Naked Mole Rats as the Outlier Species, Thriving with High Oxidative Stress

Rising levels of oxidative stress occur with aging. This term describes the presence of excessive numbers of oxidative molecules, reacting with surrounding molecular machinery to cause breakage and cellular dysfunction. It is significant enough in aging for the free radical theory of aging to have arisen some decades ago, postulating that oxidative damage was the cause of aging. Alas, matters are not that simple. Persistently raised levels of oxidative stress are a downstream consequence of deeper causes, such as mitochondrial dysfunction, chronic inflammation, cellular senescence, and the like. Further, oxidative molecules do in fact serve a necessary and useful role in healthy cellular metabolism. They act as signals to spur cellular maintenance, for example, and thus small or temporary increases in oxidative stress tend to be beneficial. This is one of the mechanisms by which exercise produces health benefits.

Naked mole rats are a strange species, an outlier among rodents. They are eusocial, like some insects. They live nine times longer than similarly sized rodent species, and show few signs of aging across most of that life span. They exhibit high levels of oxidative stress, but appear near completely immune to the consequences that would appear in rats or mice given the same flood of oxidative molecules. They show the presence of senescent cells, but appear largely unaffected by that as well, which is interesting given the very prominent role played by the harmful, inflammatory secretions of senescent cells in the aging and age-related diseases of mice. Finally, naked mole rats are near immune to cancer.

Needless to say, researchers are quite interested in learning how exactly of all this is possible. Might any of the findings result in biotechnologies that can be applied to humans, to shut down cancer, or resist aging? No-one knows. My suspicion is that it will take a while to find out, and there is a good chance that altering humans to be more like naked mole rats is not a near term project - something for the latter half of the century, not the next few decades. I would say we are better off trying to repair the metabolism we have rather than building a better one, given the present state of biotechnology. It is a much more plausible goal.

The Naked Mole Rat: A Unique Example of Positive Oxidative Stress

More than 60 years ago, it was first proposed that aging could be attributed to the deleterious effects of free radicals produced as natural by-products of aerobic metabolism. The free radical theory of aging (FRTA) is based on the hypothesis that dysfunctions observed during aging and a range of age-associated pathologies are due to the accumulation of oxidative damage to biological macromolecules (e.g., DNA damage, lipid peroxidation, and nonrepairable protein oxidation) by reactive oxygen and nitrogen species. A more precise version of the free radical theory of aging, called the mitochondrial free radical theory of aging (MFRTA), specifies that mitochondria are the main sources of reactive oxygen species (ROS) generation and are also the targets of deleterious effects: oxidative damages to mitochondrial DNA, mitochondrial proteins, or phospholipids are assumed to directly cause aging.

Naked mole rats (Heterocephalus glaber), first described in 1842, are the longest living rodents known. Several studies have investigated the production of free radicals and oxidative damages in the naked mole rat, and the results are puzzling. Despite remarkably long lives, some tissues of the naked mole rat, such as arteries, produce higher amounts of ROS (from cytoplasmic and mitochondrial sources) as compared to these tissues from the short-lived mouse. Importantly, the arteries of naked mole rats are highly resistant to the pro-apoptotic effects of ROS in vitro, whereas those of the mouse are not.

Furthermore, several studies have shown that naked mole rats have high levels of oxidative damages to macromolecules from a young age. Interestingly, these levels of damages are maintained over a 20-year period without increase. One hypothesis is that further damages are attenuated by an efficient repair system. A limit of these studies is that only damages to macromolecules were investigated: mitochondrial DNA damage has not been studied in naked mole rat tissues. Hence, further studies using this unique animal model are needed as it would be very informative to compare ROS-producing systems from cellular and mitochondrial sources and oxidative damage in nuclear, cytoplasmic, and mitochondrial targets in long-lived naked mole rat and short-lived rodents.

Many, but not all, features of the naked mole rat defy the free radical theories of aging. However, there is a recent extension of the theory, called the membrane pacemaker theory of aging, which holds true in the naked mole rat. This theory predicts that membrane fatty acid composition has an influence on lipid peroxidation and consequently may be an important determinant of aging and lifespan. Indeed, a study showed that naked mole rat membranes from different tissues contain more fatty acids resistant to peroxidation than do membranes from mice. Thus, the cellular membrane composition of the naked mole rat could partially explain their exceptional longevity. Still, the "naked mole rat exception" raises the question of whether or not ROS (cytoplasmic and mitochondrial) are responsible for aging.