Free radicals and Aging

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 environmental 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.

Evidence for free radical involvement in aging
 

Are free radical induced changes the basis of 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.

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.