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Kynurenine pathway, NAD+ synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan.
Experimental Gerontology ( IF 3.9 ) Pub Date : 2020-01-16 , DOI: 10.1016/j.exger.2020.110841
Raul Castro-Portuguez 1 , George L Sutphin 2
Affiliation  

Aging is characterized by a progressive decline in the normal physiological functions of an organism, ultimately leading to mortality. Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor that plays a critical role in mitochondrial energy production as well as many enzymatic redox reactions. Age-associated decline in NAD+ is implicated as a driving factor in several categories of age-associated disease, including metabolic and neurodegenerative disease, as well as deficiency in the mechanisms of cellular defense against oxidative stress. The kynurenine metabolic pathway is the sole de novo NAD+ biosynthetic pathway, generating NAD+ from ingested tryptophan. Altered kynurenine pathway activity is associated with both aging and a variety of age-associated diseases. Kynurenine pathway interventions can extend lifespan in both fruit flies and nematodes, and altered NAD+ metabolism represents one potential mediating mechanism. Recent studies demonstrate that supplementation with NAD+ or NAD+-precursors increase longevity and promote healthy aging in fruit flies, nematodes, and mice. NAD+ levels and the intrinsic relationship to mitochondrial function have been widely studied in the context of aging. Mitochondrial function and dynamics have both been implicated in longevity determination in a range of organisms from yeast to humans, at least in part due to their intimate link to regulating an organism's cellular energy economy and capacity to resist oxidative stress. Recent findings support the idea that complex communication between the mitochondria and the nucleus orchestrates a series of events and stress responses involving mitophagy, mitochondrial number, mitochondrial unfolded protein response (UPRmt), and mitochondria fission and fusion events. In this review, we discuss how mitochondrial morphological changes and dynamics operate during aging, and how altered metabolism of tryptophan to NAD+ through the kynurenine pathway interacts with these processes.

中文翻译:

Kynurenine途径,NAD +合成和线粒体功能:靶向色氨酸代谢以促进寿命和健康。

衰老的特征是生物体正常生理功能的逐渐下降,最终导致死亡。烟酰胺腺嘌呤二核苷酸(NAD +)是必需的辅因子,在线粒体能量产生以及许多酶促氧化还原反应中发挥关键作用。NAD +的年龄相关性下降与多种年龄相关性疾病(包括代谢性疾病和神经退行性疾病)以及针对氧化应激的细胞防御机制不足有关。犬尿氨酸代谢途径是唯一的新生NAD +生物合成途径,从摄入的色氨酸产生NAD +。犬尿氨酸途径活性的改变与衰老和多种与年龄有关的疾病有关。Kynurenine途径的干预可以延长果蝇和线虫的寿命,改变的NAD +代谢代表了一种潜在的介导机制。最近的研究表明,补充NAD +或NAD +前体可延长寿命,并促进果蝇,线虫和小鼠的健康衰老。NAD +水平和与线粒体功能的内在联系已被广泛研究衰老。线粒体功能和动力学都与从酵母到人类的各种生物的寿命确定有关,至少部分是由于它们与调节生物的细胞能源经济和抵抗氧化应激的能力密切相关。最新发现支持以下观点:线粒体与细胞核之间的复杂交流会编排一系列事件和应激反应,包括线粒体,线粒体数目,线粒体未折叠蛋白反应(UPRmt)以及线粒体裂变和融合事件。在这篇综述中,我们讨论了衰老过程中线粒体形态变化和动力学如何运作,以及色氨酸通过犬尿氨酸途径改变为NAD +的代谢如何与这些过程相互作用。
更新日期:2020-01-16
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