为什么 NAD + 在衰老过程中衰退: 它被摧毁了

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Why NAD+ Declines during Aging: It’s Destroyed

Abstract

摘要

NAD+ is required not only for life but for a long life. In this issue, Camacho-Pereira et al. (2016) implicate CD38 in the decline of NAD+ during aging, with implications for combating age-related diseases.

NAD + 不仅是生命所必需的,而且是长寿所必需的。在这一问题上,卡马乔-佩雷拉等人(2016年)暗示 CD38在衰老过程中降低 NAD + ,对抗年龄相关疾病的影响。

The discovery of nicotinamide adenine dinucleotide (NAD+) as a “cozymase” factor in fermentation has its 110th anniversary this year. Of the two billion people who were alive back in 1906, only 150 people remain. Interestingly, NAD+ itself may be the reason for their longevity. In this issue, Eduardo Chini and colleagues address an open question in biogerontology: why do NAD+ levels fall as we age? They show that the major culprit is an NADase called CD38 whose levels rise during aging. Their results also add to the body of evidence indicating that loss of SIRT3 activity in mitochondria is a cause of age-related metabolic decline (Camacho-Pereira et al., 2016) (Figure 1).

烟酰胺腺嘌呤二核苷酸作为发酵过程中的一种辅酶因子的发现今年已经110周年了。在1906年的20亿人口中,只有150人幸存下来。有趣的是,NAD + 本身可能就是它们长寿的原因。在这个问题上,Eduardo Chini 和他的同事们解决了生物老年学中的一个悬而未决的问题: 为什么 NAD + 水平会随着我们的年龄而下降?他们发现罪魁祸首是一种叫做 CD38的 NADase,它的水平在衰老过程中会上升。他们的结果也增加了身体的证据,表明线粒体中 SIRT3活性的丧失是年龄相关的代谢下降的原因(卡马乔-佩雷拉等人,2016年)(图1)。Figure 1 图1CD38 Regulates Metabolism during Aging through Modulating NAD CD38通过调节 NAD 调节衰老过程中的代谢+ Levels and SIRT3 Activity 水平和 SIRT3活动

CD38 is a membrane-bound NADase that hydrolyzes NAD+ to nicotinamide and (cyclic-)ADP-ribose. Its protein levels increase during aging, with a corresponding increase in NADase activity and declining NAD+levels. Mice deficient for CD38 are protected from mitochondrial dysfuntion and diabetes during aging. Many of these effects are mediated through the mitochondrial sirtuin SIRT3. As CD38 also degrades NMN, the CD38 knockout mice also are more sensitive to treatment with NAD+ precursors.

CD38是一种膜结合的 NADase,能水解 NAD + 生成烟酰胺和(环状) adp- 核糖。它的蛋白质水平在衰老过程中增加,相应的 NADase 活性增加,NAD + 水平下降。缺乏 CD38的小鼠在衰老过程中不会出现线粒体功能障碍和糖尿病。许多这些效应是通过线粒体 sirtuin SIRT3介导的。由于 CD38也降解 NMN,CD38基因敲除小鼠对 NAD + 前体治疗也更敏感。

NAD+, and its reduced form NADH, are best known for their roles as coenzymes in redox reactions, linking the catabolic reactions of glycolysis and the TCA cycle to oxidative phosphorylation. In the last two decades, however, another role for NAD+ has been uncovered. Perhaps equally as important (and ancient) is NAD’s role as a signaling molecule. From plants to metazoans, an increase in intracellular levels of NAD+ directs cells to make adjustments to ensure survival, including increasing energy production and utilization, boosting cellular repair, and coordinating circadian rhythms.

和它的还原形式 NADH,最著名的是它们在氧化还原反应中的辅酶作用,连接糖酵解的分解代谢反应和 TCA 循环到氧化磷酸化。然而,在过去的二十年中,NAD + 的另一个作用已经被发现。也许同样重要(而且古老)的是 NAD 作为信号分子的角色。从植物到后生动物,细胞内 NAD + 水平的升高引导细胞做出调整以确保生存,包括增加能量的产生和利用,促进细胞修复和协调昼夜节律。

NAD+ levels are converted to signals by various enzymes that have evolved to sense NAD+, including the sirtuin deacylases (SIRT1–SIRT7), CtBPs, and poly-ADP-ribose polymerases (PARPs). They can sense NAD+ fluctuations because, unlike the enzymes of glycolysis and the TCA cycle, their dissociation constants for NAD+ are near physiological concentrations. Unfortunately, NAD+ levels steadily decline during aging. By the time a mouse or human is middle aged, levels of NAD+ have fallen to half of youthful levels, with resulting loss of sirtuin and PARP activity. Several studies in recent years have shown that treatment of old mice with PARP inhibitors or precursors to NAD+ can greatly improve health. Observed effects include increased insulin sensitivity, reversal of mitochondrial dysfunction, reduced stem cell senescence, and extension of lifespan (Bai et al., 2011Gomes et al., 2013Yoshino et al., 2011Zhang et al., 2016).

NAD + 水平通过各种酶转换成信号,这些酶进化成可感知 NAD + ,包括 sirtuin deacylases (SIRT1-SIRT7)、 CtBPs 和多 adp-ribose 聚合酶(PARPs)。它们可以感觉到 NAD + 的波动,因为与糖酵解酶和 TCA 循环不同,NAD + 的解离常数接近生理浓度。不幸的是,NAD + 水平在老化过程中稳步下降。当一个老鼠或者人到了中年,NAD + 水平已经下降到年轻水平的一半,导致去乙酰化酶和 PARP 活性的丧失。近年来的一些研究表明,用 PARP 抑制剂或 NAD + 前体治疗老年小鼠可以大大改善健康状况。观察到的效果包括增加胰岛素敏感性,逆转线粒体功能障碍,减少干细胞衰老,延长寿命(Bai 等人,2011; Gomes 等人,2013; Yoshino 等人,2011; Zhang 等人,2016)。

A major question that has remained unanswered is why NAD+ levels decline in the first place. One suggestion was that the synthesis of NAD+ declines with age. Indeed, overexpression of the NAD+biosynthetic genes NPT1 and PNC1 in yeast extends lifespan by over 50% (Anderson et al., 2002). Other possibilities include increased degradation of NAD+ by hydrolysis or increased NAD+ polymerization to generate poly-ADP-ribose (PAR). Sirtuins degrade NAD+ via a deacylation reaction, but only in a limited fashion. Realistic candidates are the PARPs and the two NADases, CD38 and BST1.

一个尚未解答的主要问题是,为什么 NAD + 水平首先会下降。有一种观点认为 NAD + 的合成会随着年龄的增长而减少。实际上,酵母中 NAD + 生物合成基因 NPT1和 PNC1的过度表达延长了50% 以上的寿命(Anderson 等人,2002)。其他的可能性包括通过水解或增加 NAD + 聚合生成聚 adp- 核糖(PAR)来增加 NAD + 的降解。去乙酰化酶通过脱酰化反应降解 NAD + ,但降解的方式是有限的。现实的候选者是 PARPs 和两个 NADases,CD38和 BST1。

Which brings us to CD38. CD38 is a membrane-bound hydrolase that has been implicated in immune responses and energy metabolism. Mice lacking CD38 or treated with the CD38 inhibitor apigenin have elevated levels of NAD+ and are protected against deleterious effects of a high-fat diet (Escande et al., 2013). In this latest study, the authors show that protein levels of CD38, but not of SIRT1 or PARP1, increased in multiple tissues during aging, along with a corresponding increase in CD38 enzymatic activity (Camacho-Pereira et al., 2016). At 32 months, wild-type mice had about half the NAD+ of a young mouse, but the CD38 knockout showed no decrease.

这就是 CD38。CD38是一种膜结合水解酶,与免疫反应和能量代谢有关。缺乏 CD38或接受 CD38抑制剂芹菜素治疗的小鼠的 NAD + 水平升高,并且能够抵御高脂肪饮食的有害影响(Escande 等人,2013年)。在这项最新的研究中,作者表明,CD38的蛋白质水平,而不是 SIRT1或 PARP1的蛋白质水平,在老化过程中,随着 CD38酶活性的相应增加,在多个组织中增加(Camacho-Pereira 等人,2016年)。在32个月时,野生型小鼠的 NAD + 大约只有年轻小鼠的一半,但 CD38基因敲除并没有减少。

Mitochondrial dysfunction is a hallmark of metabolic decline during aging. Chini and colleagues found that cells overexpressing CD38 consume less oxygen, have increased lactate levels, and possess irregular mitochondria (Camacho-Pereira et al., 2016). Conversely, mitochondria from the livers of CD38 knockout mice consumed more oxygen and had greater mitochondrial membrane potential. Mitochondrial protein acetylation was decreased in the CD38 knockout mice, indicating that a mitochondrial sirtuin might be involved. Consistent with this, the knockout of SIRT3 in the CD38 knockout background abolished the protective effects of the CD38 knockout alone on mitochondrial respiration and glucose tolerance.

线粒体功能障碍是衰老过程中新陈代谢下降的标志。Chini 和他的同事们发现过度表达 CD38的细胞消耗更少的氧气,乳酸水平增加,并且拥有不规则的线粒体(Camacho-Pereira et al. ,2016)。相反,CD38基因敲除小鼠肝脏中的线粒体消耗更多的氧气,并且线粒体膜电位更大。CD38基因敲除小鼠线粒体蛋白乙酰化程度降低,提示可能与线粒体去乙酰化酶有关。与此相一致的是,在 CD38基因敲除背景下的 SIRT3基因敲除取消了单独的 CD38基因敲除对线粒体呼吸和葡萄糖耐量的保护作用。

Finally, the authors addressed how CD38 may affect therapies designed to raise NAD+ levels. Currently, the favored approach in mouse and humans is to treat with NAD+ precursors, such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN). Interestingly, CD38 not only degrades NAD+ in vivo, but also NMN. When CD38 knockout mice were given injections of NAD+, NMN, or NR (which is converted to NMN), circulating levels of NAD metabolites remained stable after 150 min, long after they began to fall in the wild-type animals. Furthermore, when compared to the wild-type, CD38 knockout mice on a high-fat diet exhibited a much larger improvement in glucose tolerance when given NR. These findings suggest that the efficacy of NAD+ precursors may be enhanced by co-supplementation with CD38 inhibitors, which have been recently identified (Escande et al., 2013Haffner et al., 2015).

最后,作者阐述了 CD38可能如何影响旨在提高 NAD + 水平的治疗。目前,治疗小鼠和人类最好的方法是使用 NAD + 前体,如烟酰胺核糖苷(NR)或烟酰胺单核苷酸(NMN)。有趣的是,CD38不仅在体内降解 NAD + ,而且降解 NMN。当 CD38基因敲除小鼠注射 NAD + 、 NMN 或 NR (转化为 NMN)后,在野生型动物开始下降后150分钟内,NAD 代谢物的循环水平保持稳定。此外,与野生型相比,高脂肪饮食中的 CD38基因敲除小鼠给予 NR 后,在葡萄糖耐量方面表现出更大的改善。这些发现表明,NAD + 前体的疗效可能通过与 CD38抑制剂的共同补充得到提高,这些抑制剂最近已经被确定(Escande 等人,2013; Haffner 等人,2015)。

As with all good studies, numerous questions have been raised. It is well established that there are relatively independent pools of NAD+ in the nucleus, cytosol, and mitochondria (Yang et al., 2007). Given that NADase activity has been detected on the plasma membrane and in mitochondria, it will be important to determine how NAD+ levels change in different compartments during aging and how CD38 affects them. Also, what role, if any, does the CD38 homolog BST1, which itself has NADase activity, play in regulating NAD+ levels? And at a more basic level, why do cells have an enzyme to destroy NAD+ and what triggers it to increase during aging? In light of the fact that CD38 expression is regulated by NF-κB (Tirumurugaan et al., 2008) and low-grade inflammation is a characteristic of aging, a possibility is that inflammation is the answer. Either way, the identification of molecules that safely maintain NAD+ levels in humans cannot come soon enough for patients who could benefit and those who hope to celebrate many more anniversaries.

正如所有好的研究一样,许多问题已经被提出。在细胞核、细胞溶胶和线粒体中存在相对独立的 NAD + 池(Yang 等人,2007)。鉴于在质膜和线粒体中已经检测到 NADase 活性,确定在衰老过程中不同部位 NAD + 水平的变化以及 CD38如何影响它们将是非常重要的。另外,CD38同源基因 BST1本身具有 NADase 活性,在调节 NAD + 水平方面起什么作用?在更基本的层面上,为什么细胞中有一种酶可以破坏 NAD + ,又是什么引发它在衰老过程中增加?考虑到 CD38的表达是由 NF-κB 调节的(Tirumurugaan et al. 2008) ,以及低度炎症是衰老的一个特征,一种可能性是炎症是答案。不管怎样,对于那些可以从中受益的患者和那些希望庆祝更多周年纪念日的患者来说,确定能够安全地维持人体 NAD + 水平的分子还不够快。Go to: 去:

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