Comparing Progeria to Natural Aging Reveals New Insights Regarding the Association of Time and Redox Imbalance

The free radical theory of aging remains controversial. A central factor underpinning this controversy is that alteration of antioxidant levels has failed to consistently impact the lifespan and health of model organisms as one would logically predict. To test the free radical theory of aging with a novel approach, we posed two hypotheses: 1) reactive species production and/or antioxidant buffering capacity change with time and 2) the same changes should occur earlier in mice that age rapidly, even if the etiology of accelerated aging is unrelated to free radical biology. To test these hypotheses, indices of oxidative damage, abundance of biomolecular free radicals, antioxidant capacity and activity of crucial redox-related enzymes were measured in young and old wild-type mice and compared to results obtained with mice that model a human progeroid syndrome caused by a DNA repair defect (Ercc1 −/Δ mice). Increased rates of superoxide (O 2 ●– ) production were detected in livers of old wild-type and Ercc1 −/Δ mice compared to young adult wild-type mice. This observation correlated with elevation in the oxidation of both lipids and DNA, indicating that naturally aged as well as prematurely aged (Ercc1 −/Δ mice) mice experience a greater degree of oxidative stress compared to young mice. In the naturally aged and Ercc1 −/Δ mice, activity of oxidant-producing enzymes xanthine oxidase (XO) and NADPH oxidase were significantly elevated while mitochondrial respiration was altered in a manner consistent with increased production of reactive species. In addition, multi-omic analysis revealed diminution in antioxidant enzyme expression with both natural and premature aging. This was validated by measuring expression and activity of catalase, MnSOD and CuZnSOD in the liver. Furthermore, GSSG/GSH was significantly increased in both natural and prematurely aged mice: all indicative of age-dependent impaired antioxidant buffering capacity. In toto, these data strongly support the free radical theory of aging. In contrast to the theory, the data also indicate that free radical damage occurs late in life due to changes in oxidant production/neutralization rather than time-dependent accumulation of damage suggesting that time may not be a seminal determinant to aging but rather a correlative bystander.