Free Radicals and Aging

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Introduction
In aging, every organ, every tissue and every cell is changed in some way--usually a decrease in functional capacity and an increase in vulnerability to age-related diseases. A distinction must be made between average life span, age-associated diseases and the aging process itself. The length of the life span depends on many different types of lethal events, such as the incidence of infectious diseases and the age-related diseases that are organ specific, whereas the aging process affects all organs. Attempts have been made since the beginning of recorded history to understand and to delay the aging process. There have been many diverse theories, and not all are mutually exclusive. One theory attributes aging to genetic programs. Indeed, there are many genetic programs that initiate "death" in specific cells as part of normal development of the body, a process known as programmed cell death. In some diseases (e.g., Huntington's where certain brain cells undergo death at "designated times") there is a genetically programmed death of specific cells. The widely accepted theory today asserts that unrepaired accumulated cellular damage, caused by free radicals generated by on-going normal metabolism and contributed to by enviromental sources, is the basis of aging. First proposed by Denham Harman (1956) and little recognized for some 40 years, this theory is now cited in every biological and medical journal and even in newspaper articles.

What are free radicals?
A free radical is any molecular species capable of independent existence, that contains one or more unpaired valence electrons not contributing to intramolecular bonding, and is--in that sense--"free". They are produced by oxidation/reduction reactions in which there is a transfer of only one electron at a time, or when a covalent bond is broken and one electron from each pair remains with each atom. Thus, a free radical has an unpaired electron. Many free radicals are highly reactive, owing to the tendency of electrons to pair--that is, to pair by the receipt of an electron from an appropriate donor or to donate an electron to an appropriate acceptor. Whenever a free radical reacts with a non-radical, a chain reaction is initiated until two free radicals react and then terminate the propagation with a 2-electron bond (each radical contributing its single unpaired electron). In biological systems free radicals have a range of transitory existences depending upon their reactivity. Some are stable, e.g. melanins can have a long lifetime, moderately stable ones such as nitric oxide can have lifetimes of ~5 seconds and highly unstable ones such as hydroxyl radicals exist for only a hundredth of a microsecond. The free radicals of special interest in aging are the oxygen free radicals. These free radicals often take an electron away from a "target" molecule to pair with their single free electron. This is called "oxidation". There are some closely related oxygen containing molecules that are not strictly free radicals but contribute to their production or are strong oxidants themselves, such as singlet oxygen and hydrogen peroxide. The term "reactive oxygen species" (ROS) is used to refer to these oxidants and the oxygen free radicals.

Where do they come from?
There are many sources of free radicals both within and external (environmental) to cells. Many are produced by normal ongoing metabolism, especially from the electron transport system in the mitochondria and from a number of normally functioning enzymes, examples are: xanthine oxidase, cytochrome p450, monoamine oxidase, nitric oxide synthase. In the brain, free radicals are produced from the autoxidation of norepinephrine and dopamine. The autoxidation of catechols to quinones generates reduced forms of molecular oxygen, sources of free radicals (e.g., superoxide and hydrogen peroxide). Bruce Ames and his colleagues, leading scientists in the field, claim that oxidants generated by mitochondria are the major source of oxidative lesions that accumulate with age.

Whate do they do?
Oxygen free radicals or ROS are implicated in many diseases including neurodegenerative diseases (ALS, Parkinson's, Alzheimer's), cataractogenesis, atherosclerosis, diabetes mellitus, ischemia-reperfusion injury, kwashiorkor, certain toxicities, to mention only a few, as well as in the aging process itself. This has created the impression that all free radicals are highly damaging--in short, all bad. A more informed examination of free radicals reveals a range of unique functions in normal physiology and even in information processing in the brain. Since free radicals can donate an electron to an appropriate acceptor ("reduction reaction") or pair their unpaired electron by taking one from an appropriate donor ("oxidation reaction") they have major influences on the so-called "redox state" in cells--important in normal regulatory reactions. Major targets are molecular complexes that readily give up or acquire a single electron, e.g., those with sulfhydryl/disulfides or with paramagnetic metals (iron, copper). Practically every type of molecule: DNA, protein, lipid, carbohydrate, can be a target and thus be damaged by a "hit" by a highly reactive radical. But it is difficult to measure the highly reactive species in vivo so most of the evidence for their roles is from the identification of products or changes induced by antioxidant chemicals--largely indirect evidence.

Evidence for free radical involvement in aging
The evidence for free radical/ROS involvement in aging is more correlative than direct. However, there is increasing evidence for the accumulation over time of damaged DNA and the modification of proteins and other molecules. It is calculated that endogenously generated oxygen free radicals make about 10,000 oxidative interactions with DNA per human cell per day (Ames et al, 1993). These modifications and damage to such vital molecules would be expected to ultimately lead to deficiencies in normal functions in a global way--AGING. The least contested, extensive animal studies on aging clearly demonstrate that caloric restriction subtantially slows the rate of aging. Furthermore, it delays the onset of age associated diseases. Weindruch (1996) concludes that caloric restriction slows aging primarily by an associated decrease in oxygen free radicals produced by the mitochondria.

PROTECTION, PREVENTION AND ANTIOXIDANTS
Under normal conditions the damaging actions of ROS are minimized by abundant protective and repair mechanisms that cells possess, including many enzymes (e.g. superoxide dismutase, catalase), and redox active molecules (e.g., glutathione, thioredoxin). In addition there are many protective substances in foods. Vegetables and fruits in particular have a broad range of protective molecules. Best known among others are the "antioxidants" and some vitamins (e.g., vitamins C and E). Many studies have demonstrated that a diet predominant in vegetables and fruits is associated with a reduced risk of several age-related serious diseases (a strong implication that they are also important in slowing the aging process). Since the vegetables and fruits that are most effective are rich in antioxidants, research has focused on the prominent antioxidants in those foods. Two strong antioxidants, lutein and lycopene, members of the carotenoids (yellow, orange and red pigments that occur widely in plants and animals often giving them a bright coloration) have received much attention as cancer preventive foodstuffs. However, the in vivo effectiveness of many food constituents (e.g., the polyphenols), is still not clear. The chemistry in vivo is highly complex, and antioxidants under unusual circumstances can become pro-oxidants. This is possible in conditions where iron or copper are not in their normal non-catalytic state, as occurs in some diseases (e.g., hemachromatosis, and iron overload) or following trauma. Thus, there is some concern about the net benefits of antioxidant supplements. The success of supplements in delaying aging or age associated diseases is still under extensive study. It seems clear at this time that protection against oxidative damage, as it relates to aging, is provided best by a diet of vegetables and fruits, not to be replaced by pills.

The question is, are free radical induced changes the basis of aging? The following observations (Sohal & Weindruch, 1996) support a major role of oxygen free radicals in aging: 1) overexpression of antioxidative enzymes retards the age-related accrual of oxidative damage and extends the maximum life-span of transgenic Drosophila melanogaster, 2) variations in longevity among different species is inversely correlated with the rates of mitochondrial generation of the superoxide anion radical and hydrogen peroxide, 3) restriction of caloric intake lowers steady-state levels of oxidative stress and damage, retards age-associated changes, and extends the maximum life-span in mammals. Once again, the hypothesis argues that cells are continuously under oxidative stress, the antioxidant defenses are not fully efficient and consequently, there is an accumulation of oxidative damage over time. The implications are that the rate of aging is a function of the rate of free radical production, the adequacy of antioxidative defenses and the efficiency of repair systems.

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