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Abstract Challenging environmental conditions can drive the evolution of extreme physiological traits. The naked mole-rat has evolved to survive and thrive in a low oxygen, high carbon dioxide environment that would be deadly to humans and most other mammals. The naked mole-rat’s lifestyle is unusual in that this species combines subterranean living and living in large, social groups of up to 300 + individuals. Many respiring animals in a closed environment can lead to depletion of oxygen (hypoxia) and accumulation of carbon dioxide (hypercapnia). Naked mole-rats display a variety of physiological traits that negate the adverse effects of living in this atmosphere. For hypoxia tolerance, naked mole-rats have a low resting metabolism, high affinity hemoglobin, intrinsic brain tolerance, the ability to use fructose for anaerobic glycolysis, and the ability to enter a low energy, suspended animation-like state. For hypercapnia tolerance, these animals have a mutation in a voltage gated sodium channel that effectively eliminates neuronal responses to tissue acidosis. In other mammals, acidosis from exposure to high concentrations of carbon dioxide induces pain and pulmonary edema. Understanding these mechanisms of extreme physiology is not only inherently interesting, but it may lead to biomedical breakthroughs in research on heart attacks, strokes, and pain pathologies. 

Noxious substances, called algogens, cause pain and are used as defensive weapons by plants and stinging insects. We identified four previously unknown instances of algogen-insensitivity by screening eight African rodent species related to the naked mole-rat with the painful substances capsaicin, acid (hydrogen chloride, pH 3.5), and allyl isothiocyanate (AITC). Using RNA sequencing, we traced the emergence of sequence variants in transduction channels, like transient receptor potential channel TRPA1 and voltage-gated sodium channel Na v 1.7, that accompany algogen insensitivity. In addition, the AITC-insensitive highveld mole-rat exhibited overexpression of the leak channel NALCN (sodium leak channel, nonselective), ablating AITC detection by nociceptors. These molecular changes likely rendered highveld mole-rats immune to the stings of the Natal droptail ant. Our study reveals how evolution can be used as a discovery tool to find molecular mechanisms that shut down pain. 

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.