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The Healthy Aging Program

Aging, Stress Response, and Mitochondrial Decay

Principal Investigator: Tory M. Hagen, Ph.D.

Our research seeks to identify the mode of action of two “age-essential” micronutrients, lipoic acid (LA) and acetyl-L-carnitine (ALCAR). This work is aligned with Dr. Pauling’s concept of “orthomolecular medicine”—varying the concentrations of substances normally present in the body to affect health. We are using LA and ALCAR as “keys” to unlock important mechanisms associated with the basic biology of aging, which may lead to effective therapies for a number of age-related diseases and enhance the quality of life. We found that ALCAR and LA improve two of the most important cellular lesions of aging: the inability to respond to oxidative and toxicological challenges and the loss of mitochondrial function. Feeding old rats LA markedly elevates both cellular ascorbic acid and glutathione levels and induces Phase II detoxification enzymes, which markedly decline with age. LA appears to improve stress-response mechanisms by activating a transcription factor, Nrf2, enabling it to again bind to DNA sequences called the “Antioxidant Response Element” (ARE) found in over 200 genes involved in protecting cells against oxidative and toxicological insults. We are currently exploring why these stress response mechanisms decline with age and are focusing on cellular signaling pathways that LA may induce to activate Nrf2-mediated gene expression.

We found that ALCAR and LA, when fed to old rats, markedly improve many indices of mitochondrial decay. Mitochondria may be the “Achilles’ heel” of cellular aging because their dysfunction adversely affects conversion of dietary fuels into useful energy, dysregulates cellular calcium levels, increases oxidative stress, and limits tissue renewal. Our goal is to determine whether these age-essential micronutrients can improve human health by maintaining mitochondrial function.

We are also interested in defining how LA and ALCAR improve such seemingly distinct aging lesions as mitochondrial decay and lost stress-response mechanisms. We have evidence that these compounds synergistically regulate the metabolism of an enigmatic class of biomolecules called sphingolipids, which may be involved in both the age-related loss of Nrf2-mediated gene expression and mitochondrial decay. Identification that sphingolipids are part of these aging deficits opens the possibility for new therapies to improve human healthspan.