Age-related changes in glutathione synthesis

谷胱甘肽合成与年龄相关的变化

• 批准号: 6756537
• 负责人: NAOMI K FUKAGAWA
• 金额: $ 37.49万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6756537
• 关键词: acetaminophen; age difference; biosynthesis; blood chemistry; clinical research; cysteine; diabetes mellitus; glutathione; human middle age (35-64); human old age (65+); human subject; oxidative stress; stable isotope; young adult human (21-34)

DESCRIPTION (provided by applicant): Oxidative stress is thought to be one of the mechanisms leading to the initiation or progression of specific diseases as well as to the general process of aging. Glutathione (GSH), a tripeptide present in high concentrations in all mammalian cells, is the body's major endogenous antioxidant and plays a vital role in detoxification reactions and in the protection of cells from the toxic effects of oxidants. Maintenance of body GSH stores is a complex, integrated phenomenon, and there has been a resurgence of interest in potential interventions that may modulate GSH levels in the whole body and in specific tissues and cells. Advancing age, known to be associated with increased oxidative stress, is also reported to be associated with low GSH concentrations. In addition, aging is associated with an increased prevalence of cardiovascular disease, impaired glucose tolerance, and diabetes mellitus; the latter has also been shown to be accompanied by lower GSH concentrations. The mechanisms that could be responsible for a compromised GSH status include decreased synthesis and/or increased utilization relative to synthetic capacity. Ideally, one would like to measure in vivo rates of both GSH synthesis and utilization. Unfortunately, the multitude of pathways consuming GSH, as well as tissue variation, makes it impossible to have meaningful simultaneous measurements of utilization by all of the different pathways in the human. Hence, the focus of this proposal will be on GSH synthesis rates. We plan to test the hypotheses that 1) older men and women (age 60+ years) will have lower GSH synthesis rates and lower GSH levels compared to younger (<35 years) subjects and these differences will be exacerbated by diabetes mellitus in the old and 2) the provision of precursors for cysteine, the rate-limiting amino acid in GSH synthesis, will attenuate these differences. The specific aims are to determine: 1) Rates of GSH synthesis in younger and older groups of non-diabetic men and women using stable isotope tracer methodology, and GSH concentrations in plasma and erythrocytes of these volunteers. 2)The effect of diabetes mellitus on GSH synthesis rates and concentrations in older men and women. 3)The effect of GSH depletion by acetaminophen on rates of GSH synthesis in young and old non-diabetics. 4) The effect of GSH depletion by acetaminophen on rates of GSH synthesis in older non-diabetics and diabetics. 5) Whether acute administration of the cysteine precursor, L-2-oxothiazolidine-4-carboxylic acid (OTZ), will increase rates of GSH synthesis and GSH levels in young and old non-diabetic volunteers. 6) Whether acute administration of the cysteine precursor, OTZ, will increase rates of GSH synthesis and GSH levels 7 older nondiabetic and diabetic men and women. Data obtained in these in vivo studies will help to integrate in humans the diverse findings obtained in experiments conducted in animals and from in vitro cell culture systems and to improve our fundamental understanding of the effect of aging on GSH homeostasis in humans. It is hoped that the data will lay the groundwork for future studies examining the efficacy of nutritional supplements aimed at modulating an individual's GSH status and potentially ameliorating the deleterious effects of oxidative stress.

描述（由申请人提供）：氧化应激被认为是导致特定疾病引发或发展的机制之一，以及衰老的一般过程。 谷胱甘肽（GSH）是所有哺乳动物细胞中高浓度的三肽，是人体主要的内源性抗氧化剂，在排毒反应和保护细胞免受氧化剂毒性的保护中起着至关重要的作用。 人体GSH商店的维持是一种复杂的综合现象，并且对潜在干预措施的兴趣兴起，这些干预措施可能调节全身以及特定的组织和细胞中的GSH水平。 据报道，已知与氧化应激增加有关的年龄也与较低的GSH浓度有关。 此外，衰老与心血管疾病，葡萄糖耐受性受损和糖尿病的患病率增加有关。后者也已显示出较低的GSH浓度。 可能导致GSH状态损害的机制包括降低合成和/或相对于合成能力的利用率增加。 理想情况下，人们希望测量GSH合成和利用率的体内速率。 不幸的是，消耗GSH的多种途径以及组织变化使得人类所有不同途径的利用都无法同时测量有意义的测量。 因此，该提案的重点将放在GSH合成率上。 我们计划测试以下假设：1）与年轻人（<35岁）的受试者相比，年长的男女（60岁以上）的GSH合成率和较低的GSH水平将较低，而这些差异将因老年糖尿病而加剧，而老年人和2个受试者的糖尿病会加剧。 具体目的是确定：1​​）使用稳定的同位素示踪方法的年轻和年龄较大的非糖尿病男性和女性组中GSH合成率，以及这些志愿者的血浆和红细胞的GSH浓度。 2）糖尿病对老年男性和女性GSH合成率和浓度的影响。 3）对乙酰氨基酚的GSH耗竭对年轻和非糖尿病的GSH合成速率的影响。 4）对乙酰氨基酚的GSH耗竭对较旧的非糖尿病和糖尿病患者GSH合成速率的影响。 5）急性施用半胱氨酸前体，L-2-氧噻唑啉-4-羧酸（OTZ）是否会提高年轻和非糖尿病志愿者的GSH合成率和GSH水平。 6）急性服用半胱氨酸前体OTZ是否会提高GSH合成的速率和GSH水平7较老的非糖尿病和糖尿病男性和女性。 在这些体内研究中获得的数据将有助于将人类整合到人类中，这些发现在动物和体外细胞培养系统中进行的实验中获得的各种发现，并提高我们对衰老对人类GSH稳态影响的基本了解。 希望这些数据将为未来的研究奠定基础，以研究旨在调节个人GSH状况并有可能改善氧化应激的有害影响的营养补充剂的功效。