The naked mole-rat response to oxidative stress: just deal with it

Abstract

Significance: The oxidative stress theory of aging has been the most widely accepted theory of aging providing insights into why we age and die for over 50 years, despite mounting evidence from a multitude of species indicating that there is no direct relationship between reactive oxygen species (ROS) and longevity. Here we explore how different species, including the longest lived rodent, the naked mole-rat, have defied the most predominant aging theory.

Recent advances: In the case of extremely long-lived naked mole-rat, levels of ROS production are found to be similar to mice, antioxidant defenses unexceptional, and even under constitutive conditions, naked mole-rats combine a pro-oxidant intracellular milieu with high, steady state levels of oxidative damage. Clearly, naked mole-rats can tolerate this level of oxidative stress and must have mechanisms in place to prevent its translation into potentially lethal diseases.

Critical issues: In addition to the naked mole-rat, other species from across the phylogenetic spectrum and even certain mouse strains do not support this theory. Moreover, overexpressing or knocking down antioxidant levels alters levels of oxidative damage and even cancer incidence, but does not modulate lifespan.

Future directions: 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.

FIG. 1.

Naked mole-rats are small, pink mouse-sized rodents with a maximum lifespan of 32 years, during which they experience very little age-related decline. Here, a very pregnant breeding female, or queen, sleeps with other members of the colony to regulate body heat. The breeding female can successfully reproduce well into her third decade of life. She may double her mass during pregnancy and may carry litters of up to 30 pups. In captivity, breeding females live as long as nonbreeding animals. Photo taken by Raymond Mendez, 1996. Reprinted with permission.

FIG. 2.

Increased levels of ROS can cause oxidative damage to all macromolecules within the cell that, if left unchecked or unrepaired, can further manifest into mutations in DNA, as well as protein and membrane dysfunction. As a direct consequence thereof, these can contribute to uncontrolled proliferation and an accumulation of damage, and eventually cancer and other age-related diseases. Different protective mechanisms in the cell are able, at least to some extent, to repair or deal with oxidative damage via detoxification, molecule turnover (i.e., proteasome, autophagy), or DNA repair. Many of these pathways have components that are largely regulated by Nrf2, a transcription factor that modulates the expression of over 600 cytoprotective molecules. The constitutive upregulation of such pathways may immediately protect against potential stressors and has been hypothesized to contribute to a healthy aging and longevity phenotype, despite existing levels of oxidative damage and antioxidant status. DNA, deoxyribonucleic acid; Nrf2, nuclear factor-erythroid 2-related factor-2; ROS, reactive oxygen species.

FIG. 3.

cGpx levels in liver lysates significantly correlate with maximum lifespan. cGpx is lowest in the naked mole-rat compared to all other rodent species measured. The highest levels were found in the traditional laboratory rodents. The extremely low levels of cGpx in the naked mole-rat are reportedly associated with low selenium levels and a divergence in its genetic sequence. cGpx, cellular glutathione peroxidase.

FIG. 4.

GSH and GSSG levels are not indicative of longevity. The ratio of GSH/GSSG levels in the cell can be indicative of an oxidative environment within the cell. GSH and GSSG levels, as well as GSH/GSSG ratios in liver tissue do not appear to correlate with maximum longevity or body size of five different rodents. A lower GSH/GSSG ratio in the naked mole-rat is indicative of a pro-oxidative environment compared to shorter lived species, like the mouse and guinea pig. GSH, glutathione; GSSG, glutathione disulfide.

FIG. 5.

Cytosolic GST levels do not correlate with species longevity, lifestyle, or body size. Nevertheless, levels are highest in the longest living rodent, the naked mole-rat. Overall, it appears the naked mole-rat may potentially be utilizing high, constitutive levels of GST as a mechanism to protect against constantly high levels of oxidative damage within the cell. GST, glutathione-S-transferase.