Update on the oxidative stress theory of aging: does oxidative stress play a role in aging or healthy aging?

Abstract

The oxidative stress theory of aging predicts that manipulations that alter oxidative stress/damage will alter aging. The gold standard for determining whether aging is altered is life span, i.e., does altering oxidative stress/damage change life span? Mice with genetic manipulations in their antioxidant defense system designed to directly address this prediction have, with few exceptions, shown no change in life span. However, when these transgenic/knockout mice are tested using models that develop various types of age-related pathology, they show alterations in progression and/or severity of pathology as predicted by the oxidative stress theory: increased oxidative stress accelerates pathology and reduced oxidative stress retards pathology. These contradictory observations might mean that (a) oxidative stress plays a very limited, if any, role in aging but a major role in health span and/or (b) the role that oxidative stress plays in aging depends on environment. In environments with minimal stress, as expected under optimal husbandry, oxidative damage plays little role in aging. However, under chronic stress, including pathological phenotypes that diminish optimal health, oxidative stress/damage plays a major role in aging. Under these conditions, enhanced antioxidant defenses exert an "antiaging" action, leading to changes in life span, age-related pathology, and physiological function as predicted by the oxidative stress theory of aging.

Figure 1

By clarifying health and lifespan under different environmental conditions, we may be able to clarify the role of oxidative stress in regulating lifespan. Lifespan is relatively unaffected by oxidative stress under optimal husbandry conditions (limited oxidative stress), but healthy aging as measured by healthspan, can be altered by oxidative stress. Clearly, under conditions of acute stress, such as during oxidative stress resistance tests (i.e., paraquat), health and lifespan are limited by antioxidants. Recent evidence has shown that under certain disease conditions, like cardiovascular disease, diabetes, or neurodegeneration, chronic oxidative stress can modulate the progression of disease; it remains to be seen what effect this has on lifespan under these condition.