|
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. |