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

基本信息

批准号：
8294789
负责人：
TORY M HAGEN
金额：
$ 37.23万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8294789
关键词：
Acetaminophen Acute Disease Adult Affect Age Aging American Americas Animals Antioxidants Atherosclerosis Binding Cell Culture Techniques Cells Cellular Stress Chronic Chronic Disease Complement Complementary Medicine Complementary and alternative medicine DNA Sequence Defense Mechanisms Development Diet Disease Drug Interactions Drug Metabolic Detoxication Effectiveness Elderly Enzymes Free Radical Scavengers Funding Gene Expression Genes Genetic Transcription Geriatrics Glutathione Goals Grant Gray unit of radiation dose Health Health Care Costs Hepatic Hepatocyte Homeostasis Human Inbred F344 Rats Knowledge Lesion Life Malignant Neoplasms Measurement Mediating Medicine Micronutrients Modeling Molecular Morbidity - disease rate Mutagens NF-E2-related factor 2 Nature Neurodegenerative Disorders Nuclear Nuclear Export Oxidants Oxidative Stress Pathology Pathway interactions Persons Phenotype Play Population Predisposition Protective Agents Proteins Quality of life Rattus Reporter Repression Resistance Response Elements Risk Risk Factors Role Runaway Site Small Interfering RNA Stress Supplementation System Techniques Testing Thioctic Acid Time Tissues Toxin Work age group age related aged antioxidant therapy biological adaptation to stress cancer chemoprevention dietary antioxidant effective therapy feeding healthy aging improved innovation loss of function meetings mortality novel palliative prevent research study resistance mechanism response transcription factor

项目摘要

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健康最低的人群。这个年龄组显示出夸大毒素，药物相互作用和氧化应激的脆弱性，这些脆弱性集体使年龄成为慢性疾病和死亡率的主要风险因素。反过来，这些病态严重限制了生活质量，并大大增加了医疗保健费用，这正在飙升与“美国的灰色”。为什么老年人的细胞防御能力无法满足压力挑战未知，代表了保持健康衰老的重要障碍。为了克服这个问题，美国人服用抗氧化剂或互补药物（CAM）试图防止长期与年龄有关疾病。不幸的是，到目前为止，这些补充剂未能改善老年人健康。回想起来，许多人这些凸轮代理可能是不完整的保护剂，因为它们无法充分补偿减少内源性抗氧化剂和老化细胞和组织中的抗氧化基因表达。因此，更好健康衰老的方法是维持内源性应力抗性机制。为此，我们发现喂养旧大鼠F？-a-硫酸（R-LA）逆转了与年龄相关的氧化损伤的敏感性通过防止内源性抗氧化剂防御的损失。 R-La提供了这种保护，而不是自由基清真寺，但通过保持NRF2的活性，这是一个转录因子，它控制了过度的表达 100抗氧化剂和含有抗氧化剂反应元件的抗氧化基因（AS）。然而，尽管最终确定了涉及年龄降低压力损失的分子病变，但确切的机制如何保持这些重要的细胞防御能力，以及长期饮食中补充饮食R-LA是否是降低与年龄相关病理风险的风险的有效互补药物。因此，本应用的目的是定义R-LA逆转NRF2依赖性压力抗性的确切机制，并降低了对毒理学损害的脆弱性。我们假设R-LA在统治NRF2的两种最重要的调节机制上起作用活动，即影响核NRF2水平的途径；以及它与基因水平上伴侣蛋白的相互作用。因此，我们建议R-LA是一种新型的健康衰老医学，可防止压力反应的损失和这种下降产生的不良健康影响。 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.提出的实验完成后，我们预计将开发出一种营养疗法，以依赖年龄依赖性压力抗性，这可能是可以作为CAM辅助剂来扩展人类“ HealthSpan”。