Lower Vulnerability to Toxins in Aging by Treatment with Lipoic Acid

65岁以上的人是美国人口中增长最快但最不健康的群体。 这个年龄组显示出对毒素、药物相互作用和氧化应激的过度脆弱性， 这些因素共同使年龄本身成为慢性病和死亡率的主要风险因素。反过来，这些 发病率严重限制了生活质量，并极大地增加了医疗费用，医疗费用沿着飙升 "美国的老龄化"为什么老年人的细胞防御不能上升以应对压力挑战， 这是一个未知的问题，是维持健康老龄化的重大障碍。为了克服这个问题， 美国人服用抗氧化剂或补充药物（CAM），试图预防与年龄有关的慢性疾病。 疾病不幸的是，到目前为止，这些补充剂未能改善老年人的健康。回顾过去，许多 这些CAM试剂中的大多数可能是不完全的保护剂，因为它们不能充分补偿 内源性抗氧化剂和抗氧化基因在细胞和组织中的表达。一个更好的 健康老龄化的方法将是保持内源性抗应激机制。为此我们 发现喂食老年老鼠α-硫辛酸（R-LA）逆转了与年龄相关的氧化损伤易感性 通过防止内源性抗氧化防御的损失。R-LA提供这种保护不是作为一种自由基 清道夫，但通过维持Nrf2的活性，Nrf2是一种转录因子，控制过度表达 100个抗氧化和解毒基因含有抗氧化反应元件（ARE）。但是，在这方面， 尽管最终确定了与随年龄而丧失应激抗性有关的分子损伤，但R-LA如何维持这些重要细胞防御的精确机制以及长期膳食R-LA补充剂是否是降低年龄相关病理风险的有效补充药物尚不清楚。因此，本申请的目的是定义R-LA逆转老年大鼠中Nrf2依赖性应激抗性的衰减并降低对毒理学损伤的脆弱性的精确机制。我们假设R-LA作用于两个最重要的调控机制，即Nrf2 活性，即影响核Nrf2水平的途径;以及其在基因水平上与伴侣蛋白的相互作用。因此，我们认为R-LA是一种新型的健康衰老药物，可以防止压力反应的丧失以及这种下降所产生的不良健康影响。这些假设将在三个特定目标中进行探索，即：1）确定R-LA逆转核Nrf2水平随年龄下降的机制; 2）确定R-LA增加ARE介导的基因转录随年龄增长的机制; 3）评估R-LA通过维持Nrf2依赖性应激反应系统随年龄增长而增加"健康寿命"的益处。在完成拟议的实验后，我们预计，第一次，将开发出一种营养疗法，用于年龄依赖性的抗应激能力丧失，这可能是可开发的CAM辅助延长人类的“健康寿命”。

People over the age of 65 comprise the fastest growing, but least healthy, segment of the U.S. population. This age-group displays an exaggerated vulnerability to toxins, drug interactions, and oxidative stress, which collectively makes age itself the leading risk factor for chronic diseases and mortality. In turn, these morbidities severely limit the quality of life and add enormously to healthcare costs, which are soaring along with the "graying of America". Why cellular defenses in the elderly cannot rise to meet stress challenges is not known and represents a significant obstacle to maintaining healthy aging. To overcome this problem, Americans take antioxidants or complementary medicines (CAM) in attempts to prevent chronic age-related diseases. Unfortunately, these supplements have, so far, failed to improve elder health. In retrospect, many of these CAM agents may be incomplete protectants as they cannot sufficiently compensate for diminished endogenous antioxidants and antioxidant gene expression in the cells and tissues of the aged. Thus, a better approach for healthy aging would be to maintain endogenous stress resistance mechanisms. To this end, we found that feeding old rats f?-a-lipoic acid (R-LA) reversed the age-related susceptibility to oxidative insults by preventing the loss in endogenous antioxidant defenses. R-LA affords this protection not as a free radical scavenger, but by maintaining the activity of Nrf2, a transcription factor that governs the expression of over 100 antioxidant and detoxification genes containing the Antioxidant Response Element (ARE). However, despite finally identifying a molecular lesion involved in lost stress resistance with age, the precise mechanism(s) how R-LA maintains these vital cellular defenses and also whether long-term dietary R-LA supplementation is an effective complementary medicine to lower risk for age-associated pathologies is not known. Thus, the objectives of the present application are to define the precise mechanism(s) by which R-LA reverses decay in Nrf2-dependent stress resistance in aged rats and lowers vulnerability to toxicological insults. We hypothesize that R-LA works on the two most important regulatory mechanisms governing Nrf2 activity, namely, pathways affecting nuclear Nrf2 levels; and its interaction with partner proteins at the gene level. We thus propose that R-LA is a novel healthy aging medicine that prevents loss of stress response and the adverse health effects this decline engenders. These hypotheses will be explored in three Specific Aims, namely, to: 1) Determine the mechanism(s) through which R-LA reverses the decline in nuclear Nrf2 levels with age: 2) Determine the mechanism(s) through which R-LA increases ARE-mediated gene transcription with age: and 3) Assess the benefits of R-LA to increase "healthspan" by maintaining Nrf2-dependent stress response systems with age. Following completion of the proposed experiments, we anticipate that, for the first time, a nutritive therapy for age-dependent loss of stress resistance will have been developed, which may be exploitable as a CAM adjunct to extend human "healthspan".