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1. Naked Mole-Rats Demonstrate Profound Tolerance to Low Oxygen, High Carbon Dioxide, and Chemical Pain

   https://doi.org/10.3390/ani13050819  

   Amoroso, Vince G.; Zhao, Aishi; Vargas, Isabel; Park, Thomas J. (March 2023, Animals)

   Naked mole-rats (Heterocephalus glaber) are very unusual among subterranean mammals in that they live in large colonies and are extremely social, spending large amounts of time gathered together in underground nests more than a meter below the surface. Many respiring individuals resting in deep, poorly ventilated nests deplete the oxygen supply and increase the concentration of carbon dioxide. Consistent with living in that atmosphere, naked mole-rats tolerate levels of low oxygen and high carbon dioxide that are deadly to most surface-dwelling mammals. Naked mole-rats appear to have evolved a number of remarkable adaptations to be able to thrive in this harsh atmosphere. In order to successfully survive low oxygen atmospheres, they conserve energy utilization by reducing the physiological activity of all organs, manifest by reduced heart rate and brain activity. Amazingly, they resort to the anaerobic metabolism of fructose rather than glucose as a fuel to generate energy when challenged by anoxia. Similarly, high carbon dioxide atmospheres normally cause tissue acidosis, while naked mole-rats have a genetic mutation preventing both acid-induced pain and pulmonary edema. Together, these putative adaptations and the tolerances they provide make the naked mole-rat an important model for studying a host of biomedical challenges. 

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2. Journal of muscle research and cell motility, focus on Extreme Physiology Extreme Tolerance to Hypoxia, Hypercapnia, and Pain in the Naked Mole-Rat

   https://doi.org/10.1007/s10974-022-09623-3  

   Park, Thomas J.; Reznick, Jane (July 2022, Journal of Muscle Research and Cell Motility)

   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. 

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3. Life without substance P: The naked mole rat

   https://doi.org/10.1016/B978-0-443-22194-1.00013-6  

   Zhao, Aishi; Lee, Jiwon; Gryszkiewicz, Weronika; Park, Thomas J (January 2025, Elsevier)

   Vink, Robert (Ed.)

   The African naked mole rat (Heterocephalus glaber) is a small, eusocial rodent that lives in large colonies consisting of up to 295 individuals. Their skin is pink and translucent, and naked mole rats have a distinct set of incisors that protrude externally from the mouth so that they can close their lips behind their teeth while using the teeth to dig tunnels, toilets, and nest chambers. They construct and inhabit complex underground tunnel systems in the Horn of Africa where they are protected from climate extremes and predators on the surface, but still face limited resources (sparsely distributed food), and a biologically challenging environment where there is a depletion of oxygen and an accumulation of carbon dioxide from many respirating individuals living in an unventilated space. This is particularly an issue in the communal nest chambers where animals gather to huddle and sleep. Data from Zions et al. show that the nest chambers in colonies of captive naked mole rats have significantly, and substantially higher concentrations of CO2 compared to other compartments in the housing system. They also showed that on average, colony members spent more than 70% of their time in the nest chamber, exposed to elevated CO2. Naked mole rats have a multitude of biological adaptations that make them specialized for life in humid, congested, poorly ventilated burrows. Subsequently, this species is a fascinating and important nontraditional model for biomedical research. Studies have focused on topics such as tolerance to hypoxia and hypercapnia, extreme longevity, resistance to cancer, and insensitivity to chemical pain. One remarkable feature that naked mole rats display is the lack of Substance P from their peripheral nerves. Substance P is associated with pain from a variety of irritants such as carbon dioxide (CO2), acid, capsaicin, and ammonia, as well as itch-like pruritogen, like histamines. Lack of Substance P is presumably an adaptation to reduce the negative effects of living in a high CO2 atmosphere, which would cause a burning sensation in the nasal cavity and around the eyes, as well as acidosis in the lungs that causes pulmonary edema. This chapter reviews how this feature affects their physiology and behavior. For example, naked mole rats show a blunted response to inflammatory pain, complete insensitivity to irritants such as capsaicin, ammonia, and acid, and they do not show a scratching response to histamine. 

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4. The naked truth: a comprehensive clarification and classification of current ‘myths’ in naked mole‐rat biology

   https://doi.org/10.1111/brv.12791  

   Buffenstein, Rochelle; Amoroso, Vincent; Andziak, Blazej; Avdieiev, Stanislav; Azpurua, Jorge; Barker, Alison J.; Bennett, Nigel C.; Brieño‐Enríquez, Miguel A.; Bronner, Gary N.; Coen, Clive; et al (September 2021, Biological Reviews)

   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. 

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5. Is the Mole Rat Vomeronasal Organ Functional?: vomeronasal organ in mole rats

   https://doi.org/10.1002/ar.24060  

   Dennis, John C.; Stilwell, Natalie K.; Smith, Timothy D.; Park, Thomas J.; Bhatnagar, Kunwar P.; Morrison, Edward E. (January 2019, The Anatomical Record)

   The colonial naked mole rat Heterocephalus glaber is a subterranean, eusocial rodent. The H. glaber vomeronasal organ neuroepithelium (VNE) displays little postnatal growth. However, the VNE remains neuronal in contrast to some mammals that possess nonfunctional vomeronasal organ remnants, for example, catarrhine primates and some bats. Here, we describe the vomeronasal organ (VNO) microanatomy in the naked mole rat and we make preliminary observations to determine if H. glaber shares its minimal postnatal VNE growth with other African mole rats. We also determine the immunoreactivity to the mitotic marker Ki67, growthassociated protein 43 (GAP43), and olfactory marker protein (OMP) in six adult and three subadult H. glaber individuals. VNE volume measurements on a small sample of Cryptomys hottentotus and Fukomys damarensis indicate that the VNE of those African mole rat species are also likely to be growth-deficient. Ki67(+) cells show that the sensory epithelium is mitotically active. GAP43 labelling indicates neurogenesis and OMP(+) cells are present though less numerous compared to GAP43(+) cells. In this respect, the VNO of H. glaber does not appear vestigial. The African mole rat VNE may be unusually variable, perhaps reflecting reduced selection pressure on the vomeronasal system. If so, African mole rats may provide a useful genetic model for understanding the morphological variability observed in the mammalian VNO. 

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