The Idiosyncratic Physiological Traits of the Naked Mole-Rat; a Resilient Animal Model of Aging, Longevity, and Healthspan.
TL;DR: The naked mole-rat (Heterocephalus glaber) as mentioned in this paper exhibits numerous unusual ecophysiological features including pronounced tolerance of thermolability, hypoxia, hypercapnia and noxious substances.
Abstract: The subterranean-dwelling naked mole-rat (Heterocephalus glaber) is an extremophilic rodent, able to thrive in the harsh underground conditions of sub-Saharan Northeast Africa. This pelage-free mammal exhibits numerous unusual ecophysiological features including pronounced tolerance of thermolability, hypoxia, hypercapnia and noxious substances. As a mammal, the naked mole-rat provides a proof-of-concept that age-related changes in physiology are avoidable. At ages far beyond their expected lifespans given both their body size and/or the timing of early developmental milestones, naked mole-rats fail to exhibit meaningful changes in physiological health or demographic mortality. Lack of physiological deterioration with age is also evident in lean and fat mass, bone quality, and reproductive capacity. Rather, regardless of age, under basal conditions naked mole-rats appear to “idle on low” with their “shields up” as is manifested by low body temperature, metabolic rate, cardiac output and kidney concentrating ability, enabling better protection of organs and cellular function. When needed, they can nevertheless ramp up these functions, increasing cardiac output and metabolism 2–5 fold. Here we review many unusual aspects of their physiology and examine how these attributes facilitate both tolerance of the diverse suite of hostile conditions encountered in their natural milieu as well as contribute to their extraordinary longevity and resistance to common, age-related chronic diseases.
Citations
More filters
University of Illinois at Chicago1, City University of New York2, Stony Brook University3, Max Delbrück Center for Molecular Medicine4, Mammal Research Institute5, King's College London6, University of Illinois at Urbana–Champaign7, Northeast Ohio Medical University8, Northwest Vista College9, Queen Mary University of London10, Newcastle University11, Paris Descartes University12, Cornell University13, University of Rochester14, Cleveland Clinic Lerner Research Institute15, University of Toronto16, Kumamoto University17, Graduate University for Advanced Studies18, University of Cambridge19, Azabu University20, Scripps Research Institute21, Johns Hopkins University22, Russian Academy of Sciences23, City College of New York24, Rockefeller University25, University of Tokyo26, University of Ottawa27, University of Cologne28, University of Texas Health Science Center at San Antonio29, Yale University30, Southern Illinois University Carbondale31, Carleton University32, Harvard University33, Université catholique de Louvain34
TL;DR: The naked mole-rat (Heterocephalus glaber) has attracted 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.
Abstract: 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.
47 citations
TL;DR: Naked mole-rats (Heterocephalus glaber) are small rodents native to east Africa, living in subterranean colonies of up to 300 individuals, and reproduction is restricted to a single breeding female and 1-3 breeding males; all other colony members are reproductively suppressed and socially subordinate unless removed from the suppressive cues of the colony.
Abstract: Naked mole-rats (Heterocephalus glaber) are small rodents native to east Africa, living in subterranean colonies of up to 300 individuals. Within each colony, reproduction is restricted to a single breeding female and 1-3 breeding males; all other colony members are reproductively suppressed and socially subordinate unless removed from the suppressive cues of the colony. Due to their striking reproductive skew, naked mole-rats are often considered eusocial mammals. Consistent with this idea, there are behavioral specializations and at least some evidence for morphological distinctions within and between the breeding and non-breeding members of the colony. Importantly, naked mole-rats show plasticity in their behavioral phenotype whereby changes in the social environment influence expression of both type and amount of social behavior. Thus, naked mole-rats provide the opportunity to examine the proximate mechanisms controlling individual differences in social behavior, shedding light on how mammals live in complex social groups.
20 citations
TL;DR: The African mole-rat superfamily as discussed by the authors is a unique group of underground rodents that are remarkable for their adaptations to a subterranean lifestyle and their range in sociality, spanning strictly solitary species to the most social of all rodents.
Abstract: The African mole-rat superfamily are a unique group of subterranean rodents that are remarkable for their adaptations to a subterranean lifestyle and their range in sociality, spanning strictly solitary species to the naked mole-rat, the most social of all rodents. Widely distributed through sub-Saharan Africa their occurrence is associated with the presence of food resources in the form of underground roots, bulbs and tubers, which form their staple diet. African mole-rats have an ancient Oligocene/Eocene origin, with the naked mole-rat, the extant species with the earliest divergence from the common ancestor of the clade. As a consequence of its early evolution the naked mole-rat appears to have acquired many extraordinary biological features, even when compared with other mole-rats. Molecular phylogenies indicate that complex sociality and cooperative breeding has been convergently gained and/or lost more than once among African mole-rats, making them a fascinating group for comparative studies of social evolution. Ultimately, ecological constraints on digging and finding food have played a role in increasing cooperative behavior and social complexity, from what was most likely a monogamous ancestor living in family groups. Phylogenetically controlled comparisons suggest that proximate control of their lifestyle shows both conservation and divergence in the underlying mechanisms.
16 citations
TL;DR: A constellation of physiological and molecular adaptations that correlate with the naked mole-rat's hypoxic/hypercapnic tolerance and which offer potential targets for ameliorating pathological conditions in humans, such as the damage caused during cerebral ischemia.
Abstract: Naked mole-rats are extremely tolerant to low concentrations of oxygen (hypoxia) and high concentrations of carbon dioxide (hypercapnia), which is consistent with the environment that they inhabit. Naked mole-rats combine subterranean living with living in very densely populated colonies where oxygen becomes depleted and carbon dioxide accumulates. In the laboratory, naked mole-rats fully recover from 5 h exposure to 5% O2 and 5 h exposure to 80% CO2, whereas both conditions are rapidly lethal to similarly sized laboratory mice. During anoxia (0% O2) naked mole-rats enter a suspended animation-like state and switch from aerobic metabolism of glucose to anaerobic metabolism of fructose. Additional fascinating characteristics include that naked mole-rats show intrinsic brain tolerance to anoxia; a complete lack of hypoxia-induced and CO2-induced pulmonary edema; and reduced aversion to high concentrations of CO2 and acidic fumes. Here we outline a constellation of physiological and molecular adaptations that correlate with the naked mole-rat’s hypoxic/hypercapnic tolerance and which offer potential targets for ameliorating pathological conditions in humans, such as the damage caused during cerebral ischemia.
13 citations
TL;DR: The African mole-rat family (Bathyergidae) includes the first mammalian species identified as eusocial: naked mole-rats as mentioned in this paper, which are found in the oxytocin, vasopressin and corticotrophin-releasing factor (CRF) systems within the nucleus accumbens, amygdala, bed nucleus of the stria terminalis and lateral septal nucleus.
Abstract: The African mole-rat family (Bathyergidae) includes the first mammalian species identified as eusocial: naked mole-rats. Comparative studies of eusocial and solitary mole-rat species have identified differences in neuropeptidergic systems that may underlie the phenomenon of eusociality. These differences are found in the oxytocin, vasopressin and corticotrophin-releasing factor (CRF) systems within the nucleus accumbens, amygdala, bed nucleus of the stria terminalis and lateral septal nucleus. As a corollary of their eusociality, most naked mole-rats remain pre-pubertal throughout life because of the presence of the colony’s only reproductive female, the queen. To elucidate the neuroendocrine mechanisms that mediate this social regulation of reproduction, research on the hypothalamo-pituitary-gonadal axis in naked mole-rats has identified differences between the many individuals that are reproductively suppressed and the few that are reproductively mature: the queen and her male consorts. These differences involve gonadal steroids, gonadotrophin-releasing hormone-1 (GnRH-1), kisspeptin, gonadotrophin-inhibitory hormone/RFamide-related peptide-3 (GnIH/RFRP-3) and prolactin. The comparative findings in eusocial and solitary mole-rat species are assessed with reference to a broad range of studies on other mammals.
12 citations
References
More filters
[...]
TL;DR: The role of vitamin D in skeletal and nonskeletal health is considered and strategies for the prevention and treatment ofitamin D deficiency are suggested.
Abstract: Once foods in the United States were fortified with vitamin D, rickets appeared to have been conquered, and many considered major health problems from vitamin D deficiency resolved. But vitamin D deficiency is common. This review considers the role of vitamin D in skeletal and nonskeletal health and suggests strategies for the prevention and treatment of vitamin D deficiency.
11,849 citations
TL;DR: An overview of the physiologic, endocrinologic, and molecular biologic characteristics of vitamin D is provided and information on new selective analogs of 1alpha,25-dihydroyvitamin D3 for therapy is provided.
2,092 citations
Book•
21 Jun 1984
TL;DR: This volume discusses water-Solute Adaptations: The Evolution and Regulation of the Internal Milieu, and the influence of Oxygen Availability on the Diving Response and Its Evolution.
Abstract: 1. The Goals and Scope of This Volume 2. Cellular Metabolism, Regulation, and Homeostasis 3. Influence of Oxygen Availability 4. The Diving Response and Its Evolution 5. Human Hypoxia Tolerance 6. Water-Solute Adaptations: The Evolution and Regulation of the Internal Milieu 7. Temperature
1,831 citations
TL;DR: It is apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues.
Abstract: Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent causes of debilitating disease and death. Tissue injury and/or death occur as a result of the initial ischemic insult, which is determined primarily by the magnitude and duration of the interruption in the blood supply, and then subsequent damage induced by reperfusion. During prolonged ischemia, ATP levels and intracellular pH decrease as a result of anaerobic metabolism and lactate accumulation. As a consequence, ATPase-dependent ion transport mechanisms become dysfunctional, contributing to increased intracellular and mitochondrial calcium levels (calcium overload), cell swelling and rupture, and cell death by necrotic, necroptotic, apoptotic, and autophagic mechanisms. Although oxygen levels are restored upon reperfusion, a surge in the generation of reactive oxygen species occurs and proinflammatory neutrophils infiltrate ischemic tissues to exacerbate ischemic injury. The pathologic events induced by I/R orchestrate the opening of the mitochondrial permeability transition pore, which appears to represent a common end-effector of the pathologic events initiated by I/R. The aim of this treatise is to provide a comprehensive review of the mechanisms underlying the development of I/R injury, from which it should be apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues.
1,565 citations
TL;DR: A reduction of fat mass without caloric restriction can be associated with increased longevity in mice, possibly through effects on insulin signaling.
Abstract: Caloric restriction has been shown to increase longevity in organisms ranging from yeast to mammals. In some organisms, this has been associated with a decreased fat mass and alterations in insulin/insulin-like growth factor 1 (IGF-1) pathways. To further explore these associations with enhanced longevity, we studied mice with a fat-specific insulin receptor knockout (FIRKO). These animals have reduced fat mass and are protected against age-related obesity and its subsequent metabolic abnormalities, although their food intake is normal. Both male and female FIRKO mice were found to have an increase in mean life-span of ∼134 days (18%), with parallel increases in median and maximum life-spans. Thus, a reduction of fat mass without caloric restriction can be associated with increased longevity in mice, possibly through effects on insulin signaling.
1,297 citations