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

TLDR

Oxidative stress is widely regarded as a key driver of aging, and interspecies differences in ROS production, antioxidant defenses, and accumulated oxidative damage are thought to underlie the wide variation in maximum lifespan. This study investigates whether the exceptional longevity of the naked mole‑rat is linked to reduced oxidative stress. The authors compared antioxidant capacity (GSH, GSH/GSSG) and markers of lipid, DNA, and protein oxidation in urine and tissues from naked mole‑rats and similarly sized mice. Naked mole‑rats displayed lower GSH and GSH/GSSG, a ten‑fold increase in lipid peroxidation, and higher oxidative damage to lipids, DNA, and proteins than age‑matched mice, indicating that attenuated oxidative stress does not explain their extraordinary lifespan.

Abstract

Summary Oxidative 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.