When the history of gerontology is written and the names of the most influential gerontologists are compiled, one name may well stand above all the rest: Denham Harman, MD, PhD.
Professor emeritus at the University of Nebraska Medical School, Harman is founder of the American Aging Association and the International Association of Biomedical Gerontology. He is best known as the having developed the “free radical theory of aging,” which grew out of the initial earlier work by Dr. R. Gerschman. This influential theory, whose foundations lay in experiments arising from the dawn of the Atomic Age, was a breathtaking leap of scientific speculation based on observations of free radical chemistry in biological systems.
Origins of Free Radical Theory
In 1954, at the peak of the Cold War, Americans were building fallout shelters in their backyards. The US government was converting the basements of schools, churches, and other public buildings into fallout shelters and offering rewards to prospectors who discovered substantial uranium deposits in the US or Canada. Nine years earlier, the first use of nuclear weapons against Japan ended World War II but also raised important scientific questions about the effects of radiation on humans.
The US Office of Naval Intelli-gence funded several studies from 1947 to 1954, including some of Harman’s early studies, in an effort to determine what caused radiation damage in humans, and to test whether antioxidants and other radioprotective compounds could protect soldiers and civilians against the effects of ionizing radiation. Researchers noted that mice produced free radical species in massive quantities during intense radiation exposure, and that cancers normally associated with advanced aging were seen immediately in the exposed mice. Articles on the chemistry of free radicals published during this period convinced Harman that radiation exposure produced a model of accelerated aging and that the same free radical species present in normal metabolism must be responsible for the ordinary aging process itself.
Although he proposed the free radical theory of aging in 1954, Harman tested it by administering dietary antioxidants to various strains of mice. By 1957, he had shown that radioprotective compounds prolonged the median life span of mice. Thus was born the first dietary antioxidant study that sought to increase the life span of mammals. Many dozens of other dietary antioxidant studies have followed over the years, confirming that free radicals play an important role in the aging process.
Theories of aging can roughly be divided into two categories: stochastic theories and pleiotropic theories. Stochastic theories argue that aging is caused by random chemical insults at the molecular level, such as damage from free radicals. Pleiotropic theories claim that aging is genetically programmed and therefore essentially unchangeable.
The popular somatic mutation theory of aging, set forth by Howard L. Curtis in 1959, pushed Harman’s free radical theory of aging into the background and became the rage in gerontology circles for more than a decade. In 1972, however, Hart and Setlow’s discovery of numerous effective but unsuspected DNA repair mechanisms completely upended the somatic mutation theory of aging along with other pleiotropic theories of aging based on the same assumptions used in Curtis’ theory.
While most of the “program-med” (pleiotropic) theories of aging have been disproven over the years, the original free radical theory of aging and numerous variations of it have withstood the test of time. Libraries full of empirical research evidence have accumulated showing the deleterious effects of free radicals on biological tissues and their protection by thousands of antioxidants, both natural and synthetic. Thanks largely to the early work of Denham Harman, many gerontologists and anti-aging advocates have a sound scientific basis for believing that natural and pharmacological interventions can significantly extend the average life span of mammals, including humans.
Pushing the Bounds of Research
In 1961, Harman published a study showing that the degree of polyunsaturation in fats had a dramatic effect on cancer rates in mice. The most highly polyunsaturated dietary fats were found to be the most carcinogenic; the least saturated dietary fats were shown to be the least carcinogenic. It took most of the scientific and medical community about 30 years to “rediscover” this fact, after decades of epidemiological studies around the world showed that olive oil and other monounsaturated fats are a far better dietary alternative in humans to polyunsaturated vegetable oils. Today, the so-called “Mediterranean diet” emphasizing monounsaturated fats is associated with low rates of cancer and heart disease, and is considered a model diet. In fact, it is now widely accepted that monounsaturated fats are “good” fats because they lower inflammation and lower the risk of cancer.
A major criticism of the early dietary antioxidant studies was that the antioxidants administered produced only modest increases in the life span of mice, generating increases in median life span that failed to exceed the maximum life span postulated for the species. In effect, the critics were saying that the large doses of antioxidants tested merely lowered the animals’ cancer rates without having any effect on their true life span. Harman was among the first to recognize the validity of this criticism. As a result, he returned to his laboratory and in 1968 published a dietary antioxidant study showing that the food preservative BHT fed over a lifetime to mice produced a 45% increase in life span. This exceeded both the median and maximum life span for that species, offering the first proof that dietary antioxidants can increase life span in mice almost equal to the effects of caloric restriction.
In 1972, Harman published a hypothesis entitled “Is the Mitochondrion the True Biological Clock?” It was by then becoming obvious that free radicals in mammals increased when their caloric output was raised. In his original theory, Harman attributed free radical production to iron- and copper-containing enzymes, which we now know to be true, but here he postulated that species of animals that had a higher metabolic rate aged faster than those with lower metabolic rates. Likewise, free radical production increased during exercise, which pointed to the energy-producing organelles called the mitochondria as a major, if not the major, source of free radicals.
Many “mitochondrial” theories of aging have since been published. Research during the 1990s confirmed that 91% of oxygen reduction occurs in the mitochondria and that the majority of free radicals are indeed generated by the mitochondria. These studies showed that mitochondrial decay plays a large role in aging, and that the antioxidants alpha-lipoic acid and acetyl carnitine reverse this decay to levels found in young animals.
Forty years of research also has proved Harman right in his original assumption that iron- and copper-containing enzymes are one of the largest sources of free radicals. These three groups of enzymes—the cyclooxegenases, monoxygenases, and lipoxygenases—act as continuous generators of the extremely reactive hydroxyl radical. It is now is well established that the liver and other cells contain monoxygenases that act as detoxifying agents but also convert harmless compounds into powerful carcinogens. We also know that many of the cyclooxygenase enzymes act as inflammatory agents that are believed to contribute to heart disease and cancers.
One of Harman’s earliest and most accurate predictions concerned the cause of heart disease in humans. Writing in 1956 in the Journal of Gerontology, he predicted that the primary initiating event in atherosclerosis was the oxidation of low-density lipoprotein (LDL) cholesterol, something that has been accepted as fact in just the past 10 years. While few of the molecular details of that process were known when Harman wrote his original article, he nevertheless predicted that antioxidants could slow or prevent LDL oxidation. Today we know that antioxidants such as vitamin E, ascorbic acid, and the flavonoids contained in green tea do indeed slow down the process of LDL oxidation.
A Pioneer Still Active Today
Today, Denham Harman, at age 88, remains active in the science of aging. He helped organize the 9th Congress of the International Association of Biomedical Geron-tology, and currently is writing a paper on various therapies to slow the aging process. He says he is disappointed with the slow pace of progress on pure aging research, which he blames in part on limited funding and on scientists who are unfamiliar with older aging research duplicating what has already been done in the past. Another problem in aging re-search, according to Harman, is that “the chemists don’t understand biology and the biologists don’t understand chemistry”—many researchers are confined to their various niches and fail to understand the work going on in other specialties.
Harman believes that Western societies are reaching a human life span plateau of about 85 years, thanks purely to medical interventions. He predicts that without further pharmacological steps to slow the aging process, we will be soon “hit a wall” with no major increases in longevity beyond that point.
Denham Harman has been unerring in predicting the causes of aging decades before others reached the same conclusions. Both his free radical theory of aging and proposal that the mitochondrion is the true biological clock have been confirmed repeatedly in empirical data. His work has blazed a trail for other researchers as they seek to further define the exact mechanisms of aging and to develop therapies to slow or halt its progression.