (KO-Sham, n=6), Sirt1+/+ mice with 5/6 nephrectomy (WT-Nx, n=6) and Sirt1+/- mice with 5/6 nephrectomy (KO-Nx, n=6). Proteinuria was determined by urine collection from 8:00 to 8:00 the next day at 20 weeks. Serum creatinine (Scr), urea nitrogen (BUN) and the renal pathological changes were measured after 20 weeks. Expressions of Sirt1, collagenⅠ and transforming growth factor β (TGF-β) were used to analyze the changes of renal fibrosis by immunohistochemistry staining. Real-time PCR and Western blotting were used to measure the mRNA and protein expressions of Sirt1, fibronectin, collagenⅠ,VEGF and Flk-1 in kidney. Results Sirt1 expressed in glomerular endothelial cells, podocytes, mesangial cells and renal tubular epithelial cells in Sirt1+/+ mice, while Sirt1 expression intensity was significantly reduced in Sirt1+/- mice. Compared with the WT-Sham group, WT-Nx group had increased proteinuria, BUN, Scr, glomerular sclerosis index and tubulointerstitial fibrosis index at 12 weeks after operation (all P＜0.01), and KO-Nx group had exacerbated the above up-regulations (all P＜0.01). Compared with those in WT-Sham group, the expressions of fibronectin, collagenⅠ and TGF-β were up-regulated in WT-Nx group (all P＜0.01), and were significantly augmented in KO-Nx group (all P＜0.01). Compared with those in WT-Sham group, renal mRNA and protein expressions of VEGF and Flk-1 were decreased in WT-Nx group, and KO-Nx group aggravated their down-regulation (all P＜0.01). Conclusions Sirt1 gene knockout can increase proteinuria and Scr, and aggravate renal pathology and renal fibrosis in 5/6 nephrectomized mice, which is associated with the inhibition of VEGF/Flk-1 signaling pathway. It is suggested that Sirt1 may be a potential therapeutic target of chronic kidney disease.     

Advances in endocrinology of aging research, 2005-2006

The purpose of this brief review is to highlight some of the more important advances in endocrinology of aging research over the past year. Four advances were chosen and briefly described. First, exploration of the early steps in the generation of the internal steroidal hormonal signal involved in lifespan extension via the insulin/IGF-like signaling pathway in the nematode by two research groups revealed that the product of cholestanoic acid derivatives metabolized by a cytochrome P-450-like protein activates a protein with homology to the mammalian nuclear receptor superfamily, a process strikingly similar to the steroid hormone signaling pathway documented in mammalian systems. Second is the discovery that sirtuins, proteins that regulate lifespan in model organisms, enhance pancreatic insulin secretion in mice following a glucose challenge, suggesting the potential to regulate mammalian lifespan through regulation of the insulin signaling pathway. Third, the newly discovered hormone klotho, which also plays a role in regulating lifespan, in this case in mice, is reported to not only negatively affect insulin sensitivity but, perhaps more importantly, significantly affects calcium and phosphate metabolism as a required cofactor of Fgf-23 signaling. Finally the gonadotropin FSH is shown to directly affect bone density in mice separate from any direct effect of estrogen, suggesting that reproductive hormones other than estrogen can directly impact menopause-associated pathophysiology in non-reproductive tissues.