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 processes that occur during life which culminate in changes that decrease an individual's 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 Rubner's is the "Rate of Living Theory," proposed by Pearl in 1928. Pearl's 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. Szilard's 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. Orgel's 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 crisis"—a 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. Johan 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 body's 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 disease—especially 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-products—such as the superoxide anion, hydrogen peroxide and the hydroxyl radical—are 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 body's 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

Read Part II

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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, JAB 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, July 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. Antioxidants—The latest weapon in the war on smoking. VRP Nutritional News Vol 11 (July ) 1997.

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