Lower Vulnerability to Toxins in Aging by Treatment with Lipoic Acid

通过硫辛酸治疗降低衰老过程中毒素的脆弱性

• 批准号: 7902740
• 负责人: TORY M HAGEN
• 金额: $ 39.27万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7902740
• 关键词: Acetaminophen; Acute; Adult; Affect; Age; Aging; Aging-Related Process; American; Americas; Animals; Antiatherogenic; Antioxidants; Atherosclerosis; Binding; Cell Culture Techniques; Cells; Cellular Stress; Chronic; Chronic Disease; Collaborations; Complement; Complementary Medicine; Complementary and alternative medicine; DNA Sequence; Defense Mechanisms; Development; Diet; Disease; Drug Interactions; Drug Metabolic Detoxication; Effectiveness; Elderly; Enzymes; Figs - dietary; Free Radical Scavengers; Funding; Gene Expression; Genes; Genetic Transcription; Geriatrics; Glutathione; Goals; Grant; Gray unit of radiation dose; Health; Health Care Costs; Heart Diseases; Hepatic; Hepatocyte; Homeostasis; Human; Inbred F344 Rats; Knowledge; Lesion; Life; Lymphocyte; Malignant Neoplasms; Measurement; Mediating; Medicine; Micronutrients; Modeling; Molecular; Morbidity - disease rate; Mutagens; NF-E2-related factor 2; Nature; Neurodegenerative Disorders; Nuclear; Nuclear Export; Oral; Oxidants; Oxidative Stress; Pathology; Pathway interactions; Peripheral; Persons; Phenotype; Play; Population; Predisposition; Process; Protective Agents; Proteins; Quality of life; Rattus; Reporter; Repression; Resistance; Response Elements; Risk; Risk Factors; Rodent; Role; Runaway; Site; Small Interfering RNA; Spinal Cord; Stress; Supplementation; System; Techniques; Testing; Thioctic Acid; Time; Tissues; Toxin; Transgenic Animals; Translating; Work; age group; age related; aged; antioxidant therapy; atherogenesis; biological adaptation to stress; cancer chemoprevention; cardiovascular disorder risk; dietary antioxidant; effective therapy; feeding; healthy aging; human subject; improved; innovation; insight; interest; loss of function; meetings; monocyte; mortality; nervous system disorder; novel; palliative; prevent; progenitor; research study; resistance mechanism; response; transcription factor

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".

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疾病和死亡率的主要风险因素。反过来，这些疾病严重限制了生活质量，极大地增加了医疗费用，这是飙升沿着“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尚不清楚，这是维持健康老龄化的一个重大障碍。为了克服这个问题，美国人服用抗氧化剂或补充药物（CAM），试图预防与年龄有关的慢性疾病。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剂中的一些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减少的内源性抗氧化剂和抗氧化剂基因表达。因此，健康老龄化的更好方法是保持内源性抗应激机制。为此，我们发现，喂养老年大鼠f？α-硫辛酸（R-LA）通过防止内源性抗氧化防御的丧失来逆转与年龄相关的对氧化损伤的易感性。R-LA提供这种保护不是作为自由基清除剂，而是通过维持Nrf 2的活性，Nrf 2是一种控制过度表达的转录因子。 100个抗氧化和解毒基因含有抗氧化反应元件（ARE）。然而，尽管最终确定了与随着年龄的增长而丧失抗应激能力有关的分子病变，但R-LA如何维持这些重要的细胞防御的确切机制以及长期膳食R-LA补充剂是否是降低年龄相关疾病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Nrf 2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控制Nrf 2活性的调节机制，即影响核Nrf 2水平的途径;以及其与基因中伴侣蛋白的相互作用。 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Nrf 2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Nrf 2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”。