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Free radical theory of aging: Beneficial effect of antioxidants on the life span of male NZB mice; role of free radical reactions in the deterioration of the immune system with age and in the pathogenesis of systemic lupus erythematosus

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Abstract

Autoimmune manifestations increase with age. Tolerance to self-antigens appears to be actively maintained mainly by T-suppressor cells derived from radio-sensitive precursors. Since endogenous free radical reactions seem to increase with age the associated increase in autoimmunity could be due, at least in part, to a disproportionate decrease in suppressor cell function, as compared to the other cells of the immune system. This possibility was evaluated using New Zealand black (NZB) mice; this strain loses T-cell suppressor function early in life and develops autoimmune manifestations which mimic those seen in old mice of normal strains.

Addition of 0.25%w (percent by weight) α-tocopheral acetate, 0.25%w Santoquin (a quinoline derivative), or 1.0%w NaH2PO2 to the diet of NZB male mice, starting shortly after weaning, increased the average life span by 7.1, 32.1 and 1.2 percent, respectively, by comparison with the control life span of 16.8 months. These data support the above-suggested explanation for the rise in autoimmunity with age.

The NZB mouse serves as a model for systemic lupus erythematosus (SLE). The present study led to the suggestion that the basic defect in SLE is an abnormality(s) which enhances the tendency for nuclear antigens to be formed from nuclear components by a free radical pathway. The nuclear antigens in turn give rise to immune complex disease. Thus the beneficial effect of antioxidants in the present study can be attributed to a decrease in the rate of: 1) formation of nuclear antigens, 2) free radical damage initiated by aggregating neutrophils, and 3) free radical reaction-induced loss of T-suppressor cell function with age owing to a reduction in damage from both “normal” endogenous free radicals and those of neutrophil origin.

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    Denham Harman M.D.

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Harman, D. Free radical theory of aging: Beneficial effect of antioxidants on the life span of male NZB mice; role of free radical reactions in the deterioration of the immune system with age and in the pathogenesis of systemic lupus erythematosus. AGE 3, 64–73 (1980). https://doi.org/10.1007/BF02431730

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