白藜芦醇和 SIRT1激活剂治疗衰老及年龄相关疾病

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Resveratrol and SIRT1 Activators for the Treatment of Aging and Age-Related Diseases

Abstract

摘要

Reduced calorie intake is a religious and medical practice known since very old times, but its direct influence on life span in all organisms, included humans, has been demonstrated in the modern era. Not only periodic fasting, but also natural or synthetic compounds that mimic this phenomenon are growing to slow aging and the onset of chronic morbidities. Resveratrol (RSV), a plant polyphenol, is an elixir of longevity for simple organisms and preclinical rodent models even if a beneficial role in humans is still debated. Its main rejuvenating mechanism copes with the activation of specific longevity genes called sirtuins. Among seven known mammalian sirtuins, sirtuin 1 is the most studied. This pleiotropic nicotinamide adenine dinucleotide (NAD)-based deacetylase maintains longevity by removing acetyl group in nuclear histones, transcription factors, and other DNA repairing proteins. Actually, an exciting challenge is to discover and test novel sirtuin 1 activators to extend life span and to treat age-associated disabilities. This chapter updates on the antiaging effect of RSV and sirtuin 1 activators in experimental animals and in humans. Finally, pros and cons on RSV analogues and sirtuin 1 activators tested in preclinical and clinical trials to hamper neurological deficit, cardiovascular complications, diabetes, bone and muscle deterioration, and cancer are discussed.

减少卡路里的摄入量是一种自古以来就为人们所知的宗教和医学实践,但是在现代社会,它对包括人类在内的所有生物体的寿命都有直接影响。不仅周期性禁食,而且模仿这种现象的自然或合成化合物正在增长,以延缓衰老和慢性疾病的发病。白藜芦醇(RSV) ,一种植物多酚,是一种长寿灵丹妙药简单的生物体和临床前啮齿动物模型,即使有益的作用,在人类仍然是争论。其主要的返老还童机制与特异性长寿基因 sirtuins 的激活有关。在已知的7种哺乳动物去乙酰化酶中,去乙酰化酶1的研究最多。这种基于多效性烟酰胺腺嘌呤二核苷酸(NAD)的去乙酰化酶通过去除核组蛋白、转录因子和其他 DNA 修复蛋白中的乙酰基来维持长寿。实际上,一个令人兴奋的挑战是发现和测试新的 sirtuin 1激活剂,以延长寿命和治疗年龄相关的残疾。本章更新了 RSV 和 sirtuin 1激活剂在实验动物和人体中的抗衰老作用。最后,正反两方面的呼吸道合胞病毒类似物和 sirtuin 1激活剂测试的临床前和临床试验,以防止神经缺陷,心血管并发症,糖尿病,骨骼和肌肉恶化,和癌症进行了讨论。

Keywords

关键词

  • sirtuin 1
  • resveratrol 白藜芦醇
  • aging 老化
  • neurodegeneration 神经退行性疾病
  • diabetes 糖尿病
  • myopathy 肌病

Chapter and author info

第一章及作者简介

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1. Introduction

1. 引言

The increase in average life expectancy is a global consequence of sanitary welfare, proper nutrition, and healthy life style [12], but unfortunately, longevity is linked to the onset of chronic irreversible diseases like neurological decline, cardiovascular damage, bone and muscle frailty, diabetes, and metabolic diseases with high economic and social costs [345]. Specific international clinical objectives are to maintain a “healthy aging” defined by World Health Organization (WHO) as the “functional ability that enables wellbeing in old age” by firstly preserving the quality of life together with its duration [67]. Besides unchangeable genetic background, in this context, great credit is due to the quality but also the quantity of dietary nutrients [8910].

平均预期寿命的增加是卫生福利、适当营养和健康生活方式的全球后果[1,2] ,但不幸的是,长寿与不可逆转的慢性疾病的发病有关,如神经衰退、心血管损伤、骨骼和肌肉脆弱、糖尿病和代谢性疾病,这些疾病的经济和社会成本很高[3,4,5]。具体的国际临床目标是维持世界卫生组织(世卫组织)所定义的”健康老龄化” ,即通过首先保持生活质量及其持续时间来实现老年幸福的功能能力[6,7]。除了不变的遗传背景,在这种情况下,很大的功劳是由于质量和数量的膳食营养素[8,9,10]。

Historically, since fifth century BC, the famous Greek physician Hippocrates declared that fasting was the best practice to block sickness progression, and, on the contrary, too much feeding gave rise to a disease. This old and simple medical concept, i.e., caloric restriction without malnutrition, has maintained for centuries but without a direct impact on life extension. Only in modern times since early 1930s, a pioneering Mc Cay discovery confirmed that undernutrition caused prolonged life span in laboratory rats [11]. By 2000s, Longo and coworkers systematically studied dietary restriction as a therapy for slowing aging and related diseases in human settings [12131415]. Periodic reduction of dietary calorie intake or an intermittent fasting, under medical control, appears alternative tools to pharmacology to delay the onset of aging comorbidities, like metabolic diseases, and to improve health outcomes [16171819]. “Geroscience,” a definition coined by Burch et al. [20], identifies the branch of aging biology aimed to reduce human frailty and the impact of associated chronic diseases. However, considering the difference in the duration of life between lower organisms versus humans, to fill this gap, caloric limitation has been used also in nonhuman primates like monkeys. Anyway, significant translational value has been attributed to dietary studies in short-life animals versus nonhuman primates and humans that enhanced their life span under reduced nutrients intake.

从历史上看,自20世纪90年代前5世纪以来,著名的希腊医生希波克拉底就宣称禁食是阻止疾病恶化的最佳方法,相反,过多的进食会导致疾病。这个古老而简单的医学概念,即没有营养不良的热量限制,已经维持了几个世纪,但对延长寿命没有直接的影响。直到20世纪30年代早期的现代,Mc Cay 的一项开创性发现才证实了营养不良会延长实验室大鼠的寿命[11]。到2000年,Longo 和他的同事们系统地研究了饮食限制作为一种在人类环境中延缓衰老和相关疾病的治疗方法[12,13,14,15]。在医学控制下,定期减少膳食卡路里摄入量或间歇性禁食,似乎成为药理学的替代工具,以延缓老化的共病发作,如代谢性疾病,并改善健康结果[16,17,18,19]。“老年科学” ,由 Burch 等人提出的定义[20] ,确定了衰老生物学的分支,旨在减少人类的脆弱性和相关慢性疾病的影响。然而,考虑到低等生物与人类在寿命上的差异,为了填补这一空白,热量限制也被用于非人类灵长类动物,比如猴子。无论如何,重要的转化价值已经被归功于饮食研究,在短寿命动物与非人灵长类动物和人类,以提高寿命的营养素摄入量减少。

This chapter is focused on a natural dietary polyphenol, resveratrol (RSV), able to mimic calorie restriction and to prolong life duration in simple organisms and experimental animal models, but controversial in humans [2122]. RSV has been firstly identified as a modulator of conserved survival genes family called sirtuins [23]. Sirtuins, crucial modulators of life span extension and metabolism, have been firstly discovered by Guarente team as product of silent information regulator 2 (Sir 2) gene in yeast, Saccharomyces cerevisiae [24], worm, Caenorhabditis elegans, and fly fruit, Drosophila melanogaster [25]. In mammals, among seven known members, sirtuin 1 (SIRT1) enzyme was most beneficial against aging by mimicking calorie reduction [2627]. Moreover, other natural or synthetic compounds, more effective than RSV, like stimulate molecular longevity pathways via SIRT1 or pan-sirtuin activation, are currently under study [282930]. Therefore, here major attention has been focused on newest preclinical experimental studies on laboratory animals, mainly rodents, and clinical trials based on RSV and other SIRT1 activators published over last 10 years. Due to the impressive wide scientific literature on longevity, we select only more recent articles or reviews and apologize in advance for unintentional omissions. We believe that a primary scope of this chapter is to steer readers, even if not expert in the field, to study in detail if interested, the newest antiaging therapeutic perspectives. Intriguingly, we stressed on the role of SIRT1 activators in cancer but a dichotomy exists based on specific type of cancer and clinical outcome. Indeed, SIRT1 activators (STACs) that will promote benefits in selected tumors may obtain opposite detrimental effects in others. Therefore, to date, particular caution must be taken in the pharmacological use of SIRT1 modulators in oncology. So best understanding on SIRT1 activation and maintenance by specific modulators is essential to fight age-derived inevitable disorders.

这一章的重点是一种天然的膳食多酚,白藜芦醇(RSV) ,它能够模拟卡路里限制,并在简单的生物体和实验动物模型中延长寿命,但在人类中存在争议[21,22]。RSV 首次被确定为保守的存活基因家族的一个调节体,称为 sirtuins [23]。Sirtuins 是延长寿命和新陈代谢的重要调节剂,首次被 Guarente 研究小组发现,它是酵母、酿酒酵母、蠕虫、秀丽隐桿线虫和果蝇黑腹果蝇中沉默信息调节因子2(Sir 2)基因的产物。在哺乳动物中,在7个已知成员中,sirtuin 1(SIRT1)酶通过模拟降低热量而对抗衰老最有效[26,27]。此外,其他比 RSV 更有效的天然或合成化合物,如通过 SIRT1或泛 sirtuin 激活刺激分子长寿途径,目前正在研究中[28,29,30]。因此,这里的主要注意力集中在最新的临床前实验研究的实验动物,主要是啮齿动物,和基于 RSV 和其他 SIRT1激活剂的临床试验在过去10年发表。由于关于长寿的科学文献广泛而令人印象深刻,我们只选择最近的文章或评论,并为无意的遗漏提前道歉。我们相信这一章的主要范围是引导读者,即使不是该领域的专家,如果感兴趣的话,仔细研究最新的抗衰老治疗观点。有趣的是,我们强调了 SIRT1激活因子在癌症中的作用,但是基于特定类型的癌症和临床结果存在一种二分法。事实上,SIRT1激活剂(STACs) ,将促进选择性肿瘤的益处可能获得相反的不利影响在其他人。因此,迄今为止,在肿瘤学中 SIRT1调节剂的药理应用必须特别谨慎。因此,最好的理解 SIRT1激活和维持的特定调节器是必不可少的对抗年龄衍生的不可避免的障碍。

2. Sirtuin 1 history

2. Sirtuin 1的历史

The history of sirtuin family (silent information regulator 2—Sir 2) as antiaging proteins started in yeast, Saccharomyces cerevisiae, where they prolonged life span and regulated the number of replications from a mother cell [31]. Later, it was demonstrated in yeast that Sir 2 was further able to block the formation of extrachromosomal DNA linked to aging and genetic “toxicity.” Indeed, an excess of Sir 2 gene ameliorated reproductive cycle and sustained longevity in yeast budding [32]. Moreover, sirtuins were able to influence longevity in other lower organisms like worms, Caenorhabditis elegans [33], and dose-dependently in fruit fly, Drosophila melanogaster [3435]. Guarente team in 2000 demonstrated that the main action of sirtuins was to remove, as deacetylase enzymes, acetyl groups from specific lysine sites in nuclear histones, so allowing DNA silencing and chromosome stability [36]. This peculiar role is basic for an epigenetic regulation of DNA and telomere health and stabilization. Besides on class III DNA histones, sirtuin deacetylation activity has been extended to a plethora of other nonhistone proteins, transcription factors, and cytoplasmic proteins, which, by this posttranslational event, changed their structure and consequently function or signaling [37]. Recently, sirtuins have been considered not only deacetylases but also able to perform other posttranslational changes in their targets and for this reason defined “deacylases” [38]. Moreover, for their enzymatic activity, sirtuins used nicotinamide dinucleotide (NAD+) as a specific substrate, so their role has been related to NAD+ availability in the cell and to the NAD+/NADH ratio. In particular, it is known that during dietary caloric limitation and regular physical exercise, abundant NAD+ is produced and sirtuins are more active. There are two different ways to produce NAD+: one ex novo and another by conversion of nicotinamide (NAM) into nicotinamide mononucleotide (NMN) then charged with adenine nucleotide to become NAD. For vertebrates, the limiting enzyme necessary for the final step in the NAD synthesis is nicotinamide phosphoribosyltransferase (NAMPT) that is regulated by circadian rhythm regulator and clock genes (CLOCK and BMALI) [39]. The strict connection between NAD+ availability and sirtuin activity has been recently demonstrated and implied that competition for NAD+ substrate by different enzymes may affect sirtuin level, so contributing to age-associated diseases in mice [404142]. In particular, NAMPT-mediated NAD synthesis is associated to the transcription of circadian-regulated genes and sirtuin in metabolically active tissues [43]. However, another crucial step in the long sirtuin history was the characterization of mammalian sirtuins, seven different isoforms (sirtuin 1–7) [44]. SIRT1 is the most studied nuclear member, pleiotropic transcriptional factor that drives many cellular activities, like energy metabolism, cell survival, DNA stability, inflammation, and circadian rhythms [4546]. SIRT1 is involved not only in deacetylation of a specific histone but in complex chemical reactions for different pathways involved in metabolism, like target of rapamycin (mTOR) [47], insulin signaling [48], and forkhead box O (FOXO) [49] (Figure 1). Moreover, different mice overexpressing SIRT1 have been characterized that presented better metabolism, less inflammation, and cancer but a sex-dependent longevity (longer mean life span in males vsfemales) [50]. In these last 5 years, the involvement of SIRT1 in crucial cellular pathways has been demonstrated and the research of new drugs acting as SIRT1 modulators and relative patents exploded [28305152]. A common intriguing idea is that if SIRT1 acts as a therapeutic target, specific drugs able to activate its signaling might be effective in specific age-related pathologies and in cancer. Herein, we resumed and discuss recent scientific data on SIRT1 modulators (STACs) and their potentiality assessed in vivo, in preclinical rodent models or in clinical settings.

Sirtuin 家族(silent information regulator 2ー sir 2)作为抗衰老蛋白的历史起源于酵母,酿酒酵母,它们延长了寿命,并且控制了来自母细胞的复制数量。后来,在酵母中发现 Sir 2能够进一步阻止与衰老和遗传“毒性”有关的外因子控制的DNA 的形成事实上,过量的 Sir 2基因可以改善生殖周期和延长酵母出芽的寿命[32]。此外,去乙酰化酶能够影响其他低等生物体的寿命,如蠕虫,秀丽隐桿线虫,以及与剂量有关的果蝇,黑腹果蝇。2000年,瓜伦特团队证明,去乙酰化酶的主要作用是从核组蛋白的特定赖氨酸位点去除乙酰基团,从而使 DNA 沉默和染色体稳定[36]。这种特殊的作用是基本的表观遗传调控的 DNA 和端粒健康和稳定。除了第 III 类 DNA 组蛋白外,去乙酰化去乙酰化活性已经扩展到其他非组蛋白、转录因子和细胞质蛋白,这些蛋白通过这种翻译后事件改变了它们的结构,从而改变了它们的功能或信号传导[37]。最近,去乙酰化酶不仅被认为是去乙酰化酶,而且还能在其靶标上发生其他翻译后改变,因此定义了“去乙酰化酶”[38]。此外,去乙酰化酶的酶活性以烟酰胺二核苷酸(NAD +)为特异底物,因此它们的作用与细胞内 NAD + 的利用率和 NAD +/NADH 的比值有关。特别是,众所周知,在限制饮食热量和定期体育锻炼,大量的 NAD + 产生和抗衰老蛋白更活跃。生成 NAD + 有两种不同的途径: 一种是从头合成,另一种是将烟酰胺(NAM)转化为烟酰胺单核苷酸(NMN) ,然后加入腺嘌呤核苷酸(adenine nucleotide)合成 NAD。对于脊椎动物来说,NAD 合成最后一步所必需的限制性酶是烟酰胺磷酸核糖转移酶(NAMPT) ,它受昼夜节律调节基因和生物钟基因(CLOCK 和 BMALI)调节。NAD + 的利用率和 sirtuin 活性之间的密切联系最近得到了证实,这意味着不同酶对 NAD + 底物的竞争可能影响 sirtuin 水平,从而导致小鼠的年龄相关性疾病[40,41,42]。特别是,nampt 介导的 NAD 合成与昼夜节律调节基因和 sirtuin 在代谢活跃组织中的转录相关[43]。然而,在漫长的去乙酰化酶历史中,另一个关键的步骤是哺乳动物去乙酰化酶的角色塑造,7种不同的异构体(去乙酰化酶1-7)[44]。SIRT1是研究最多的核成员,多效转录因子,驱动许多细胞活动,如能量代谢,细胞存活,DNA 稳定性,炎症和昼夜节律[45,46]。SIRT1不仅参与特异性组蛋白的脱乙酰化,而且参与代谢不同途径的复杂化学反应,如雷帕霉素靶蛋白[47]、胰岛素信号转导[48]和叉头盒 o (FOXO)[49](图1)。此外,过度表达 SIRT1的不同小鼠表现出更好的新陈代谢、较少的炎症和癌症,但是具有性别依赖性的长寿(男性相对于女性的平均寿命更长)[50]。在过去的5年中,SIRT1在关键的细胞通路中的作用得到了证实,作为 SIRT1调节剂的新药的研究和相关专利数量激增[28,30,51,52]。一个共同的有趣的想法是,如果 SIRT1作为一个治疗目标,特定的药物能够激活其信号传导可能是有效的特定年龄相关的疾病和癌症。在此,我们回顾并讨论了 SIRT1调节器的最新科学数据及其在体内、临床前啮齿动物模型或临床环境中的潜力。

Figure 1.图1Sirtuin 1 deacetylase activity and its downstream substrates involved in longevity. The red square indicates the inhibited pathways and the green square the activated pathways. Stars indicate acetyl groups; (AMPK): 5′ AMP-activated protein kinase; (eNOS): endothelial nitric oxide synthase; (FOXO1/3): forkhead box protein O 1/3; (NAM): nicotinamide; (NAD+): nicotinamide dinucleotide; (NAMPT): nicotinamide phosphoribosyltransferase; (NF-kB): nuclear factor k B; (p53): protein 53; (PGC1α): peroxisome proliferatoractivated receptor G coactivator 1α; (mTOR): mammalian target of rapamycin.Sirtuin 1去乙酰化酶活性及其下游底物与寿命的关系。红色方块代表被抑制的路径,绿色方块代表被激活的路径。星号表示乙酰基; (AMPK) : 5′ AMP活化蛋白激酶; (eNOS) : 内皮细胞一氧化氮合酶; (FOXO1/3) : 叉头盒蛋白 o 1/3; (NAM) : 烟酰胺; (NAD +) : 烟酰胺二核苷酸; (NAMPT) : 烟酰胺磷酸核糖转移酶; (NF-kB) : 核因子 k b; (p53) : 蛋白53; (pgc1α) : 过氧化阿霉素激活受体 gcoactivator 1α; (mTOR) : 增殖性哺乳动物靶标。

3. Resveratrol and its derivatives as sirtuin 1 activators in aging

3. 白藜芦醇及其衍生物作为 sirtuin 1的老化激活剂

Since 2006 Sinclair’s team in Harvard University reported that RSV, 3,5,4′-trihydroxystilbene, has a therapeutic potential to extend life span by miming caloric restriction to limit metabolic alterations in rodents in more than 140 genic pathways [2353]. RSV was added to the rodent diet at concentrations similar to human use (5.2 and 22.4 mg/kg/day) for 6 months. RSV was firstly isolated in late 1930s in leaves of white hellebore Veratrum grandiflorum and characterized as a phytoalexin [54], but later in 1990s, it was found in red wine and grapevines [55], in traditional herbs in Asia [565758] in response to adverse conditions, in over 70 different plants and fruits like blueberry, raspberry, and mulberry [59]. Its first function was to reduce inflammation and to limit oxidant damage in cardiovascular diseases, the so-called “French paradox.” Intriguingly, the use of a glass of red wine reduced the extent of platelet aggregation and cardiovascular side effects in French people despite a high fat diet as reviewed in [60]. However, RSV is a photosensitive molecule, chemically composed by two aromatic rings linked by a methylene bridge, existing in two isomeric configurations, called trans-RSV and cis-RSV (Figure 2). Intriguingly, the most beneficial therapeutic properties are linked to trans-RSV even if, when exposed to light and high temperature, more than 80% of trans-RSV changes into cis-RSV with low solubility and stability [61].

自2006年以来,Sinclair 在哈佛大学的研究小组报告了 RSV,3,5,4′-三羟基二苯乙烯,通过模拟热量限制来限制啮齿动物代谢改变的140多个基因通路,有延长寿命的治疗潜力。在啮齿动物饲料中加入呼吸道合胞病毒,浓度与人类相似(5.2和22.4毫克/公斤/天) ,持续6个月。RSV 最早于20世纪30年代末从毛叶藜芦的叶子中分离出来,其特征为植物抗毒素,但是在20世纪90年代后期,在红酒和葡萄藤中发现了 RSV,在亚洲的传统草本植物中发现了 RSV,这是为了应对不利的条件,在70多种不同的植物和水果中发现了 RSV,如蓝莓、覆盆子和桑椹。它的第一个功能是减轻炎症和限制心血管疾病中氧化损伤,这就是所谓的“法国悖论”有趣的是,正如文献[60]所述,尽管法国人的饮食是高脂肪的,但使用一杯红葡萄酒还是降低了血小板聚集的程度和心血管副作用。然而,RSV 是一种光敏分子,由两个由亚甲基桥连接的芳香环组成,存在于两种异构构型中,称为反式 RSV 和顺式 RSV (图2)。有趣的是,最有益的治疗特性与反式呼吸道合胞病毒有关,即使当暴露在光和高温下时,超过80% 的反式呼吸道合胞病毒转变成低溶解度和稳定性的顺式呼吸道合胞病毒[61]。

Figure 2.图2Resveratrol, 3′,5, 4′-trihydroxystilbene, isomers adapted from Nawaz et al. [78].白藜芦醇,3′ ,5,4′-三羟基二苯乙烯,同分异构体来自 Nawaz 等[78]。

Nevertheless, it has been calculated that more than 110 glasses of wine should be drunk to achieve an anticancer effect in humans [62]. Unfortunately, lipophilicity of RSV conditioned its bioavailability, low intestinal absorption, and rapid clearance from the plasma, making necessary a high dosage in preclinical and clinical trials [6364]. In humans, RSV was administered as a dose of 25 mg, then grew in the range from 25 to 1000 mg, up to 5 g daily for almost 1 month still well tolerated [65]. However, when administered in healthy volunteers in the morning, RSV bioavailability and pharmacokinetic ameliorated [66] and tolerability was maintained if associated with other drugs, like quercetin and alcohol [67]. To ameliorate half-life in the plasma, a modified version of RSV was produced, called Longevinex, able to prevent isomerization from trans to cisand it is rich of vitamin D3 (at a dose 1200 IU) and quercetin very effective in the metabolic syndrome [68] and cardiac health in mice [69]. Interestingly, also in humans, RSV mimicked caloric restriction [70] and attenuated obesogenic changes in the metabolic syndrome but had no effects under normal weight patients [71]. Herein, the RSV ability to sustain SIRT1 expression/activity is effective when the deacetylase is scarce, but unnecessary if SIRT1 level/activity is normal like in postmenopausal women with normal glucose tolerance or in slightly obese men and women (trans-RSV was taken at a dose 150 mg daily for 4 weeks) [72]. However, despite extensive data on efficacy of RSV in rodent preclinical trials, actually its beneficial role in humans is still debated, greatly depending from doses and time of administration [73]. Antiaging properties of RSV via SIRT1 and mitochondrial health are addressed on amelioration of oxidative metabolism in crucial organs like heart and vessels, muscles, kidney but the mechanism is strictly cell-dependent [747576]. Remarkably, at high doses, RSV has been reported to induce mild toxicity in humans where somnolence, headache, rash, and myalgia occurred [77]. Herein, to overcome these problems, in the past few years, different RSV derivatives have been synthesized ex novo by substituting hydroxyl with methoxy groups, so enhancing lipophilicity, or by adding a 4-hydroxy group in trans-RSV or a halogen group to potentiate the therapeutic efficacy [78], although different promising antimicrobial, antioxidant, and cardioprotective effects have been obtained in vitro. Moreover, to improve oral bioavailability of RSV-specific complexes with liposomes, lipid or synthetic nanoparticles have been made, even if they resulted with low therapeutic potential [7980]. In respiratory diseases reproduced in rodent like pulmonary hypertension, RSV ameliorates asthma and fibrosis via SIRT1 activation [8182] and also its derivative, trimethoxystilbene, demonstrated antioxidant and anti-inflammatory properties in rats exposed to hypoxia [83]. Recently, Bastin and Djouadi [84] reviewed RSV potentiality against mitochondrial damage and myopathies, and promising results in an animal model of a fatal genetic disease called Duchenne muscular dystrophy were reported. In dystrophic mice (mdx model), RSV supplementation (0.5% in the diet for 3 weeks) ameliorated muscle atrophy and prevented sciatic denervation signaling [85]. However, caution must be taken to extrapolate successful data obtained in animal models to humans where RSV might modulate different pathways in a dose-dependent manner. Autoimmune diseases represent an emerging type of chronic diseases often associated to aging that affect specific or multiple organs at the same time like rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and type I diabetes [86]. RSV inhibited transcription factors crucial in autoinflammation, like nuclear factor k B (NF-kB) [87], and curiously in these pathologies, stopped SIRT1 activity. Intriguingly, RSV behaves as a potent drug mainly in animal models, although actually poor patient outcome and reduced number of clinical trials made necessary further studies in humans to exclude side effects or competition with other drugs [88]. RSV has been tested successfully in neuronal inflammation, psychotic mice (up to 30 mg/kg/daily) [8990], depressed menopausal women (orally 25 mg/day for 12 weeks) [91], and in patients with minimal hepatic encephalopathy, a frequent complication of cirrhosis [92]. However, the oral dosing of RSV seemed to cross the blood-brain barrier but more potent polyphenols specifically addressed on brain with promising preventive and not only therapeutic properties are under research [93]. Moreover, RSV administered 48 h prior the induction of a subarachnoid hemorrhage activated SIRT1 thereby reducing mortality and improving neurological functions in rats [94]. Pterostilbene is a natural phenolic drug found in sandalwood and some fruits like grapes and blueberries that ameliorated neuronal aging and memory deficit in rats [95]. Chemically, it is a dimethylether analogue of RSV with better pharmacokinetic and oral bioavailability in rats (80% in comparison to 20% RSV) [96]. Recently, pterostilbene demonstrated better efficacy than RSV in the modulation of behavior and functional improving in SAMP8 mouse, a rodent model of accelerated aging validated to study Alzheimer’s disease [97]. Moreover, recent evidences indicated that pterostilbene worked well as cardioprotective and anti-inflammatory drug in rodents with ischemia-reperfusion [98]. However, both pterostilbene and RSV efficacy on aging and longevity have been reviewed recently by Li et al. [99], but conclusive data are lacking due to poor water solubility, low bioavailability, and rapid elimination (half-life only 9 h in humans), the main obstacles to work in clinical trials. However, different strategies have been also undertaken to optimize the delivery of RSV to strengthen its clinical utility: one strategy was to complex it to controlled release devices, another avenue was to use micronized powder (called SRT501) [100]. A crucial year in the history of RSV pharmacology was 1997 when Jang et al. [101] firstly reported an antitumoral effect in vitro and in vivo in a murine model of skin cancer. However, SIRT1 played a double opposite role in cancer linked to severity grade. Indeed, in early cancer phases, when cellular mutations are scarce, to activate SIRT1 is a good strategy, but in advanced stages with many mutations, SIRT1 may potentiate and accelerate oncogenesis, as demonstrated in breast cancer [102]. Remarkably, Li et al. [103] provided evidences that dietary RSV for 4–5 weeks reduced prostate neoplastic lesions by about 50% in mice through SIRT1-mediated autophagy. More recently in chondrosarcoma cells, xenografted in mice, RSV via SIRT1 stimulated apoptosis and decreased tumor growth [104].

尽管如此,据计算,为了达到对人类的抗癌效果,应该喝110杯以上的葡萄酒。不幸的是,RSV 的亲脂性决定了其生物利用度、小肠吸收和从血浆中的快速清除,因此在临床前和临床试验中需要高剂量。在人类中,呼吸道合胞病毒以25毫克的剂量给药,然后在25至1000毫克的范围内增长,几乎一个月每天增长到5克,仍然耐受良好[65]。然而,当早晨在健康志愿者身上使用时,RSV 的生物利用度和药代动力学改善[66] ,如果与其他药物,如槲皮素和酒精联合使用,则可维持耐受性[67]。为了改善血浆中的半衰期,人们制造了一种改良版的呼吸道合胞病毒,称为 Longevinex,能够防止异构化从反式转化为顺式,它富含维生素 d 3(剂量为1200iu)和槲皮素,对代谢症候群和小鼠心脏健康非常有效。有趣的是,在人类身上,RSV 也模仿了卡路里限制[70]和减毒的代谢症候群变化,但是在正常体重的病人身上没有效果[71]。在这里,RSV 维持 SIRT1表达/活性的能力在去乙酰化酶缺乏时是有效的,但是如果 SIRT1水平/活性正常,就像在绝经后的正常葡萄糖耐量妇女或轻度肥胖的男性和女性一样(反式 RSV 每天服用150毫克,连续4周)[72]。然而,尽管有关呼吸道合胞病毒在啮齿动物临床前试验中的疗效的大量数据,实际上它在人类中的有益作用仍然存在争议,这主要取决于给药的剂量和时间[73]。通过 SIRT1研究 RSV 的抗衰老特性和线粒体健康是为了改善心脏、血管、肌肉、肾脏等关键器官的唿吸作用,但其机制严格依赖于细胞[74,75,76]。值得注意的是,在高剂量的情况下,呼吸道合胞体病毒已被报道对发生嗜睡、头痛、皮疹和肌痛的人类产生轻度毒性。为了克服这些问题,近年来,人们用甲氧基取代羟基合成了不同的 RSV 衍生物,从而提高了 RSV 的亲脂性,或者在反式 RSV 中加入4- 羟基或卤素基以提高治疗效果[78] ,虽然在体外获得了不同的抗菌、抗氧化和保护作用。此外,为了提高 rsv 特异性脂质体复合物的口服生物利用度,已经制备了脂质或合成纳米粒,即使它们的治疗潜力很低[79,80]。在啮齿类动物所复制的呼吸道疾病中,RSV 通过 SIRT1激活[81,82]改善哮喘和纤维化,其衍生物,三甲氧基二苯乙烯,在暴露于缺氧的大鼠中表现出抗氧化和抗炎性能[83]。最近,Bastin 和 Djouadi 回顾了 RSV 对抗线粒体损伤和肌病的潜力,并在一种称为杜兴氏肌肉营养不良症的致命性遗传疾病的动物模型中取得了有希望的结果。在营养不良模型小鼠(mdx 模型)中,RSV 补充(0.5% 的饲料喂养3周)可以改善肌肉萎缩和防止坐骨神经失神经信号传导[85]。然而,必须谨慎地将在动物模型中获得的成功数据外推给人类,因为呼吸道合胞病毒可能以剂量依赖的方式调节不同的途径。自身免疫性疾病是一种新出现的慢性疾病,通常与衰老有关,同时影响特定或多个器官,如类风湿性关节炎、炎症性肠病、红斑性狼疮和 i 型糖尿病。RSV 抑制了对自身炎症至关重要的转录因子,比如核因子 k b (NF-kB)[87] ,奇怪的是,在这些病理学中,SIRT1的活性停止了。有趣的是,呼吸道合胞病毒主要在动物模型中表现为一种有效的药物,尽管实际上病人的治疗效果很差,临床试验数量减少,因此需要对人类进行进一步的研究,以排除副作用或与其他药物的竞争[88]。RSV 已经在神经性炎症、精神病小鼠(高达每日30毫克/公斤)、抑郁的绝经期妇女(12周内每天口服25毫克/公斤)以及肝硬化常见并发症—- 肝性脑病微量患者中成功地进行了检测。然而,口服剂量的呼吸道合胞病毒似乎越过血脑屏障,但更有效的多酚特别是针对大脑与有希望的预防和不仅治疗性能的研究[93]。此外,呼吸道合胞病毒在诱导蛛网膜下腔出血激活 SIRT1之前48小时给药,从而降低死亡率,改善大鼠的神经功能[94]。紫檀是一种天然酚类药物,存在于檀香和一些水果中,如葡萄和蓝莓,可以改善大鼠的神经元老化和记忆缺陷[95]。从化学角度看,它是 RSV 的二甲醚类似物,在大鼠体内具有较好的药代动力学和口服生物利用度(80% 与20% RSV 相比)[96]。最近,翼点芪在 SAMP8小鼠的行为调节和功能改善方面表现出比 RSV 更好的效果,这是一个用于研究阿尔茨海默病的加速老化的啮齿动物模型。此外,最近的证据表明紫檀作为心肌保护和抗炎药物对啮齿动物缺血再灌注有良好的作用[98]。然而,最近 Li 等人审查了紫檀二苯乙烯和 RSV 对衰老和长寿的疗效,但由于水溶性差、生物利用度低和快速消除(人体半衰期只有9小时) ,缺乏确凿的数据,这是临床试验工作的主要障碍。然而,也采取了不同的策略来优化呼吸道合胞病毒的输送,以增强其临床应用: 一种策略是将其复合成控制释放装置,另一种方法是使用微粉(称为 SRT501)[100]。RSV 药理学史上的关键一年是1997年,Jang 等人首次报道了皮肤癌小鼠模型的体外和体内抗肿瘤作用。然而,SIRT1在与严重程度相关的癌症中扮演着双重相反的角色。事实上,在早期癌症阶段,当细胞缺乏突变时,激活 SIRT1是一个很好的策略,但是在有许多突变的晚期,SIRT1可能会加强和加速癌症发生,乳腺癌就证明了这一点[102]。值得注意的是,Li 等人[103]提供的证据表明,4-5周饮食中的 RSV 通过 sirt1介导的自噬作用,减少了小鼠前列腺肿瘤性损害约50% 。最近在软骨肉瘤细胞,异种移植的小鼠,呼吸道合胞病毒通过 SIRT1刺激凋亡和减少肿瘤生长[104]。

4. Synthetic sirtuin 1 activators (STACs) in aging

4. 合成去乙酰化酶1激活剂(STACs)在衰老中的作用

RSV and natural polyphenols, like quercetin and butein, have been included into the first generation of SIRT1 activators (STACs). However, to overcome limitations in RSV pharmacology, its aspecific interaction with several sirtuins like human sirtuin 5 and the competition with SIRT1 for the catalytic site [105], Sinclair laboratory since 2000s produced novel synthetic STACs [28] to fight aging-associated disabilities. The screening of potential STACS began in vitro looking for more than 18,000 drugs and resulted in 21 compounds able to stimulate the catalytic site in SIRT1 deacetylase enzyme [106]. Using a fluorescence polarization assay verified by mass spectrometry, novel synthetic STACs were obtained but a strong scientific controversy occurred on the efficacy of different drugs on SIRT1 activation. To date, the research on synthetic STACs (came to the fifth generation) has produced more soluble and specific compounds [30] with an in vitro 1000-fold greater potency than RSV to mimic calorie restriction. Intriguingly, STACs extended life span in obese mice [107] but also in mice fed a standard diet. [108]. Interestingly, SRT2104 was able to preserve muscle mass, strength, and bone integrity in muscle-atrophy induced by hind limb suspension and fasting [109]. Moreover, also SRT1720 behaved as an effective SIRT1 agonist in vivo in two independent rodent models of osteoporosis, where after 1 month or 3 months of oral treatment, femoral bone mass grew about 30% [110]. These studies have great translational implications considering the high frequency of fractures in human osteoporosis. Oral administration of SRT3025 (50 or 100 mg/kg/day) for 6 weeks, starting 6 weeks after ovariectomy, successfully reversed scarcity of bone mass and osteoporosis in mice [111]. Remarkably, SRT1720 intraperitoneally injected daily in female obese mice for 6 weeks improved the vitality of follicles via sustained SIRT1 able to reduce atresia and the abnormal primordial follicles activation [112]. In human plasmacytoma xenografted mice, a model utilized to validate new therapies against multiple myeloma, oral treatment with SRT1720 (200 mg/kg) on five consecutive days/week schedule for 4 weeks reduced tumor growth in combination with other drugs, like bortezomib, potentiated antimyeloma effects [113]. Several STACS have been tested as SIRT1 modulators in preclinical rodent model to fight diabetes, obesity, neurodegeneration, atherosclerosis, bone and muscle mass [114], and most relevant diseases investigated in the preclinical trials have been resumed in Figure 3.

呼吸道合胞病毒和天然多酚,如槲皮素和布替因,已列入第一代 SIRT1激活剂(STACs)。然而,为了克服 RSV 药理学的局限性,克服它与一些 sirtuin 的特殊相互作用,如人 sirtuin 5,以及与 SIRT1的催化位点竞争[105] ,辛克莱实验室自2000年以来生产了新颖的合成 STACs [28]来对抗衰老相关的残疾。潜在的 STACS 的筛选开始在体外寻找18,000多种药物,并导致了21个化合物能够刺激 SIRT1脱乙酰酶的催化位点[106]。使用荧光偏振分析法证实了质谱法,新的合成 STACs 被获得,但在不同药物对 SIRT1激活的功效上发生了强烈的科学争论。到目前为止,对于合成 STACs (进入第五代)的研究已经产生了更多的可溶性和特异性化合物[30] ,在体外模拟卡路里限制的效力是 RSV 的1000倍。有趣的是,STACs 延长了肥胖小鼠的寿命[107] ,同时也延长了标准饮食小鼠的寿命。[108].有趣的是,SRT2104能够在后肢悬吊和禁食诱导的肌肉萎缩中保持肌肉质量、力量和骨骼完整性[109]。此外,SRT1720在骨质疏松症的两个独立的啮齿动物模型体内也表现为有效的 SIRT1激动剂,经过1个月或3个月的口服治疗,股骨骨量增长约30% [110]。考虑到人类骨质疏松性骨折的高发率,这些研究具有重要的转化意义。从卵巢切除术后6周开始,连续6周服用 SRT3025口服给药(50或100毫克/千克/天) ,成功地扭转了小鼠骨量缺乏和骨质疏松症的状况[111]。显著地,雌性肥胖小鼠腹腔内每日注射 SRT1720,持续6周,可以减少闭锁和原始卵泡异常激活,改善卵泡活力[112]。在人类浆细胞瘤异种移植小鼠中,一个用于验证新疗法的模型,SRT1720(200mg/kg)连续5天/周进行口服治疗,并与其他药物联合,如硼替佐米,增强抗黄斑瘤效应[113]。一些 STACS 已经作为 SIRT1调节剂在临床前啮齿动物模型中进行了测试,以对抗糖尿病、肥胖、神经退行性疾病、动脉粥样硬化、骨骼和肌肉质量[114] ,在临床前试验中调查的大多数相关疾病已经在图3中恢复。

Figure 3.图3Synthetic SIRT1 activators (STACs) effective in rodent models.合成 SIRT1激活剂对啮齿动物模型有效。

Later, since 2012, an STAC phase I clinical trials started in humans [115]. SRT2104 in doses ranged from 0.03 to 3 g was well tolerated with a bioavailability about 14% in male and female volunteers. Remarkably, the same drug was also tested in elderly volunteers with no side effects [116]. In these last years, various human clinical trials with STACs have been started but to date the only ended with SRT2104 in patients with moderate to severe psoriasis demonstrated a promising efficacy [117]. Despite some encouraging evidences, in other clinical trials, SRT2104 administration for 28 days to diabetic patients (n = 15) was ineffective on insulin resistance and endothelial function but induced a striking weight reduction not observed in placebo [118]. Moreover, patients with mild to moderate ulcerative colitis were treated with SRT2104 at 50–500 mg daily for 8 weeks, and they not presented any clinical remission so the clinical trials stopped [119]. However, the times are ripe to start further clinical trials and to test novel STACs for longer times, hoping in new exciting results.

后来,自2012年以来,STAC 一期临床试验开始在人体上进行[115]。SRT2104在0.03ー3克剂量范围内耐受性良好,男性和女性志愿者的生物利用度约为14% 。值得注意的是,同样的药物也在没有副作用的老年志愿者身上进行了测试。在过去的几年中,已经开始了各种 STACs 的人体临床试验,但是到目前为止只有 SRT2104在中重度银屑病患者中显示出有希望的疗效[117]。尽管有一些令人鼓舞的证据,在其他临床试验中,给予 srt210428天的糖尿病患者(n = 15)对胰岛素抵抗和内皮功能无效,但是引起了显著的体重减轻,安慰剂中没有观察到[118]。此外,轻度至中度溃疡性结肠炎患者接受 SRT2104治疗,每天50-500毫克,持续8周,他们没有出现任何临床缓解,因此临床试验停止[119]。然而,时机已经成熟,可以开始进一步的临床试验,并对新型 STACs 进行更长时间的测试,希望能得到新的令人兴奋的结果。

5. Recommendation

5. 建议

RSV, the main member of the first generation STACs, is not found in meat or dairy but is present in vegetables and herbs. Renisalo et al. [120] have indicated main sources of RSV in vegetables and seeds like cocoa, grape, hop, peanuts, pistachios, tomato, and berries. However, RSV is also present in common Asian herbs like Polygonum cuspidatum, known as Japanese knotweed. Its dried roots have been infused to produce “Itadori” tea, which means “well-being” in Japanese, a folk beverage largely used for the treatment of heart disease and stroke [59].

呼吸道合胞病毒是第一代 STACs 的主要成员,不存在于肉类或奶制品中,而存在于蔬菜和草药中。Renisalo 等人[120]指出,主要来源的呼吸道合胞病毒的蔬菜和种子,如可可,葡萄,啤酒花,花生,开心果,番茄和浆果。然而,呼吸道合胞病毒也存在于常见的亚洲草本植物,如虎杖,被称为虎杖。它的干燥根部被注入到生产“板织”茶中,这在日语中意为“幸福” ,一种主要用于治疗心脏病和中风的民间饮料[59]。

To date, pleiotropic effects of trans-RSV in degenerative and metabolic diseases in elderly are recognized, but despite a lot of evidences in vitro and in rodent model, their therapeutic role in humans is still debated. Firstly, its beneficial effect is strictly dose-dependent, and to potentiate mitochondria health, it is required at least an oral dose of RSV of 1 g/day in Alzheimer’s patients and generally from 0.5 g up to 5 g/day to reach a therapeutic level in plasma (5 μM) [121]. Furthermore, RSV efficacy is also time-dependent, and an oral daily intake for 2 months is effective in patients with angina pectoris only if trans-RSV (at 20 mg) is associated with calcium fructoborate [122]. Moreover, controversial RSV effects reported on nonalcoholic fatty liver (NAFLD) are probably linked to different oral doses (from 500 mg/day up to 3000 mg/day), time of administration (from 56 days up to 6 months), and number of patients considered in clinical trials [123]. On the contrary, promising results have been recently obtained on 119 patients with mild to moderate Alzheimer’s disease orally supplemented with RSV at 1 g twice a day for 52 weeks, which presented reduced inflammatory markers in plasma and cerebrospinal fluid [124]. Herein, there is still a lot of research to do on the RSV and other STACs drug and caution must be taken to sustain their definitive clinical therapeutic effects in humans.

到目前为止,人们已经认识到反式呼吸道合胞体(trans-RSV)在老年人退行性疾病和代谢性疾病中的多效性作用,但尽管在体外和啮齿动物模型中有大量的证据,它们对人类的治疗作用仍然存在争议。首先,它的有益作用是严格的剂量依赖性的,为了增强线粒体的健康,阿尔茨海默病患者至少需要口服1克/天的 RSV,一般从0.5克/天到5克/天才能达到血浆中的治疗水平(5μM)[121]。此外,RSV 的疗效也是时间依赖性的,只有当反式 RSV (20mg)与果糖硼酸钙有关时,2个月的每日口服量对心绞痛患者才有效。此外,非酒精性脂肪肝(NAFLD)上有争议的 RSV 效应可能与不同的口服剂量(从500毫克/天到3000毫克/天)、给药时间(从56天到6个月)以及临床试验中考虑的患者人数有关[123]。相反,最近在119名轻度至中度阿尔茨海默病患者口服补充呼吸道合胞病毒,每天两次1克,持续52周,取得了有希望的结果,血浆和脑嵴液中的炎症标志物减少[124]。在此,仍有许多关于 RSV 和其他 STACs 药物的研究工作要做,必须谨慎行事,以维持其对人类的决定性临床治疗效果。

6. Conclusions

6. 结论

A constant effort has been made to synthesize novel drugs to extend life span, to prolong the quality of the life in elderly, and to limit age-associated diseases. Unfortunately, to date, there is no drug that could be an elixir of longevity for humans even if more than a hundred clinical trials on natural or synthetic SIRT1 activators are ongoing worldwide. However, there are still many challenges to discover and test the efficacy of antiaging drugs in clinics together with the necessity to get funds for a long time. The main final message from this chapter may be that a big scientific awareness is placed in the aging research, as indicated by the tremendous number of published articles on this topic. Indeed, all actors in the biogerontology scenario agree that not only the extension of the life is important in elderly, but it is fundamental its quality, maintaining a good health. To reach this aim, dietary intervention with caloric restriction mimetics is crucial, but remember to start early during adult age to best adapt your metabolism to counteract aging.

人们一直在努力合成新的药物,以延长寿命,延长老年人的生活质量,并限制与年龄有关的疾病。不幸的是,到目前为止,没有药物可以长寿,即使超过100个自然或合成的 SIRT1激活剂的临床试验正在世界各地进行。然而,在临床上发现和检验抗衰老药物的有效性,以及长期筹集资金的必要性,仍然存在许多挑战。这一章的最后一个主要信息可能是,在衰老研究中存在着巨大的科学意识,正如关于这个主题的大量发表文章所表明的那样。事实上,生物老年学的所有参与者都同意,延长寿命不仅对老年人很重要,而且对保持健康的基本质量也很重要。为了达到这个目的,饮食干预与热量限制模型是至关重要的,但请记住开始早在成人年龄,以最好地适应您的新陈代谢抵消衰老。

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