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"""""""".

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Program Projects (P01)
Project #
5P01AT002034-10
Application #
8377899
Study Section
Special Emphasis Panel (ZAT1-SM)
Project Start
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
10
Fiscal Year
2012
Total Cost
$376,619
Indirect Cost
$141,231
Name
Oregon State University
Department
Type
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
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