Effect of renin–angiotensin system on senescence

The renin–angiotensin system (RAS) plays crucial roles in the control of blood pressure and sodium homeostasis. Moreover, RAS also acts as a key player in cell and organ senescence, mainly by activation of the classical axis of angiotensin (Ang) converting enzyme (ACE)/Ang II/Ang II type 1 receptor via overproduction of reactive oxygen species. Overactivation of the classical RAS axis induces organ dysfunction in the vasculature, brain, kidney and skeletal muscle, resulting in atherosclerosis, stroke, chronic kidney disease and sarcopenia. Moreover, RAS has been shown to regulate lifespan, using gene‐modification models. Recently, mice lacking the Ang II type 1 receptor were shown to exhibit an increase in lifespan compared with control mice. Here, the effect of RAS on age‐related tissue dysfunction in several organs is reviewed, including not only the classical axis but also protective functions of RAS such as the ACE2/Ang (1–7)/Mas axis. Geriatr Gerontol Int 2020; ??: ??–?? .     

Mammalian Sir2-related protein (SIRT) 2-mediated modulation of resistance to axonal degeneration in slow Wallerian degeneration mice: a crucial role of tubulin deacetylation

It has been shown that Wallerian degeneration, an anterograde degeneration of transected axons, is markedly delayed in a mutant mouse called slow Wallerian degeneration (Wld(S)). These mice also show resistance to axonal degeneration caused by microtubule depolymerizing drugs, suggesting that axonal microtubules are stabilized. Here, we have focused on tubulin acetylation, a post-translational modification associated with microtubule stability. We found that the basal level of microtubule acetylation was increased in cultured cerebellar granule cells from Wld(S) mice. Nicotinamide but not 3-aminobenzamide, an inhibitor for poly(ADP)ribose polymerase, enhanced tubulin acetylation and resistance to axonal degeneration in cultured cerebellar granule cells from wild-type (WT) mice, suggesting that mammalian Sir2-related protein (SIRT) 2, a nicotinamide adenine dinucleotide (NAD)--dependent tubulin deacetylase, could modulate resistance to axonal degeneration. Indeed, the levels of NAD and SIRT2 were decreased in the cytoplasm from Wld(S) granule cells. Moreover, SIRT2 overexpression abrogated microtubule hyperacetylation and resistance to axonal degeneration in these cells. Conversely, SIRT2 knockdown by using a lentiviral vector expressing small interfering RNA, enhanced microtubule acetylation and resistance to axonal degeneration in WT granule cells. Taken together, these results suggest that SIRT2-mediated tubulin deacetylation is involved in both microtubule hyperacetylation and resistance to axonal degeneration in Wld(S) granule cells.     

视网膜色素上皮氧化损伤SIRT1表达改变

目的明确氧化应激对视网膜色素上皮细胞(RPE)中去乙酰化酶1(SIRT1)表达的影响。方法以人RPE细胞为实验对象,不同浓度H_2O_2(0、200、300μmol/L)处理RPE细胞,观察处理后24 h细胞形态的改变情况,检测处理后24 h与72 h细胞中SIRT1的mRNA与蛋白表达情况。结果 H_2O_2作用后,随H_2O_2浓度的增加,RPE细胞的形态受损,有凋亡小体的出现;在氧化应激24 h后细胞内SIRT1的转录水平增加,而在氧化应激72 h后SIRT1的蛋白表达显著下降。结论氧化应激可导致RPE细胞形态改变,SIRT1在RPE细胞内维持着氧化与抗氧化应激系统平衡,因此将SIRT1可作为临床上年龄相关性黄斑变性病(AMD)治疗的靶点。     

Melatonin prevents deterioration of erectile function in streptozotocin-induced diabetic rats via sirtuin-1 expression

A review of the literature indicated that sirtuin-1 expression, a regulator of nitric oxide bioavailability in erectile dysfunction (ED) after melatonin therapy, has not yet been investigated. The objective of this study was to evaluate the protective effects of melatonin for erectile function with sirtuin-1 protein expression in type 1 diabetic rat models. Fifty male Sprague Dawley rats were placed into five groups. Except for those in the control group (C), each animal received a single dose (60 mg/kg) of streptozotocin to induce diabetes. The animals were placed into the diabetes (D) group, insulin (I) group (6 U/kg/day), melatonin (Mel) group (10 mg kg⁻¹ day⁻¹) and combined treatment (I + Mel) group. Ten weeks later, the serum testosterone levels, intracavernosal pressure (ICP), mean arterial pressure (MAP), malondialdehyde (MDA), cyclic guanosine monophosphate (c-GMP), 8-hydroxydeoxyguanosine (8-OHdG), nitric oxide synthase (NOS), caspase-3 activity, sirtuin-1 and endothelial nitric oxide synthase (eNOS) protein expression and histological findings were assessed. The mean ICP/MAP ratio for the D group was lower than the mean ratios for the other groups. The treatment groups, particularly the I + Mel group, exhibited lower 8-OHdG and MDA levels and caspase-3 activity than the D group. The sirtuin-1 and eNOS expression and cavernosal tissue (CT) histology seemed to have been preserved by the melatonin and/or insulin therapy. These results were indicative of a profound protective effect of melatonin by the activation of sirtuin-1 protein expression against hyperglycemia-induced oxidative CT injury.     

Calorie restriction upregulated sirtuin 1 by attenuating its ubiquitin degradation in cancer cells

Sirtuin (SIRT) 1 is a key protein in mediating the benefits of calorie restriction (CR) in mammals. However, the molecular mechanisms underlying CR‐induced SIRT1 upregulation in mammals remain unclear. Herein we show that the elevated SIRT1 levels are not due to increased SIRT1 mRNA expression. but rather to enhanced SIRT1 protein stability as a result of reduced ubiquitin‐proteasome degradation of SIRT1 under limited nutrient conditions. Our observations have important implications for improving healthy aging in humans.     

右美托咪啶上调sirtuin3减轻小鼠肾缺血-再灌注损伤

目的研究右美托咪啶(DEX)在肾缺血-再灌注(I/R)损伤小鼠中的保护作用及其机制。方法将小鼠分为假手术(sham)组、siRNA+sham组、肾I/R组(常规法)、DEX+I/R组(腹腔注射25μg/kg DEX)、siRNA+I/R组及siRNA+DEX+I/R组;siRNA+sham组、siRNA+I/R组、siRNA+DEX+I/R组术前3 d经尾静脉注射5×10^9TU/kg慢病毒-去乙酰化酶3(SIRT3) siRNA。生化分析仪测定肾功能;HE染色法观察肾组织形态学;Tunel染色法检测肾组织凋亡;Western blot检测SIRT3、亲环素D(Cyp D)和细胞色素C(Cyt C)表达。结果 DEX可降低小鼠肾I/R后肾脏损伤,上调SIRT3表达并下调Cyt C及乙酰化Cyp D蛋白表达水平(P<0. 05)。抑制SIRT3后可减轻DEX对肾脏的保护作用(P<0. 05)。结论 DEX减轻肾I/R损伤的作用可能与上调SIRT3相关。     

Sirtuin activators

Background: Sirtuin 1 – 7 (SIRT1 – 7) are deacetylases that are dependent on NAD⁺ for their activity. SIRT1 down-regulates p53 activity, increasing lifespan, cell survival, and neuroprotection; it also deacetylates peroxisome proliferator-activated receptor-γ and its coactivator 1α, promoting fat mobilization, increasing mitochondrial size and number, and positively regulating insulin secretion. Sirtuins link nutrient availability and energy metabolism. Calorie restriction, which increases lifespan and is beneficial in age-related disorders, activates sirtuin. Major efforts are thus focused to developing sirtuin activators. Objective: After discussing the potential involvement of sirtuins in pathophysiological processes, this review looks at new, synthetic sirtuin activators. Conclusions: To date, resveratrol is the most potent natural compound able to activate SIRT1, mimicking the positive effect of calorie restriction. Resveratrol might help in the treatment or prevention of obesity and in preventing the aging-related decline in heart function and neuronal loss. As resveratrol has low bioavailability and interacts with multiple molecular targets, the development of new molecules with better bioavailability and targeting sirtuin at lower concentrations is a promising field of the medicinal chemistry. New SIRT1 activators that are up to 1000 times more effective than resveratrol have recently been identified. These improve the response to insulin and increase the number and activity of mitochondria in obese mice. Human trials with a formulation of resveratrol with improved bioavailability and with a synthetic SIRT1 activator are in progress.