Lower Vulnerability to Toxins in Aging by Treatment with Lipoic Acid

65岁以上的人构成了美国人口中增长最快但最不健康的部分。 这一年龄组显示出对毒素、药物相互作用和氧化应激的夸大脆弱性，这些因素共同使年龄本身成为慢性病和死亡的主要风险因素。反过来，这些疾病严重限制了生活质量，并极大地增加了医疗保健成本，随着“美国老龄化”，医疗成本正在飙升。为什么老年人的细胞防御系统不能应对压力挑战，目前尚不清楚，这是维持健康衰老的一个重大障碍。为了克服这个问题，美国人服用抗氧化剂或补充药物(CAM)，试图预防与年龄相关的慢性疾病。不幸的是，到目前为止，这些补充剂并没有改善老年人的健康。回想起来，许多人 其中，CAM剂可能是不完全的保护剂，因为它们不能充分补偿老年人细胞和组织中内源性抗氧化剂和抗氧化剂基因表达的减少。因此，健康衰老的更好方法是维持内源性应激抵抗机制。为此，我们发现，给老年大鼠喂食α-硫辛酸(R-LA)可以通过防止内源性抗氧化防御系统的丧失来逆转与年龄相关的氧化损伤易感性。R-LA不是作为自由基清除剂提供这种保护，而是通过维持Nrf2的活性来提供这种保护，Nrf2是一种控制Over表达的转录因子 100个含有抗氧化反应元件(ARE)的抗氧化和解毒基因。然而，尽管最终确定了与随年龄丧失的应激抵抗力有关的分子损伤，但R-LA如何维持这些重要的细胞防御以及长期膳食补充R-LA是否是降低与年龄相关的病理风险的有效补充药物的确切机制(S)尚不清楚。因此，本申请的目的是确定R-LA逆转老年大鼠NRF2依赖的应激抗性衰退并降低对毒物侮辱的易感性的精确机制(S)。我们假设，R-LA作用于两个最重要的调控Nrf2活性的机制，即影响核Nrf2水平的途径；以及它与基因上的伙伴蛋白的相互作用 水平。因此，我们认为R-LA是一种新型的健康衰老药物，可以防止应激反应的丧失和这种下降所产生的不良健康影响。这些假说将在三个特定的目标中进行探讨，即：1)确定R-LA逆转核NRF2水平随年龄下降的机制(S)：2)确定R-LA通过介导基因转录随年龄增加的机制(S)：以及3)评估R-LA通过维持随年龄增长的NRF2依赖的应激反应系统而增加“健康寿命”的益处。在拟议的实验完成后，我们预计将首次开发出一种针对年龄相关性应激抵抗力丧失的营养疗法，该疗法可能被开发为CAM的辅助工具，以延长人类的“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".