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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. Naked Mole‐Rats: Blind, Naked, and Feeling No Pain

   https://doi.org/10.1002/ar.23996  

   Browe, Brigitte M. ; Vice, Emily N. ; Park, Thomas J. ( November 2018 , The Anatomical Record)

   Around the world and across taxa, subterranean mammals show remarkable convergent evolution in morphology (e.g., reduced external ears, small eyes, shortened limbs and tails). This is true of sensory systems as well (e.g., loss of object vision and high frequency hearing). The naked mole‐rat (Heterocephalus glaber) displays these typical subterranean features, but also has unusual characteristics even among subterranean mammals. Naked mole‐rats are cold‐blooded, completely furless, very long‐lived (> 30 years), and eusocial (like termites). They also live in large colonies, which is very unusual for subterraneans. Their cortical organization has reduced area for visual processing, utilizing 30% more cortex for tactile processing. They are extremely tolerant to oxygen deprivation, and can recover from 18 min of anoxia. Their pain pathway is reduced and they feel no pain from acidosis. They are the only rodent tested to date whose pheromone‐detecting vomeronasal organ shows no postnatal growth. These features may be a result of this species' “extreme subterranean lifestyle” that combines living underground and living in large colonies. Many respiring animals cramped together in unventilated burrows elevates CO₂levels, high enough to cause acidosis pain, and depletes O₂concentrations low enough to kill other mammals. The naked mole‐rat may be an extreme model of adaptation to subterranean life and provides insights into the complex interplay of evolutionary adaptations to the constraints of subterranean living. Anat Rec, 2018. © 2018 American Association for Anatomy.

    

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3. Morphological and genomic shifts in mole-rat ‘queens’ increase fecundity but reduce skeletal integrity

   https://doi.org/10.7554/eLife.65760  

   Johnston, Rachel A ; Vullioud, Philippe ; Thorley, Jack ; Kirveslahti, Henry ; Shen, Leyao ; Mukherjee, Sayan ; Karner, Courtney M ; Clutton-Brock, Tim ; Tung, Jenny ( April 2021 , eLife)

   Some social animals are highly cooperative creatures that live in tight-knit colonies. Bees and ants are perhaps the most well-known examples of social insects, while Damaraland mole-rats and naked mole-rats, two rodent species found in southern and eastern Africa, are among the most cooperative mammal species. In these colony-forming animals, only one or a few females reproduce and these fertile females are frequently referred to as “queens”. When an animal becomes a queen, her body shape can change dramatically to support the demands of high fertility and frequent reproduction. The molecular basis of such changes has been well-described in social insects. However, they are poorly understood in mammals. To address this knowledge gap, Johnston et al. studied how transitioning to queen status affects bone growth and structural integrity in Damaraland mole-rats, as well as body shape and size. The experiments compared non-breeding female mole-rats with other adult females recently paired with a male to become the sole breeder of a new colony. Johnston et al. also used bone-derived cells grown in the laboratory to assess underlying gene regulatory changes in new queen mole-rats. Johnston et al. showed that transitioning to the role of queen leads to a cascade of skeletal changes accompanied by shifts in the regulation of genetic pathways linked to bone growth. Queen mole-rats show accelerated growth in the spinal column of their lower back. These bones are called lumbar vertebrae and this likely allows them to have larger litters. However, queen mole-rats also lose bone growth potential in their leg bones and develop thinner thigh bones, which may increase the risk of bone fracture. Therefore, unlike highly social insects, mole-rats do not seem to have escaped the physical costs of intensive reproduction. This work adds to our understanding of the genes and physical traits that have evolved to support cooperative behaviour in social animals, including differences between insects and mammals. It also shows, with a striking example, how an animal’s genome responds to social cues to produce a diverse range of traits that reflect their designated social role. 

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4. Physiological responses to hypoxia are constrained by environmental temperature in heterothermic tenrecs

   https://doi.org/10.1242/jeb.245324  

   Devereaux, Maiah E. ; Silva Rubio, Claudia ; van Breukelen, Frank ; Pamenter, Matthew E. ( March 2023 , Journal of Experimental Biology)

   ABSTRACT Malagasy tenrecs are placental hibernating mammals that seal the entrances to their burrows and hibernate either singly or in groups for 8–9 months, which is likely to create a hypoxic and hypercapnic burrow environment. Therefore, we hypothesized that tenrecs are tolerant to environmental hypoxia and hypercapnia. Many hypoxia- and hypercapnia-tolerant fossorial mammals respond to hypoxia by decreasing metabolic rate and thermogenesis, and have blunted ventilatory responses to both environmental hypoxia and hypercapnia. However, tenrecs exhibit extreme metabolic and thermoregulatory plasticity, which exceeds that of most heterothermic mammals and approaches that of ectothermic reptiles. Thus, we predicted that tenrecs would have abnormal physiological responses to hypoxia and hypercapnia relative to other fossorial mammals. To test this, we exposed common tenrecs (Tenrec ecaudatus) to moderate and severe hypoxia (9 and 4% O2) or hypercapnia (5 and 10% CO2) in either 28 or 16°C while non-invasively measuring metabolic rate, thermogenesis and ventilation. We found that tenrecs exhibit robust metabolic decreases in both hypoxia and hypercapnia. Furthermore, tenrecs have blunted ventilatory responses to both hypoxia and hypercapnia, and these responses are highly temperature sensitive such that they are reduced or absent in 16°C. Thermoregulation was highly variable in 16°C but constrained in 28°C across all treatment conditions and was not impacted by hypoxia or hypercapnia, unlike in other heterothermic mammals. Taken together, our results indicate that physiological responses to hypoxia and hypercapnia in tenrecs are highly dependent on environmental temperature and differ from those of other mammalian heterotherms. 

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5. Resilience in a Natural Model of Metabolic Dysfunction Through Changes in Longevity and Ageing-Related Metabolites

   https://doi.org/10.1101/2020.10.27.358077  

   Medley, J Kyle Persons ( July 2021 , bioRxiv)

   null (Ed.)

   Insights from extreme-adapted organisms, which have evolved natural strategies for promoting survivability under severe environmental pressures, may help guide future research into novel approaches for enhancing human longevity. The cave-adapted Mexican tetra,Astyanax mexicanus, has attracted interest as a model system for metabolic resilience, a term we use to denote the property of maintaining robust health and longevity under conditions that would have highly deleterious effects in other organisms (Fig 1). Cave-dwelling populations of Mexi-can tetra exhibit elevated blood glucose and possess a mutation in the insulin receptor that in humans has been linked to Rabson-Mendenhall syndrome, a condition characterized by severe insulin resistance that causes numerous developmental abnormalities, is highly associated with debilitating progression, and drastically reduces lifespan. In addition, cavefish develop large numbers of hypertrophic visceral adipocytes and possess vastly enriched stores of body fat compared to surface-dwelling counterparts. However, cavefish appear to avoid the progression of the respective pathologies typically associated with these conditions, such as accumulation of advanced glycation end products (AGEs), chronic tissue inflammation, impaired growth due to insulin dysregulation, and low survivability due to arterial disease. The metabolic strategies underlying the resilience properties of A. mexicanus cavefish, and how they relate to environmental challenges of the cave environment, are poorly understood. Here, we provide an untargeted metabolomics study of long- and short-term fasting in two A. mexicanus cave populations and one surface population. We find that, although cave-fish share many similarities with metabolic syndrome normally associated with the human state of obesity, important differences emerge, including a reduction in cholesteryl esters and intermediates of protein glycation, and an increase in antioxidants and metabolites associated with hypoxia and longevity. We find important overlaps between metabolic alterations in cave-dwelling Mexican tetra and other models of resilience and extreme longevity, such as naked mole-rats, including enhanced reliance on sugars as an energy source and a trend toward more potent antioxidant activity. This work suggests that certain metabolic features associated with human pathologies are not intrinsically harmful, but are rather consequences of suboptimal adaptation of humans to survival under adverse metabolic conditions, and suggests promising avenues for future investigation into the role of metabolic strategies in evolutionary adaptation and health. We provide a transparent pipeline for reproducing our analysis and a Shiny app for other researchers to explore and visualize our dataset. 

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