In all mammals, tissue inflammation leads to pain and behavioral sensitization to thermal and mechanical stimuli called hyperalgesia. We studied pain mechanisms in the African naked mole-rat, an unusual rodent species that lacks pain-related neuropeptides (e.g., substance P) in cutaneous sensory fibers. Naked mole-rats show a unique and remarkable lack of pain-related behaviors to two potent algogens, acid and capsaicin. Furthermore, when exposed to inflammatory insults or known mediators, naked mole-rats do not display thermal hyperalgesia. In contrast, naked mole-rats do display nocifensive behaviors in the formalin test and show mechanical hyperalgesia after inflammation. Using electrophysiology, we showed that primary afferent nociceptors in naked mole-rats are insensitive to acid stimuli, consistent with the animal's lack of acid-induced behavior. Acid transduction by sensory neurons is observed in birds, amphibians, and fish, which suggests that this tranduction mechanism has been selectively disabled in the naked mole-rat in the course of its evolution. In contrast, nociceptors do respond vigorously to capsaicin, and we also show that sensory neurons express a transient receptor potential vanilloid channel-1 ion channel that is capsaicin sensitive. Nevertheless, the activation of capsaicin-sensitive sensory neurons in naked mole-rats does not produce pain-related behavior. We show that capsaicin-sensitive nociceptors in the naked mole-rat are functionally connected to superficial dorsal horn neurons as in mice. However, the same nociceptors are also functionally connected to deep dorsal horn neurons, a connectivity that is rare in mice. The pain biology of the naked mole-rat is unique among mammals, thus the study of pain mechanisms in this unusual species can provide major insights into what constitutes "normal" mammalian nociception.
The naked mole-rat is the longest living rodent with a maximum lifespan exceeding 28 years. In addition to its longevity, naked mole-rats have an extraordinary resistance to cancer as tumors have never been observed in these rodents. Furthermore, we show that a combination of activated Ras and SV40 LT fails to induce robust anchorage-independent growth in naked mole-rat cells, while it readily transforms mouse fibroblasts. The mechanisms responsible for the cancer resistance of naked mole-rats were unknown. Here we show that naked mole-rat fibroblasts display hypersensitivity to contact inhibition, a phenomenon we termed "early contact inhibition." Contact inhibition is a key anticancer mechanism that arrests cell division when cells reach a high density. In cell culture, naked mole-rat fibroblasts arrest at a much lower density than those from a mouse. We demonstrate that early contact inhibition requires the activity of p53 and pRb tumor suppressor pathways. Inactivation of both p53 and pRb attenuates early contact inhibition. Contact inhibition in human and mouse is triggered by the induction of p27(Kip1). In contrast, early contact inhibition in naked mole-rat is associated with the induction of p16(Ink4a). Furthermore, we show that the roles of p16(Ink4a) and p27(Kip1) in the control of contact inhibition became temporally separated in this species: the early contact inhibition is controlled by p16(Ink4a), and regular contact inhibition is controlled by p27(Kip1). We propose that the additional layer of protection conferred by two-tiered contact inhibition contributes to the remarkable tumor resistance of the naked mole-rat.
The naked mole-rat (Heterocephalus glaber) is a subterranean eusocial rodent with a markedly long lifespan and resistance to tumorigenesis. Multiple data implicate modulation of protein translation in longevity. Here we report that 28S ribosomal RNA (rRNA) of the naked mole-rat is processed into two smaller fragments of unequal size. The two breakpoints are located in the 28S rRNA divergent region 6 and excise a fragment of 263 nt. The excised fragment is unique to the naked mole-rat rRNA and does not show homology to other genomic regions. Because this hidden break site could alter ribosome structure, we investigated whether translation rate and amino acid incorporation fidelity were altered. We report that naked mole-rat fibroblasts have significantly increased translational fidelity despite having comparable translation rates with mouse fibroblasts. Although we cannot directly test whether the unique 28S rRNA structure contributes to the increased fidelity of translation, we speculate that it may change the folding or dynamics of the large ribosomal subunit, altering the rate of GTP hydrolysis and/or interaction of the large subunit with tRNA during accommodation, thus affecting the fidelity of protein synthesis. In summary, our results show that naked mole-rat cells produce fewer aberrant proteins, supporting the hypothesis that the more stable proteome of the naked mole-rat contributes to its longevity.
SIGNIFICANCE: The oxidative stress theory of aging has been the most widely accepted theory of aging providing insights into why we age and die for over 50 years, despite mounting evidence from a multitude of species indicating that there is no direct relationship between reactive oxygen species (ROS) and longevity. Here we explore how different species, including the longest lived rodent, the naked mole-rat, have defied the most predominant aging theory. RECENT ADVANCES: In the case of extremely long-lived naked mole-rat, levels of ROS production are found to be similar to mice, antioxidant defenses unexceptional, and even under constitutive conditions, naked mole-rats combine a pro-oxidant intracellular milieu with high, steady state levels of oxidative damage. Clearly, naked mole-rats can tolerate this level of oxidative stress and must have mechanisms in place to prevent its translation into potentially lethal diseases. CRITICAL ISSUES: In addition to the naked mole-rat, other species from across the phylogenetic spectrum and even certain mouse strains do not support this theory. Moreover, overexpressing or knocking down antioxidant levels alters levels of oxidative damage and even cancer incidence, but does not modulate lifespan. FUTURE DIRECTIONS: Perhaps, it is not oxidative stress that modulates healthspan and longevity, but other cytoprotective mechanisms that allow animals to deal with high levels of oxidative damage and stress, and nevertheless live long, relatively healthy lifespans. Studying these mechanisms in uniquely long-lived species, like the naked mole-rat, may help us tease out the key contributors to aging and longevity.
BACKGROUND: Studies comparing similar-sized species with disparate longevity may elucidate novel mechanisms that abrogate aging and prolong good health. We focus on the longest living rodent, the naked mole-rat. This mouse-sized mammal lives ~8 times longer than do mice and, despite high levels of oxidative damage evident at a young age, it is not only very resistant to spontaneous neoplasia but also shows minimal decline in age-associated physiological traits. OBJECTIVES: We assess the current status of stress resistance and longevity, focusing in particular on the molecular and cellular responses to cytotoxins and other stressors between the short-lived laboratory mouse and the naked mole-rat. RESULTS: Like other experimental animal models of lifespan extension, naked mole-rat fibroblasts are extremely tolerant of a broad spectrum of cytotoxins including heat, heavy metals, DNA-damaging agents and xenobiotics, showing LD(50) values between 2- and 20-fold greater than those of fibroblasts of shorter-lived mice. Our new data reveal that naked mole-rat fibroblasts stop proliferating even at low doses of toxin whereas those mouse fibroblasts that survive treatment rapidly re-enter the cell cycle and may proliferate with DNA damage. Naked mole-rat fibroblasts also show significantly higher constitutive levels of both p53 and Nrf2 protein levels and activity, and this increases even further in response to toxins. CONCLUSION: Enhanced cell signaling via p53 and Nrf2 protects cells against proliferating with damage, augments clearance of damaged proteins and organelles and facilitates the maintenance of both genomic and protein integrity. These pathways collectively regulate a myriad of mechanisms which may contribute to the attenuated aging profile and sustained healthspan of the naked mole-rat. Understanding how these are regulated may be also integral to sustaining positive human healthspan well into old age and may elucidate novel therapeutics for delaying the onset and progression of physiological declines that characterize the aging process.
Naked mole-rats are fossorial, eusocial rodents that naturally exhibit high levels of inbreeding. Persistent inbreeding in animals often results in a substantial decline in fitness and, thus, dispersal and avoidance of kin as mates are two common inbreeding avoidance mechanisms. In the naked mole-rat evidence for the former has recently been found. Here we address the latter mechanism by investigating kin recognition and female mate choice using a series of choice tests in which the odour, social and mate preferences of females were determined. Discrimination by females appears to be dependent on their reproductive status. Reproductively active females prefer to associate with unfamiliar males, whereas reproductively inactive females do not discriminate. Females do not discriminate between kin and non-kin suggesting that the criterion for recognition is familiarity, not detection of genetic similarity per se. In the wild, naked mole-rats occupy discrete burrow systems and dispersal and mixing with non-kin is thought to be comparatively rare. Thus, recognition by familiarity may function as a highly efficient kin recognition mechanism in the naked mole-rat. A preference by reproductively active females for unfamiliar males is interpreted as inbreeding avoidance. These findings suggest that, despite an evolutionary history of close inbreeding, naked mole-rats may not be exempt from the effects of inbreeding depression and will attempt to outbreed should the opportunity arise.
This volume brings together more than a decade of information collected in the field and lab on the naked mole-rat (Heterocephalus glaber), a northeast African mammal unique for its physical characteristics and eusociality. Nearly blind and virtually hairless, naked mole-rats inhabit large subterranean colonies in which only one female and her one to three mates conceive offspring, while the young from previous litters maintain and defend the group as do workers in colonies of the social insects. In this first major treatise on naked mole-rats an international group of researchers covers such topics as the evolution of eusociality, phylogeny and systematics of the rodent family Bathyergidae, population and behavioral ecology and genetics of naked mole-rats in the field, vocal and nonvocal behaviors, social organization and divisions of labor within colonies, and climatic, social, and physiological factors affecting growth, reproduction, and reproductive suppression.In addition to the editors, the contributors are D. H. Abbott, M. W. Allard, N. C. Bennett, R. A. Brett, S. H. Braude, B. Crespi, S. V. Edwards, C. G. Faulkes, L. M. George, R. L. Honeycutt, E. A. Lacey, C. E. Liddell, E. McDaid, K. Nelson, K. M. Noonan, J. O'Riain, J. W. Pepper, H. K. Reeve, and D. A. Schlitter.
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We investigated naked mole-rat somatosensory cortex to determine how brain areas are modified in mammals with unusual and extreme sensory specializations. Naked mole-rats (Heterocephalus glaber) have numerous anatomical specializations for a subterranean existence, including rows of sensory hairs along the body and tail, reduced eyes, and ears sensitive to low frequencies. However, chief among their adaptations are behaviorally important, enlarged incisors permanently exterior to the oral cavity that are used for digging, object manipulation, social interactions, and feeding. Here we report an extraordinary brain organization where nearly one-third (31%) of primary somatosensory cortex is devoted to the representations of the upper and lower incisors. In addition, somatosensory cortex is greatly enlarged (as a proportion of total neocortical area) compared with closely related laboratory rats. Finally, somatosensory cortex in naked mole-rats encompasses virtually all of the neocortex normally devoted to vision. These findings indicate that major cortical remodeling has occurred in naked mole-rats, paralleling the anatomical and behavioral specializations related to fossorial life.
) social and subterranean lifestyle generates a hypoxic niche. Under experimental conditions, naked mole-rats tolerate hours of extreme hypoxia and survive 18 minutes of total oxygen deprivation (anoxia) without apparent injury. During anoxia, the naked mole-rat switches to anaerobic metabolism fueled by fructose, which is actively accumulated and metabolized to lactate in the brain. Global expression of the GLUT5 fructose transporter and high levels of ketohexokinase were identified as molecular signatures of fructose metabolism. Fructose-driven glycolytic respiration in naked mole-rat tissues avoids feedback inhibition of glycolysis via phosphofructokinase, supporting viability. The metabolic rewiring of glycolysis can circumvent the normally lethal effects of oxygen deprivation, a mechanism that could be harnessed to minimize hypoxic damage in human disease.
Cryptomys damarensis occurs in semiarid regions of southwestern and central Africa. It lives in colonies in which reproduction is restricted to one or two of the largest-sized males and the largest female in the colony. Some division of labor, into frequent and infrequent workers, occurs within the remaining colony members. Reproduction and details of colony size and the number of breeding animals in a colony are described for two complete and five incomplete wild-captured colonies; one of the complete colonies and mole-rats from the incomplete colonies were maintained in captivity for more than 2 years. The breeding female initiated precopulatory behavior, mating occurred for about 2 weeks, the gestation length was 78–92 days, mean litter size was 2.8 (n = 10), and a maximum of four pups was born. The pups were precocial, wandered out of the nest within 24 h after birth, began to eat solids when 6 days old, and were fully weaned when 3 weeks old. When 6 weeks old, pups began to spar with each other and with some colony members, but levels of aggression were never high and the pups were incorporated into the colony. In the colony, subordinate and frequent-worker mole-rats weighed less than dominant animals and infrequent workers; mass, therefore, was not necessarily indicative of the age of the animal. During the 2-year study period, three mole-rats that were frequent workers on capture changed their castes to infrequent workers, two of them showed a concomitant increase in body mass. The colony structure and reproduction of C. damarensis are compared with those of the eusocial Heterocephalus glaber.
Acid evokes pain by exciting nociceptors; the acid sensors are proton-gated ion channels that depolarize neurons. The naked mole-rat (Heterocephalus glaber) is exceptional in its acid insensitivity, but acid sensors (acid-sensing ion channels and the transient receptor potential vanilloid-1 ion channel) in naked mole-rat nociceptors are similar to those in other vertebrates. Acid inhibition of voltage-gated sodium currents is more profound in naked mole-rat nociceptors than in mouse nociceptors, however, which effectively prevents acid-induced action potential initiation. We describe a species-specific variant of the nociceptor sodium channel Na(V)1.7, which is potently blocked by protons and can account for acid insensitivity in this species. Thus, evolutionary pressure has selected for an Na(V)1.7 gene variant that tips the balance from proton-induced excitation to inhibition of action potential initiation to abolish acid nociception.
Tremendous variation in maximum life span among species overshadows modest increases in longevity resulting from experimental manipulation. Few aging studies focus on long-lived mammals even though these species may expose mechanisms involved in resisting aging. Naked mole-rats (NMRs approximately 35 grams) are the longest-living (>28.3 years) rodents known. This review describes their biology and potential use in aging research. Lifestyle features concur with most evolutionary theories with the exception of the disposable soma theory. Indeed, maximum life span is similar in breeders and nonbreeders, and these highly fecund animals reproduce until they die. Shared characteristics with calorie-restricted, methionine-restricted, and dwarf mice models of extended longevity include reduced body temperature; reduced thyroid, and blood glucose concentrations; and low glycated hemoglobin; in addition to reduced incidence of cancer. Young naked mole-rats surprisingly have high levels of accrued oxidative damage. With their similar longevity quotient to humans, these rodents may provide a novel opportunity to examine mechanisms modulating aging.
Using the technique of DNA fingerprinting, we investigated the genetic structure within and among four wild-caught colonies (n = 50 individuals) of a eusocial mammal, the naked mole-rat (Heterocephalus glaber; Rodentia: Bathyergidae). We found that DNA fingerprints of colony-mates were strikingly similar and that between colonies they were much more alike than fingerprints of non-kin in other free-living vertebrates. Extreme genetic similarity within colonies is due to close genetic relationship (mean relatedness estimate +/- SE, r = 0.81 +/- 0.10), which apparently results from consanguineous mating. The inbreeding coefficient (F = 0.45 +/- 0.18) is the highest yet recorded among wild mammals. The genetic structure of naked mole-rat colonies lends support to kin selection and ecological constraints models for the evolution of cooperative breeding and eusociality.
The naked mole-rat (Heterocephalus glaber) is a subterranean mouse-sized African mammal that shows astonishingly few age-related degenerative changes and seems to not be affected by cancer. These features make this wild rodent an excellent model to study the biology of healthy aging and longevity. Here we characterize for the first time the intestinal microbial ecosystem of the naked mole-rat in comparison to humans and other mammals, highlighting peculiarities related to the specific living environment, such as the enrichment in bacteria able to utilize soil sulfate as a terminal electron acceptor to sustain an anaerobic oxidative metabolism. Interestingly, some compositional gut microbiota peculiarities were also shared with human gut microbial ecosystems of centenarians and Hadza hunter-gatherers, considered as models of a healthy gut microbiome and of a homeostatic and highly adaptive gut microbiota-host relationship, respectively. In addition, we found an enrichment of short-chain fatty acids and carbohydrate degradation products in naked mole-rat compared to human samples. These data confirm the importance of the gut microbial ecosystem as an adaptive partner for the mammalian biology and health, independently of the host phylogeny.
The African mole-rats (Bathyergidae) are a model taxon on which to test evolutionary theories of the origin and maintenance of mammalian social behaviour, since species within the family range in social complexity from solitary to eusocial. The aridity food-distribution hypothesis suggests that sociality within the Bathyergidae has evolved as a consequence of habitat aridity, and the subsequent pattern of geophyte abundance and distribution. In more arid environments, because of the patchiness of this food resource, and the fact that burrowing is only possible during brief periods where rainfall has softened the soil, the risk of unsuccessful foraging is high. This risk may decrease when large numbers of animals are involved in cooperative searching. We examined 25 burrows of seven species within the Bathyergidae and used a simple box-counting method to determine their fractal dimension, which we propose as a measure of burrow architecture that allows explicit testing of differences in African mole-rat burrows within the theoretical framework of the aridity food-distribution hypothesis. We investigate the effect of habitat type and colony size on this parameter, and conclude that habitat type is reflected in burrow architecture in the common mole-rat, Cryptomys hottentotus hottentotus. We also found evidence that the burrows of species with larger maximum group size explore the surrounding area more thoroughly. The results support the contention that larger group size offers adaptive benefits in terms of how thoroughly the surrounding area is explored, and is not simply a consequence of the increased costs of dispersal and colonization in arid areas.
, has a reported maximum lifespan of >30 years and exhibits delayed and/or attenuated age-associated physiological declines. We questioned whether these mouse-sized, eusocial rodents conform to Gompertzian mortality laws by experiencing an exponentially increasing risk of death as they get older. We compiled and analyzed a large compendium of historical naked mole-rat lifespan data with >3000 data points. Kaplan-Meier analyses revealed a substantial portion of the population to have survived at 30 years of age. Moreover, unlike all other mammals studied to date, and regardless of sex or breeding-status, the age-specific hazard of mortality did not increase with age, even at ages 25-fold past their time to reproductive maturity. This absence of hazard increase with age, in defiance of Gompertz's law, uniquely identifies the naked mole-rat as a non-aging mammal, confirming its status as an exceptional model for biogerontology.
Mammalian brains have extremely high levels of aerobic metabolism and typically suffer irreversible damage after brief periods of oxygen deprivation such as occur during stroke or cardiac arrest. Here we report that brain tissue from naked mole-rats, rodents that live in a chronically low-oxygen environment, is remarkably resistant to hypoxia: naked mole-rat neurons maintain synaptic transmission much longer than mouse neurons and can recover from periods of anoxia exceeding 30 min. We suggest that brain tolerance to hypoxia may result from slowed or arrested brain development in these extremely long-lived animals.
The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. Surprisingly, data from the longest-living rodent known, naked mole-rats [MRs; mass 35 g; maximum lifespan (MLSP) > 28.3 years], when compared with mice (MLSP 3.5 years) exhibit higher levels of lipid peroxidation, protein carbonylation, and DNA oxidative damage even at a young age. We hypothesize that age-related changes in protein structural stability, oxidation, and degradation are abrogated over the lifespan of the MR. We performed a comprehensive study of oxidation states of protein cysteines [both reversible (sulfenic, disulfide) and indirectly irreversible (sulfinic/sulfonic acids)] in liver from young and old C57BL/6 mice (6 and 28 months) and MRs (2 and >24 years). Furthermore, we compared interspecific differences in urea-induced protein unfolding and ubiquitination and proteasomal activity. Compared with data from young mice, young MRs have 1.6 times as much free protein thiol groups and similar amounts of reversible oxidative damage to cysteine. In addition, they show less urea-induced protein unfolding, less protein ubiquitination, and higher proteasome activity. Mice show a significant age-related increase in cysteine oxidation and higher levels of ubiquitination. In contrast, none of these parameters were significantly altered over 2 decades in MRs. Clearly MRs have markedly attenuated age-related accrual of oxidation damage to thiol groups and age-associated up-regulation of homeostatic proteolytic activity. These pivotal mechanistic interspecies differences may contribute to the divergent aging profiles and strongly implicate maintenance of protein stability and integrity in successful aging.
The rudimentary eyes of the mole rat (Spalax ehrenbergi) are located under the skin and do not respond to light stimuli. However, removal of the eyes disturbs photoperiod perception in these animals. To help clarify the possibly remaining function of the eyes in this species, the authors studied their development and ultrastructure. In the early embryos the presumptive eye regions--the epithelium, lens vesicle, and optic cup--appear initially normal. As development progresses, the iris-ciliary body complex originates prematurely from the margin of the optic cup and shows a very rapid and massive growth. This pigment-laden tissue mass remains attached to the corneal stroma, obliterates the anterior chamber, and prevents the formation of the corneal endothelium and Descemet's membrane. In the developing lens the elongation of the lens fibers leads to the formation of a rudimentary lens nucleus that becomes disorganized and vacuolated and eventually also becomes vascularized. The optic fissure fails to close, the eyes remain colobomatous, and the optic disc appears atrophic. In contrast, retinal histogenesis progresses relatively normally, resulting in structurally reduced but well-differentiated photoreceptor, neuronal, and ganglion cell layers in the adult eye. Immunohistochemically, the presence of opsin could be demonstrated in the photoreceptor cells. The latter features may indicate that these rudimentary eyes are still functioning in the complex neuroendocrine pathways mediating photoperiodicity.