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From the Townsend Letter
December 2015

briefed by Jule Klotter
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The Mitochondrial Free Radical Theory of Aging
The mitochondrial free radical theory of aging (MFRTA) attributes age-related decline to damaged cellular and mitochondrial DNA and RNA caused by high levels of reactive oxygen species (ROS) (e.g., hydrogen peroxide and superoxide). ROS are produced during metabolism and take part in cell signaling pathways that affect numerous processes, including proliferation, differentiation, and death. The theory that ROS-mediated oxidative damage is the cause of aging has not lived up to expectations. Researchers have failed to find predictable correlations between ROS production, ROS neutralization, or macromolecular damage, and lifespan. In a 2014 review, Jeffrey A. Stuart and Canadian colleagues discuss the theory's seeming failure to explain lifespan differences. Although the Canadians do not argue for discarding the theory, they suggest that it needs modification.
If ROS damage is the cause of aging, one would expect to find changes in ROS levels when animals eat a calorie-restricted diet. Calorie restriction is known to increase lifespan. Michael E. Walsh et al. reviewed data from decades of studies that examined tissues and diverse organs from rodents on calorie-restricted diets. Even though oxidative damage decreased, the researchers found no consistent effect on mitochondrial ROS production or antioxidant activity: "In a majority of studies, dietary restriction had little effect on mitochondrial ROS production or antioxidant activity. On the other hand, DR [dietary restriction] decreased oxidative damage in the majority of cases … the effects of DR on endogenous antioxidants are mixed."
In addition to calorie restriction research, MFRTA has been tested using mice whose genetic expression of mitochondrial enzymes has been altered. Even though oxidative damage biomarkers rise or fall in correlation with antioxidant enzyme gene expression, "… there are seldom corresponding effects on longevity," report Stuart et al. Longevity has also failed to increase in most studies with mice with overexpression of base excision repair (BER) genes – a major pathway for repairing oxidative damage in DNA.
Stuart et al. propose "a more refined view of mitochondrial ROS." They suggest that age-related decline is due to ROS's role in signaling pathways that regulate aging and longevity rather than to oxidative damage alone.

Stuart JA, Maddalena LA, Merilovich M, Robb EL. A midlife crisis for the mitochondrial free radical theory of aging. Longev Healthspan. 2014;3(4). Available at Accessed September 18, 2015.
Walsh ME, Shi Y, van Remmen H. The effects of dietary restriction on oxidative stress in rodents. Free Radic Biol Med. January 2014;66:88–99. Available at Accessed October 9, 2015.
Zimniak P. What is the proximal cause of aging? Front Genet. September 25, 2012. Available at Accessed September 19, 2015.

Jule Klotter

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