| The Oxidative Stress Theory proposes that aging results from a progressive accrual of oxidative damage to cellular components, which reflects an imbalance between endogenous Reactive Oxygen Species generation and the capacity of organismal defenses to prevent damage accumulation. Inter-specific longevity variation may thus result from disparate oxidative damage accrual. Naked mole-rats (Heterocephalus glaber; NMRs) are the longest-living rodent species known (>28.3y) and live 9-times longer than mass-allometric predictions. I tested the Oxidative Stress Theory by comparing various biochemical markers in NMRs and in similar-sized (∼35g), yet much shorter-living mice (∼3.5y), at physiologically equivalent ages. Activities of four enzymatic antioxidants were compared to assess if NMRs possess superior antioxidant defenses than mice. Tissue non-heme-iron content and ratios of glutathione redox pair (GSH/GSSG) were determined to establish if NMRs experience attenuated levels of oxidative stress. Urinary and tissue markers of lipid (isoprostanes, malondialdehyde), protein (protein carbonyls) and DNA oxidation (8-hydroxy-2'-deoxyguanosine) were assayed to asses if long-living NMRs generate and accrue less oxidative damage than mice. NMRs do not posses superior antioxidant defenses, since their glutathione peroxidase activity was 0.014-times that of mice, with only a moderate up-regulation of other enzymatic antioxidants. Higher iron levels and lower GSH/GSSG ratios in NMRs suggest a more pro-oxidative cellular environment in NMRs. A 10-fold greater urinary isoprostane excretion in NMRs indicates high oxidative damage generation in this rodent, while lower urinary 8-hydroxy-2'-deoxyguanosine excretion imply attenuated oxidative damage repair. Contrary to the predictions of the Oxidative Stress Theory, NMRs had more accrued oxidative lipid, protein and DNA damage than mice, even at a young age. Age-related patterns of lipid damage generation and accrual differed between mice and NMRs. Isoprostanes declined in NMRs and remained unchanged in mice, while malondialdehyde increased in mice but not in NMRs. Together these results demonstrate that quantitative differences in oxidative damage accrual do not explain the 9-fold difference in longevity between mice and NMRs, and thus do not support the Oxidative Stress Theory. Although oxidative damage may be a component of organismal aging, age-related changes in its levels, as well as their impact on physiological function are likely to be species specific. |
