Oxygen Free Radicals and Aging Part I

We all intuitively know what aging means, but it is difficult to define in words. One
widely accepted definition of aging is the process(es) that occur during life which
culminate in changes that decrease an individuals ability to handle biological
challenges. (Whew!) This concept can sometimes be illustrated more easily than it can
be described. Figure 1 illustrates the decline that occurs with age in a number of
physiological functions. As these functions decline, our ability to withstand assaults by
disease or the environment also decreases. Dr. Edward Masoro from the University of
Texas, San Antonio, has recently reviewed the major theories of how and why we age.
This article will review the most viable of these proposed theories of aging.

Probably the earliest modern scientific theory was proposed by Rubner in 1908 when he
presented evidence linking metabolic rate and aging. Another closely-related theory to
Rubners is the Rate of Living Theory, proposed by Pearl in 1928. Pearls theory is
based on the concept that the duration of life varies inversely with the rate of energy
expenditure.1 Another theory that has had a significant influence on aging research is the
Somatic Mutation Theory, proposed by Dr. Leo Szilard in 1959. Prior to devoting his
intellectual energy to the aging process, Dr. Szilard had been a key player in the
development of the atomic bomb. After completing this work, he devoted the rest of his
life to the cause of peace and the study of aging. Szilards theory implied that genetic
mutations of DNA accumulate with time, ultimately resulting in miscopying and
functional failure. Although this theory made a great deal of common sense, it has been
exhaustively investigated by many researchers, who have found little confirmatory
evidence. Conversely, a number of studies have been published which indicate that
somatic mutation is not involved in the aging process.1

Another somewhat related theory is the The Error Catastrophe Theory, proposed by Dr.
Leslie Orgel in 1963. Orgels hypothesis was that if an error were made in the molecular
copying processes (transcription or translation) that result in the synthesis of a given
protein(s), the faulty protein could then set off a chain of flawed events which would
result in an error crisisa cascade of altered biochemical processes that impair cellular
functioning, such as that which occurs in aging. This theory differed from the somatic
mutation theory in that it postulated an error in information transfer which occurs at some
site other than in the DNA. This theory was attractive because it could be tested and
validated. Although the error-catastrophe theory has a few hardy supporters, experimental
support for it is not consistent.1

In 1968, Dr. J ohan Bjorksten proposed the Crosslinkage Theory which implied that an
alteration occurred in structural proteins which caused them to develop inter-and
intramolecular cross-links with other proteins.2 The presence of crosslinking agents in
living organisms was equated by Bjorksten with factory-workers being handcuffed a few
at a time. If the mad-handcuffer were not stopped, at some point the factory production
would slow and ultimately grind to a halt (Fig. 2). Bjorksten proposed that just such a
process, progressive crosslinking in the body, was responsible for the changes that
occurred with aging. Bjorksten devised an aggressive experimental approach to discover
safe, effective anti-crosslinking agents. He believed that two of the best approaches to
preventing crosslinking were physical exercise and chelation therapy with EDTA.

More recently, Dr. A. Cerami has proposed the Glycation Theory of Aging which
implies that nonenzymatic reactions of glucose and other reducing sugars with amino
groups of proteins and nucleic acids result in a series of events which alter protein and
nucleic acid structure and function.3 This is the same process that causes the
caramelization of sugar.

Neuroendocrine Theory of Aging
The Neuorendocrine Theory of the late Professor Vladimir Dilman of the Petrov
Institute of Oncology in St. Petersberg, Russia, was first proposed by Dilman in English
in 1983 and was revised and updated in 1992 by Dilman and Dr. Ward Dean.4 This
theory proposes that aging is due to the loss of receptor sensitivity to feedback inhibition
with time, resulting in a progressive shifting of homeostasis and alterations of hormone
levels and their effects with time.

Free Radical Theory of Aging
By far, one of the most popular theories of aging is the Free Radical Theory of Aging.
This theory was first proposed by Dr. Denham Harman,5 and postulates that aging results
from an accumulation of changes caused by reactions in the body initiated by highly
reactive molecules known as free radicals. The changes induced by free radicals are
believed to be a major cause of aging, disease development or death. A major premise in
this theory is that free radicals and their precursors may be produced endogenously
(within the body) through normal metabolic processes, or exogenously (outside the body)
from sources such as cigarette smoking.

The bodys defense mechanisms against these free radicals are referred to as antioxidants.
When the amount of antioxidants in the body is insufficient to do battle with the free
radicals, these very reactive molecules easily react with vital molecules in the body, such
as DNA, causing mutations (alterations) in the sequence of genetic material. The
accumulation of changes is then thought to lead to the development of aging and
degenerative diseases.

There are a number of reasons why the free radical theory has remained popular and
withstood the test of time.6 First, it provides many plausible explanations for the process
of aging. Second, there are a growing number of studies that implicate free radical
reactions in the development of many chronic, age-related diseases (these will be
reviewed in part II of this series). Third, the free radical theory of aging can easily be
tested indirectly, using dietary experiments with antioxidant supplements. Specific
benefits of antioxidant supplements in the prevention or treatment of age-related diseases
will be discussed in part III of this series. Fourth, the free radical theory is the only one
that encompasses all the concepts in almost all the other theories of aging (except the
neuroendocrine theory).

For instance, the free radical theory integrates all the theories which pertain to
metabolism and energy expenditure with the theories dealing with molecular changes
(mutations) at the DNA level. Thus, it is easy to see how increasing the metabolic rate
would generate an explosion of free radicals or reactive oxygen species (ROS). The
reactive oxygen species would, in turn, react with DNA to cause mutations which could
lead to the development of diseaseespecially cancer.
Sources Of Free Radicals

As stated previously, free radicals (oxidants) come from two major sources: (a)
endogenous and (b) exogenous. Endogenous free radicals are produced in the body by
four different mechanisms.7 First, from the normal metabolism of oxygen-requiring
nutrients. Mitochondria (Fig. 3)the intracellular powerhouses which produce the
universal energy molecule, adenosine triphosphate (ATP)normally consume oxygen in
this process and convert it to water. However, unwanted by-productssuch as the
superoxide anion, hydrogen peroxide and the hydroxyl radicalare inevitably produced,
due to incomplete reduction of the oxygen molecule. It has been estimated that more than
20 billion molecules of oxidants per day are produced by each cell during normal
metabolism. Imagine what happens with inefficient cell metabolism!

the free radical theory is the only one that encompasses all the concepts in almost all
the other theories of aging (except the neuroendocrine theory).

Second, white blood cells destroy parasites, bacteria and viruses by using oxidants such
as nitric oxide, superoxide and hydrogen peroxide. Consequently, chronic infections
result in prolonged phagocytic activity and increased exposure of body tissues to the
oxidants.

Third, other cellular components called peroxisomes produce hydrogen peroxide as a
byproduct of the degradation of fatty acids and other molecules. In contrast to the
mitochondria which oxidize fatty acids to produce ATP and water, peroxisomes oxidize
fatty acids to produce heat and hydrogen peroxide. The peroxide is then degraded by an
enzymatic antioxidant called catalase. Under certain conditions, some of the hydrogen
peroxide escapes to wreak havoc into other compartments in the cell.5

Finally, an enzyme in the cells called cytochrome P450 is one of the bodys primary
defenses against toxic chemicals ingested with food. However, the induction of these
enzymes to prevent damage by toxic foreign chemicals like drugs and pesticides also
results in the production of oxidant by-products.

Exogenous sources of free radicals include air pollution, of which industrial waste and
cigarette smoke are major contributors.

Exogenous sources of free radicals include air pollution, of which industrial waste and
cigarette smoke are major contributors. Cigarette smoke, which literally bristles with
oxidants, was discussed in a previous review.8 Radiation and trace metals, notably lead,
mercury, iron and copper, are also major sources of free radical generation.7 Normal
diets containing plant foods with large quantities of certain compounds such as phenols
and even caffeine may contribute to the exogenous supply of oxidants to the body.7

The combination of oxidative damage by exogenously and endogenously produced free
radicals has ominous consequences for body tissues. The oxidants induce alterations in
the structures of tissues and in their functions which manifest as aging and chronic
degenerative diseases like arthritis, atherosclerosis, and cancer. The mechanisms by
which free radicals cause these changes leading to aging and disease will be covered in
part II of this series.

Fortunately, one approach to preventing free radical damage to cells is through the liberal
supplementation of antioxidant nutrients like vitamins A, C and E, minerals like
selenium, and nutritional antioxidant cofactors like lipoic acid. Another approach is to
use chelating substances like chlorella and EDTA to remove free-radical promoting toxic
heavy metals. These approaches will also be amplified in a later part of this series

Highly recommended source of nutrients and supplements.



References

1. Masoro EJ . Theories of aging. In: Free Radicals in aging, Yu, BY (ed.); CRC Press,
Inc. Boca Raton, FL, LJ 1993.
2. Bjorksten J . Longevity 2: Past, Present and Future, J AB Publications, Charleston, SC,
1987.
3. Cerami A. Hypothesis: glucose as a mediator of aging. J Am Geriatr Soc 33: 626,
1985.
4. Dilman V, and Dean W. The Neuroendocrine Theory of Aging and Degenerative
Disease, The Center for Bio-Gerontology, Pensacola, 1992.
5. Harman D. Aging: A theory based on free radical and radiation chemistry. Univ. Calif.
Rad. Lab. Report No. 3078, J uly 14, 1955.
6. Harman D. Free radical theory of aging. In: Free Radicals and Aging, Emerit I and
Chance B (eds.), Birkhauser Verlag, Basel, 1992.
7. Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and the degenerative
diseases of aging. Proc Natl Acad Sci (USA) 90: 7915, 1993.
8. Opara EC. AntioxidantsThe latest weapon in the war on smoking. VRP Nutritional
News Vol 11 (J uly ) 1997.