High oxidative damage levels in the longest‐living rodent, the naked mole‐rat

Abstract

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.

Taking a “good” look at free radicals in the aging process

“…Indeed, these animals exhibit higher levels of ROS generation [55] and ROSdependent macromolecular modifications than similar-sized but shorter-lived mice [56]. These observations are not only hard to reconcile with the MFRTA, they also suggest that ROS play a beneficial role in this species [24].…”

“…Mclk1 +/− mice sustain high mitochondrial oxidative stress but live longer than their wild type siblings [48,50]. High levels of oxidative damage have been observed in several tissues of very long-lived naked mole rats (NMRs) [56].…”

Caloric restriction or catalase inactivation extends yeast chronological lifespan by inducing H 2 O 2 and superoxide dismutase activity

“…However, the results of a number of recent studies have failed to provide support for the free radical theory or suggest that this theory is at best incomplete (2). Studies of naked mole rats, for example, demonstrated that this extremely long-lived rodent exhibits high levels of oxidative damage compared with mice or rats, whose lifespans are ≈1/10 that of naked mole rats (3). In addition, caloric restriction (CR), which extends the lifespans of a variety of eukaryotic organisms, promotes longevity in Caenorhabditis elegans by a mechanism that involves increased oxidative stress (4).…”

Rejuvenation in distinct cell populations – What does it mean?

“…For example, the long-lived naked mole-rat can cope with high levels of oxidative damage without the promotion of aging [Andziak et al, 2006]. In contrast, increased oxidative stress in mice with a deficiency of the anti-oxidative enzyme manganese superoxide dismutase express higher incidents of cancer instead of premature aging [Van Remmen et al, 2003].…”