烟酰胺腺嘌呤二核苷酸和Sirtuins在衰老和疾病中的作用

烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide, NAD⁺)作为氧化还原反应的重要辅酶,是能量代谢的核心。NAD⁺也是非氧化还原NAD⁺依赖性酶的共底物,包括沉默信息调节因子(Sirtuins)、聚ADP-核糖聚合酶(poly ADP-ribose polymerases, PARPs)、CD38/CD157胞外酶等。NAD⁺已成为细胞信号转导和细胞存活的关键调节剂。最近的研究表明,Sirtuins催化多种NAD⁺依赖性反应,包括去乙酰化、脱酰基化和ADP-核糖基化。Sirtuins催化活性取决于NAD⁺水平的高低。因此,Sirtuins是细胞代谢和氧化还原状态关键传感器。哺乳动物中已经鉴定并表征了7个Sirtuins家族成员(SIRT1-7),其参与炎症、细胞生长、生理节律、能量代谢、神经元功能、应激反应和健康衰老等多种生理过程。本文归纳了NAD⁺的生理浓度及状态、NAD⁺的生物合成途径,并阐述了Sirtuins的生物学功能,重点讨论了SIRT1-7表达及活性与衰老和疾病之间的关系。此外,本文还进一步探讨了NAD⁺和Sirtuins依赖的衰老机制,机体NAD⁺水平随着年龄增长而下降,导致Sirtuins活性下降,尤其是SIRT1、SIRT3和SIRT6,引发细胞核和线粒体功能下降,衰老及老化相关疾病也随之发生。研究表明,NAD⁺前体补充剂能够快速提高机体NAD⁺水平和Sirtuins活性,是一种有效的抗衰老干预措施,为全球老龄化社会带来希望。

Roles of NAD+ and Sirtuins in Aging and Disease

Nicotinamide adenine dinucleotide (NAD⁺) is an important coenzyme for redox reactions, making it central to energy metabolism. NAD⁺ is also a cosubstrate for non-redox NAD⁺-dependent enzymes, including Sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38/157 ectoenzymes. NAD⁺has also emerged as a key modulator of cell signaling and survival pathways. Recent works have revealed that Sirtuins catalyze a variety of NAD⁺-dependent reactions, including deacetylation, deacylation and ADP-ribosylation. The catalytic activity of Sirtuins depends on the level of NAD⁺. Therefore, Sirtuins are critical sensors of cell metabolic and redox states. Seven Sirtuins family members (SIRT1-7) have been identified and characterized in mammals, which are involved in various physiological processes such as inflammation, cell growth, circadian rhythm, energy metabolism, neuron function, and stress response. This review summarized the physiological concentration and state of NAD⁺, the biosynthesis pathway of NAD⁺, the biological functions of Sirtuins, especially the relationship between the expression and activity of SIRT1-7 and aging and disease. Furthermore, this review also delineated the mechanism of NAD⁺and Sirtuins-dependent aging. The level of NAD⁺ decreases with age, leading to the decline of Sirtuins activity, especially SIRT1, SIRT3, and SIRT6, causing defects in nuclear and mitochondrial functions, and the occurrence of aging and age-related diseases. The study showed that NAD⁺ precursor supplement can rapidly improve the NAD⁺ level and Sirtuins activity, which is an effective anti-aging intervention, providing hope to aging societies worldwide.