Oxidative stress as a causal factor in differentiation and aging: a unifying hypothesis.


Sohal RS, Allen RG.




Exp Gerontol


In this article, the authors have pointed out flaws in the current version of the free radical hypothesis of aging and have advanced a new hypothesis that reconciles and encapsulates existing information. The main premise of this hypothesis is that aging is a continuation of development and is thus influenced by genetically programmed phenomena. Completion of various genetic programs and the duration of life are linked to a metabolic potential which is itself a genetically determined sum of energy expenditure. Nevertheless, the rate at which metabolic potential is reached is linked to the rate of metabolism and the level of oxidative stress both of which are influenced by epigenetic stimuli. The current version of the free radical hypothesis postulates that partially reduced oxygen species are produced in aerobic cells in an uncontrolled fashion and do not play any useful physiological function. The principle tenet of the free radical hypothesis is that molecular damage is the underlying cause of aging and that O2- radicals and derivatives induce most of the damage sustained by cells during aging. The authors regard this hypothesis as flawed because it fails to explain either low randomly occurring damage can lead to age-associated changes that are species-specific, or the sequential nature of the changes that occur in aging organisms. In contrast to the free radical hypothesis, our hypothesis can explain the specific and sequential nature of aging-related changes because they are postulated to be neither dependent upon uncontrolled damage nor the cellular capacity to prevent it. Instead, the authors suggest that the damage accumulated during aging is a secondary effect rather than a direct cause of senescence. The authors have shown that cells exert control not only on their level of antioxidant defense but also on their rate of oxidant production. The authors postulate that aging is the terminal stage of development, and as such is influenced genetically. The authors also postulate that a definite sum of energy is required to complete the genetic programs associated with aging. Thus, the rate of aging is linked to the level of oxidative stress; the rate of energy utilization is postulated to determine the level of oxidative stress. Oxidative stress is one of the factors which appears to govern changes in gene expression during differentiation and we suggest that it causes alterations in gene expression during aging. In the authors revised hypothesis, free radicals promote aging by affecting specific genetic programs and the incidental damage they inflict in cells is only a by-product of this process.