Don’t Count Harman Out!

T he free-radical theory of aging (FRadTA) holds that aging results when cells accumulate damage over time from the destructive effects of free radicals—atoms or molecules that have a single unpaired electron in an outer shell. Most biologically relevant free radicals are highly reactive and cause oxidative damage to biological structures. Within this framework, antioxidants are reducing agents, and limit damage by diffusing free radicals. The major free radicals are oxygen radicals such as superoxide (O2-), reactive oxygen species (ROS), such as H2O2, (hydrogen peroxide) or OH- (the brutal hydroxyl radical), and reactive nitrogen species such as peroxynitrite (ONOO-).

Denham Harman, M.D., PhD., proposed FRadTA in the 1950s, and extended his idea in the 1970s to incriminate mitochondria in the production of ROS.

However, after decades of FRadTA’s domination, a crevice has appeared in the theory. The core generalization maintains that aging per se is a free radical process (the “strong” hypothesis), while a new variation holds that the degenerative diseases associated with aging generally involve free radical processes, and accumulated errors are only part of aging (the “weak” hypothesis). While the latter is increasingly accepted today, the “strong” hypothesis has become controversial. Harman’s work is attributed as the basis for both of these variations.

Scientific “skepticism” has arisen because in diseases involving ROS, some studies have shown little progress in developing effective antioxidant treatments. Also, mega-doses of dietary antioxidants have generally failed to prevent human disease, in part because they do not decrease oxidative damage in vivo (as revealed by robust biomarkers). On the other hand, some supplement strategies are known to delay disease onset, at least in part by decreasing oxidative damage levels. Moreover, a deeper understanding of how some ROS can act as signaling molecules has led to more precise antioxidant strategies (see article on page 4).

Dr. Harman was promoted for a Nobel Prize by no less than Nobel Prize winner Peter Medawar, who died during the nominating process. Harman did not win, although he came close. Had he won the Prize, there would have been much more work to determine whether FRadTA is a strong or weak hypothesis, and if so, how to optimize therapies.

Marin County, California—where I live—has recently been found to have the longest life expectancy for men in the U.S. (81.6 years), and the second-longest for women (85.1 years), as reported by the Institute for Health Metrics and Evaluation (see ­http://www.healthmetricsandevaluation.org and search on “Marin.”) While this is attributed to lifestyle, exercise, better diets, nonsmoking, and so-forth, over the years it is very common to see bags of vitamins consumed in restaurants along with meals. Antioxidants are a large portion of any supplement program. However, association is not causality, so only more research and time will tell!

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