Leaders in Modern Gerontology: Denham Harman Takes on the Free Radicals

The father of The Free Radical Theory of Aging, Denham Harman, deserves a special place in the history of science and in the field of geronotology. In 1946, he read a New York Times article that suggested that we should be able to slow the aging process (even given our level of science at that time). This propelled him on a path that would lead to some important research in the effects of free radicals on aging and the potentials of dietary antioxidants.

In 1954, Harman became a research associate at the Donner Laboratory of Medical Physics in California. Given the recent detonation of atomic bombs at Hiroshima and Nagasaki, the effects of radiation on living things was a subject of major interest and funding. The government funded this early radiation research through the Office of Naval Intelligence, the funding conduit of many top secret projects, including Harman’s study.

Harman’s work on radiation with experimental animals showed him that the symptoms that appear in the aging process has many things in common with what occurs as the result of massive exposure to radiation — including cancer induction, cell death or necrosis, and tissue changes similar to what is seen in aged animals. He knew from his own research results — and earlier research at other laboratories — that ionizing radiation generated enormous amounts of free radicals, particularly hydroxyl radical and hydrogen radical. Hydrogen radical is not normally generated in significant amounts in living things. These two radicals — resulting from radiation exposure — are primarily produced by the splitting of water via the impact of high intensity radiation particles. Water comprises about 70-80% of animal mass.

In 1954, Harman hypothesized that the steady state production of hydroxyl radicals from metabolism and the radicals generated by the copper and iron-containing enzymes found in all cells over the lifetime of an organism was a major contributor to aging — or the actual cause of the aging process itself.

Harman published the first dietary antioxidant study in 1957, using 2-mercaptoetylamine, the most potent radioprotective compound known at the time. He added this to mouse chow. The result of this study was a modest 20% increase in the lifespan, showing a definite connection between free radicals and aging. Harman’s theory and his results were overshadowed in 1959 when Howard L. Curtis published The Somatic Mutation Theory of Aging, which proved to be extremely popular in scientific circles. The Curtis theory was finally disproven in 1974 by an article on DNA by scientists R.W. Hart and R.B. Sellow, published in "Proceedings of the National Academy of Science.

Theories of aging are often divided into two classes: pleiotropic, or ‘programmed’ theories and stochastic theories. Pleiotropic theories of aging have one thing in common — the belief that aging is controlled purely by genetics. Stochastic theories are based on the notion that molecular events like free radical damage are purely random but appear to be uniform over a lifetime.

Regardless of aging theory classification, Denham Harman’s first dietary antioxidant longevity study began a generation of studies demonstrating animal lifespan increases up to 50% using single antioxidants and 240% increases in lifespan in vitro cell studies.

In 1972, Harman took on the next problem — investigating where the free radicals were being generated inside the cell. He published the first mitochondrial free radical theory of aging, entitled "The Biological Clock: The Mitochondria?" The mitochondria are small organelles found by the hundreds inside cells that produce energy for the cell by means of the Krebs cycle.

Thanks to the early work by Harman on his first free radical theory and later work that showed random processes were at work causing the aging process, pleiotropic, or ‘programmed’ theories of aging have fallen by the wayside. There is now a solid scientific basis for believing that aging is an open-ended process. This should be a source of great optimism to scientists and advocates of longevity, demonstrating that there are no fixed or determinate limits to lifespan. Pharmacological and natural product interventions have been shown to significantly increase the median, average and maximum age limits postulated for numerous animal species.

This short biography of Denham Harman would be incomplete without mentioning other important studies he conducted. In 1961, Harman tested the theory that the degree of polyunsaturation of dietary fats had a major impact on cancer rates in animals. The results showed that monounsaturated fats like olive oil had the least carcinogenic effects on mice, while very long chain polyunsaturates like menhaden fish oil resulted in higher cancer rates and decreased longevity. These results have been confirmed by large amounts of data published decades later.

In a 1956 edition of The Journal of Gerontology, Harman predicted that the oxidation of LDL cholesterol was the earliest molecular event leading to cardiovascular disease. Today, tests measuring OXY-LDL are becoming standard analyses amongst state-of-the-art laboratories and cardiologists.

In 1968, Harman conducted a dietary lifespan study feeding the food preservative BHT to rodents. It increased their lifespans 45% longer than average and exceeded their maximum species lifespan, the first experiment to demonstrate this can be done with antioxidants. This increase in maximum species lifespan came close to results from calorie restriction experiments that achieved 50% lifespan increases.

In 1985, Harmon was a founder of the International Association of Biomedical Gerontology (IABG). At 93, he continues his work as Professor Emeritus at the University of Nebraska Medical School. He first entered the institution as chair of cardiovascular research in 1958. Harman’s early pioneering work on the causes of the aging process will stand preserved forever in the history of gerontology.