The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. Surprisingly, data from the longest-living rodent known, naked molerats [MRs; mass 35 g; maximum lifespan (MLSP) > 28.3 years], when compared with mice (MLSP 3.5 years) exhibit higher levels of lipid peroxidation, protein carbonylation, and DNA oxidative damage even at a young age. We hypothesize that age-related changes in protein structural stability, oxidation, and degradation are abrogated over the lifespan of the MR. We performed a comprehensive study of oxidation states of protein cysteines [both reversible (sulfenic, disulfide) and indirectly irreversible (sulfinic/sulfonic acids)] in liver from young and old C57BL/6 mice (6 and 28 months) and MRs (2 and >24 years). Furthermore, we compared interspecific differences in urea-induced protein unfolding and ubiquitination and proteasomal activity. Compared with data from young mice, young MRs have 1.6 times as much free protein thiol groups and similar amounts of reversible oxidative damage to cysteine. In addition, they show less urea-induced protein unfolding, less protein ubiquitination, and higher proteasome activity. Mice show a significant age-related increase in cysteine oxidation and higher levels of ubiquitination. In contrast, none of these parameters were significantly altered over 2 decades in MRs. Clearly MRs have markedly attenuated age-related accrual of oxidation damage to thiol groups and age-associated up-regulation of homeostatic proteolytic activity. These pivotal mechanistic interspecies differences may contribute to the divergent aging profiles and strongly implicate maintenance of protein stability and integrity in successful aging.cysteine oxidation ͉ Heterocephalus glaber ͉ mechanisms of aging ͉ proteasome activity ͉ protein homeostasis

SummaryOxidative stress is reputed to be a significant contributor to the aging process and a key factor affecting species longevity. The tremendous natural variation in maximum species lifespan may be due to interspecific differences in reactive oxygen species generation, antioxidant defenses and/or levels of accrued oxidative damage to cellular macromolecules (such as DNA, lipids and proteins). The present study tests if the exceptional longevity of the longest living (> 28.3 years) rodent species known, the naked mole-rat (NMR, Heterocephalus glaber ), is associated with attenuated levels of oxidative stress. We compare antioxidant defenses (reduced glutathione, GSH), redox status (GSH/GSSG), as well as lipid (malondialdehyde and isoprostanes), DNA (8-OHdG), and protein (carbonyls) oxidation levels in urine and various tissues from both mole-rats and similar-sized mice. Significantly lower GSH and GSH/GSSG in mole-rats indicate poorer antioxidant capacity and a surprisingly more pro-oxidative cellular environment, manifested by 10-fold higher levels of in vivo lipid peroxidation. Furthermore, mole-rats exhibit greater levels of accrued oxidative damage to lipids (twofold), DNA (~two to eight times) and proteins (1.5 to 2-fold) than physiologically age-matched mice, and equal to that of same-aged mice. Given that NMRs live an order of magnitude longer than predicted based on their body size, our findings strongly suggest that mechanisms other than attenuated oxidative stress explain the impressive longevity of this species.

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SummaryA key tenet of the oxidative stress theory of aging is that levels of accrued oxidative damage increase with age. Differences in damage generation and accumulation therefore may underlie the natural variation in species longevity. We compared age-related profiles of wholeorganism lipid peroxidation (urinary isoprostanes) and liver lipid damage (malondialdehyde) in long living naked mole-rats [maximum lifespan (MLS) > 28.3 years] and shorter-living CB6F1 hybrid mice (MLS ∼ ∼ ∼ ∼ 3.5 years). In addition, we compared age-associated changes in liver nonheme iron to assess how intracellular conditions, which may modulate oxidative processes, are affected by aging. Surprisingly, even at a young age, concentrations of both markers of lipid peroxidation, as well as of iron, were at least twofold ( P < 0.005) greater in naked mole tats than in mice. This refutes the hypothesis that prolonged naked mole-rat longevity is due to superior protection against oxidative stress. The age-related profiles of all three parameters were distinctly species specific. Rates of lipid damage generation in mice were maintained throughout adulthood, while accrued damage in old animals was twice that of young mice. In naked mole-rats, urinary isoprostane excretion declined by half with age ( P < 0.001), despite increases in tissue iron ( P < 0.05). Contrary to the predictions of the oxidative stress theory, lipid damage levels did not change with age in mole-rats. These data suggest that the patterns of age-related changes in levels of markers of oxidative stress are species specific, and that the pronounced longevity of naked mole-rats is independent of oxidative stress parameters.

Perhaps, it is not oxidative stress that modulates healthspan and longevity, but other cytoprotective mechanisms that allow animals to deal with high levels of oxidative damage and stress, and nevertheless live long, relatively healthy lifespans. Studying these mechanisms in uniquely long-lived species, like the naked mole-rat, may help us tease out the key contributors to aging and longevity.

The naked mole‐rat (Heterocephalus glaber) has fascinated zoologists for at least half a century. It has also generated considerable biomedical interest not only because of its extraordinary longevity, but also because of unusual protective features (e.g. its tolerance of variable oxygen availability), which may be pertinent to several human disease states, including ischemia/reperfusion injury and neurodegeneration. A recent article entitled ‘Surprisingly long survival of premature conclusions about naked mole‐rat biology’ described 28 ‘myths’ which, those authors claimed, are a ‘perpetuation of beautiful, but falsified, hypotheses’ and impede our understanding of this enigmatic mammal. Here, we re‐examine each of these ‘myths’ based on evidence published in the scientific literature. Following Braude et al., we argue that these ‘myths’ fall into four main categories: (i) ‘myths’ that would be better described as oversimplifications, some of which persist solely in the popular press; (ii) ‘myths’ that are based on incomplete understanding, where more evidence is clearly needed; (iii) ‘myths’ where the accumulation of evidence over the years has led to a revision in interpretation, but where there is no significant disagreement among scientists currently working in the field; (iv) ‘myths’ where there is a genuine difference in opinion among active researchers, based on alternative interpretations of the available evidence. The term ‘myth’ is particularly inappropriate when applied to competing, evidence‐based hypotheses, which form part of the normal evolution of scientific knowledge. Here, we provide a comprehensive critical review of naked mole‐rat biology and attempt to clarify some of these misconceptions.

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