SIRTUINS(去乙酰化酶),一个减缓衰老过程的有希望的目标

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Sirtuins, a promising target in slowing down the ageing process

Abstract

摘要

Ageing is a plastic process and can be successfully modulated by some biomedical approaches or pharmaceutics. In this manner it is possible to delay or even prevent some age-related pathologies. There are some defined interventions, which give promising results in animal models or even in human studies, resulting in lifespan elongation or healthspan improvement. One of the most promising targets for anti-ageing approaches are proteins belonging to the sirtuin family. Sirtuins were originally discovered as transcription repressors in yeast, however, nowadays they are known to occur in bacteria and eukaryotes (including mammals). In humans the family consists of seven members (SIRT1-7) that possess either mono-ADP ribosyltransferase or deacetylase activity. It is believed that sirtuins play key role during cell response to a variety of stresses, such as oxidative or genotoxic stress and are crucial for cell metabolism. Although some data put in question direct involvement of sirtuins in extending human lifespan, it was documented that proper lifestyle including physical activity and diet can influence healthspan via increasing the level of sirtuins. The search for an activator of sirtuins is one of the most extensive and robust topic of research. Some hopes are put on natural compounds, including curcumin. In this review we summarize the involvement and usefulness of sirtuins in anti-ageing interventions and discuss the potential role of curcumin in sirtuins regulation.

老化是一个可塑性过程,可以通过一些生物医学方法或药剂成功地调控。通过这种方式,就有可能延迟甚至预防某些与年龄有关的疾病。有一些明确的干预措施,在动物模型甚至在人类研究中给出了有希望的结果,导致寿命延长或健康跨度的改善。抗衰老方法最有希望的靶点之一是 sirtuin 家族的蛋白质。Sirtuins 最初是作为酵母中的转录抑制因子被发现的,但是现在已知它们存在于细菌和真核生物(包括哺乳动物)中。在人类中,该家族由7个成员组成(SIRT1-7) ,这些成员或者拥有单 adp 核糖基转移酶或者去乙酰化酶活性。相信去乙酰化酶在细胞对各种压力的反应中起着关键作用,如氧化或基因毒性压力,对细胞的新陈代谢至关重要。虽然有些数据质疑抗衰老蛋白直接参与延长人类寿命,但有文献记载,包括体育活动和饮食在内的适当生活方式可以通过提高抗衰老蛋白水平影响健康寿命。寻找去乙酰化酶的催化剂是一个最广泛和强有力的研究课题。人们把希望寄托在包括姜黄素在内的天然化合物上。本文综述了抗衰老干预中去乙酰化酶的作用,并讨论了姜黄素在去乙酰化酶调节中的潜在作用。Keywords: 关键词:Sirtuins, Ageing, Senescence, Curcumin 衰老,衰老,姜黄素Go to: 去:

Introduction

引言

In the year 1979 a paper announcing discovery of mating-type regulator 1 (MAR1) in Saccharomyces cerevisiae was published (Klar et al. 1979). Lack of this protein resulted in the inhibition of silencing of HM loci, which control the mating type and sterility in yeast. Three more proteins with similar function were discovered later in 1979 and the nomenclature was unified thus creating a family of Sir (silent information regulator) proteins (Michan and Sinclair 2007). Shortly, it was shown that sirtuins are evolutionarily conserved from bacteria to humans (Vaquero 2009). We now know a number of processes sirtuins are involved in and we still discover their new functions. In bacteria phosphoribosyltransferases cobT and cobB catalyze the synthesis of the cobalamin biosynthetic intermediate (which transfers a ribose-phosphate moiety from nicotinic acid mononucleotide (NaMN) to dimethyl benzimidazole 2) and in archaea Sir-2-Af1 and Sir2-Af2 participate in transcription regulation (Tsang and Escalante-Semerena 1998). While in prokaryotes there are usually one or two sirtuin genes, eukaryotes can have multiple sirtuin genes. In yeast, in addition to the chief representative, Sir2, there are four more homologous proteins (Michan and Sinclair 2007). In mammals there are seven enzymes belonging to the sirtuin family, among which SIRT1 (silent information regulator T1) has the highest sequence homology to Sir2 in yeast and is the best studied family member. Modulation of sirtuin activity in mammals can regulate many processes such as gene expression, cell metabolism, apoptosis, DNA repair, cell cycle, development, immune response and neuroprotection (Michan and Sinclair 2007).

在1979年,一篇宣布在酿酒酵母发现交配型调节因子1(MAR1)的论文发表了(Klar et al. 1979)。该蛋白的缺乏导致 HM 基因位点的沉默抑制,而 HM 基因位点控制着酵母的交配型和不育性。1979年后期又发现了三个具有类似功能的蛋白质,并统一了命名法,从而创建了一个 Sir (沉默信息调节器)蛋白家族(Michan 和 Sinclair 2007)。很快,研究表明去乙酰化酶在进化上从细菌到人类都是保守的(Vaquero 2009)。我们现在知道了 sirtuins 参与的一些过程,并且我们仍然发现了它们的新功能。在细菌中 cobT 和 cobB 催化 cobalamin 生物合成中间体(从烟酸单核苷酸(NaMN)转化为二甲基苯并咪唑2)的合成,在古细菌中 Sir-2-Af1和 Sir2-Af2参与转录调控(Tsang 和 Escalante-Semerena 1998)。原核生物中通常有一个或两个去乙酰化酶基因,而真核生物可以有多个去乙酰化酶基因。在酵母中,除了主要代表 Sir2之外,还有四个同源蛋白(Michan 和 Sinclair 2007)。哺乳动物中有7种 sirtuin 家族的酶,其中 SIRT1(沉默信息调节因子 T1)与 Sir2的序列同源性最高,是研究最多的家族成员。Sirtuin 活性的调节可以调节许多过程,如基因表达,细胞代谢,凋亡,DNA 修复,细胞周期,发展,免疫反应和神经保护(Michan 和 Sinclair 2007)。

A significant rise in the interest in sirtuins occurred in 1999 when it was reported that Sir2 overexpression can extend yeast lifespan by as much as 70% (Kaeberlein et al. 1999). The anti-ageing action of sirtuins appears to be conserved from yeast to mammals, however the complexity of their function increases with the complexity of the organism. In yeast, the positive effect of sirtuins activity can be attributed to the increase in genomic stability in two ways. There are from 100 to 200 copies of ribosomal DNA (rDNA) in each yeast cell, however, only half of them are transcriptionally active, the rest remains silent (Sinclair and Guarente 1997). Together with other proteins, Sir2 participates in silencing of these regions. Such silencing prevents recombination between rDNA repeats and formation and accumulation of extrachromosomal rDNA circles (ERCs), which are a leading cause of yeast ageing (Sinclair and Guarente 1997). Mutations in Sir2 gene lead to accelerated accumulation of toxic ERCs, whereas Sir2 overexpression extends S. cerevisiae lifespan by silencing HML/R loci and inhibiting ERCs formation (Kaeberlein et al. 1999). Furthermore, along with yeast ageing Sir2 dissociates from HM loci, which results in termination of HM silencing and in sterility, which is a sign of yeast senescence (Sinclair and Guarente 1997). Therefore, changes in the localization of Sir2 result in epigenetic alterations that favor ageing. It was shown that Sir2 is indispensable for mediating positive effects of calorie restriction in yeast (Lin et al. 2000). It was also observed that the level of Sir2 increases during calorie restriction in S. cerevisiae (Bordone and Guarente 2005).

对 sirtuins 的兴趣在1999年显著增加,当时报道过度表达 Sir2可以延长酵母寿命多达70% (Kaeberlein 等人,1999年)。去乙酰化酶的抗衰老作用从酵母到哺乳动物似乎是保守的,但其功能的复杂性随着生物体的复杂性而增加。在酵母中,去乙酰化酶活性的积极作用可以从两个方面归因于基因组稳定性的增加。每个酵母细胞中有100到200个核糖体 DNA (rDNA)拷贝,然而,其中只有一半是转录活跃的,其余的保持沉默(Sinclair 和 Guarente 1997)。与其他蛋白质一起,Sir2参与了这些区域的沉默。这种沉默阻止了 rDNA 重复序列之间的重组和染色体外 rDNA 环(ERCs)的形成和积累,这是酵母衰老的主要原因(Sinclair 和 Guarente 1997)。Sir2基因的突变导致毒性 ERCs 的加速积累,而 Sir2过表达通过沉默 HML/R 位点和抑制 ERCs 的形成来延长酿酒酵母的寿命(Kaeberlein et al. 1999)。此外,随着酵母老化 Sir2游离于 HM 位点,导致 HM 沉默和不育,这是酵母衰老的标志(辛克莱和瓜伦特1997年)。因此,Sir2定位的改变导致了有利于衰老的表观遗传改变。结果表明,Sir2在酵母中介导卡路里限制的阳性效应是必不可少的(Lin et al. 2000)。还观察到,在酿酒酵母(Bordone 和瓜伦特,2005年)的卡路里限制期间 Sir2水平上升。

Further research revealed that sirtuin overexpression leads to lifespan extension also in other model organisms such as Caenorhabditis elegans and Drosophila melanogaster. In mammals sirtuins regulate numerous signaling pathways (not only those directly involved in ageing and senescence). This complex influence of sirtuins on mammalian ageing is discussed in this review.

进一步的研究表明 sirtuin 的过度表达也会导致其他模式生物如秀丽隐桿线虫和黑腹果蝇的寿命延长。在哺乳动物中,去乙酰化酶调节许多信号通路(不仅仅是那些直接参与衰老和衰老的通路)。本文就去乙酰化酶对哺乳动物衰老的复杂影响作一综述。

Function, structure and localization

功能、结构和本地化

In the early 1990s Braunstein et al. showed that regions silenced by Sir2 were characterized by reduced histone acetylation at the ε-amino group of N-terminal lysine residues (Braunstein et al. 1993). Some authors also observed that Sir2 overexpression in yeast led to global hypoacetylation. Soon it was discovered that the main activity of sirtuins is deacetylation of lysine residues. This is a two-step reaction—firstly sirtuins cleave nicotinamide adenine dinucleotide (NAD) to nicotinamide (NAM) and, subsequently, an acetyl/acyl group is transferred from the substrate to the ADP-ribose moiety of NAD; this results in the formation of 2′-O-acetyl-ADP-ribose and a deacetylated substrate (Tanner et al. 2000).

在20世纪90年代早期,Braunstein 等人发现 Sir2沉默的区域在 n- 端赖氨酸残基的-氨基组上的组蛋白乙酰化拥有属性减少。一些作者还观察到 Sir2在酵母中的过度表达导致整体乙酰化水平降低。很快发现去乙酰化酶的主要活性是赖氨酸残基的脱乙酰化。这是一个两步反应,首先 sirtuins 裂解烟酰胺腺嘌呤二核苷酸(NAD)到烟酰胺(NAM) ,然后一个乙酰基/酰基从底物转移到 NAD 的 adp- 核糖部分,这导致了2′-o- 乙酰基 -adp- 核糖和去乙酰化底物的形成(等等,2000)。

Sirtuins belong to class III histone deacetylases (HDAC). A distinguishing feature of this class is that the catalytic activity of the enzymes depends on NAD+ and is regulated by dynamic changes in NAD+ level and the NAD+/NADH ratio. Such requirement for NAD+ as a co-substrate suggests that sirtuins might have evolved as sensors of energy and redox status in the cell (Michan and Sinclair 2007). There are two pathways of NAD+ biosynthesis—de novo production and the so called salvage pathway. In the salvage pathway NAM is converted to nicotinamide mononucleotide (NMN) by nicotinamide phosphoribosyltransferase (NAMPT), a limiting enzyme for the whole pathway. Subsequently, NMN is converted to NAD+ by NMN/NaMN adenylyltransferase (NMNAT) (Chung et al. 2010). The level of NAMPT can influence sirtuin activity. NAD+ synthesis is coupled with the circadian/daily cycle due to the fact that NAMPT is regulated by a complex consisting of CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1) (Nakagawa and Guarente 2011). Unlike NAMPT, PARP1 activation by DNA damage results in a decrease in the NAD+ level (PARP1 uses NAD+ as a cofactor) and inhibition of sirtuin activity (Zhang 2003). NAM (another product of the reaction catalyzed by sirtuins) is a non-competitive inhibitor of sirtuin activity (Chung et al. 2010).

Sirtuins 属于 III 类组蛋白去乙酰化酶(HDAC) 。这类酶的一个显著特点是,它们的催化活性依赖于 NAD + ,并受 NAD + 水平和 NAD +/NADH 比值动态变化的调节。这种对 NAD + 作为共基质的要求表明 sirtuins 可能已经演变为细胞中能量和氧化还原状态的传感器(Michan 和 Sinclair,2007)。NAD + 生物合成有两条途径: 从头生产和所谓的补救途径。在补救途径中,NAM 被整个途径的限制性酶——烟酰胺磷酸核糖转移酶(NAMPT)转化为烟酰胺单核苷酸(NMN)。随后,NMN 被 NMN/namn 腺苷酰转移酶(NMNAT)转化为 NAD + (Chung 等人,2010)。NAMPT 的水平可以影响 sirtuin 的活性。NAD + 合成与昼夜/日周期相结合,这是因为 NAMPT 由一个由 CLOCK (昼夜运动输出周期 kaput)和 BMAL1(大脑和肌肉芳香烃受体核转运器样1)组成的复合体(Nakagawa 和 Guarente 2011)调节。与 NAMPT 不同,PARP1通过 DNA 损伤激活可以降低 NAD + 水平(PARP1使用 NAD + 作为辅助因子) ,并抑制 sirtuin 活性(Zhang,2003)。NAM (去乙酰化酶催化反应的另一个产物)是一种非竞争性去乙酰化酶活性抑制剂(Chung 等人,2010年)。

Sirtuins deacetylate not only histones but also some transcription factors and cytoplasmic proteins. Recent research shed some new light on sirtuins as it was shown that in addition to deacetylation they can remove some other moieties as well. For example, SIRT6 catalytic activity increases with the size of the aliphatic tail it removes, so that palmitoyl, myristoyl or butyryl are favored over acetyl moiety (Gertler and Cohen 2013). Therefore, it is now considered that sirtuins are not deacetylases but a more general term is proposed—deacylases (Jiang et al. 2013). Acetylation is a post-translational protein modification which can affect, among others, catalytic activity, stability and ability to bind to other proteins or chromatin (which is especially important in the case of histones).

去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化去乙酰化酶。最近的研究对去乙酰化酶有了新的认识,因为它们除了去乙酰化作用外,还可以去除其他一些基团。例如,SIRT6的催化活性随着它去除的脂肪族尾巴的大小而增加,因此棕榈酰、十四烷基或丁酰基比乙酰基更受青睐(Gertler 和 Cohen 2013)。因此,现在认为去乙酰化酶不是去乙酰化酶,但提出了一个更广泛的名词ーー去乙酰化酶(Jiang 等,2013)。乙酰化是一种蛋白质翻译后的修饰,它能影响蛋白质的催化活性、稳定性和与其他蛋白质或染色质结合的能力(这在组蛋白中尤其重要)。

In human we can distinguish seven sirtuins (SIRT1-7). Their catalytic domain consists of 275 amino acids and is common to all family members. Activity of some sirtuins is not limited only to protein deacetylation. ADP-ribosylation is the main activity for SIRT4, which lacks deacetylase activity, and is also characteristic for SIRT6 (Morris 2013). Moreover, SIRT5 can demalonylate and desuccinylate proteins (Du et al. 2011). SIRT1, SIRT6 and SIRT7 localize mainly in the nucleus. SIRT7 has been found to be a part of the RNA Pol I transcription machinery and is expressed in the nucleoli where it can bind to histones and positively regulate rDNA transcription (Ford et al. 2006). SIRT2 can be found mostly in the cytoplasm where its main substrate is α-tubulin (Li et al. 2007). Still, a fraction of SIRT2 can translocate to the nucleus where it takes part in regulation of the cell cycle (Dryden et al. 2003). SIRT3, SIRT4 and SIRT5 have been termed mitochondrial sirtuins. SIRT3 is cleaved to its active form by the mitochondrial matrix processing peptidase (Schwer et al. 2002). Full-length SIRT3 resides in the nucleus, however, in response to stress (such as DNA damage) it translocates to the mitochondria (Scher et al. 2007).

在人类中,我们可以区分出7种去乙酰化酶(SIRT1-7)。它们的催化结构域由275个氨基酸组成,是所有家族成员共有的结构域。某些去乙酰化酶的活性不仅限于蛋白质的脱乙酰化。ADP核糖基化是 SIRT4的主要活性,缺乏去乙酰化酶活性,也是 SIRT6的特征(Morris 2013)。此外,SIRT5可以去甲醛化和去琥珀酸化蛋白(Du et al. 2011)。SIRT1、 SIRT6和 SIRT7主要定位于细胞核内。已经发现 SIRT7是 RNA Pol i 转录机制的一部分,在核仁中表达,在核仁中它可以结合到组蛋白并正向调节 rDNA 转录(Ford 等人,2006年)。SIRT2主要存在于细胞质中,其主要基质是微管蛋白(Li et al. 2007)。尽管如此,SIRT2的一部分可以转移到细胞核中,参与细胞周期的调节(Dryden 等人,2003年)。SIRT3、 SIRT4和 SIRT5被称为线粒体去乙酰化酶。3被线粒体基质处理肽酶切割成活性形式(Schwer 等人,2002年)。然而,全长的 SIRT3位于细胞核内,在应激(如 DNA 损伤)时,它会转移到线粒体(Scher 等人,2007)。

Anti-ageing potential of sirtuins: in vivo and in vitro studies

去乙酰化酶抗衰老作用的体内外研究

Ageing is associated with numerous changes at the organismal, tissue as well as cellular level. With age, senescent cells accumulate in many tissues impairing their proper functioning. Senescent cells have a strong impact on surrounding cells. They modify the microenvironment by secreting certain cytokines, chemokines and mediators of inflammation. Such secretory phenotype is one of the causes of a low grade inflammation observed in old individuals and can induce senescence in neighboring cells as well as support tumor progression. Senescent cells, apart from the secretory phenotype, possess a set of features such as increased: level of cell cycle inhibitors, activity of senescence associated β-galactosidase, granularity and DNA damage. The elevation of DNA damage with age is the result of impaired efficiency of DNA repair systems. It is believed that DNA damage is the main cause of cellular senescence. It concerns both replicative (critically short telomeres are considered as DNA double strand breaks) and stress (oxidative, genotoxic) induced senescence. DNA damage is associated with normal functioning of cells and efficient repair systems are sufficient to protect cells from its accumulation. However, age-related decrease in the ability to repair DNA, causes increased damage accumulation and, in consequence, cell senescence. Sirtuins are indispensable for DNA repair, controlling inflammation and antioxidative defense which makes them good anti-senescence/anti-ageing targets.

老化与生物、组织和细胞层面的许多变化有关。随着年龄的增长,衰老细胞在许多组织中积累,损害了它们的正常功能。衰老细胞对周围细胞有强烈的影响。它们通过分泌特定的细胞因子、趋化因子和炎症介质来改变微环境。这种分泌表型是老年人低度炎症的原因之一,可以诱导邻近细胞衰老,并支持肿瘤进展。衰老细胞除了具有分泌表型外,还具有细胞周期抑制剂水平增高、衰老相关的半乳糖苷酶活性增高、细胞粒度增大和 DNA 损伤等特点。随着年龄的增长,DNA 损伤的增加是 DNA 修复系统效率降低的结果。认为 DNA 损伤是细胞衰老的主要原因。它涉及复制(极短的端粒被认为是 DNA 双链断裂)和应激(氧化,基因毒性)诱导衰老。DNA 损伤与细胞的正常功能有关,有效的修复系统足以保护细胞免受其累积。然而,年龄相关的 DNA 修复能力下降,导致损伤积累增加,结果,细胞衰老。去乙酰化酶是 DNA 修复、炎症控制和抗氧化防御不可缺少的物质,使其具有良好的抗衰老/抗衰老作用。

Calorie restriction (CR) is so far the only effective way to extend lifespan without genetic or pharmacological intervention (more information about CR in the chapter concerning Intervention). The effects of calorie restriction (besides lifespan extension) are manifested by physiological and behavioral changes such as reduced size, decreased level of growth factors, glucose, triglycerides and increase in the locomotor and foraging activity (McCarter et al. 1997; Weed et al. 1997). The level of almost all sirtuins, except SIRT4, increases as an effect of calorie restriction (Watroba and Szukiewicz 2016). Therefore, it is believed that sirtuins mediate beneficial effects elicited by such diet. However, sirtuin anti-ageing activity is not limited to mediating the CR effects. Plethora of in vivo and in vitro studies show importance of these enzymes for reaching a lifespan characteristic for a particular species.

到目前为止,在没有基因或药物干预的情况下,卡路里限制是延长寿命的唯一有效方法。卡路里限制的影响(除了延长寿命之外)通过生理和行为的变化表现出来,例如体型缩小,生长因子水平降低,葡萄糖,甘油三酯和增加运动和觅食活动(McCarter et al. 1997; Weed et al. 1997)。几乎所有 sirtuins 的水平,除了 SIRT4,增加作为卡路里限制的影响(Watroba 和 Szukiewicz 2016)。因此,可以认为去乙酰化酶介导了这种饮食所引起的有益作用。然而,去乙酰化酶的抗衰老活性并不局限于介导 CR 效应。大量的体内和体外研究表明,这些酶对于特定物种达到寿命特征的重要性。

SIRT1

SIRT1 is the best studied in the family. It plays an important role during fetal development. In the case of mouse zygotes lacking both copies of SIRT1 gene only half of the expected individuals are born of which only 20% reach maturity. Such mice are sterile, smaller than normal individuals, develop more slowly and experience abnormalities in morphogenesis of the eye and heart. The latter likely contributes to the neonatal lethality of SIRT1 depleted mice (McBurney et al. 2003; Cheng et al. 2003). Additionally, among heterozygous embryos cases of anencephaly were reported.

SIRT1是家族中被研究得最好的。在胎儿发育过程中起着重要作用。在缺乏两个 SIRT1基因副本的小鼠受精卵中,只有一半的预期个体出生,其中只有20% 达到成熟。这些小鼠是不育的,比正常个体小,发育更慢,眼睛和心脏的形态发生异常。后者可能有助于 SIRT1耗竭小鼠的新生儿致死性(McBurney 等人,2003; Cheng 等人,2003)。此外,在杂合子胚胎中报道了例无脑畸形。

The level of SIRT1 decreases in the liver with age, probably due to lower NAD+ availability (Braidy et al. 2011) while a simultaneous increase in accumulation of DNA damage occurs. Age-dependent decrease in the level of SIRT1 was observed also in the arteries, suggesting its involvement in the ageing of the cardiovascular system (Bai et al. 2014). Decrease in SIRT1, caused by accelerated senescence of cord blood endothelial cells, was also a cause of early vascular dysfunction observed in low birth weight preterm infants (Vassallo et al. 2014). SIRT1 deficiency promoted expression of genes characteristic for ageing (Hwang et al. 2013).

随着年龄的增长,肝脏 SIRT1水平下降,可能是由于 NAD + 的可用性降低(Braidy 等人,2011年) ,同时 DNA 损伤的积累增加。在动脉中也观察到 SIRT1水平的年龄依赖性下降,这表明它参与了心血管系统的老化(Bai 等人,2014年)。SIRT1的减少是由脐带血内皮细胞的加速衰老引起的,也是低出生体重早产儿早期血管功能障碍的原因(Vassallo 等人,2014年)。SIRT1缺陷促进衰老特征基因的表达(Hwang 等人,2013年)。

Mice with an extra copy of SIRT1 gene are characterized by a lower level of DNA damage and of p16, which are the hallmarks of ageing (Herranz et al. 2010). It was shown, that tissue-specific overexpression of SIRT1 in cardiac muscle cells diminished the area affected by myocardial infarction and facilitated recovery (Hsu et al. 2010). It was also shown that some single-nucleotide polymorphisms (SNP) in the SIRT1 gene could affect SIRT1 activity and correlate with BMI and a tendency to diet-induced obesity (Clark et al. 2012). However, no correlation between changes in SIRT1 activity (caused by SNP) and lifespan extension was found (Flachsbart et al. 2006).

拥有额外 SIRT1基因拷贝的老鼠,其 DNA 损伤拥有属性较低,而 p16基因损伤是老化的标志。结果表明,心肌细胞中组织特异性过度表达的 SIRT1减少了受心肌梗死影响的区域,促进了恢复(Hsu 等人,2010)。研究还表明,SIRT1基因的一些单核苷酸多态性(SNP)可能影响 SIRT1的活性,并与 BMI 和饮食诱导肥胖的趋势相关(Clark 等人,2012年)。然而,没有发现 SIRT1活性的改变(由 SNP 引起)和寿命延长之间的相关性(Flachsbart 等人,2006年)。

SIRT1 was shown to delay replicative senescence of normal human umbilical cord fibroblasts and regulate both replicative and premature senescence in stem cells and differentiated cells exposed to oxidative stress (Bellizzi et al. 2005; Brown et al. 2013). Activation of the salvage pathway in vascular smooth muscle cells (VSMC) results in an increase in the replicative lifespan of these cells due to SIRT1 activation (Canto et al. 2009). Moreover, it was demonstrated that inhibition of NAMPT led to premature replicative senescence, while its overexpression delayed it (Yang and Sauve 2006). The level of SIRT1 decreases in tissues, in which cells proliferate during the organismal lifespan or during long term in vitro culture, as we have recently also shown for VSMC (Bielak-Zmijewska et al. 2014), but not in immortalized cells (Sasaki et al. 2006). In H2O2– or genotoxic stress-induced cellular senescence PARP1 becomes activated, which results in depletion of NAD+ resources and leads to a decrease in SIRT1 activity (Furukawa et al. 2007). There are data suggesting that SIRT1 can be involved in decision-making over cellular senescence or apoptosis. In the 3′UTR region of the SIRT1 transcript there is a HuR binding site. HuR is an RNA-binding protein, which can stabilize a transcript when bound. The level of HuR decreases dramatically during senescence (which can also be the cause of the decrease in SIRT1 level observed with ageing). In response to oxidative DNA damage HuR is phosphorylated by Chk2, which leads to its dissociation from SIRT1 mRNA. As a result, there is a decrease in the level of SIRT1 and cells become more prone to apoptosis (Abdelmohsen et al. 2007). It is possible that the described phenomenon is one of the mechanisms responsible for sustaining the balance between DNA repair, senescence and apoptosis. High level of DNA damage can activate Chk2, which leads to a decrease in SIRT1 level and moves the balance towards apoptosis (Bosch-Presegué and Vaquero 2011).

SIRT1被证明可以延缓正常人类脐带成纤维细胞的复制性衰老,并且调节暴露于氧化应激中的干细胞和分化细胞的复制性和早衰。由于 SIRT1的激活,血管平滑肌细胞(VSMC)的抢救通路的激活导致这些细胞的复制寿命延长(Canto 等人,2009年)。结果表明,抑制 NAMPT 可导致复制早衰,而过度表达可延缓复制早衰(Yang 和 Sauve 2006)。SIRT1水平在组织中降低,在有机体寿命期间或长期体外培养期间细胞增殖,正如我们最近在 VSMC (Bielak-Zmijewska 等人,2014年)中所显示的那样,但在永生化细胞中未显示出来(Sasaki 等人,2006年)。在 H2O2或基因毒性应激中,诱导的细胞衰老性 PARP1被激活,导致 NAD + 资源耗竭,并导致 SIRT1活性下降(Furukawa 等人,2007年)。有数据表明,SIRT1可以参与决策细胞衰老或凋亡。在 SIRT1转录本的3′ UTR 区域有一个 HuR 结合位点。HuR 是一种 rna 结合蛋白,绑定后能稳定转录本。HuR 水平在衰老过程中急剧下降(这也可能是老化过程中 SIRT1水平下降的原因)。Chk2对 DNA 氧化损伤修饰的 HuR 进行磷酸化,使其与 SIRT1 mRNA 分离。结果,SIRT1水平下降,细胞更容易发生凋亡(Abdelmohsen 等人,2007年)。这种现象可能是维持 DNA 修复、衰老和细胞凋亡之间平衡的机制之一。高水平的 DNA 损伤可以激活 Chk2,从而导致 SIRT1水平下降,并将平衡转向细胞凋亡(bosch-presegué and Vaquero 2011)。

Pleiotropic activity of SIRT1 makes it an important marker of cellular senescence as well as some diseases such as cardiovascular and neurodegenerative diseases, diabetes or cancer (Nakagawa and Guarente 2011).

SIRT1的多效性使其成为细胞衰老以及心血管和神经退行性疾病、糖尿病或癌症等一些疾病的重要标志物(Nakagawa 和 Guarente,2011年)。

SIRT2

Expression of SIRT2 decreases in fat tissue of obese people (Krishnan et al. 2012). On the other hand, the level of SIRT2 increases in white fat tissue and kidneys of mice subjected to calorie restriction (Wang et al. 2007). Recent studies suggest that SIRT2 can serve as a cellular senescence marker. It was shown that the level of SIRT2 increased in senescent cells (regardless of whether the inducing factor was stress, oncogene or exhaustion of replicative potential) but not in quiescent cells or in cells that entered apoptosis (Anwar et al. 2016). At the same time, the authors excluded SIRT2 as an indispensable factor in senescence induction. This suggests that the increase in the level of SIRT2 is rather the effect of the changes occurring in cells during senescence, than the cause of senescence.

SIRT2在肥胖者脂肪组织中的表达减少(Krishnan 等人,2012)。另一方面,服用卡路里限制的小鼠的白色脂肪组织和肾脏中 SIRT2的水平增加。最近的研究表明,SIRT2可以作为一个细胞衰老标记。结果表明,在衰老细胞中(无论诱导因素是压力、致癌基因还是复制潜能的耗竭) ,SIRT2水平增加,但在静止细胞或进入凋亡的细胞中没有增加(Anwar 等人,2016年)。同时,作者排除了 SIRT2作为衰老诱导不可缺少的因素。这表明 SIRT2水平的升高与其说是衰老的原因,不如说是衰老过程中细胞发生变化的结果。

SIRT3

SIRT3 is the only sirtuin for which evidence exists that it can influence longevity in humans. It was shown that a certain polymorphism in SIRT3 gene can be found more often in long-lived people (Bellizzi et al. 20072005). A variable number of tandem repeats in intron five enhancer region can affect activity of this enhancer. People carrying the allele with the least active enhancer were less likely to survive to an old age. Such variant was practically absent in men over 90 years old living in Italy (Bellizzi et al. 2005). However, studies of other larger populations did not confirm those findings, suggesting that SIRT3 influence on longevity is negligible or even nonexistent (Lescai et al. 2009; Rose et al. 2003).

SIRT3是唯一一种有证据表明它可以影响人类长寿的 sirtuin。结果表明,SIRT3基因的某种多态性在长寿者中更常见(Bellizzi 等人,2007年,2005年)。内含子五个增强子区域中可变数目的串联重复序列会影响该增强子的活性。携带活性增强子最少的等位基因的人活到老年的可能性较小。这种变异在居住在意大利的90岁以上的男性中几乎不存在(Bellizzi 等人,2005年)。然而,对其他较大人口的研究并没有证实这些发现,表明 SIRT3对长寿的影响微不足道,甚至不存在(Lescai 等人,2009年; Rose 等人,2003年)。

Mice lacking SIRT3 are characterized by decreased oxygen consumption and simultaneous increase in reactive oxygen species (ROS) production as well as higher oxidative stress in muscle (Jing et al. 2011). Such observations were confirmed in cell culture—cells lacking SIRT3 had increased ROS level, which could induce DNA damage and activate HIF1α (Finley et al. 2011; Bell et al. 2011). SIRT3 activates enzymes, that play key roles during CR, such as 3-hydroxy-3-methyl-glutaryl-CoA synthase responsible for ketone formation (Shimazu et al. 2010) and long chain acyl-CoA dehydrogenase responsible for long-chain fatty acid oxidation (Hirschey et al. 2010).

缺乏 SIRT3的老鼠拥有属性消耗减少,同时活性氧类(ROS)产生增加,肌肉氧化应激增加。这些观察在细胞培养中得到证实ー缺乏 SIRT3的细胞增加了活性氧水平,这可能导致 DNA 损伤并激活 hif1(Finley 等人,2011; Bell 等人,2011)。SIRT3激活了在 CR 过程中起关键作用的酶,如3- 羟基 -3- 甲基戊二酰辅酶 a 合成酶负责酮的形成(Shimazu 等人,2010年)和长链酰辅酶 a 脱氢酶负责长链脂肪酸氧化(Hirschey 等人,2010年)。

SIRT1, SIRT2, SIRT3

1,SIRT2,SIRT3

Recent data have shown that the ageing protection mechanism involving sirtuins is quite universal and concerns also germ cells. The ageing of oocytes reduces the quality of metaphase II oocytes, which undergo time-dependent deterioration following ovulation. In mouse oocytes aged in vivo or in vitro the expression of SIRT1, SIRT2 and SIRT3 was dramatically reduced. On the other hand, it has been shown that prolonged expression of SIRT1, SIRT2 and SIRT3 reduced mouse oocyte ageing both in vitro and in vivo (Zhang et al. 2016a), which suggests a potential protective role of these enzymes against postovulatory ageing. SIRT1 and SIRT3 are the sensors and guardians of the redox state in oocytes, granulosa cells and early embryos and therefore play a crucial role in female fertility especially when oocyte ageing is concerned (reviewed in Tatone et al. 2015).

最近的数据表明,去乙酰化酶的衰老保护机制是相当普遍的,也涉及到生殖细胞。卵母细胞的老化降低了中期 II 期卵母细胞的质量,使其在排卵后经历时间依赖性的退化。在体内或体外老化的小鼠卵母细胞中,SIRT1、 SIRT2和 SIRT3的表达显著降低。另一方面,已经证明延长 SIRT1、 SIRT2和 SIRT3的表达可以减少小鼠卵母细胞在体外和体内的老化(Zhang 等人,2016a) ,这表明这些酶对排卵后老化具有潜在的保护作用。SIRT1和 SIRT3是卵母细胞、颗粒细胞和早期胚胎中氧化还原状态的传感器和监护者,因此在女性生育中发挥着关键作用,尤其是在卵母细胞老化的问题上(Tatone 等人,2015年)。

The age-dependent changes in sirtuin level could be used as a diagnostic tool. Serum sirtuins are considered as a novel noninvasive protein marker of frailty (Kumar et al. 2014a). Frailty is a complex clinical state described as a characteristic set of features among older patients. Diagnosis of frailty is often difficult because of subtle and subjective clinical features, especially at the early stage of the syndrome. To the features of frailty belong: sarcopenia, cognitive decline, abnormal functioning of immune and neuroendocrine systems, poor energy regulation (Clegg et al. 2013). Currently, there is no defined treatment for frailty. It will be useful to find a set of biochemical abnormalities associated with frailty for better and earlier diagnosis. Sirtuins circulating in serum could be potential markers of frailty. As suggested by analysis of people diagnosed as frail in comparison to non frail individuals, lower levels of SIRT1 and SIRT3 were associated with frailty.

去乙酰化酶水平的年龄依赖性变化可作为一种诊断工具。血清去乙酰化酶被认为是一种新的无创性的脆弱蛋白标记物(Kumar et al. 2014a)。虚弱是一种复杂的临床状态,被描述为老年患者的一系列特征。脆弱性的诊断往往是困难的,因为微妙和主观的临床特点,特别是在早期阶段的综合征。其特点是: 骨骼肌减少,认知功能下降,免疫和神经内分泌系统功能异常,能量调节不良(Clegg 等人,2013年)。目前,对于虚弱还没有明确的治疗方法。这将是有益的,找到一套生化异常与脆弱相关的更好和更早的诊断。血清中的去乙酰化酶可能是体质虚弱的潜在标志。正如对被诊断为体弱者与非体弱者相比的分析所表明的那样,SIRT1和 SIRT3的低水平与体弱有关。

SIRT6

The first evidence that sirtuins can be involved in regulation of mammalian ageing came from mice lacking SIRT6. It appears that among sirtuins, SIRT6 depletion exhibits the most severe phenotype as it seems to be indispensable for reaching a normal lifespan. Three weeks after birth such mice exhibit symptoms of degeneration and premature ageing such as sudden decrease in subcutaneous fat, lordokyphosis, colitis, severe lymphopenia, osteopenia, which all together result in death in about the fourth week of life. SIRT6−/− mice are also smaller than wild type individuals. Furthermore, severe metabolic abnormalities were observed i.e. low level of IGF-1 and glucose (Mostoslavsky et al. 2006). Later, it was shown that the main reason of premature death was hypoglycemia caused by increased glucose uptake (due to higher expression of GLUT1 and GLUT 4 transporters) (Xiao et al. 2010; Zhong et al. 2010). On the other hand, Kanfi et al. demonstrated that overexpression of SIRT6 could also reduce the activity of the IGF-1 pathway. They observed a decrease in the level of IGF-1, the level of IGF-binding protein was increased, and the phosphorylation status of the main components of the IGF-1 signaling pathway was altered. Such changes facilitated glucose tolerance and reduced fat accumulation, which resulted in lifespan extension of male mice (Kanfi et al. 2012).

去乙酰化酶参与调节哺乳动物衰老的第一个证据来自缺乏 SIRT6的小鼠。看来,在去乙酰化酶中,SIRT6缺失表现出最严重的表型,因为它似乎是达到正常寿命所不可或缺的。出生三周后,这些小鼠表现出退化和过早衰老的症状,如皮下脂肪突然减少,脊柱前凸,结肠炎,严重的淋巴细胞减少,骨质减少,这些都导致生命的第四周左右死亡。SIRT6-/-小鼠也比野生型个体小。此外,还观察到严重的代谢异常,即 IGF-1和葡萄糖水平低(Mostoslavsky 等人,2006年)。后来,研究表明,早逝的主要原因是由于葡萄糖摄取增加(由于 GLUT1和 GLUT 4转运体的高表达)引起的低血糖(Xiao 等人,2010; Zhong 等人,2010)。另一方面,Kanfi 等人证明 SIRT6的过度表达也会降低 IGF-1通路的活性。他们观察到 IGF-1水平下降,IGF-1结合蛋白水平上升,IGF-1信号通路主要成分的磷酸化状态改变。这种变化促进了葡萄糖耐量和减少脂肪堆积,从而导致雄性小鼠寿命延长(Kanfi 等人,2012年)。

Mouse embryonal fibroblasts (MEF) and embryonal stem (ES) cells devoid of SIRT6 are characterized by decreased proliferation rate and increased genomic instability as well as sensitivity to stress manifested by chromosome fragmentation, detached centromeres, chromosome loss and translocations. SIRT6 level decreases in human fibroblasts during senescence (Sharma et al. 2013) but also in vascular smooth muscle cells and endothelial cells isolated from human aorta as we have recently demonstrated (Grabowska et al. 2016).

缺乏 SIRT6的小鼠胚胎成纤维细胞(MEF)和胚胎干细胞(ES)增殖速率降低,基因组不稳定性增加,对应激敏感,表现为染色体断裂、着丝粒脱落、染色体丢失和易位。在衰老过程中,成纤维细胞的 SIRT6水平下降(Sharma 等人,2013年) ,但是我们最近已经证明,从人主动脉分离的血管平滑肌和内皮细胞的 SIRT6水平也下降(Grabowska 等人,2016年)。

SIRT7

SIRT7−/− mice age prematurely and are characterized by a progeroid phenotype and lethal heart hypertrophy (Vakhrusheva et al. 2008). During replicative senescence SIRT7 translocates from nucleoli to chromatin and cytoplasm (Grob et al. 2009), which can result in reduced rDNA transcription. Localization, activity, functions and role in senescence/ageing of all sirtuins are summarized in Table 1.

SIRT7-/-小鼠过早衰老,呈现早衰表型和致命性心脏肥大(Vakhrusheva 等人,2008年)拥有属性。在复制衰老过程中,SIRT7从核仁转移到染色质和细胞质(Grob 等人,2009年) ,这会导致 rDNA 转录减少。所有去乙酰化酶的定位、活性、功能和在衰老/老化中的作用在表1中总结。

Table 1

表一

Summary of the effects of various mammalian sirtuins, their localization, and intracellular targets

各种哺乳动物去乙酰化酶的作用、定位和细胞内靶点的概述

Sirtuin and localization Sirtuin 与本地化Enzymatic activity 酶活性Targets and substrates 目标和基质Function 功能Tissue expression组织表达Ageing and age-related diseases 老化和与年龄有关的疾病
Modification修改Activation激活Inhibition抑制Increase/involvement in CR 增加/参与公司注册处服务Decrease 减少
SIRT1 nuclear/cytosolic SIRT1核/胞质Deacetylase 脱乙酰基酶H1, H3, H4, (H1K26, H1K9, H3K9, H3K56, H3K14, H4K16) α tubulin, p53-(stabilization) H1,H3,H4,(H1K26,H1K9,H3K9,H3K56,H3K14,H4K16)微管蛋白,p53-(稳定)Suv39h1, LKB1, AMPK, NBS1, XPA, Mn-SOD, WRN, Ku70 Suv39h1,LKB1,AMPK,NBS1,XPA,Mn-SOD,WRN,Ku70NFκB, p300, p66shc, mTOR 300,p66shc,mTORDNA repair, glucose metabolism, differentiation, neuroprotection, insulin secretion, vascular protection DNA 修复、糖代谢、分化、神经保护、胰岛素分泌、血管保护Brain, adipose tissue, heart, kidney, liver, retina, skeletal muscle, vessels, uterus 大脑、脂肪组织、心脏、肾脏、肝脏、视网膜、骨骼肌、血管、子宫Cell survival, longevity, physical activity/increase in CR 细胞存活,寿命,体力活动/增加 CRCellular senescence, oxidative stress, inflammation, neurodegeneration, cardiovascular diseases, adiposity, insulin resistance, liver steatosis 细胞衰老,氧化应激,炎症,神经退行性疾病,心血管疾病,肥胖,胰岛素抵抗,肝脏脂肪变性
FOXO, PGC-1α FOXO,pgc-1
SIRT2 cytosolic/nuclear SIRT2胞质/核Deacetylase 脱乙酰基酶α tubulin, H4K16 微管蛋白 H4K16FOXONFκB, p53 Nf b,p53Cell-cycle control (transition from G2 to M phase), adipose tissue development and functionality 细胞周期调控(从 G2期过渡到 m 期) ,脂肪组织的发育和功能Adipose tissue, brain, heart, kidney, liver, skeletal muscle, vessels 脂肪组织、脑、心、肾、肝、骨骼肌、血管Longevity/increase in CR 长寿/体重增加Oxidative stress, neurodegeneration 氧化应激,神经退行性疾病
SIRT3 mitochondrial/nuclear/cytosolic SIRT3线粒体/核/胞质Deacetylase 脱乙酰基酶H3, H4 (H3K9, H4K16) H3,H4(H3K9,H4K16)FOXO, Ku70, Mn-SOD, catalase, IDH2 FOXO,Ku70,Mn-SOD,过氧化氢酶,IDH2p53, HIF1α 53,hif1Regulation of mitochondrial metabolism, ATP production 线粒体代谢的调节,ATP 的产生Adipose tissue, brain, heart, kidney, liver, oocytes, skeletal muscle, vessels 脂肪组织、脑、心、肾、肝、卵母细胞、骨骼肌、血管Longevity, metabolic health, glucose homeostasis/increase in CR 长寿,代谢健康,葡萄糖稳态/增加 CROxidative stress, neurodegeneration, cardiac hypertrophy, adiposity, liver steatosis 氧化应激,神经退行性疾病,心脏肥大,肥胖,肝脏脂肪变性
SIRT4 mitochondrial SIRT4线粒体ADP-ribosyl-transferase Adp- 核糖基转移酶GDH, AMPK 地球物理学家,AMPKInsulin secretion, regulation of mitochondrial metabolism, DNA repair 胰岛素分泌、线粒体代谢调控、 DNA 修复Brain, heart, kidney, liver, vessels, pancreatic β-cells 脑、心、肾、肝、血管、胰腺细胞Fatty acid oxidation 脂肪酸氧化
SIRT5 mitochondrial/cytosolic/nuclear SIRT5线粒体/胞质/核Deacetylase demalonylase desuccinylase 脱乙酰酶脱核酶SOD1Urea cycle 尿素循环Brain, heart, kidney, liver, vessels, thymus, testis, skeletal muscle 脑、心、肾、肝、血管、胸腺、睾丸、骨骼肌Increase in CR 增加公司注册处服务Oxidative stress, fatty acid oxidation 氧化应激、脂肪酸氧化
SIRT6 nuclear (associated with chromatin) SIRT6核(与染色质相关)Deacetylase, ADP-ribosyl-transferase 脱乙酰酶,adp- 核糖基转移酶H2B, H3 (H2BK12, H3K9, H3K56), WRN (stabilization) H2B,H3(H2BK12,H3K9,H3K56) ,WRN (稳定)FOXO, PARP1, CtIP 1,CtIPNFκB, IGF-1 Nf b,IGF-1DNA repair, telomere protection, genome stability, cholesterol homeostasis, regulation of glycolysis and gluconeogenesis DNA 修复、端粒保护、基因组稳定性、胆固醇稳态、糖酵解和糖异生调节Brain, heart, kidney, liver, vessels, retina, skeletal muscle, thymus, testis, ovary 脑、心、肾、肝、血管、视网膜、骨骼肌、胸腺、睾丸、卵巢Longevity, glucose homeostasis/increase in CR 长寿,葡萄糖稳态/增加 CRCardiac hypertrophy, adiposity, liver steatosis, inflammation, insulin resistance 心肌肥大、肥胖、肝脂肪变性、炎症、胰岛素抵抗
SIRT7 nucleolar/nuclear SIRT7核仁/核Deacetylase 脱乙酰基酶H2A, H2B, H3 (H3K18) H2A,H2B,H3(H3K18)FOXORNA poly-merase I 聚合酶 iRegulation of rRNA transcription, cell cycle regulation, cardioprotection Rna 转录调控,细胞周期调控,心肌保护Heart, vessels, liver, brain, skeletal muscle, peripheral blood cells, spleen, testis 心脏、血管、肝脏、脑、骨骼肌、外周血细胞、脾脏、睾丸Increase in CR 增加公司注册处服务Cardiac hypertrophy 心脏肥大

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AMPK AMP-dependent kinase, CtIP C-terminal binding protein interacting protein, DNA-PKcs DNA-dependent protein kinase catalytic subunit, FOXO (FOXO3a, FOXO1) Forkhead box “O” transcription factor, GDH glutamate dehydrogenase, H1, H2A, H2B, H3, H4 histone; HIF1α hypoxia-inducible factor 1α, IGF-1 insulin-like growth factor 1, IDH2 isocitrate dehydrogenase 2, LKB1 liver kinase B1, Mn-SOD manganese superoxide dismutase, mTORmammalian target of rapamycin, NBS1 Nijmegen breakage syndrome 1, NFκB nuclear factor κB, PARP1 poly(ADP-ribose) polymerase 1, PGC-1α PPARγ coactivator1α, SOD1 superoxide dismutase 1, Suv39H1 suppressor of variegation 3–9 homolog 1, WRN Werner syndrome ATP-dependent helicase, XPA xeroderma pigmentosum group A

AMPK 依赖性激酶,CtIP c 末端结合蛋白相互作用蛋白,DNA-PKcs dna 依赖性蛋白激酶催化亚单位,FOXO (FOXO3a,FOXO1)转录因子,GDH 谷氨酸脱氢酶,H1,H2A,H2B,H3,H4组蛋白;缺氧诱导因子1,IGF-1美卡舍明,异柠檬酸脱氢酶2,LKB1肝激酶 b 1,锰超氧化物歧化酶超氧化物歧化酶,mTOR 哺乳动物雷帕霉素靶蛋白,NBS1 Nijmegen 断裂综合征1,核因子 b,PARP1 poly (ADP-ribose) polymerase 1,pgc-1 ppar 辅活化素1,SOD1超氧化物歧化酶1,Suv39H1抑制因子3-9同源基因1,WRN Werner 综合征 atp 依赖性解旋酶,XPA 着色性干皮症 a 组

The mechanisms of senescence modulation by sirtuins

去乙酰化酶调节衰老的机制

The data presented above support the notion that sirtuins play an important role during ageing. It is best evidenced by a widely observed decrease in the level of almost all sirtuins in senescent cells. The mechanism of their action is very complex and not entirely understood yet.

上述数据支持去乙酰化酶在衰老过程中发挥重要作用的观点。衰老细胞中几乎所有去乙酰化酶水平的下降是最好的证明。它们的作用机制非常复杂,目前还没有完全弄清楚。

During cellular senescence changes in chromatin condensation and gene expression occur. Such changes in chromatin structure can influence genome stability, making DNA more susceptible to damage, which is considered the main cause of senescence. Sirtuins play a vital role in sustaining genome integrity. They take part in maintaining normal chromatin condensation state, in DNA damage response and repair, modulate oxidative stress and energy metabolism. Let us take a closer look at the role of each sirtuin in these processes.

在细胞衰老过程中,染色质凝聚和基因表达发生变化。染色质结构的这种改变可以影响基因组的稳定性,使 DNA 更容易受到损伤,这被认为是衰老的主要原因。去乙酰化酶在维持基因组完整性中起着至关重要的作用。它们参与维持正常的染色质凝聚状态,参与 DNA 损伤反应和修复,调节氧化应激和能量代谢。让我们仔细研究一下每一种去乙酰化酶在这些过程中的作用。

Influence on chromatin condensation and gene expression

染色质浓缩对基因表达的影响

Among cells isolated from mice lacking both copies of SIRT1 gene, almost 40% have impaired chromosome structure including breaks or relaxed/disorganized chromatin (in comparison to 5% in normal individuals) (Wang et al. 2008). It is suggested that such abnormalities can be the effect of an increase in the acetylation of H3K9, caused by lack of SIRT1. Acetylation of H3K9 prevents its trimethylation and impairs binding of heterochromatin protein 1 alpha (HP1α) responsible for keeping chromatin in a closed state (Wang et al. 2008). SIRT1 (and also other sirtuins), through histone deacetylation, takes part in formation of the constitutive as well as facultative heterochromatin. The removal of acyl groups from histones enhances their affinity to DNA and impedes the access of transcription factors to DNA resulting in silencing of genes neighboring the deacetylated histones (Michan and Sinclair 2007). SIRT1 preferentially deacetylates H4K16, H3K9, H3K56 and H1K26 (Poulose and Raju 2015) and also H1K9 and H3K14 during heterochromatin formation (Michan and Sinclair 2007). It was shown that SIRT1 can be found in telomere and pericentromere regions. Oxidative stress inhibits this interaction, which results in altered gene expression (Oberdoerffer et al. 2008; Palacios et al. 2010). Moreover, SIRT1 deficient mice lack pericentromeric heterochromatin foci (Bosch-Presegué et al. 2011), which suggest its involvement in formation of constitutive heterochromatin.

从同时缺乏 SIRT1基因拷贝的小鼠身上分离出的细胞中,几乎40% 的细胞染色体结构受损,包括断裂或松弛/紊乱的染色质(相比之下,正常个体中只有5%)(Wang 等,2008年)。提示这种异常可能是由于缺乏 SIRT1导致 H3K9乙酰化水平升高所致。H3K9的乙酰化可以阻止其三甲基化并损害异染色质蛋白1α (hp1)的结合,而异染色质蛋白1α (hp1)负责将染色质保持在闭合状态(Wang 等人,2008年)。SIRT1(还有其他去乙酰化酶)通过组蛋白脱乙酰化参与组成性和兼性异染色质的形成。从组蛋白中去除酰基增强了它们与 DNA 的亲和力,并阻碍转录因子与 DNA 的接触,导致邻近去乙酰化组蛋白的基因沉默(Michan 和 Sinclair,2007)。SIRT1在异染色质形成过程中优先脱乙酰 H4K16、 H3K9、 H3K56和 H1K26(Poulose 和 Raju,2015) ,还有 H1K9和 H3K14(Michan 和 Sinclair,2007)。结果表明,SIRT1位于端粒和着丝粒周围区域。氧化应激抑制了这种相互作用,导致了基因表达的改变。此外,SIRT1缺陷小鼠缺乏熵异染色质灶(bosch-presegué et al. 2011) ,这表明其参与形成组成型异染色质。

SIRT1 can influence chromatin condensation not only by deacetylating histones, but also by regulating histone expression and modulating the level and activity of some histone modifying enzymes (Vaquero et al. 2007). SIRT1 can inhibit Suv39h1 methyltransferase degradation by inhibiting polyubiquitination of this methyltransferase by MDM2. Moreover, deacetylation of K266 in the catalytic domain of Suv39h1 activates it (Vaquero et al. 2007). Therefore, SIRT1 promotes H3K9 trimethylation not only by deacetylation but also through cooperation with Suv39h1 (Bosch-Presegué and Vaquero 2011). Under oxidative stress, SIRT1 along with Suv39h1 and nucleomethylin initiate formation of facultative heterochromatin in the rDNA region. This, in turn, inhibits ribosome formation and decreases protein expression in general, which protects cells from energy deprivation-dependent apoptosis (Murayama et al. 2008) and, facilitates repair. Moreover, SIRT1 can deacetylate TBP [TATA-box-binding protein]-associated factor I 68 (TAFI68) impairing its DNA-binding activity, and in this way, inhibiting RNAPolI-dependent transcription of rDNA (Muth et al. 2001). In addition to Suv39h1, SIRT1 can modulate the activity of p300 histone acetyltransferase. SIRT1 inhibits p300 activity by deacetylating K1020 and K1024 (Bouras et al. 2005). In this way it contributes to the decreased level of histone acetylation.

SIRT1不仅可以通过去乙酰化组蛋白影响染色质凝聚,还可以通过调节组蛋白的表达和某些组蛋白修饰酶的水平和活性来影响染色质凝聚。SIRT1可以通过 MDM2抑制甲基转移酶对 Suv39h1的泛素降解,从而抑制甲基转移酶的泛素化。此外,在 Suv39h1的催化区域中 K266的脱乙酰化激活了它(瓦奎罗等人,2007)。因此,SIRT1不仅通过脱乙酰基而且通过与 Suv39h1(bosch-presegué 和 Vaquero 2011)的合作促进 H3K9三甲基化。在氧化应激下,SIRT1与 Suv39h1和核酸甲基一起在 rDNA 区域引发兼性异染色质的形成。这反过来,抑制核糖体的形成和减少蛋白质的表达,从而保护细胞免受能量剥夺依赖的凋亡(Murayama 等人,2008年) ,促进修复。此外,SIRT1还可以去乙酰化 TBP [ tata-box 结合蛋白]-associated factor i 68(TAFI68)损伤其 dna 结合活性,从而抑制 rna 依赖的 rDNA 转录(等人,2001)。除了 Suv39h1,SIRT1可以调节 p300组蛋白乙酰转移酶的活性。SIRT1通过去乙酰化 K1020和 K1024抑制 p300活性(Bouras 等人,2005年)。这种方式有助于组蛋白乙酰化水平的降低。

SIRT2 participates in formation of metaphase chromosomes via H4K16 deacetylation (Vaquero et al. 2006). The level of SIRT2 fluctuates during cell cycle reaching its peak at the M phase and G2/M transition (Vaquero et al. 2006). Overexpression of SIRT2 can delay mitotic exit (Dryden et al. 2003).

SIRT2通过 H4K16去乙酰化参与中期染色体的形成(瓦奎罗等人,2006)。SIRT2的水平在细胞周期中波动,在 m 期和 G2/M 转变期达到峰值(瓦奎罗等人,2006年)。SIRT2的过度表达可以延迟有丝分裂退出(Dryden 等人,2003年)。

SIRT3, as the main mitochondrial deacetylase, plays an important role in homeostasis of these organelles. Under stress the nuclear fraction of SIRT3 can deacetylate H4K16 and H3K9 regulating expression of genes involved in mitochondrial biogenesis and metabolism (Scher et al. 2007). Moreover, no hyperacetylation is observed in SIRT3−/− cells, which suggests that SIRT3 is involved in regulation of only specific genes or regions (Scher et al. 2007).

SIRT3作为主要的线粒体脱乙酰酶,在这些细胞器的稳态中起着重要作用。在应激条件下,SIRT3的核碎片可以脱乙酰基 H4K16和 H3K9调节线粒体生物发生和代谢相关基因的表达(Scher 等人,2007年)。此外,在 SIRT3-/-细胞中没有观察到高乙酰化现象,这表明 SIRT3只参与了特定基因或区域的调控(Scher 等人,2007年)。

SIRT6 is a deacetylase as well as ADP-ribosylase acting mainly on histones. This sirtuin deacetylates H3K9 in the promotor regions of, among others, genes involved in metabolism (Zhong et al. 2010). In MEF and ES cells derived from SIRT6 knockout mice, H3K9 hyperacetylation in telomeres was observed. Such hyperacetylation caused a decrease in the level of trimethylated H3K9 in telomeres and chromatin relaxation in these regions. This suggests that SIRT6 can protect cells from telomere dysfunction (Cardus et al. 2013). In particular, SIRT6 deacetylates H3K9 in telomere regions in response to DNA damage (Gertler and Cohen 2013), which results in tightening and stabilization of the telomere structure. SIRT6 telomere binding is dynamic, and the strongest interaction is observed during the S phase of the cell cycle (Michishita et al. 2008). Moreover, SIRT6 stabilized ATP-dependent helicase WRN and prevented telomere dysfunction during DNA replication (Gertler and Cohen 2013). SIRT6 substrates also include H2BK12 and H3K56, increased acetylation level of the latter is associated with genomic instability (Jiang et al. 2013; Gertler and Cohen 2013). The role of SIRT1 and SIRT6 in chromatin condensation is presented in Fig. 1.

SIRT6是一种去乙酰化酶和 adp- 核糖基化酶,主要作用于组蛋白。该去乙酰化去乙酰化去乙酰化酶在启动子区域的 H3K9,除其他外,参与新陈代谢的基因(钟等人,2010)。在来源于 SIRT6基因敲除小鼠的 MEF 和 ES 细胞中,观察到端粒中有 H3K9高乙酰化现象。这种高乙酰化导致端粒中三甲基化的 H3K9水平下降,染色质松弛在这些区域。这表明 SIRT6可以保护细胞免受端粒功能障碍的影响(Cardus et al. 2013)。特别是,SIRT6在端粒区域去乙酰化 H3K9以应对 DNA 损伤(Gertler 和 Cohen 2013) ,这导致端粒结构的紧缩和稳定。SIRT6端粒结合是动态的,在细胞周期的 s 期观察到最强的相互作用(Michishita 等人,2008年)。此外,SIRT6稳定了 atp 依赖的解旋酶 WRN,并在 DNA 复制过程中防止端粒功能障碍(Gertler 和 Cohen 2013)。SIRT6基因还包括 H2BK12和 H3K56,后者的乙酰化水平升高与基因组不稳定性有关(Jiang 等人,2013; Gertler 和 Cohen,2013)。SIRT1和 SIRT6在染色质浓缩中的作用见图1。

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Fig. 1 图一

Role of SIRT1 and SIRT6 in chromatin condensation. SIRT1 and SIRT6 promote formation of heterochromatin in three ways. Firstly, both of the sirtuins deacetylate H3K9 enabling its trimethylation and subsequent binding of HP1α indispensable for heterochromatin formation. Secondly, SIRT1 decreases activity of p300 histone acetyltransferase. Lastly, SIRT1 activates Suv39h1 methyltransferase by deacetylating K266 in its catalytic domain. Moreover, SIRT1 inhibits polyubiquitination of Suv39h1 by MDM2 and prevents its degradation. Arrows indicate positive regulation. Lines with T-shaped ending indicate inhibition. Thick upward and downward arrows inside boxes indicate increase or decrease during aging, respectively. (Color figure online)

SIRT1和 SIRT6在染色质浓缩中的作用。SIRT1和 SIRT6通过三种途径促进异染色质的形成。首先,去乙酰化去乙酰化酶 H3K9使其三甲基化,并与异染色质形成所必需的 hp1结合。其次,SIRT1降低 p300组蛋白乙酰转移酶的活性。最后,SIRT1通过在催化区域去乙酰化 K266来激活 Suv39h1甲基转移酶。此外,SIRT1还能抑制 MDM2对 Suv39h1的泛泛素化作用,防止其降解。箭头表示积极的监管。末端呈 t 形的线表示抑制。方框中向上和向下的粗箭头分别表示衰老过程中的增加或减少。(网上彩色图片)

SIRT7 interacts with promoter as well as transcribed regions of rDNA genes. This sirtuin deacetylates histones, in particular H2A and H2B (Ford et al. 2006), however, its main substrate is H3K18 (Barber et al. 2012). Deacetylation of this histone is associated with repression of tumor suppressor genes. Therefore, SIRT7 can support cancer phenotype by inhibiting expression of tumor suppressors. However, it must be noted that SIRT7 is required only to sustain cancer phenotype and does not promote oncogenic transformation of normal cells (Barber et al. 2012; Kim et al. 2013).

SIRT7与 rDNA 基因的启动子和转录区相互作用。这种去乙酰化去乙酰化的去乙酰化组蛋白,特别是 H2A 和 H2B (Ford 等人,2006年) ,然而,它的主要底物是 H3K18(Barber 等人,2012年)。这种组蛋白的去乙酰化与肿瘤抑制基因的阻遏有关。因此,SIRT7可以通过抑制肿瘤抑制基因的表达来支持肿瘤表型。然而,必须指出的是,SIRT7只能维持癌症表型,而不能促进正常细胞的致癌转化(Barber 等人,2012; Kim 等人,2013)。

Influence on DNA damage and DNA repair

DNA 损伤与 DNA 修复

Unrepairable DNA damage is believed to be one of the basic causes of cellular senescence (Sedelnikova et al. 2004). Already in yeast it was observed that Sir2 takes part in DNA repair. Changes in the localization of Sir2 occur not only during senescence but also as a result of DNA damage. Sir2 dissociates from HM loci and moves to the sites of DNA breaks (Oberdoerffer et al. 2008). This has two effects: firstly, it induces expression of HM genes (involved in DNA damage repair) and secondly, inhibits proliferation giving time for DNA repair to occur. Moreover, at sites of DNA breaks, Sir2 deacetylates histones and DNA damage response proteins that recruit proteins responsible for DNA damage repair (Oberdoerffer et al. 2008). The involvement of sirtuins in DNA damage recognition and repair has been also observed in more complex organisms.

不可修复的 DNA 损伤被认为是细胞衰老的基本原因之一(Sedelnikova 等人,2004年)。在酵母中已经观察到 Sir2参与 DNA 修复。Sir2定位的改变不仅发生在衰老过程中,而且也是 DNA 损伤的结果。2从 HM 基因座游离并转移到 DNA 断裂的位点(oberdordorerffer 等人,2008年)。这有两个作用: 一是诱导 HM 基因表达(参与 DNA 损伤修复) ,二是抑制增殖,使 DNA 修复有时间发生。此外,在 DNA 断裂的位置,Sir2去乙酰化组蛋白和 DNA 损伤反应蛋白招募负责 DNA 损伤修复的蛋白质(Oberdoerffer 等人,2008年)。去乙酰化酶在 DNA 损伤识别和修复中的作用在更复杂的生物体中也被观察到。

Under normal conditions SIRT1 is bound to hundreds of gene promoters in the mouse genome. The binding pattern is disturbed as a result of genotoxic stress as SIRT1 moves to DNA damage sites where it plays an important role in the recruitment and activation of repair proteins (Chung et al. 2010). In cells derived from SIRT1 knockout mice, aside from chromosomal aberrations, impaired DNA damage repair was observed further proving that this sirtuin is involved in double helix repair (Wang et al. 2008). SIRT1 interacts directly with NBS1 and maintains it in a hypoacetylated state, which allows for phosphorylation of S343 that is necessary for efficient DNA damage repair response and activation of the S-phase checkpoint (Yuan et al. 2007). Acetylation of WRN promotes its translocation to the nucleus while subsequent deacetylation by SIRT1 increases its activity and efficiency of DNA damage repair by HR (Li et al. 2008). In response to DNA damage Ku70 is acetylated on multiple lysine residues. This facilitates dissociation of Ku70 from BAX, which results in translocation of the latter to the mitochondria and induction of apoptosis. SIRT1 deacetylates Ku70 sustaining its interaction with BAX. This, in turn, inhibits apoptosis and facilitates Ku70-dependent DNA damage repair (Bosch-Presegué and Vaquero 2011). A similar role was shown for SIRT3. SIRT1 is also involved in the repair of single strand DNA breaks via nucleotide excision repair (NER). UV radiation (NER is the main pathway responsible for repair of UV-induced breaks) stimulates interaction of SIRT1 with xeroderma pigmentosum group A (XPA)—one of the key factors in NER. XPA recognizes DNA damage and recruits proteins essential for the repair process. SIRT1 deacetylates XPA on K63 and K67 facilitating its interaction with RPA32 (which stabilizes single-stranded DNA) and DNA damage repair (Fan and Luo 2010). Additionally, SIRT1 overexpression in mice inhibits telomere erosion while its silencing accelerates telomere shortening (Palacios et al. 2010).

在正常条件下,SIRT1与小鼠基因组中的数百个基因启动子结合。当 SIRT1转移到 DNA 损伤位点,在修复蛋白的补充和激活中发挥重要作用时,基因毒性应激扰乱了结合模式(Chung 等人,2010)。在 SIRT1基因敲除小鼠的细胞中,除了染色体畸变外,还观察到 DNA 损伤修复受损,进一步证明这种去乙酰化酶参与了双螺旋修复(Wang 等人,2008年)。SIRT1直接与 NBS1相互作用,使其处于低乙酰化状态,这使得 S343磷酸化,这是有效的 DNA 损伤修复反应和 s 期检查点激活所必需的(Yuan 等人,2007年)。WRN 的乙酰化促进其向细胞核的转运,而随后的 SIRT1的脱乙酰化增加了其活性和 DNA 损伤修复的效率。为了应对 DNA 损伤,Ku70在多个赖氨酸残基上被乙酰化。这促进了 Ku70和 BAX 的分离,从而导致后者向线粒体移位并诱导细胞凋亡。SIRT1脱乙酰化 Ku70维持与 BAX 的相互作用。这反过来抑制细胞凋亡,促进 ku70依赖性 DNA 损伤修复(bosch-presegué and Vaquero 2011)。SIRT3也显示了类似的作用。SIRT1也参与了通过核苷酸切除修复修复单链 DNA 断裂的过程。紫外线辐射(NER 是负责修复紫外线诱导的断裂的主要途径)刺激 SIRT1与着色性干皮症 a 组(XPA)的相互作用,这是 NER 的关键因素之一。XPA 可以识别 DNA 损伤,并招募修复过程所必需的蛋白质。SIRT1在 K63和 K67上脱乙酰化 XPA,促进其与 RPA32(稳定单链 DNA)的相互作用和 DNA 损伤修复(Fan 和 Luo 2010)。此外,SIRT1在小鼠中的过度表达抑制端粒侵蚀,而其沉默加速端粒缩短(Palacios 等人,2010年)。

SIRT6 also plays a considerable role in DNA repair and maintenance of genomic stability by integrating signals of DNA damage with activation of repair enzymes (Mao et al. 2011). This sirtuin is involved in HR, non-homologous end-joining (NHEJ) as well as base excision repair (BER) (Mostoslavsky et al. 2006). SIRT6 poly-ADP-ribosylates proteins localized in the vicinity of DNA breaks promoting recruitment of repair enzymes (Gertler and Cohen 2013). Moreover, in response to DNA damage SIRT6 dynamically binds to chromatin and induces global decrease in H3K9 acetylation. In this way it stabilizes the binding to DNA of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs)—a key component of NHEJ that facilitates the access of repair enzymes to double strand breaks. In response to oxidative stress SIRT6 mono-ADP-ribosylates K521 of PARP-1 increasing its activity and facilitating DNA repair via NHEJ and HR (Beneke 2012). SIRT6 increases the activity of C-terminal binding protein interacting protein (CtIP)—an enzyme responsible for excision of damaged DNA fragments during HR. Under normal conditions CtIP is acetylated, however, after DNA damage SIRT6 deacetylates it on K432, K526 and K604 promoting resection of damaged fragments (Kaidi et al. 2010). It was shown that SIRT6 is also indispensable for BER to occur, however neither direct interaction with any of the components involved in this pathway nor co-localization on the damage site were proven (Mostoslavsky et al. 2006; Tennen and Chua 2011).

SIRT6还通过整合 DNA 损伤信号和修复酶的激活,在 DNA 修复和维持基因组稳定性方面发挥着重要作用(Mao et al. 2011)。这种去乙酰化酶参与了 HR,非同源末端连接(NHEJ)和碱基切除修复(BER)(Mostoslavsky 等人,2006)。SIRT6多 adp- 核糖基化蛋白定位于 DNA 断裂附近,促进修复酶的招募(Gertler 和 Cohen 2013年)。此外,为了应对 DNA 损伤,SIRT6与染色质动态结合,引起 H3K9乙酰化整体下降。通过这种方式,它稳定了 DNA 依赖性蛋白激酶(DNA-pkcs)催化亚基与 DNA 的结合,而 DNA-pkcs 是 NHEJ 的关键组成部分,能促进修复酶进入双链断裂。针对氧化应激 SIRT6单 adp- 核糖核酸酶,通过 NHEJ 和 HR 增加 PARP-1的 K521活性,促进 DNA 修复。SIRT6增加 c 末端结合蛋白相互作用蛋白(CtIP)的活性,CtIP 是一种在 HR 过程中切除受损 DNA 片段的酶。在正常条件下,CtIP 被乙酰化,但是,DNA 损伤后,SIRT6在 K432,K526和 K604上脱乙酰化,促进受损片段的切除(Kaidi 等人,2010年)。结果表明,SIRT6对于实现 BER 也是必不可少的,但是,既没有证明与这条通路中的任何组件直接相互作用,也没有证明在损害现场的共同定位(Mostoslavsky 等人,2006年; Tennen 和 Chua,2011年)。

The negative feedback loop between DNA damage and NAD+ level may also contribute to cell senescence. DNA damage can induce a decrease in the level of NAD+ due to increased PARP1 activity, which requires NAD+ as a co-factor. Repeated or chronic DNA damage can result in substantial depletion of NAD+ and decrease in sirtuin activity. This in turn, can disrupt DNA damage repair (causing increase in the number of DNA breaks) and impair mitochondria function. The latter may result in increased ROS production and further DNA damage (Imai and Guarente 2014). Therefore, NAD+ level and sirtuin activity can provide an interface between DNA damage and mitochondria function and combine DNA damage theory with Harman’s mitochondrial theory of ageing.

DNA 损伤与 NAD + 水平之间的负反馈环也可能参与细胞衰老。DNA 损伤可以引起 NAD + 水平的下降,这是由于 PARP1活性的增加,这需要 NAD + 作为一个辅助因子。重复或慢性 DNA 损伤可导致 NAD + 的大量耗竭和 sirtuin 活性的降低。这反过来又会破坏 DNA 损伤修复(引起 DNA 断裂数量的增加)并损害线粒体功能。后者可能导致 ROS 产生增加和进一步的 DNA 损伤(Imai 和 Guarente 2014)。因此,NAD + 水平和去乙酰化酶活性可以提供 DNA 损伤与线粒体功能之间的界面,并将 DNA 损伤理论与哈曼的线粒体衰老理论相结合。

Not only direct involvement in DNA repair is important, as in the case of SIRT1 or SIRT6, which can modify a variety of proteins engaged in repair of DNA damage. Glucose and glutamine metabolism is also relevant in this process. Glutamine is the main nitrogen donor, not only for protein, but also nucleotide synthesis. SIRT4 plays an important role in DNA damage response by regulating mitochondrial glutamine metabolism. During DNA damage response SIRT4 inhibits the transport of intermediates to the Krebs cycle so that the nitrogen atom from glutamine can be used for the synthesis of purine nucleotides crucial in DNA repair process (Jeong et al. 2013). SIRT4 is also a negative regulator of glutamate dehydrogenase (GDH), the first enzyme in glutamine metabolism (Haigis et al. 2006). Lack of SIRT4 disturbed DNA damage repair and promoted accumulation of the damage, while SIRT4 overexpression supported the removal of γH2AX foci (Jeong et al. 2013).

不仅直接参与 DNA 修复是重要的,例如在 SIRT1或 SIRT6的情况下,它可以修改参与修复 DNA 损伤的各种蛋白质。葡萄糖和谷氨酰胺代谢也与这一过程有关。谷氨酰胺是主要的氮供体,不仅用于蛋白质合成,也用于核苷酸的合成。SIRT4通过调节线粒体谷氨酰胺代谢参与 DNA 损伤反应。在 DNA 损伤反应过程中,SIRT4抑制中间体向 Krebs 循环的运输,以便谷氨酰胺中的氮原子可用于合成在 DNA 修复过程中至关重要的嘌呤核苷酸(Jeong 等人,2013年)。SIRT4也是谷氨酰胺代谢的第一种酶—- 谷氨酸脱氢酶的负调节剂(Haigis et al. 2006)。SIRT4缺乏干扰 DNA 损伤修复和促进损伤积累,而 SIRT4过表达支持 h2ax 病灶的清除(Jeong 等人,2013年)。

Influence on oxidative stress and energy metabolism

对氧化应激和能量代谢的影响

Among sirtuins the most important role in anti-oxidative defense is played by SIRT3. Deacetylation of mitochondrial complex I and III by SIRT3 results in an increase in the efficiency of electron transport, which prevents ROS production (Haigis et al. 2012). Loss of this sirtuin results in hyper-acetylation of the components of mitochondrial complex I and a decrease in its activity and in ATP level (Ahn et al. 2008). Sirtuins can counteract oxidative stress also by modulating antioxidant enzymes. SIRT1 can influence the level of manganese superoxide dismutase (MnSOD) via cooperation with FOXO transcription factors. Deacetylation of FOXO3a by SIRT1 leads to an increase in the level of MnSOD and catalase (Chung et al. 2010), while recruitment of SIRT1 to the promoter region of MnSOD gene along with FOXO1 is indispensable to co-activate expression of this antioxidant enzyme (Daitoku et al. 2004). Sirtuins modulate not only the level of antioxidant enzymes but also their activity. It was shown that deacetylation of isocitrate dehydrogenase (IDH2) and of MnSOD on K122 by SIRT3 increases activity of these enzymes (Bell et al. 2011). Moreover, activity of SOD1 increased after desuccinylation by SIRT5 (Lin et al. 2013).

在去乙酰化酶中,SIRT3在抗氧化防御中的作用最为重要。SIRT3对线粒体复合物 i 和 III 的去乙酰化导致了电子传递效率的提高,从而阻止了 ROS 的产生(Haigis 等人,2012年)。缺失这种 sirtuin 导致线粒体复合物 i 的组分高度乙酰化,其活性和 ATP 水平下降(Ahn 等人,2008年)。去乙酰化酶还可以通过调节抗氧化酶来中和氧化应激。SIRT1通过与 FOXO 转录因子的协同作用影响锰超氧化物歧化酶的水平。SIRT1对 FOXO3a 的去乙酰化导致 MnSOD 和过氧化氢酶水平升高(Chung et al. 2010) ,而与 FOXO1一起将 SIRT1补充到 MnSOD 基因启动子区是共同激活这种抗氧化酶表达的必要条件(Daitoku et al. 2004)。去乙酰化酶不仅调节抗氧化酶的水平,而且调节其活性。结果表明,SIRT3对异柠檬酸脱氢酶(IDH2)和 K122上 MnSOD 的去乙酰化可以增加这些酶的活性(Bell 等人,2011年)。此外,SOD1的活性增加后脱 uccinylation 的 SIRT5(林等人,2013年)。

Interactions with other proteins involved in senescence

与衰老相关的其他蛋白质的相互作用

Interaction with p53

与 p53的相互作用

Regulation of SIRT1 and p53 activity is mutual and complicated. In response to stress SIRT1 deacetylates p53 on K320, K373 and K382 in the C-terminal regulatory domain. Deacetylation inhibits p53-dependent transcription and apoptosis, which facilitates DNA damage repair (Cheng et al. 2003). It was shown that SIRT1 colocalizes with p53 in PML nuclear bodies where it antagonizes PML-induced acetylation of p53 and inhibits premature senescence (Langley et al. 2002). SIRT1 can also regulate localization of p53. In mouse embryonic stem cells SIRT1 deacetylates p53 on K379 in response to oxidative stress, which prevents its translocation to the nucleus. This results in an increase in p53 level in the cytoplasm and in mitochondrial-dependent apoptosis (Han et al. 2008). However, in SIRT1 knockout animals, the effects associated with modulation of p53 activity are not observed. This inconsistency can be explained by a redundant action of sirtuins—SIRT2 and SIRT3 can also interact with p53 (see below). SIRT2 can inhibit the activity of p53. It is suggested that SIRT3 can act as a regulator in p53-dependent senescence by inhibiting p53 ability to promote cell cycle arrest and senescence (Li et al. 2010).

SIRT1和 p53活性的调节是相互作用的,也是复杂的。在应激条件下,K320、 K373和 K382位于 c 末端调控区的 SIRT1脱乙酰基 p53蛋白发生反应。脱乙酰基抑制 p53依赖的转录和凋亡,从而促进 DNA 损伤修复(Cheng et al. 2003)。结果表明,SIRT1在 PML 核体中与 p53共定位,可拮抗 PML 诱导的 p53乙酰化,抑制早衰(Langley 等人,2002)。SIRT1还可以调节 p53的定位。在小鼠胚胎干细胞中,K379上的 SIRT1去乙酰化 p53是对氧化应激的反应,它阻止了 p53向细胞核的移位。这导致了细胞质中 p53水平的增加和线粒体依赖性凋亡(Han 等人,2008年)。然而,在 SIRT1基因敲除的动物中,没有观察到与 p53活性调节相关的影响。这种不一致性可以用 sirtuins 的冗余作用来解释ー sirt2和 SIRT3也可以与 p53相互作用(见下文)。SIRT2可抑制 p53的活性。提示 SIRT3可以通过抑制 p53促进细胞周期阻滞和衰老的能力,作为 p53依赖性衰老的调节因子(Li 等人,2010)。

The sirtuins-p53 interaction is reciprocal and also p53 can influence the activity of these enzymes. In the promoter region of SIRT1 and SIRT2 there are two p53-binding sites (Bosch-Presegué and Vaquero 2011; Anwar et al. 2016). Moreover, 3′UTR fragment of SIRT1 mRNA has a miR-34a-responsive element. miR-34a is a small noncoding RNA that can inhibit expression of some proteins. Active p53 can induce expression of miR-34a. Therefore, increased activity of p53 increases the level of miR-34a, which inhibits SIRT1 translation. This interplay can in part explain the decrease in SIRT1, which we and others observed during cellular senescence (see Grabowska et al. 2015 and Grabowska et al. 2016). There is also indirect interplay between SIRT1 and p53 activity. Both proteins depend on NAD+ level since sirtuins require it as a co-factor while NAD+ can bind to p53 tetramers and affect their conformation thus preventing DNA binding (McLure et al. 2004). p53 can also positively regulate the level of SIRT6 (Kanfi et al. 2008).

去乙酰化酶与 p53的相互作用是相互的,p53也可以影响这些酶的活性。在 SIRT1和 SIRT2的启动子区域有两个 p53结合位点(bosch-presegué 和 Vaquero,2011年; Anwar 等人,2016年)。此外,SIRT1基因3′ UTR 片段含有 mir-34a 反应元件。miR-34a 是一种小的非编码 RNA,可以抑制某些蛋白质的表达。活化 p53可诱导 miR-34a 的表达。因此,p53活性的增加提高了 miR-34a 的水平,从而抑制了 SIRT1的翻译。这种相互作用在一定程度上可以解释我们和其他人在细胞衰老过程中观察到的 SIRT1的下降(见 Grabowska 等人2015和 Grabowska 等人2016)。SIRT1与 p53之间也存在间接的相互作用。这两种蛋白质都依赖于 NAD + 水平,因为 sirtuins 需要它作为一个辅助因子,而 NAD + 可以与 p53四聚体结合并影响它们的构象从而阻止 DNA 结合(McLure 等人,2004)。P53也可以正向调节 SIRT6的水平(Kanfi 等人,2008年)。

Interaction with FOXO family

与 FOXO 家族的互动

FOXO transcription factors are believed to promote longevity although the precise mechanism in not yet fully understood. However, it has been shown that they act as sensors of the insulin/IGF-1 signaling pathway, which is crucial for ageing and longevity (Martins et al. 2016), and regulate expression of key antioxidant enzymes such as MnSOD and catalase (see above). Activity of the FOXO family can be regulated by phosphorylation and acetylation. Acetylation of these factors facilitates phosphorylation and inactivation therefore decreases their ability to bind to DNA (Matsuzaki et al. 2005). Sirtuins can deacetylate some members of the FOXO family such as FOXO1, FOXO3a and FOXO4 whereby inducing their activity (Michan and Sinclair 2007). It has been shown that deacetylation of FOXO3a increases expression of proteins involved not only in protection against oxidative stress but also in DNA repair and cell cycle checkpoints (Michan and Sinclair 2007). SIRT2 was demonstrated to be the main deacetylase of cytoplasmic FOXO1 (Zhao et al. 2010). On the other hand, FOXO1 can regulate expression of SIRT1 by binding to its gene promoter region (Xiong et al. 2011), which creates an autoregulatory feedback loop regulating SIRT1 expression.

FOXO 转录因子被认为能够促进长寿,但其确切机制尚未完全弄清。然而,已经证明,它们作为胰岛素/igf-1信号通路的传感器,这是至关重要的老化和寿命(马丁斯等人2016年) ,并调节表达关键的抗氧化酶,如 MnSOD 和过氧化氢酶(见上文)。FOXO 家族的活性可以通过磷酸化和乙酰化来调节。这些因子的乙酰化可以促进磷酸化和失活,因此降低了它们与 DNA 结合的能力(松崎等人,2005年)。Sirtuins 可以使 FOXO1、 FOXO3a 和 FOXO4等 FOXO 家族的某些成员脱乙酰,从而诱导其活性(Michan 和 Sinclair,2007)。已经证明 FOXO3a 的去乙酰化增加了蛋白质的表达,这些蛋白质不仅涉及对抗氧化应激的保护,还涉及 DNA 修复和细胞周期检查点(Michan 和 Sinclair 2007)。SIRT2被证明是胞质 FOXO1的主要去乙酰化酶(赵等人,2010)。另一方面,FOXO1可以通过结合其基因启动子区域来调节 SIRT1的表达(Xiong et al. 2011) ,从而创建一个自我调节反馈环来调节 SIRT1的表达。

Interaction with NFκB

与 nf b 的相互作用

NFκB transcription factor was shown to regulate the process of ageing and it seems that its main role is to transactivate genes the products of which contribute to the senescence associated secretory phenotype (SASP). It was shown that SIRT1 (and also SIRT2) can inhibit NFκB signaling by deacetylating p65 (RELA) on K310, which modulates its ability to bind DNA and induces transcription of proteins involved in inflammation. In consequence, SIRT1 activity leads to a decrease in inflammation (Chung et al. 2010). SIRT6 can also inactivate NFκB by direct interaction with its RELA subunit. Such effect is followed by inhibition and destabilization of RELA binding at target gene promoters (Gertler and Cohen 2013), which can contribute to inhibition of apoptosis and senescence. Moreover, SIRT6 destabilizes binding of this transcription factor by deacetylating H3K9 in gene promoters of NFκB target genes (Gertler and Cohen 2013). On the other hand, NFκB can decrease the activity of SIRT1, in a similar way to p53, by modulating miR-34a expression (Kauppinen et al. 2013).

结果表明,转录因子因子 b 可以调节衰老过程,其主要作用似乎是转录基因,这些基因的产物有助于衰老相关的分泌表型(SASP)。结果表明,SIRT1(以及 SIRT2)通过去乙酰化 p65(RELA)抑制 K310的 nf b 信号传导,从而调节其结合 DNA 的能力,诱导炎症相关蛋白的转录。结果,SIRT1活性导致炎症的减少(Chung 等人,2010年)。SIRT6也可以通过与 RELA 亚基直接相互作用使 nf b 失活。其次是 RELA 结合在靶基因启动子上的抑制和不稳定作用(Gertler 和 Cohen 2013) ,这有助于抑制细胞凋亡和衰老。此外,SIRT6通过在 nf b 靶基因启动子中去乙酰化 H3K9来破坏这种转录因子的结合。另一方面,nf b 可以通过调节 miR-34a 的表达,以类似于 p53的方式降低 SIRT1的活性(Kauppinen 等人,2013年)。

Interaction with AMPK

与 AMPK 的相互作用

Many studies revealed that increased AMPK (AMP-activated protein kinase) activity can extend the lifespan of some model organisms. It was also shown that AMPK can regulate several signaling pathways involved in senescence and ageing such as those engaging p53, mTOR and NFκB (Salminen and Kaarniranta 2012). Moreover, AMPK can regulate cellular energy expenditure/status through modulation of NAD+ level, which suggests that this kinase may be involved in regulation of sirtuin activity. Both AMPK and SIRT1 are activated as a result of CR, have similar molecular targets and biological activities (Ruderman et al. 2010). Activation of AMPK elevates the level of NAD+ (among others through increase in the level and activity of NAMPT) thereby increasing SIRT1 activity (Canto et al. 2009). On the other hand, SIRT1 activation increases the activity of AMPK by LKB1 deacetylation on K48. Deacetylated LKB1 migrates from the nucleus to the cytoplasm, binds to STE20-related adaptor protein (STRAD) and mouse embryo scaffold protein (MO25). The latter interaction induces LKB1 kinase activity and AMPK phosphorylation (Wang et al. 2011). This creates a positive feedback loop. SIRT4, on the other hand, inhibits AMPK activity (Ho et al. 2013).

许多研究表明,增加 AMPK (AMP活化蛋白激酶)活性可以延长一些模式生物的寿命。研究还表明,AMPK 可以调节与衰老和老化相关的多种信号通路,如 p53、 mTOR 和 nf b (Salminen 和 Kaarniranta,2012)。此外,AMPK 通过调节 NAD + 水平调节细胞能量消耗/状态,这表明该激酶可能参与调节 sirtuin 活性。AMPK 和 SIRT1都被 CR 激活,具有相似的分子靶点和生物活性(Ruderman 等人,2010年)。腺苷酸活化蛋白激酶的激活提高了 NAD + 的水平(除其他外,通过增加 NAMPT 的水平和活性) ,从而增加了 SIRT1的活性(Canto 等人,2009年)。另一方面,SIRT1活化增加了 K48细胞的 LKB1脱乙酰基活性。去乙酰化的 LKB1从细胞核游走到细胞质,结合 ste20相关的适配蛋白(STRAD)和小鼠胚胎骨架蛋白(MO25)。后者相互作用诱导 LKB1激酶活性和 AMPK 磷酸化(Wang 等人,2011年)。这就形成了一个积极的反馈循环。另一方面,SIRT4抑制 AMPK 活性(Ho 等人,2013)。

Interaction with P66shc

与 P66shc 的相互作用

SIRT1 negatively regulates the expression of P66shc (Chen et al. 2013), one of the three isoforms of the ShcA family. This protein is involved in oxidative stress because it stimulates mitochondrial ROS generation, and downregulates antioxidant enzyme synthesis (Miyazawa and Tsuji 2014). It also controls the lifespan/longevity (reviewed in Kong et al. 2016). SIRT1 decreases both the P66shc level and oxidative stress intensity (Zhou et al. 2011) because it binds to the gene promoter of P66shc and deacetylates histone H3, which reduces the transcription rate. P66shc knockout mice had longer lifespan and enhanced resistance to oxidative stress and age-related pathologies (Berry et al. 2007; Vikram et al. 2014; Kumar et al. 2014b; Ma et al. 2014). Moreover, P66shc inhibits the activity of FOXO3a transcription factor (Miyazawa and Tsuji 2014). Ageing-initiated P66shc-mediated endothelial dysfunction was shown both in clinical trials and animal experiments, however, not in P66shc knockout mice (Francia et al. 2004). This suggested that P66shc knockout mice were protected from endothelial dysfunctions. Moreover, such mice had 30% longer lifespan than control ones. SIRT1 seems to be involved in this protection (Berry et al. 2007). It has been also observed that CR, which evokes an increase in sirtuin activity, could reduce P66shc level (Zhou et al. 2011).

SIRT1负性调节 P66shc 的表达(Chen et al. 2013) ,这是 ShcA 家族的三种亚型之一。这种蛋白质与氧化应激有关,因为它刺激线粒体 ROS 的生成,并下调抗氧化酶的合成(Miyazawa 和 Tsuji 2014)。它还控制寿命/寿命(在 Kong 等人2016年的评论中)。SIRT1降低了 P66shc 水平和氧化应激强度(Zhou et al. 2011) ,因为它与 P66shc 的基因启动子结合并去乙酰化组蛋白 h 3,从而降低了转录率。P66shc 基因敲除小鼠寿命更长,对氧化应激和年龄相关疾病的抵抗力增强(Berry et al. 2007; Vikram et al. 2014; Kumar et al. 2014b; Ma et al. 2014)。此外,P66shc 抑制 FOXO3a 转录因子的活性(Miyazawa 和 Tsuji 2014)。临床试验和动物实验都显示了老化引起的 P66shc 介导的内皮功能障碍,然而在 P66shc 基因敲除小鼠中却没有(Francia 等人,2004年)。这表明 P66shc 基因敲除小鼠对内皮功能障碍有保护作用。此外,这种老鼠的寿命比对照老鼠长30% 。SIRT1似乎参与了这种保护(Berry 等人,2007年)。还观察到,引起 sirtuin 活性增加的 CR 可以降低 P66shc 水平(Zhou 等人,2011年)。

Doubts

怀疑

Despite plethora of research documenting beneficial influence of sirtuins on ageing and longevity there are also some conflicting data. Some authors completely exclude sirtuin involvement in CR-induced lifespan extension (as it was shown that CR can extend lifespan of Sir2-deficient yeast) (Tsuchiya et al. 2006). Others state that the fact that Sir2 overexpression combined with CR resulted in greater lifespan extension than each intervention alone suggests that sirtuins do not mediate the positive effect of CR (Kaeberlein et al. 2004). There are studies implying that increased longevity of some model organisms (such as D. melanogaster and C. elegans) after sirtuin overexpression is due to a lack of genetic background standardization and incorrectly matched controls (Burnett et al. 2011). Some data also show that SIRT1 can promote replicative senescence. Mouse embryonic fibroblasts lacking SIRT1 are characterized by increased replicative potential under conditions of chronic sublethal stress (Chua et al. 2005).

尽管过多的研究证明去乙酰化酶对衰老和长寿有益的影响,但也有一些相互矛盾的数据。一些作者完全排除了 sirtuin 参与 CR 诱导的寿命延长(因为已经证明 CR 可以延长缺陷 sir2酵母的寿命)(Tsuchiya 等人,2006)。其他人指出,Sir2过度表达与 CR 相结合导致寿命延长,这一事实表明 sirtuins 并不能调和 CR 的积极作用(Kaeberlein 等人,2004年)。有研究表明,sirtuin 过度表达后某些模式生物(如黑腹果蝇和秀丽隐杆线虫)寿命的延长是由于缺乏遗传背景标准化和错误匹配的对照(Burnett 等人,2011年)。一些数据还表明,SIRT1可以促进复制性衰老。缺乏 SIRT1的小鼠胚胎成纤维细胞在慢性亚致死应激条件下增加了拥有属性的复制潜能。

One of the reasons for such contradictory data can be the context-dependency of sirtuins. Activity of these deacetylases depends on the tissue and/or experimental conditions e.g. the presence of stress. The impact of sirtuin level was emphasized in the study of Alcendor et al. (2007). It was shown that 2.5–7.5 fold increase in SIRT1 level in mouse heart prevented age-associated cardiac hypertrophy, apoptosis, cardiac dysfunction and expression of senescence markers such as p15INK4b, p19ARF, p53. On the other hand, 12.5 fold increase in SIRT1 level promoted cardiac hypertrophy, induced apoptosis and promoted cardiomyopathy. The authors suggested that the beneficial effects could be the consequence of oxidative stress modulation since low and moderate overexpression of SIRT1 protects against oxidative stress, by eliciting an increase in the level of antioxidant enzymes and proteins such as catalase, heat shock proteins (Hsp40, Hsp70 and Hsp90), telomere repeat binding factor 2 (TRF2) and telomere reverse transcriptase (TERT). On the other hand, high SIRT1 level increased oxidative stress. High level of NAD+ dependent deacetylase can deplete the pool of this vital PARP1 cofactor and in this way impair DNA repair and mitochondrial respiration followed by decreased ATP production. Importantly, mice with moderate SIRT1 overexpression did not exhibit extended lifespan, while high sirtuin level shortened the animal life expectancy to a half. There is also a discrepancy of opinions as to SIRT1 contribution to atherosclerosis progression. It seems that the role of SIRT1 in this process depends on the cellular/physiological context as there are reports suggesting its protective function, and those implying promotion of plaque formation (Watroba and Szukiewicz 2016).

这种矛盾数据的原因之一可能是 sirtuins 的上下文依赖性。这些去乙酰化酶的活性取决于组织和/或实验条件,例如压力的存在。在 Alcendor 等人(2007)的研究中强调了 sirtuin 水平的影响。结果表明,小鼠心脏 SIRT1水平增高2.5ー7.5倍,可抑制年龄相关性心肌肥大、细胞凋亡、心功能障碍和 p15INK4b、 p19ARF、 p53等衰老标志物的表达。另一方面,SIRT1水平增高12.5倍可促进心肌肥厚,诱导细胞凋亡,促进心肌病的发生。作者认为,这种有益的影响可能是氧化应激调节的结果,因为低度和中度过度表达的 SIRT1可以保护对抗氧化应激,引起抗氧化酶和蛋白质水平的增加,如过氧化氢酶,热休克蛋白(Hsp40,Hsp70和 Hsp90) ,端粒重复结合因子2(TRF2)和端粒逆转录酶(TERT)。另一方面,高 SIRT1水平增加了氧化应激。高水平的 NAD + 依赖性去乙酰化酶可以消耗这个重要的 PARP1辅助因子库,从而损害 DNA 修复和线粒体呼吸,继而减少 ATP 的产生。重要的是,具有适度 SIRT1过表达的小鼠没有表现出延长的寿命,而高水平的去乙酰化酶将动物的寿命缩短到一半。对于 SIRT1在动脉粥样硬化进展中的作用也有不同的看法。似乎 SIRT1在这一过程中的作用取决于细胞/生理背景,因为有报告表明其保护功能,并暗示促进斑块形成(Watroba 和 Szukiewicz 2016)。

Intervention in organismal ageing by sirtuin regulation

去乙酰化酶调节对生物体衰老的干预作用

It has been proven that ageing is an extremely plastic process and its modulation can be very efficient. Ageing can be accelerated, slowed down, and, in some cases, even stopped or reversed under certain experimental conditions (Fahy et al. 2010). Anti-ageing interventions delay and prevent age-related disease onset. They include behavioral, dietary and pharmacological approaches. Also, many protein targets and many drugs are being tested for their effects on healthspan and lifespan. The intervention strategies include: (1) dietary interventions mimicking chronic dietary restriction, (2) inhibition of the mTOR–S6K pathway, (3) inhibition of the GH/IGF1 axis and (4) drugs that activate AMPK or specific sirtuins (Longo et al. 2015). In fact, all of the mentioned approaches are related to sirtuins. These enzymes are involved in mimicking dietary restriction, as it has been shown, for example, for resveratrol. Furthermore, inhibition of the mTOR–S6K pathway is caused by AMPK, which is regulated by sirtuins. In turn, the SIRT1-p53 pathway has been described to antagonize IGF-1-induced premature cellular senescence (Tran et al. 2014). Therefore sirtuins are extensively studied in the context of their role in alleviating symptoms of ageing and age-related diseases (Houtkooper et al. 2012; Hall et al. 2013; Poulose and Raju 2015).

已经证明,老化是一个极具可塑性的过程,其调制是非常有效的。在某些实验条件下,衰老可以加速、减缓,甚至在某些情况下可以停止或逆转(Fahy 等人,2010)。抗衰老干预措施推迟和预防与年龄有关的疾病发作。它们包括行为、饮食和药理学方法。此外,许多蛋白质靶点和许多药物正在测试其对健康寿命的影响。干预策略包括: (1)模拟慢性饮食限制的饮食干预,(2)抑制 mTOR-S6K 通路,(3)抑制 GH/IGF1轴,(4)激活 AMPK 或特异性 sirtuins 的药物(Longo 等人,2015年)。事实上,所有提到的方法都与去乙酰化酶有关。这些酶参与模仿限制饮食,例如,已经证明,白藜芦醇。此外,抑制 mTOR-S6K 通路是由 AMPK 引起的,该通路由去乙酰化酶调节。反过来,SIRT1-p53途径已被描述为拮抗 igf-1诱导的细胞早衰(Tran 等人,2014年)。因此,在减轻衰老症状和与年龄有关的疾病方面,对 sirtuins 进行了广泛研究(Houtkooper 等人,2012年; Hall 等人,2013年; Poulose 和 Raju,2015年)。

Dietary restriction

限制饮食

Dietary/caloric restriction (DR)/(CR) (the reduction of calorie intake without causing malnutrition) is the only known intervention able to increase the lifespan in many species, including yeast, fruit flies, nematodes, fish, rats, mice, hamsters and dogs (Weindruch 1996; Masoro 2005; Ingram and Roth 2015) and possibly even primates (Ingram et al. 2006; Colman et al. 2009). Much research has suggested that lifespan extension and healthspan improvement brought by caloric restriction are mediated by mechanisms involving sirtuins. For example, some of the effects of caloric restriction in flies, worms and mammals have been shown to be mediated by SIRT1 (Rogina and Helfand 2004; Tissenbaum and Guarente 2001; Chen et al. 2005; Boily et al. 2008). Diet-induced aortic stiffness, developed within 2 months in mice fed HFD (high fat diet), can be prevented by SIRT1 induction in VSMC (Fry et al. 2016). Reduction of arterial stiffness can be also achieved by overnight fasting in mice fed HFD for 2 or 8 months but not in mice lacking functional SIRT1 in VSMC. Similar effect was observed after SIRT1 overexpression or treatment with SIRT1 activators. DR was also shown to induce SIRT6, which delayed ageing by suppressing NFκB signaling in aged mice after 6-month treatment or in cells cultured in low glucose condition (resistance to cellular senescence) (Zhang et al. 2016b). Dietary restriction is one of the most promising strategies for increasing lifespan and healthspan also in humans (reviewed in Longo et al. 2015). In humans such interventions are effective in lowering the prevalence of age-related loss of function and protecting against age-related pathologies, as evidenced by changes in the level of markers for type 2 diabetes, hypertension, cardiovascular disease, cancer, and dementia (Cava and Fontana 2013). Because long lasting DR is not recommended for most people and could be associated with undesirable side effects, less drastic dietary interventions should be considered and therefore drugs or supplements, which mimic the effects of DR are searched for. A promising strategy, potentially useful for humans, could be short-term fasting that could mimic DR. Because sirtuins can mediate many of the beneficial effects of DR (Satoh et al. 2013), therefore activators of the sirtuin pathway are very attractive candidates considered to mimic DR. To such compounds belongs resveratrol, the role of which in DR is well recognized and described (Chung et al. 2012), and probably also curcumin as has recently been shown by us (Grabowska et al. 2016).

饮食/热量限制(DR)/(CR)(减少热量摄入而不引起营养不良)是已知的唯一能够延长许多物种寿命的干预措施,包括酵母、果蝇、线虫、鱼、大鼠、小鼠、仓鼠和狗(Weindruch 1996; Masoro 2005; Ingram 和 Roth 2015) ,甚至可能是灵长类动物(Ingram et al. 2006; Colman et al. 2009)。许多研究表明,限制热量摄入所带来的寿命延长和健康跨度的改善是通过抗衰老蛋白介导的。例如,已经证明,SIRT1(Rogina 和 Helfand,2004年; Tissenbaum 和 Guarente,2001年; Chen 等人,2005年; Boily 等人,2008年)介导了限制热量对苍蝇、蠕虫和哺乳动物的一些影响。饮食诱导的主动脉僵硬,发达国家在2个月内在小鼠喂食高脂肪饮食(高脂肪饮食) ,可以防止 SIRT1诱导血管平滑肌细胞(Fry 等人,2016年)。在喂食 HFD 2或8个月的小鼠中,隔夜禁食也可以降低动脉僵硬度,但在缺乏功能性 SIRT1的 VSMC 中,这种效果并不明显。在 SIRT1过表达或用 SIRT1激活剂治疗后也观察到类似的效果。DR 还可以诱导 SIRT6,通过抑制老龄小鼠6个月后的 nf b 信号转导延缓衰老,或者在低糖条件下培养的细胞中诱导 SIRT6(Zhang 等人,2016b)。饮食限制也是延长人类寿命和健康跨度的最有前途的策略之一(隆戈等人2015年的评论)。对人类而言,这种干预措施有效地降低了与年龄有关的功能丧失的发生率,并防止了与年龄有关的疾病,2型糖尿病、高血压、心血管疾病、癌症和痴呆症的标志物水平的变化证明了这一点(Cava 和 Fontana,2013年)。由于大多数人不推荐长效 DR,而且可能会有不良副作用,因此应考虑采取较少激烈的饮食干预措施,因此应寻找类似 DR 效果的药物或补充剂。一个很有前途的策略,可能对人类有用,可以模仿 DR 的短期禁食,因为 sirtuins 可以调解 DR 的许多有益作用(Satoh 等人,2013年) ,因此 sirtuin 途径的激活因子是非常有吸引力的候选人,被认为是模仿 DR。

mTOR inhibition

mTOR 抑制

Inhibitors of the mTOR signaling are the major candidates for targeted interventions. This signaling pathway has been linked to lifespan and healthspan extension in model organisms (Johnson et al. 2013) because reduced mTOR signaling benefited both these phenomena. The best recognized inhibitor of mTOR is rapamycin, although a long term treatment can bring about some side effects (Hartford and Ratain 2007). S6 kinase (S6K) is a target of mTOR. Loss of S6K promoted longevity in yeast, flies, worms, and mice (Johnson et al. 2013). Sirtuins and AMPK are regulators of this kinase. It has been shown that increased SIRT1 activity resulting from resveratrol diet supplementation inhibited the mTOR/S6K pathway in mice (Liu et al. 2016).

mTOR 信号的抑制剂是有针对性干预的主要候选药物。这种信号通路与模式生物的寿命和健康跨度延长有关(Johnson 等人,2013年) ,因为 mTOR 信号的减少对这两种现象都有利。公认最好的 mTOR 抑制剂是雷帕霉素,尽管长期治疗会带来一些副作用(Hartford 和 Ratain 2007)。S6激酶(S6K)是 mTOR 的靶标。S6K 的缺失促进了酵母、苍蝇、蠕虫和小鼠的长寿(Johnson et al. 2013)。去乙酰化酶和 AMPK 是这种激酶的调节因子。研究表明,由于白藜芦醇饮食补充而增加的 SIRT1活性抑制了小鼠 mTOR/S6K 通路(Liu 等人,2016)。

Attenuation of IGF1/insulin signaling pathway

胰岛素样生长因子1/胰岛素信号通路的衰减

The IGF1/insulin signaling pathway is a very well recognized target in postponing ageing. In mammals upstream of IGF1 is a growth hormone (GH) (Brown-Borg and Bartke 2012). GH mutant mice (a reduction of plasma levels or disruption of the receptor) live 50% longer than wild-type ones. GH fulfills key metabolic functions, controls circulating IGF1 levels and acts also independently of IGF1. The insulin and IGF1 signaling pathway is strongly evolutionarily conserved. Both insulin and IGF are important in the maintenance of proper metabolism and organismal homeostasis. They control growth, development and regulate stress resistance. Activation of this pathway leads to phosphorylation of transcription factors belonging to the FOXO family. In turn, it has been shown that these transcription factors are required for impairing insulin/IGF-1 signaling to extend lifespan in worms (Kenyon et al. 1993; Melendez et al. 2003). Sirtuins are among the regulators of the transcriptional activity of FOXO proteins. Human IGF-1 receptor gene polymorphisms are associated with exceptional longevity (Suh et al. 2008) and low plasma IGF-1 concentrations predict further survival in long-lived people (Milman et al. 2014). Moreover, treatment with IGF-1 triggered premature cellular senescence (human primary IMR90 fibroblast and MEFs, mouse embryonic fibroblasts) in a p53-dependent manner and a recent study explained this result as being due to attenuation of SIRT1 functioning, followed by enhanced p53 acetylation and stabilization, and premature cellular senescence (Tran et al. 2014). DR is very effective in inhibiting insulin/IGF-1 signaling.

胰岛素样生长因子1/胰岛素信号通路是一个公认的延缓衰老的靶点。在哺乳动物中,IGF1的上游是生长激素(GH)(Brown-Borg 和 Bartke,2012)。生长激素突变小鼠(血浆水平降低或受体中断)的寿命比野生型小鼠长50% 。生长激素完成关键的代谢功能,控制循环中的 IGF1水平,并独立于 IGF1发挥作用。胰岛素和 IGF1信号通路在进化上是高度保守的。胰岛素和胰岛素样生长因子对维持正常的代谢和生物体内环境稳定都很重要。它们控制生长、发育和调节抗逆性。激活这一通路导致磷酸化的转录因子属于 FOXO 家族。反过来,已经证明这些转录因子是削弱胰岛素/igf-1信号以延长蠕虫寿命所必需的(凯尼恩等人,1993年; Melendez 等人,2003年)。Sirtuins 是 FOXO 蛋白转录活性的调节因子之一。人类 IGF-1受体基因多态性与异常长寿有关(Suh 等人,2008年) ,低血浆 IGF-1浓度预示着长寿者的进一步生存(Milman 等人,2014年)。此外,IGF-1治疗以 p53依赖的方式触发了细胞早衰(人类初级 IMR90成纤维细胞和 MEFs,小鼠胚胎成纤维细胞) ,最近的一项研究解释了这一结果是由于 SIRT1功能的衰减,其次是增强 p53乙酰化和稳定,以及细胞早衰(Tran 等人,2014年)。DR 在抑制胰岛素/igf-1信号转导方面非常有效。

Dietary and pharmacological interventions

饮食和药物干预

Functional foods and nutraceuticals/dietary ingredients are a great promise for health and longevity promotion and prevention of age-related chronic diseases (Ferrari 2004). The potent sirtuin-activating compounds (STACs) include several classes of plant-derived metabolites such as flavones, stilbenes, chalcones, and anthocyanidins, which directly activate SIRT1 in vitro. Several substances are reported to have anti-senescent effect in vitro by modulating the SIRT1 pathway. These compounds include a number of agents such as resveratrol (Kao et al. 2010), cilostazol (Ota et al. 2008), paeonol (Jamal et al. 2014), statins (Ota et al. 2010), hydrogen sulfide (Suo et al. 2013; Zheng et al. 2014) and persimmon (Lee et al. 2008). It is documented that polyphenols, to which curcumin also belongs, are able to modulate sirtuins (reviewed in Jayasena et al. 2013; Chung et al. 2010). The best recognized and described natural compound is resveratrol and there are a lot of papers summarizing its role in sirtuin stimulation on both the organismal and cellular level (Howitz et al. 2003; Ramis et al. 2015). Activation of SIRT1 by resveratrol supplementation led to increased lifespan and improved healthspan of several species i.e., mimicked the anti-ageing effect of DR (Baur et al. 2006; Mouchiroud et al. 2010). In human diploid fibroblasts resveratrol decreased or delayed cellular senescence (Huang et al. 2008). Other natural anti-ageing compounds are: quercetin, butein, fisetin, kaempferol, catechins and proanthocyanidins (reviewed in Jayasena et al. 2013). Several reports emphasized that dietary supplementation of polyphenols may protect against neurodegenerative, cardiovascular, inflammatory, metabolic diseases and cancer by enhancing SIRT1 deacetylase activity. However, in humans, the therapeutic and pharmacological potential of these natural compounds remains to be validated in clinical conditions. Their efficiency is, however, put into doubt because many natural compounds, including curcumin are bad leads for drugs (Baell and Walters 2014). However, polyphenols may act as prophylactic agents in terms of dietary intake rather than as therapeutic ones. Some natural compounds from Traditional Chinese Medicines (TCMs) are potent SIRT1 activators (Wang et al. 2016).

保健食品和营养食品/饮食成分对于促进健康和长寿以及预防与年龄有关的慢性疾病是一个巨大的承诺(法拉利2004)。去乙酰化酶激活化合物包括多种植物源性代谢产物,如黄酮类、二苯乙烯类、查尔酮类和花青素类,它们在体外直接激活 SIRT1。通过调控 SIRT1通路,已有多种物质在体外具有抗衰老作用。这些化合物包括白藜芦醇(Kao et al. 2010)、西洛他唑(Ota et al. 2008)、丹皮酚(Jamal et al. 2014)、他汀类(Ota et al. 2010)、硫化氢(Suo et al. 2013; Zheng et al. 2014)和柿子(Lee et al. 2008)。姜黄素也属于多酚类物质,它能够调节去乙酰化酶(2013年在 Jayasena 等人的回顾; Chung 等人的2010年)。公认和描述最好的天然化合物是白藜芦醇,有许多论文从组织和细胞层面总结了它在去乙酰化刺激中的作用(Howitz 等人,2003年; Ramis 等人,2015年)。通过补充白藜芦醇激活 SIRT1,可以延长几个物种的寿命,改善其健康状况,即模仿 DR 的抗衰老作用(Baur 等人,2006年; Mouchiroud 等人,2010年)。在人类二倍体成纤维细胞中,白藜芦醇降低或延缓细胞衰老(Huang et al. 2008)。其他天然抗衰老化合物有: 槲皮素、布替因、非瑟酮、山奈酚、儿茶素和原花青素。一些报道强调,饮食补充多酚可以保护神经退行性疾病,心血管,炎症,代谢疾病和癌症的增强 SIRT1脱乙酰酶活性。然而,在人类,这些天然化合物的治疗和药理潜力仍有待于在临床条件验证。然而,由于许多天然化合物,包括姜黄素,对药物来说都是有害的线索,因此它们的效率受到质疑。然而,多酚可能作为预防剂的膳食摄入量,而不是作为治疗的。一些来自中药的天然化合物是强有力的 SIRT1激活剂(Wang 等人,2016)。

Another compound considered as anti-ageing one is melatonin. It is able to activate sirtuins and it has been observed that its level decreases with age (Ramis et al. 2015). It has been shown that melatonin prevents age-related alterations in apoptosis in dentate gyrus, which are associated with neurodegeneration, by increasing SIRT1 (Kireev et al. 2013). Adjudin, a derivative of lonidamine, an activator of SIRT3 (Bellizzi et al. 2005; Brown et al. 2013; Kincaid and Bossy-Wetzel 2013), is also considered as an anti-ageing factor (Xia and Geng 2016). Another compound that possesses anti-ageing function is icariin, an active ingredient of Epimedium in Berberidaceae (Lee et al. 1995). It is able to enhance the expression of SIRT6 (Chen et al. 2012). A polysaccharide derived from Cornus officinalis could slow down the progression of age-related cataracts by significantly increasing expression of SIRT1 mRNA and FOXO1 mRNA (Li et al. 2014). Oligonol, an antioxidant polyphenolic compound showing anti-inflammatory and anti-cancer properties, mainly found in lychee fruit, may act as an anti-ageing molecule by modulating the SIRT1/autophagy/AMPK pathway (Park et al. 2016). Spleen lymphocytes derived from old mice treated with oligonol showed increased cell proliferation. Moreover, this compound extended the lifespan of C. elegans infected with lethal Vibrio cholera (Park et al. 2016). Also, metformin, a herbal compound widely prescribed as oral hypoglycaemic drug for the treatment of type 2 diabetes, acts by SIRT1 activation (and FOXO1 elevation) in endothelial dysfunction caused by diabetes-related microvascular disease associated with accelerated endothelium senescence and ageing (Arunachalam et al. 2014).

另一种被认为是抗衰老的化合物是褪黑激素。它能够激活抗衰老蛋白,并且已经观察到它的水平随着年龄的增长而降低(Ramis 等人,2015年)。研究表明,褪黑激素通过增加 SIRT1,防止齿状回中与年龄相关的凋亡改变,这种改变与神经退行性疾病有关。阿扎丁,一种 lonidamine 的衍生物,SIRT3的激活剂(Bellizzi 等人,2005年; Brown 等人,2013年; 金凯德和 Bossy-Wetzel,2013年) ,也被认为是一种抗衰老因素(夏和耿,2016年)。另一种具有抗衰老作用的化合物是淫羊藿苷,是小檗科淫羊藿属的一种原料药(Lee et al. 1995)。它能够增强 SIRT6的表达(Chen 等人,2012年)。一种来自山茱萸的多糖可以通过显著增加 SIRT1 mRNA 和 FOXO1 mRNA 的表达来减缓老年性白内障的进展。齐聚醇是一种抗氧化多酚化合物,具有抗炎和抗癌的特性,主要存在于荔枝果实中,它可能通过调节 sirt1/自噬/ampk 途径起到抗衰老分子的作用(Park 等人,2016年)。老龄小鼠脾淋巴细胞经寡聚醇处理后,细胞增殖增加。此外,这种化合物延长了受致命性霍乱弧菌感染的线虫的寿命(Park 等人,2016年)。此外,二甲双胍,一种被广泛用作治疗2型糖尿病的口服降血糖药物,通过 SIRT1激活(和 FOXO1升高)作用于糖尿病相关的微血管疾病引起的内皮功能障碍,这些疾病与加速内皮衰老和老化有关(Arunachalam 等人,2014年)。

Natural phytochemicals are effective sirtuin activators, but synthetic STACs, such as SRT1720, SRT2104, SRT1460, SRT2183, STAC-5, STAC-9, STAC-10 are considerably more potent, soluble, and bioavailable (Hubbard and Sinclair 2014; Minor et al. 2011). In preclinical models, STACs have shown effectiveness in treating age-related diseases and complications associated with ageing, including cancer, type 2 diabetes, inflammation, cardiovascular disease, stroke, and hepatic steatosis (Hubbard and Sinclair 2014). Based on mouse models, STACs could also be beneficial in neurodegeneration (Alzheimer’s or Parkinson’s disease) (Zhao et al. 2013; Graff et al. 2013; Hubbard and Sinclair 2014). SRT2104 extended both the mean and maximal lifespan of male mice fed a standard diet and this effect concurred with improved health, including enhanced motor coordination and decreased inflammation (Mercken et al. 2014).

天然植物化学物质是有效的 sirtuin 激活剂,但是人工合成的 STACs,如 SRT1720,SRT2104,SRT1460,SRT2183,STAC-5,STAC-9,STAC-10是相当有效的,可溶的,和生物可利用的(Hubbard 和 Sinclair 2014; Minor 等人2011)。在临床前模型中,STACs 在治疗与年龄有关的疾病和与衰老相关的并发症方面显示出了有效性,包括癌症、2型糖尿病、炎症、心血管疾病、中风和肝脏脂肪变性(Hubbard 和 Sinclair,2014年)。基于小鼠模型,STACs 也可能对神经退行性疾病有益(赵等人,2013; Graff 等人,2013; Hubbard 和 Sinclair,2014)。SRT2104延长了喂食标准食物的雄性小鼠的平均寿命和最大寿命,这一效应同时改善了健康状况,包括增强运动协调性和减少炎症(Mercken 等人,2014年)。

An alternative approach to activating sirtuins is regulation of NAD + level by activating enzymes involved in biosynthesis of NAD or by inhibiting the CD38 NAD hydrolase (Wang et al. 2014; Escande et al. 2013; Braidy et al. 2014). Manipulation of the level of NAD+ leads to variations in the lifespan elongation effect of SIRT1. The compound that can antagonize nicotinamide inhibition of sirtuin deacetylating activity is isonicotinamide (Sauve et al. 2005). Inhibitors of NAM (natural inhibitor of sirtuin) exert the same effect as sirtuin activators (Sauve et al. 2005). Glucose restriction, which mimics DR, extended the lifespan of human Hs68 fibroblasts due to increased NAMPT expression, NAD+ level and sirtuin activity (Yang et al. 2015). In turn, lifespan extension was diminished by inhibition of NAMPT and sirtuins. Moreover, malate dehydrogenase, MDH1, which is involved in energy metabolism and reduces NAD+ to NADH during its catalytic reaction, plays also a critical role in cellular senescence. Its activity is reduced in human fibroblasts derived from elderly individuals and knock down of this enzyme in young fibroblast induces a senescence phenotype (Lee et al. 2012). Decrease in MDH1 and subsequent reduction in NAD/NADH ratio led to SIRT1 inhibition. Mice engineered to express additional copies of SIRT1 or SIRT6, or treated with STACs (resveratrol, SRT2104) or with NAD+ precursors, have improved organ function, physical endurance, disease resistance and longevity (Bonkowski and Sinclair 2016).

激活去乙酰化酶的另一种方法是通过激活参与 NAD 生物合成的酶或抑制 CD38 NAD 水解酶来调节 NAD + 水平(Wang 等人,2014年; Escande 等人,2013年; Braidy 等人,2014年)。操纵 NAD + 水平导致 SIRT1的寿命延长效应发生变化。能拮抗烟酰胺去乙酰化活性抑制的化合物是异烟酰胺(Sauve 等人,2005年)。NAM 抑制剂(天然去乙酰化酶抑制剂)具有与去乙酰化酶激活剂相同的效果(Sauve 等人,2005年)。葡萄糖限制,模仿 DR,延长了人类 Hs68成纤维细胞的寿命,由于增加了 NAMPT 表达,NAD + 水平和 sirtuin 活性(Yang 等人,2015年)。反过来,寿命延长被抑制的 NAMPT 和去乙酰化酶。此外,苹果酸脱氢酶,MDH1,参与能量代谢,并减少 NAD + 到 NADH 在其催化反应,也发挥了关键作用,在细胞衰老。它在老年人成纤维细胞中的活性降低,并且这种酶在年轻成纤维细胞中的降低引起衰老表型(Lee 等人,2012)。MDH1的减少和 NAD/NADH 比值的下降导致 SIRT1的抑制作用。通过基因工程表达 SIRT1或 SIRT6的额外拷贝的小鼠,或用 STACs (白藜芦醇,SRT2104)或 NAD + 前体治疗的小鼠,有改善器官功能、身体耐力、抵抗疾病和寿命的作用(Bonkowski 和 Sinclair,2016)。

Activators of the AMPK pathway are considered as anti-ageing factors. SIRT1 increases the activity of AMPK through LKB1 activation, and, conversely, the activity of sirtuins is stimulated by AMPK. In turn, AMPK downregulates the mTOR pathway by inhibiting of S6K. To AMPK activators belong: 5-aminoimidazole-4-carboxamide riboside (AICAR), biguanides, salicylates, resveratrol, quercetin, catechins and, in certain range of concentrations, also curcumin (Coughlan et al. 2014; Grabowska et al. 2016).

AMPK 途径的激活因子被认为是抗衰老因子。SIRT1通过激活 LKB1增加 AMPK 的活性,反过来,激活 sirtuins 的活性。AMPK 通过抑制 S6K 而下调 mTOR 信号通路。AMPK 激活剂包括: 5- 氨基咪唑 -4- 羧基核糖苷(AICAR)、双胍类、水杨酸类、白藜芦醇、槲皮素、儿茶素,在一定浓度范围内,还有姜黄素(Coughlan 等人,2014年; Grabowska 等人,2016年)。

Sirtuins are also responsible for epigenetic modifications (histone and non-histone proteins), which lead to changes in transcriptional activity of many genes. It is proposed that epigenetic factors contribute to ageing. Such factors are regulated by lifestyle, diet and exogenous stress. It is believed that epigenetic modifications (of both histones and DNA) have a comparable impact on gene expression to genetic modifications. It is suggested that manipulation of sirtuins could be beneficial for liefspan/healthspan modulation due to epigenetic changes. In humans, only nontoxic natural substances, such as curcumin or resveratrol, which could lead to histone deacetylation, should be considered for clinical testing as sirtuins activator. In general, functional food is a very promising element of anti-ageing intervention, including its potential influence on epigenetic modifications. Modulation of SIRT1 expression may represent a new means to counteract the effect of ageing.

去乙酰化酶还负责表观遗传修饰(组蛋白和非组蛋白) ,这导致了许多基因转录活性的改变。有人提出,表观遗传因素有助于衰老。这些因素受到生活方式、饮食和外源性压力的调节。人们认为表观遗传修饰(组蛋白和 DNA)对基因表达和基因修饰有类似的影响。提示去乙酰化酶的调控可能与表观遗传变化有关,有利于脂跨/健跨的调控。在人体中,只有无毒的天然物质,如姜黄素或白藜芦醇,可导致组蛋白去乙酰化,应考虑作为去乙酰化酶激活剂进行临床试验。一般来说,功能性食品是一个非常有前途的抗衰老干预元素,包括其对表观遗传修饰的潜在影响。SIRT1基因表达的调控可能代表了一种抵消衰老影响的新方法。

Physical activity

体力活动

Regular physical training is able to improve the quality of life. Exercise improves the resistance to oxidative stress, which could influence the pace of ageing and help maintaining the brain function (Marton et al. 2010). Extensive physical activity induces inflammation, increases ROS production and may impair the antioxidant defense system as it has been shown in skeletal muscle and blood (Banerjee et al. 2013). Mildly intense exercise can act as hormetin by eliciting a mild stress, which in turn activates defense mechanisms and brings beneficial effects including reduction of oxidative stress. Chronic exercise reduces oxidative stress by upregulating the activity of antioxidant enzymes (Greathouse et al. 2005). Mild physical activity is a potent activator of sirtuins (Csiszar et al. 2009; Radak et al. 2008). SIRT1 is suggested to be a master regulator of exercise-induced beneficial effects. It has been shown that long-term moderate exercise (36 weeks) induced increase in SIRT1 level in adult rat muscle, liver and heart (Bayod et al. 2012). Also, physical training promoted SIRT1 (as well as AMPK and FOXO3a) activity in muscle tissue in aged rat (Ferrara et al. 2008; Huang et al. 2016; Sahin et al. 2016). Similar effects were also described in humans (Bori et al. 2012). It has been demonstrated that in human skeletal muscle of both young and aged subjects, SIRT1 and AMPK gene expression increase after exercise. Exercise can at least partially recover the adaptive capacity to cope with mild oxidative stress that is lost in ageing and is the most effective intervention against several age-related pathologies such as sarcopenia, metabolic alterations (Pasini et al. 2012), neurodegeneration (Bayod et al. 2011; Mirochnic et al. 2009; Van Praag 2009) and cognitive loss (Kramer et al. 2006). Moderate forced exercise performed from an early age to adulthood has an important long-term impact on animal health. Exercise reduced plasma levels of glucose, cholesterol and triglycerides (Lalanza et al. 2012). In adult and older adult humans moderately intense exercise, for 30 min, 5 days a week, has beneficial effects (Colcombe and Kramer 2003; Rolland et al. 2010; Slentz et al. 2011). Exercise stimulates glucose uptake and mitochondrial biogenesis. Administration of AICAR is able to mimic the effect of physical activity (Hayashi et al. 1998; Song et al. 2002). Physical activity also elevated the level of NAMPT in human skeletal muscle (Costford et al. 2010). Even single bout of exercise increased SIRT1 expression in young individuals but such effect was not observed in old ones (Bori et al. 2012). Beneficial effect of exercise can be also observed at the cellular level. It has been shown that exercise inhibited replicative senescence of adipocytes (Schafer et al. 2016) and decreased the level of apoptosis in rat cardiomyocytes. With age, apoptotic pathway protein expression increases and the expression of the pro-survival p-Akt protein decreases significantly. Exercise increased activity of the IGF1R/PI3K/Akt survival pathway in the heart of young rats, however, in old animals the level of SIRT1 increased as a compensatory mechanism. Moreover, physical activity enhanced the SIRT1 longevity compensation pathway instead of elevating IGF1 survival signaling and in this manner improved cardiomyocyte survival (Lai et al. 2014). Physical activity is able to reduce the harmful effects of a fast food diet (FFD), prevent premature senescent cell accumulation and appearance of SASP in mice adipose tissue (Schafer et al. 2016). This suggests that exercise may provide restorative benefit by mitigating accrued senescent burden.

有规律的体育锻炼可以提高生活质量。运动可以提高对氧化应激的抵抗力,这种抵抗力可以影响衰老的速度并帮助维持大脑功能。广泛的身体活动诱发炎症,增加活性氧的产生,并可能损害抗氧化防御系统,因为它已经显示在骨骼肌肉和血液(Banerjee 等人。2013年)。温和的高强度运动可以引起轻微的压力,从而起到激素的作用,这反过来激活防御机制,并带来有益的效果,包括减少氧化应激。长期运动可以通过增加抗氧化酶的活性来减少氧化应激。轻微的体力活动是 sirtuins 的有效激活剂(Csiszar 等人,2009年; Radak 等人,2008年)。SIRT1可能是运动诱导有益效应的主要调节因子。研究表明,长期适度运动(36周)可以增加成年大鼠肌肉、肝脏和心脏的 SIRT1水平(Bayod 等人,2012年)。此外,体育锻炼促进老龄大鼠肌肉组织中 SIRT1(以及 AMPK 和 FOXO3a)活性(Ferrara 等人,2008年; Huang 等人,2016年; Sahin 等人,2016年)。类似的影响在人类中也有描述(Bori 等人,2012年)。已有研究表明,无论是青年人还是老年人的骨骼肌,运动后 SIRT1和 AMPK 基因的表达增加。运动至少可以部分恢复适应能力,以应对在衰老过程中丧失的轻度氧化应激,并且是对抗一些与年龄相关的疾病的最有效的干预措施,如骨骼肌减少、代谢改变(Pasini 等人,2012)、神经退行性疾病(Bayod 等人,2011; Mirochnic 等人,2009; Van Praag 等人,2009)和认知损失(等人,2006)。从幼年到成年期进行的适度强迫运动对动物健康有重要的长期影响。运动可降低血糖、胆固醇和甘油三酯的水平(Lalanza 等人,2012年)。对于成年人和老年人来说,每周5天,每天进行30分钟的中等强度的锻炼,有益健康。运动刺激葡萄糖摄取和线粒体生物合成。AICAR 的管理能够模拟身体活动的效果(Hayashi 等人,1998; Song 等人,2002)。体力活动也提高了人体骨骼肌中的 NAMPT 水平(Costford 等人,2010年)。即使是一次运动也会增加年轻人 SIRT1的表达,但这种效应在老年人身上没有观察到(Bori 等人,2012年)。运动的有益效果也可以在细胞水平上观察到。有研究表明,运动可以抑制脂肪细胞的复制性衰老(Schafer 等人,2016年) ,并降低大鼠心肌细胞的凋亡水平。随着年龄的增长,凋亡途径蛋白表达增加,p-Akt 蛋白表达显著降低。运动可增加幼年大鼠心脏 IGF1R/PI3K/Akt 存活通路的活性,而老年大鼠心脏 SIRT1水平升高是一种代偿机制。此外,体力活动增强了 SIRT1的长寿补偿途径,而不是提高 IGF1的存活信号,以这种方式提高了心肌细胞存活率(Lai 等人,2014年)。体力活动能够减少快餐饮食(FFD)的有害影响,防止 SASP 在小鼠脂肪组织中的过早衰老细胞积累和出现(Schafer 等人,2016年)。这表明,运动可以提供恢复性的好处,减轻累积衰老负担。

As mentioned above, sirtuin activation (by phytochemicals, CR, exercise, etc.) elicits an adaptive response to continuous mild exposures to stressors, in agreement with the hormesis principle (Bhakta-Guha and Efferth 2015). The involvement of sirtuins in lifespan/healthspan elongation strategies is summarized in Fig. 2.

如上所述,去乙酰化酶激活(通过植物化学物质、 CR、运动等)对持续轻度暴露于压力源产生适应性反应,符合毒物兴奋效应原理(Bhakta-Guha and Efferth 2015)。去乙酰化酶在寿命/健康跨度延长策略中的作用见图2。

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Fig. 2 图二

Involvement of sirtuins in lifespan/healthspan elongation pathways. Sirtuins modulate multiple pathways involved in mediating positive effects of some anti-ageing interventions, such as calorie/diet restriction (CR/DR) or exercise. Such effect can also be mimicked by sirtuin activating compounds (STACs). Prolonged activation of IGF1 pathway, involving PI3K-AKT, leads to phosphorylation and inhibition of FOXO and to inhibition of SIRT1 activity resulting in increased level of acetylated p53. Acetylation stabilizes p53, increases its activity and leads to premature cell senescence. Sirtuins contribute to life extension in animals with overactivated insulin/IGF1 signaling by increasing FOXO activity. Furthermore, sirtuins activate LKB1/AMPK pathway by deacetylating LKB1. AMPK downregulates mTOR/S6K activity preventing onset of senescence in cell cycle arrested cells. Moreover, AMPK can increase NAMPT activity, the enzyme indispensable in a salvage pathway, leading to NAD+ upregulation, which promotes sirtuin activity. Arrowsindicate positive regulation. Lines with T-shaped ending indicate inhibition. Targets of lifespan/healthspan strategies are in light color boxesLight color boxes with frame—pathways to be inhibited, without frame—beneficial activities. (Color figure online)

去乙酰化酶在寿命/健康延长途径中的作用。去乙酰化酶调节多种途径参与介导一些抗衰老干预的积极效果,如热量/饮食限制(CR/DR)或运动。这种效果也可以通过去乙酰化酶激活化合物(STACs)来模拟。IGF1途径的延长激活,涉及 PI3K-AKT,导致磷酸化和抑制 FOXO 和抑制 SIRT1活性导致乙酰化 p53水平增加。乙酰化稳定 p53,增加其活性,导致细胞早衰。去乙酰化酶通过增加 FOXO 活性促进过度激活胰岛素/igf1信号转导的动物延长寿命。此外,sirtuins 通过去乙酰化 LKB1激活 LKB1/AMPK 信号通路。AMPK 下调 mTOR/S6K 活性防止细胞周期阻滞细胞衰老。此外,AMPK 可以增加 NAMPT 活性,这是一种补救途径中不可缺少的酶,导致 NAD + 上调,促进去乙酰化酶的活性。箭头表示积极的监管。末端呈 t 形的线表示抑制。寿命/健康跨度策略的目标是浅色盒子。有框架的浅色盒子ーー通道被抑制,没有框架ーー有益的活动。(网上彩色图片)

Curcumin in sirtuins regulation

姜黄素对去乙酰化酶的调节作用

Curcumin is a natural polyphenol extracted from a yellow pigment spice plant, turmeric, used for millennia in traditional medicine. Some polyphenols activate SIRT1 directly or indirectly, as has been shown in a variety of research models (Queen and Tollefsbol 2010). It has been proposed that curcumin possesses multiple biological properties including anti-oxidant, anti-inflammatory and anti-cancer activity, however there is also some rationale to consider this compound as an anti-ageing factor (Sandur et al. 2007; Sikora et al. 2010ab; Salvioli et al. 2007). Curcumin was able to extend the lifespan of such organisms as fruit fly, nematodes and mice, and alleviated symptoms of some diseases including age-related ones (Liao et al. 2011). It reduced the impact of some harmful factors such as radiation or chemicals. Moreover, it increased the ability of cells to differentiate during replicative senescence as it was show in human epidermal keratinocytes (Berge et al. 2008). Curcumin possesses numerous target proteins and there are data showing that it is able to act by sirtuin activation. Several studies note that pretreatment with curcumin significantly enhances SIRT1 activation and attenuates oxidative stress (Sun et al. 2014; Yang et al. 2013). For example, pretreatment with curcumin attenuated mitochondrial oxidative damage induced by myocardial ischemia reperfusion injury through activation of SIRT1 (Yang et al. 2013). Likewise, curcumin blocked the neurotoxicity of amyloid-beta in rat cortical neurons by the same mechanism (Sun et al. 2014). The protective properties of curcumin, owed to the induction of sirtuins, help to reduce cisplatin chemotherapy-induced nephrotoxicity (Ugur et al. 2015) and protect kidney from gentamicin-induced acute kidney injury in animals (He et al. 2015). It has been shown that curcumin can elongate the lifespan of Caenorhabditis elegans but not when Sirt2 (the homolog of mammalian SIRT1) is mutated (Liao et al. 2011). Moreover, curcumin increased the level of SIRT1, which could help to prevent muscle damage (Sahin et al. 2016). Data concerning the impact of curcumin on cellular senescence are, however, confusing. On the one hand, it has been shown that curcumin attenuates hydrogen peroxide-induced premature senescence in HUVECs via activation of SIRT1 (Sun et al. 2015). Moreover, it was demonstrated that another curcuminoid, bisdemethoxycurcumin, could also antagonize the oxidative stress-induced premature senescence in WI38 fibroblasts through activation of the SIRT1/AMPK signaling pathway (Kitani et al. 2007). On the other hand, we showed that curcumin did not protect cells building the vasculature from premature senescence induced by DNA damaging agent, doxorubicin and did not postpone replicative senescence despite SIRT1 and AMPK upregulation (Grabowska et al. 2016). It is difficult to adjudicate whether curcumin can protect cells from senescence in vivo, but its role in sirtuin stimulation is convincing. Moreover, a lot of data show the reduction of symptoms of age-related diseases as a result of curcumin treatment. In particular, beneficial role of curcumin in the cardiovascular system is supported by numerous research data (Srivastava and Mehta 2009; Olszanecki et al. 2005; Yang et al. 2006). An animal study demonstrated that curcumin supplementation significantly ameliorated arterial dysfunction and oxidative stress associated with ageing (Fleenor et al. 2013). It seems justified to consider curcumin as a beneficial anti-pathological factor in the cardiovascular system. The neuroprotective role of curcumin is also mediated by SIRT1 induction, observed in primary cortical neurons in vitro. Accumulation of extracellular glutamate, the most abundant neurotransmitter in the brain involved in synaptic plasticity, learning, memory and other cognitive functions, can provoke neuronal injuries. Curcumin protected cortical neurons against glutamate excitotoxicity by SIRT1-mediated deacetylation of PGC-1α and preservation of mitochondrial functioning (Jia et al. 2016).

姜黄素是一种天然多酚提取自一种黄色色素香料植物,姜黄,使用了几千年的传统医药。一些多酚类物质直接或间接地活化 SIRT1,这已经在各种研究模型中得到证实(Queen 和 Tollefsbol 2010)。有人提出,姜黄素具有多种生物学特性,包括抗氧化、抗炎和抗癌活性,但也有理由认为这种化合物是一种抗衰老因子(Sandur 等人,2007年; Sikora 等人,2010a,b; Salvioli 等人,2007年)。姜黄素能够延长果蝇、线虫和小鼠等生物的寿命,并减轻一些疾病的症状,包括与年龄有关的疾病(廖等人,2011年)。它减少了一些有害因素的影响,如辐射或化学品。此外,它增加了细胞在复制衰老过程中的分化能力,正如它在人表皮角质形成细胞中所显示的那样(Berge 等人,2008年)。姜黄素具有众多的目标蛋白,有数据表明,它能够作用于去乙酰化酶激活。一些研究指出,姜黄素预处理显著增强 SIRT1的激活,并减弱氧化应激。例如,姜黄素预处理通过激活 SIRT1减轻冠状动脉疾病再灌注损伤引起的线粒体氧化损伤(Yang et al. 2013)。同样,姜黄素通过相同的机制阻断了大鼠皮层神经元中 β 淀粉样蛋白的神经毒性(Sun 等人,2014)。姜黄素的保护性能,归功于去乙酰化酶的诱导,有助于减少顺铂化疗引起的肾毒性(Ugur et al. 2015)和保护肾脏免受庆大霉素引起的动物急性肾损伤(He et al. 2015)。研究表明,姜黄素可以延长秀丽隐桿线虫的寿命,但是当 Sirt2(哺乳动物 SIRT1的同源基因)发生突变时,姜黄素就不能延长它的寿命。此外,姜黄素增加了 SIRT1的水平,这可能有助于防止肌肉损伤(Sahin 等人,2016年)。然而,关于姜黄素对细胞衰老的影响的数据令人困惑。一方面,已经证明姜黄素通过激活 SIRT1来减缓过氧化氢诱导的人脐静脉内皮细胞早衰(Sun 等人,2015)。此外,另一种姜黄素,双去甲氧基姜黄素,也能通过激活 SIRT1/AMPK 信号通路,拮抗氧化应激诱导的 WI38成纤维细胞早衰(Kitani 等,2007)。另一方面,我们发现姜黄素不能保护构建血管系统的细胞免受 DNA 损伤剂阿霉素诱导的早衰,而且尽管 SIRT1和 AMPK 上调,姜黄素也不能延缓复制衰老(Grabowska 等人,2016年)。姜黄素是否能保护细胞在体内的衰老尚难判断,但其在去乙酰化酶刺激中的作用是令人信服的。此外,大量的数据显示,减少症状的年龄有关的疾病作为姜黄素治疗的结果。尤其是,姜黄素在心血管系统中的有益作用得到了大量研究数据的支持(Srivastava 和 Mehta 2009; Olszanecki 等人2005; Yang 等人2006)。一项动物研究表明,补充姜黄素可以显著改善动脉功能障碍和老化相关的氧化应激(Fleenor et al. 2013)。似乎有理由认为姜黄素作为一个有益的抗心血管系统的病理因素。姜黄素的神经保护作用也是通过 SIRT1诱导介导的,在体外观察原代皮质神经元。细胞外谷氨酸的积累—- 大脑中最丰富的神经递质,参与突触可塑性、学习、记忆和其他认知功能—- 可以引起神经元损伤。姜黄素通过 sirt1介导 pgc-1去乙酰化和保护线粒体功能,保护皮层神经元免受谷氨酸兴奋毒性(Jia 等人,2016)。

The effect of curcumin action strongly depends on its concentration. Curcumin belongs to hormetins, which means that at low concentration it may exert beneficial effects but is harmful at high concentrations (Calabrese 2014; Demirovic and Rattan 2011). Hormetins, by inducing a mild stress, and in consequence hormesis, are considered to be a promising strategy to slow down ageing and prevent or delay the onset of age-related diseases (Rattan 2012). The sensitivity to curcumin depends on cell type and probably the phase of the cell cycle. In vitro, in a certain range of concentrations, curcumin is toxic for all cell types, in another range inhibits the cell cycle and, at lower concentrations, seems to have no visible impact on cells (potentially beneficial doses according to the hormetic activity of curcumin). We showed that cytostatic doses of this factor induced cellular senescence in cancer cells (Mosieniak et al. 20122016) and in cells building the vasculature (Grabowska et al. 2015). Curcumin-induced senescence of both vascular smooth muscle (VSMC) and endothelial (EC) cells was associated with decreased level of SIRT1 and SIRT6. Such downregulation seems to be characteristic for cell senescence not for curcumin. On the other hand, the level of mitochondrial SIRT3 and SIRT5 increased after curcumin treatment. These enzymes are stimulated in response to stress conditions and SIRT3, in particular, is an anti-oxidative protein which increases the activity of e.g. MnSOD. We postulate that activation of mitochondrial sirtuins is characteristic for dual curcumin action and could be considered as a protective mechanism induced by increased ROS production. Curcumin simultaneously increased ROS generation and activated proteins involved in anti-oxidative defense. This compound has also an impact on SIRT7. Downregulation of SIRT7 was observed at cytostatic concentration of curcumin. This could explain the arrest of the cell cycle, because it was documented that downregulation of SIRT7 may stop cell proliferation (Ford et al. 2006). Decreased activity of SIRT7 is associated with induction of nucleolar stress, which is related to inhibition of rDNA transcription (Lewinska et al. 2015). In turn, low doses of curcumin did not impair SIRT7 expression and even slightly increased its level (Grabowska et al. 2016). We tested also such concentrations of curcumin which have no impact on the proliferation of cells building the vasculature. We expected that such doses could delay the symptoms of cellular senescence, however, our results excluded this possibility, even though we observed that curcumin was able to increase sirtuin level, namely that of sirtuin 1, 3, 5, 6 and 7 (Grabowska et al. 2016). Therefore we concluded that curcumin anti-ageing activity is not due to delaying cellular senescence but is rather related to sirtuin elevation.

姜黄素的作用强烈取决于其浓度。姜黄素属于激素,这意味着在低浓度下它可能发挥有益作用,但在高浓度下是有害的(Calabrese 2014; Demirovic and Rattan 2011)。Hormetins,通过诱导轻度应激和随之而来的毒物兴奋效应,被认为是延缓衰老和预防或延缓与年龄相关疾病发生的有希望的策略(Rattan 2012)。对姜黄素的敏感性取决于细胞类型和可能的细胞周期阶段。在体外,在一定浓度范围内,姜黄素对所有类型的细胞都有毒性,在另一个范围内,姜黄素抑制细胞周期,在较低浓度下,似乎对细胞没有明显的影响(根据姜黄素的仿生活性,可能有益的剂量)。我们证明,这种因子的细胞抑制剂量会诱导癌细胞和构建血管的细胞衰老(Mosieniak 等人,2012年,2016年)。姜黄素诱导血管平滑肌和内皮细胞衰老与 SIRT1和 SIRT6水平降低有关。这种下调似乎是细胞衰老的特点,而不是姜黄素。另一方面,姜黄素处理后线粒体 SIRT3和 SIRT5水平升高。这些酶在应激条件下受到刺激,尤其是 SIRT3,是一种抗氧化蛋白质,可以增加例如 MnSOD 的活性。我们推测线粒体去乙酰化酶的激活是姜黄素双重作用的特征,可以认为是由于活性氧产生增加而引起的一种保护机制。姜黄素同时增加活性氧产生和参与抗氧化防御的活性蛋白。这种化合物对 SIRT7也有影响。在姜黄素细胞静止浓度下,SIRT7表达下调。这可以解释细胞周期的停滞,因为有文献证明 SIRT7的下调可能会阻止细胞增殖(Ford 等人,2006年)。SIRT7的活性降低与诱导核仁应激有关,这与抑制 rDNA 转录有关(Lewinska 等人,2015年)。反过来,低剂量的姜黄素并不损害 SIRT7的表达,甚至略微增加其水平(Grabowska 等人,2016年)。我们也测试了这样浓度的姜黄素,它对构建血管的细胞的增殖没有影响。我们原以为这样的剂量可以延缓细胞衰老的症状,然而,我们的结果排除了这种可能性,即使我们观察到姜黄素能够增加 sirtuin 水平,即 sirtuin 1、3、5、6和7(Grabowska 等人,2016年)。因此,我们认为姜黄素的抗衰老作用不是由于延缓了细胞的衰老,而是与去乙酰化酶的升高有关。

It has been demonstrated that in senescence-accelerated mice a combination of resveratrol intake and habitual exercise is able to suppress the ageing-associated decline in physical performance (Murase et al. 2009). Resveratrol improves the effects of exercise in elderly rat hearts by enhancing FOXO3 phosphorylation via synergetic activation of SIRT1 and PI3K/Akt signaling (Lin et al. 2014). A similar effect was observed for curcumin supplementation. It has been documented that curcumin together with physical performance upregulates SIRT1 even more efficiently than dietary curcumin alone (Sahin et al. 2016). Curcumin supplementation affected the time of exhaustion in exercised rats. Moreover, curcumin treatment enhanced the effect of exercise and, together with exercise increased AMPK phosphorylation, NAD+/NADH ratio and SIRT1 expression in the muscle (Ray Hamidie et al. 2015). Improved exercise performance and fatigue prevention in mice was the result of increased resistance to stress conditions (Huang et al. 2015). Figure 3 summarizes the proposed mechanisms of sirtuin activation by curcumin.

已经证明,在快速衰老老鼠中,白藜芦醇的摄入和习惯性运动的结合能够抑制衰老相关的体能下降(Murase 等人,2009年)。白藜芦醇通过协同激活 SIRT1和 PI3K/Akt 信号通路来增强 FOXO3磷酸化,从而改善老年大鼠心脏的运动效应(Lin 等人,2014)。姜黄素的补充也有类似的效果。已有文献证明,姜黄素联合物理性能提高 SIRT1的效率甚至比单独使用姜黄素更高(Sahin 等人,2016年)。补充姜黄素对运动大鼠疲劳时间的影响。此外,姜黄素治疗增强运动的效果,同时运动增加 AMPK 磷酸化,NAD +/NADH 比率和 SIRT1在肌肉中的表达(Ray Hamidie 等人,2015年)。提高小鼠的运动能力和疲劳预防是增强对应激条件的抵抗力的结果(Huang 等人,2015年)。图3总结了姜黄素激活 sirtuin 的机制。

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Fig. 3 图3

Mechanism of sirtuin activation by curcumin. We propose that curcumin increases sirtuins level and activity through upregulation and activation of AMPK. Such action can be a result of ATP reduction and initial increase in superoxide production (which is later neutralized by elevated expression of antioxidant enzymes). AMPK activation promotes NAD+ production via increase in NAMPT activity. Moreover, AMPK activates FOXO transcription factors which can induce sirtuin expression. Upregulation and activation of sirtuins promote LKB1/AMPK activity creating a positive feedback loop. Additionally, curcumin can contribute to postponing of ageing by inhibiting AKT/mTOR pathway. Thin arrows indicate positive regulation. Lines with T-shaped ending indicate inhibition. Thick arrows indicate decreasing or increasing level as described in Grabowska et al. (2016). The level/activity of proteins in dark color boxes increased upon curcumin supplementation, in light color boxes, decreased. (Color figure online)

姜黄素激活去乙酰化酶的机制。我们认为姜黄素通过上调和激活 AMPK 来提高去乙酰化酶的水平和活性。这种作用可能是 ATP 减少和超氧化物产生的初始增加(后来被抗氧化酶的高表达所中和)的结果。AMPK 活化通过增加 NAMPT 活性促进 NAD + 的产生。此外,AMPK 激活 FOXO 转录因子,可以诱导 sirtuin 的表达。去乙酰化酶的上调和激活促进 LKB1/AMPK 活性产生正反馈环。此外,姜黄素可通过抑制 AKT/mTOR 通路而延缓衰老。细箭头表示正向调节。末端呈 t 形的线表示抑制。粗箭头表示正如 Grabowska 等人(2016)所描述的水平下降或上升。补充姜黄素后,深色盒中蛋白质水平/活性升高,浅色盒中蛋白质水平/活性降低。(网上彩色图片)

Considering curcumin as a potential anti-ageing factor it is important to mention that it could act not only by mimicking of DR and exercise but is also able to inhibit the Akt/mTOR signaling pathway (Zhu et al. 2016; Guo et al. 2016; Jiao et al. 2016; Sikora et al. 2010a).

考虑到姜黄素作为一种潜在的抗衰老因子,有必要指出的是,它不仅可以通过模仿 DR 和运动发挥作用,而且还能够抑制 Akt/mTOR 信号通路(Zhu 等人,2016年; Guo 等人,2016年; 焦等人,2016年; Sikora 等人,2010a)。

The impact of curcumin on lifespan/healthspan elongation strategies and protection from age-related pathologies is summarized in Fig. 4.

姜黄素对寿命/健康跨度延长策略的影响和年龄相关疾病的保护总结在图4。

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Fig. 4 图4

Dose-dependent activity of curcumin. Curcumin in high concentrations can be toxic while low concentrations may exert beneficial effects. In cytotoxic concentrations curcumin can be useful for eliminating cancer cells (a beneficial role), but may induce cell death in normal cells (a detrimental role). Cytostatic doses of curcumin induce senescence both in cancer and primary cells. In some situations this could be beneficial (senescence of cancer cells, protection from atherosclerosis), in others on the contrary (premature senescence of primary cells). Senescence upon curcumin treatment is associated with increased ROS production, upregulation of mitochondrial sirtuins (sirtuin 3 and 5), decrease in the level of sirtuins 1, 6 and 7 and upregulation of proteins involved in anti-oxidative defense. In turn, in low doses curcumin is able to upregulate the level of sirtuins. Animal studies show that supplementation of diet with curcumin can attenuate symptoms of some age-related diseases and improve exercise performance. Such effect is elicited via direct influence of curcumin on processes such as inflammation and/or indirectly via sirtuin upregulation and activation. Arrows indicate positive regulation. Lines with T-shaped ending indicate inhibition. Low, cytostatic and toxic refer to the range of curcumin concentrations

姜黄素的剂量依赖性活性。高浓度的姜黄素是有毒的,而低浓度的姜黄素可以发挥有益的作用。在细胞毒性浓度下,姜黄素可以用于消除癌细胞(一种有益的作用) ,但可能诱导正常细胞的细胞死亡(一种有害的作用)。姜黄素的细胞静态剂量可诱导癌细胞和原代细胞的衰老。在某些情况下,这可能是有益的(衰老的癌细胞,防止动脉粥样硬化) ,在其他相反的(早衰的原始细胞)。姜黄素处理后衰老与活性氧产生增加、线粒体 sirtuin 3和5表达上调、 sirtuin 1、6和7表达下降以及抗氧化防御相关蛋白表达上调有关。反过来,低剂量的姜黄素能够上调 sirtuins 的水平。动物研究表明,补充饮食与姜黄素可以减轻症状的一些年龄有关的疾病和提高运动能力。这种效应是通过姜黄素对炎症等过程的直接影响和/或间接通过 sirtuin 上调和激活引起的。箭头表示积极的监管。末端呈 t 形的线表示抑制。低,细胞抑制和毒性是指姜黄素的浓度范围Go to: 去:

Conclusions

结论

Numerous data presented in the literature show sirtuins as a powerful tool in anti-ageing medicine/approach. Results from animal models, observations at the cellular level and data obtained from human studies suggest that sirtuins could be considered as a key regulator of ageing. The level of these enzymes decreases with age while their upregulation alleviates the symptoms of ageing/cellular senescence. Natural compounds present in the diet, classed as functional food/nutraceutics, could be an invaluable element of anti-ageing prophylactics or even intervention. Such compounds are nontoxic, easy to use and commonly available and could be included into a normal diet for long lasting supplementation. The huge amount of data describing curcumin activity provided convincing evidence concerning its beneficial effects. One of them could be regulation of sirtuin level/activity. However, it has to be kept in mind that all natural compounds, including curcumin, have pleiotropic activity and many molecular and cellular targets. On the other hand, the ageing process per se is multifactorial, and modulation of sirtuin level/activity, especially in such complex organism as the human being, could not be sufficient to slow it down.

文献中提供的大量数据表明去乙酰化酶是抗衰老药物/方法的有力工具。动物模型的结果,细胞水平的观察和从人类研究中获得的数据表明去乙酰化酶可以被认为是衰老的关键调节因子。这些酶的水平随着年龄的增长而降低,而它们的上调缓解了衰老/细胞衰老的症状。日常饮食中存在的天然化合物,被归类为功能性食品/营养品,可能是抗衰老预防甚至干预的无价元素。这种化合物是无毒的,易于使用,通常可以得到,并可纳入正常饮食的长期持久的补充。描述姜黄素活性的大量数据为其有益作用提供了令人信服的证据。其中之一可能是去乙酰化酶水平/活性的调节。然而,它必须记住,所有的天然化合物,包括姜黄素,具有多效性活动和许多分子和细胞的目标。另一方面,衰老过程本身是多因素的,对去乙酰化酶水平/活性的调节,特别是在像人类这样的复杂生物体中,不足以减缓衰老。

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