[Evolution of cancer resistance in the animal kingdom]. / Évolution de la résistance au cancer dans le monde animal.

Cancer is an inevitable collateral problem inherent in the evolution of multicellular organisms, which appeared at the end of the Precambrian. Faced to this constraint, a range of diverse anticancer defenses has evolved across the animal kingdom. Today, investigating how animal organisms, especially those of large size and long lifespan, manage cancer-related issues has both fundamental and applied outcomes, as it could inspire strategies for preventing or treating human cancers. In this article, we begin by presenting the conceptual framework for understanding evolutionary theories regarding the development of anti-cancer defenses. We then present a number of examples that have been extensively studied in recent years, including naked mole rats, elephants, whales, placozoa, xenarthras (such as sloths, armadillos and anteaters) and bats. The contributions of comparative genomics to understanding evolutionary convergences are also discussed. Finally, we emphasize that natural selection has also favored anti-cancer adaptations aimed at avoiding mutagenic environments, for example by maximizing immediate reproductive efforts in the event of cancer. Exploring these adaptive solutions holds promise for identifying novel approaches to improve human health.

Title: Évolution de la résistance au cancer dans le monde animal. Abstract: Le cancer est un dommage collatéral inévitable inhérent à l'évolution des organismes multicellulaires, apparus à la fin du Précambrien. L'exploration de la manière dont les animaux, en particulier ceux de grande taille et de longue durée de vie, font face au cancer, comporte des enjeux à la fois fondamentaux et appliqués. Dans cet article, nous commençons par présenter le cadre conceptuel nécessaire pour comprendre les théories qui traitent de l'évolution des défenses anti-cancéreuses. Nous présentons ensuite un certain nombre d'exemples, notamment les rats-taupes nus, les éléphants, les baleines, les xénarthres (paresseux, tatous et fourmiliers), les chauves-souris et les placozoaires1. Les contributions de la génomique comparative à la compréhension des convergences évolutives sont également abordées. Enfin, nous indiquons que la sélection naturelle a également favorisé des adaptations visant à éviter les zones mutagènes, par exemple, ou à maximiser l'effort de reproduction immédiat en cas de cancer. L'exploration de ces solutions, intéressante conceptuellement, pourrait aussi permettre d'envisager de nouvelles approches thérapeutiques pour la santé humaine.

Evolution of T cells in the cancer-resistant naked mole-rat.

Naked mole-rats (NMRs) are best known for their extreme longevity and cancer resistance, suggesting that their immune system might have evolved to facilitate these phenotypes. Natural killer (NK) and T cells have evolved to detect and destroy cells infected with pathogens and to provide an early response to malignancies. While it is known that NMRs lack NK cells, likely lost during evolution, little is known about their T-cell subsets in terms of the evolution of the genes that regulate their function, their clonotypic diversity, and the thymus where they mature. Here we find, using single-cell transcriptomics, that NMRs have a large circulating population of γδT cells, which in mice and humans mostly reside in peripheral tissues and induce anti-cancer cytotoxicity. Using single-cell-T-cell-receptor sequencing, we find that a cytotoxic γδT-cell subset of NMRs harbors a dominant clonotype, and that their conventional CD8 αßT cells exhibit modest clonotypic diversity. Consistently, perinatal NMR thymuses are considerably smaller than those of mice yet follow similar involution progression. Our findings suggest that NMRs have evolved under a relaxed intracellular pathogenic selective pressure that may have allowed cancer resistance and longevity to become stronger targets of selection to which the immune system has responded by utilizing γδT cells.

Adenosine and γ-aminobutyric acid partially regulate metabolic and ventilatory responses of Damaraland mole-rats to acute hypoxia.

Fossorial Damaraland mole-rats (Fukomys damarensis) mount a robust hypoxic metabolic response (HMR) but a blunted hypoxic ventilatory response (HVR) to acute hypoxia. Although these reflex physiological responses have been described previously, the underlying signalling pathways are entirely unknown. Of particular interest are contributions from γ-aminobutyric acid (GABA), which is the primary inhibitory neurotransmitter in the nervous system of most adult mammals, and adenosine, the accumulation of which increases during hypoxia as a breakdown product of ATP. Therefore, we hypothesized that GABAergic and/or adenosinergic signalling contributes to the blunted HVR and robust HMR in Damaraland mole-rats. To test this hypothesis, we injected adult animals with saline alone (controls), or 100 mg kg-1 aminophylline or 1 mg kg-1 bicuculline, to block adenosine or GABAA receptors, respectively. We then used respirometry, plethysmography and thermal RFID probes to non-invasively measure metabolic, ventilator and thermoregulatory responses, respectively, to acute hypoxia (1 h in 5 or 7% O2) in awake and freely behaving animals. We found that bicuculline had relatively minor effects on metabolism and thermoregulation but sensitized ventilation such that the HVR became manifest at 7% instead of 5% O2 and was greater in magnitude. Aminophylline increased metabolic rate, ventilation and body temperature in normoxia, and augmented the HMR and HVR. Taken together, these findings indicate that adenosinergic and GABAergic signalling play important roles in mediating the robust HMR and blunted HVR in Damaraland mole-rats.

The Naked Mole-Rat as a Model for Healthy Aging.

Naked mole-rats (NMRs, Heterocephalus glaber) are the longest-lived rodents with a maximum life span exceeding 37 years. They exhibit a delayed aging phenotype and resistance to age-related functional decline/diseases. Specifically, they do not display increased mortality with age, maintain several physiological functions until nearly the end of their lifetime, and rarely develop cancer and Alzheimer's disease. NMRs live in a hypoxic environment in underground colonies in East Africa and are highly tolerant of hypoxia. These unique characteristics of NMRs have attracted considerable interest from zoological and biomedical researchers. This review summarizes previous studies of the ecology, hypoxia tolerance, longevity/delayed aging, and cancer resistance of NMRs and discusses possible mechanisms contributing to their healthy aging. In addition, we discuss current issues and future perspectives to fully elucidate the mechanisms underlying delayed aging and resistance to age-related diseases in NMRs.

Not just a cousin of the naked mole-rat: Damaraland mole-rats offer unique insights into biomedicine.

Evolutionary medicine has been a fast-growing field of biological research in the past decade. One of the strengths of evolutionary medicine is to use non-traditional model organisms which often exhibit unusual characteristics shaped by natural selection. Studying these unusual traits could provide valuable insight to understand biomedical questions, since natural selection likely discovers solutions to those complex biological problems. Because of many unusual traits, the naked mole-rat (NMR) has attracted attention from different research areas such as aging, cancer, and hypoxia- and hypercapnia-related disorders. However, such uniqueness of NMR physiology may sometimes make the translational study to human research difficult. Damaraland mole-rat (DMR) shares multiple characteristics in common with NMR, but shows higher degree of similarity with human in some aspects of their physiology. Research on DMR could therefore offer alternative insights and might bridge the gap between experimental findings from NMR to human biomedical research. In this review, we discuss studies of DMR as an extension of the current set of model organisms to help better understand different aspects of human biology and disease. We hope to encourage researchers to consider studying DMR together with NMR. By studying these two similar but evolutionarily distinct species, we can harvest the power of convergent evolution and avoid the potential biased conclusions based on life-history of a single species.

The endocrine control of reproductive suppression in an aseasonally breeding social subterranean rodent, the Mahali mole-rat (Cryptomys hottentotus mahali).

Cooperative behaviour, sociality and reproductive suppression in African mole-rats have been extensively studied. Nevertheless, endocrine correlates of some species of social mole-rats have been neglected, and these species may hold the key to understanding the behavioural and physiological complexity that allows the maintenance of social groups in African mole-rats. In this study, we investigated endocrine correlates implicated in the suppression of reproduction and cooperative behaviours, namely glucocorticoids (a stress-related indicator) through faecal glucocorticoid metabolites (fGCMs), plasma testosterone (an indicator of aggression) and plasma prolactin in the Mahali mole-rat (Cryptomys hottentotus mahali) across reproductive classes (breeding females and males, non-breeding females and males) and season (wet and dry). Breeders possessed higher levels of testosterone than non-breeders. In reproductively suppressed non-breeding females, fGCMs were significantly higher than in breeders. Furthermore, an adrenocorticotropic hormone stimulation test (ACTH challenge test) on both male and female non-breeders revealed that female non-breeders show a more significant response to the ACTH challenge than males. At the same time, plasma prolactin levels were equally elevated to similar levels in breeding and non-breeding females. Chronically high levels of prolactin and fGCM are reported to cause reproductive suppression and promote cooperative behaviours in non-breeding animals. Furthermore, there was a negative relationship between plasma prolactin and progesterone in non-breeding females. However, during the wet season, a relaxation of suppression occurs through reduced prolactin which corresponds with elevated levels of plasma progesterone in non-breeding females. Therefore, prolactin is hypothesised to be the primary hormone controlling reproductive suppression and cooperative behaviours in non-breeding females. This study provides new endocrine findings for the maintenance of social suppression in the genus Cryptomys.

Lactate inhibits naked mole-rat cardiac mitochondrial respiration.

In aerobic conditions, the proton-motive force drives oxidative phosphorylation (OXPHOS) and the conversion of ADP to ATP. In hypoxic environments, OXPHOS is impaired, resulting in energy shortfalls and the accumulation of protons and lactate. This results in cellular acidification, which may impact the activity and/or integrity of mitochondrial enzymes and in turn negatively impact mitochondrial respiration and thus aerobic ATP production. Naked mole-rats (NMRs) are among the most hypoxia-tolerant mammals and putatively experience intermittent hypoxia in their underground burrows. However, if and how NMR cardiac mitochondria are impacted by lactate accumulation in hypoxia is unknown. We predicted that lactate alters mitochondrial respiration in NMR cardiac muscle. To test this, we used high-resolution respirometry to measure mitochondrial respiration in permeabilized cardiac muscle fibres from NMRs exposed to 4 h of in vivo normoxia (21% O2) or hypoxia (7% O2). We found that: (1) cardiac mitochondria cannot directly oxidize lactate, but surprisingly, (2) lactate inhibits mitochondrial respiration, and (3) decreases complex IV maximum respiratory capacity. Finally, (4) in vivo hypoxic exposure decreases the magnitude of lactate-mediated inhibition of mitochondrial respiration. Taken together, our results suggest that lactate may retard electron transport system function in NMR cardiac mitochondria, particularly in normoxia, and that NMR hearts may be primed for anaerobic metabolism.

Supermole-rat to the rescue: Does the naked mole-rat offer a panacea for all that ails us?

Over the previous several decades, many non-traditional research models have offered new avenues of exploration for biomedical research. The promise of these animals is primarily derived from adaptations to unique or challenging environments that share key factors with a disease or pathology of interest (e.g., hypoxemia or hypercarbia are clinically relevant and are also in vivo consequences of environmental hypoxia and hypercapnia, respectively). Animals adapted to such environments allow us to ask the question: how has nature solved a particular problem and what can we learn to inform novel translational research into the treatment of related diseases and pathologies? One of the most promising mammalian models that have garnered increasing attention from researchers and the public are naked mole-rats (NMRs). The NMR is a small and eusocial subterranean rodent species that live in a putatively hypoxic and hypercapnic burrow environment. Intriguingly, whereas most non-traditional biomedical models offer insight into one or only a few diseases related to a common physiological stress, NMRs in contrast have proven to be resistant to a very wide range of ailments, including aging, cancer, and hypoxia- and hypercapnia-related disorders, among many others. In the present commentary, we discuss progress made in understanding how NMRs overcome these challenges and speculate on the origins of their remarkable abilities.

Na+/K+-ATPase activity is regionally regulated by acute hypoxia in naked mole-rat brain.

Matching ATP supply and demand is key to neuronal hypoxia-tolerance and failure to achieve this balance leads to excitotoxic cell death in most adult mammalian brains. Ion pumping is the most energy-demanding process in the brain and some hypoxia-tolerant vertebrates coordinately down-regulate ion movement across neuronal membranes to reduce the workload of energy-expensive ion pumps, and particularly the Na+/K+-ATPase. Naked mole-rats are among the most hypoxia-tolerant mammals and achieve a hypometabolic state while maintaining brain [ATP] during severe hypoxia; however, whether ionic homeostasis is plastic in naked mole-rat brain is unknown. To examine this question, we exposed animals to 4 h of normoxia or moderate or severe hypoxia (11 or 3% O2, respectively) and measured changes in brain Na+/K+-ATPase activity. We found that 1) whole body metabolic rate decreased ∼25 and 75% in moderate and severe hypoxia, respectively, and 2) Na+/K+-ATPase activity decreased ∼50% in forebrain but increased 2-fold in cerebellum and was unchanged in brainstem. These results indicate that naked mole-rats acutely modulate brain energy demand in a region-specific manner to prioritize energy usage by the cerebellum. This may support exploration, navigation, and escape behaviours, while also enabling ATP savings when encountering hypoxia in nature.

Uncovering molecular mechanisms of regulated cell death in the naked mole rat.

The naked mole rat (NMR), Heterocephalus glaber, is the longest-living rodent species, and is extraordinarily resistant to cancer and aging-related diseases. The molecular basis for these unique phenotypic traits of the NMR is under extensive research. However, the role of regulated cell death (RCD) in the longevity and the protection from cancer in the NMR is still largely unknown. RCD is a mechanism restricting the proliferation of damaged or premalignant cells, which counteracts aging and oncotransformation. In this study, DNA damage-induced cell death in NMR fibroblasts was investigated in comparison to RCD in fibroblasts from Mus musculus. The effects of methyl methanesulfonate, 5-fluorouracil, and etoposide in both cell types were examined using contemporary cell death analyses. Skin fibroblasts from Heterocephalus glaber were found to be more resistant to the action of DNA damaging agents compared to fibroblasts from Mus musculus. Strikingly, our results revealed that NMR cells also exhibit a limited apoptotic response and seem to undergo regulated necrosis. Taken together, this study provides new insights into the mechanisms of cell death in NMR expanding our understanding of longevity, and it paves the way towards the development of innovative therapeutic approaches.

The hypoxia adaptation of small mammals to plateau and underground burrow conditions.

Oxygen is one of the important substances for the survival of most life systems on the earth, and plateau and underground burrow systems are two typical hypoxic environments. Small mammals living in hypoxic environments have evolved different adaptation strategies, which include increased oxygen delivery, metabolic regulation of physiological responses and other physiological responses that change tissue oxygen utilization. Multi-omics predictions have also shown that these animals have evolved different adaptations to extreme environments. In particular, vascular endothelial growth factor (VEGF) and erythropoietin (EPO), which have specific functions in the control of O2 delivery, have evolved adaptively in small mammals in hypoxic environments. Naked mole-rats and blind mole-rats are typical hypoxic model animals as they have some resistance to cancer. This review primarily summarizes the main living environment of hypoxia tolerant small mammals, as well as the changes of phenotype, physiochemical characteristics and gene expression mode of their long-term living in hypoxia environment.

Naked mole-rat very-high-molecular-mass hyaluronan exhibits superior cytoprotective properties.

Naked mole-rat (NMR), the longest-living rodent, produces very-high-molecular-mass hyaluronan (vHMM-HA), compared to other mammalian species. However, it is unclear if exceptional polymer length of vHMM-HA is important for longevity. Here, we show that vHMM-HA (>6.1 MDa) has superior cytoprotective properties compared to the shorter HMM-HA. It protects not only NMR cells, but also mouse and human cells from stress-induced cell-cycle arrest and cell death in a polymer length-dependent manner. The cytoprotective effect is dependent on the major HA-receptor, CD44. We find that vHMM-HA suppresses CD44 protein-protein interactions, whereas HMM-HA promotes them. As a result, vHMM-HA and HMM-HA induce opposing effects on the expression of CD44-dependent genes, which are associated with the p53 pathway. Concomitantly, vHMM-HA partially attenuates p53 and protects cells from stress in a p53-dependent manner. Our results implicate vHMM-HA in anti-aging mechanisms and suggest the potential applications of vHMM-HA for enhancing cellular stress resistance.

Effect of colony disruption and social isolation on naked mole-rat endocrine correlates.

The social environment of animals can have profound implications on their behaviour and physiology. Naked mole-rats (Heterocephalus glaber) are highly social with complex dominance hierarchies that influence both stress- and reproduction-related hormones. Homeostasis may be affected by aggressive interactions, colony instability and social isolation. Furthermore, naked mole-rat colonies are characterised by a marked reproductive skew; a single female and few males are reproductively active while other colony members are reproductively suppressed. Thus, there are distinct differences in related hormone concentrations between reproductively active and non-active animals; however, this changes when non-reproductive individuals are removed from the colony. We investigated the effects of social isolation and colony disruption on plasma cortisol and progesterone concentrations in non-breeding naked mole-rats. During colony disruption, we found a significant increase in cortisol concentrations in females removed from the colony for social isolation (experimental) as well as in females that remained in the colony (control). Cortisol concentrations were reduced in both groups after experimental animals were paired up. No changes in cortisol concentrations were observed in control or experimental males after removal from the colony or pairing. This suggests that the females, but not the males, found colony disruption and social isolation stressful. Upon removal from the colony, both control and experimental females showed a small increase in progesterone, which returned to basal levels again in the control animals. Experimental females showed a dramatic spike in progesterone when they were paired with males, indicating reproductive activation. The sex difference in the stress responses may be due to the stronger reproductive suppression imposed on females, or the increased likelihood of dispersal for males. It is clear that the social environment reflects on the endocrine correlates of animals living in a colony, and that the colony structure may affect the sensitivity of the animals to changes in their environment.

Naked mole rats activate neuroprotective proteins during hypoxia.

Naked mole rats are a long-lived animal model that age much like humans, but that can also withstand oxidative damage, cancer, neurodegenerative diseases, and severe hypoxic conditions, which is of particular interest to this study. The conditions of their underground burrows result in competition for oxygen consumption, yet despite this oxygen deprivation they emerge unscathed. To understand the mechanisms in place to facilitate neuronal preservation during hypoxia, we investigated the protein levels of well-known cell-stress factors. We found that under hypoxic conditions, nearly half of the proteins measured increased expression in brain, while only a few decreased. Under hypoxic conditions there appeared to be a HIF1α-centered response, where HIF1α and its interactors carbonic anhydrase 9, CITED2, p21/CIP1, and NFκB1, among others, were upregulated. Concurrently, a hypoxia-induced decrease of cytochrome c was consistent with decreased mitochondrial function and protection from apoptosis. The picture that emerges is one of neuroprotection, cell-cycle arrest, and the promotion of antiapoptotic functions, all of which are consistent with conserving energy and maintaining neural integrity under low oxygen levels. These results suggest how this species may be poised to face hypoxia and contribute to its remarkable ability to deal with myriad of other damaging factors and sets the stage for future work on the neuroprotective facilitators we identified.

Normal physiological functions in two animal species with highly different vitamin d status compared to that of humans / Funciones fisiológicas normales en dos especies animales con estatus de vitamina d muy diferentes del actual en seres humanos

Mole rats live in permanent darkness, in networks of underground tunnels (which extend up to 1 km in the subsoil), excavated with their incisors, in warm and semi-arid areas of South Africa. Mole rats have an unusually impoverished vitamin D3 status with undetectable and low plasma concentrations of 25- hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3, respectively. They express 25-hydroxylase in the liver and 1-hydroxylase and 24-hydroxylase in their kidneys. The presence of specific receptors (VDR) was confirmed in the intestine, kidney, Harderʼs glands and skin. In spite of their poor vitamin D3 status, the apparent fractional intestinal absorption of calcium, magnesium and phosphate was high, always greater than 90%. Oral supplementation with cholecalciferol to mole rats did not improve the efficiency of gastrointestinal absorption of these minerals. Mole ratsdo not display the typical lesion of rickets: hypertrophic and radiolucent growth cartilages. Histological studies reported normal parameters of trabecular and cortical bone quality. Marmosets (monkeys of the New World) are not hypercalcaemic, eventhough they exhibit much higher levels of 25-hydroxyvitamin D3, 1α,25-dihydroxyvitamin D3 and parathyroid hormonethan that of rhesus monkeys and humans. Fed a high vitamin D3 intake (110 IU/day/100 g of body weight), a fraction of the experimental group was found to display osteomalacic changes in their bones: distinct increases in osteoid surface, relative osteoid volume, and active osteoclastic bone resorption. These findings suggest that some marmosets appears to suffer vitamin D-dependent rickets, type II. The maximum binding capacity of the VDR or the dissociation constant of VDR1α,25(OH)2D3 complex of mole rats and New World monkeys are distinctly different of VDR isolated from human cells. Health status of those species appears to be adaptations to the mutations of their VDR. Though rare, as mutations may occur at any time in any patient, the overall message of this review to clinicians may be: recent clinical studies strongly suggests that the normality of physiological functions might be a better indicator of the health status than the serum levels of vitamin D metabolites. (AU)

Las ratas topo viven en la oscuridad permanente, en redes de túneles subterráneos excavadas con sus incisivos (que se extienden hasta 1 km en el subsuelo), en áreas cálidas y semiáridas de Sudáfrica. Las ratas topo tienen un estatus de vitamina D3 inusualmente empobrecido con concentraciones plasmáticas indetectables de 25-hidroxivitamina D3 y bajas de 1α, 25-dihidroxivitamina D3. Poseen 25-hidroxilasa en el hígado y 1-hidroxilasa y 24-hidroxilasa en sus riñones. La presencia de receptores específicos (VDR) ha sido confirmada en el intestino, el riñón, las glándulas de Harder y la piel. A pesar de su pobre estatus de vitamina D3,la absorción fraccional intestinal aparente de calcio, magnesio y fosfato fue alta, siempre superior al 90%. La suplementación oral con colecalciferol a las ratas topo no mejoró la eficacia de la absorción gastrointestinal de estos minerales. No muestran la lesión típica del raquitismo: cartílagos de crecimiento hipertróficos y radiolúcidos. Varios estudios histológicos confirman los hallazgos radiológicos y se informan parámetros normales de la calidad ósea trabecular y cortical. Los titíes (monos del Nuevo Mundo) exhiben calcemias normales con niveles más elevados de 25-hidroxivitamina D3, 1α,25-dihidroxivitamina D3 y hormona paratiroidea que los monos rhesus y los seres humanos. Un tercio de un grupo de titíes alimentados con una alta ingesta de vitamina D3 (110 I/día/100 g de peso corporal) exhibió cambios osteomalácicos en sus huesos: aumento en la superficie osteoide, volumen osteoide y activa reabsorción osteoclástica. Estos hallazgos sugieren que una fracción de la población de titíes padece raquitismo dependiente de vitamina D, tipo II. Debido a mutaciones ocurridas hace millones de años, las máximas capacidades de ligamiento del VDR o los valores de la constante de disociación del complejo VDR-1α,25(OH)2D3 de las ratas topo o monos del Nuevo Mundo son muy diferentes de los verificables en receptores aislados de células humanas actuales. El mensaje de esta revisión a los médicos clínicos podría ser: varios estudios clínicos recientes indican que la normalidad de las funciones fisiológicas de un paciente es un mejor indicador de su salud que los niveles séricos de los metabolitos de la vitamina D. (AU)

Hypoxia tolerance, longevity and cancer-resistance in the mole rat Spalax - a liver transcriptomics approach.

The blind subterranean mole rat Spalax shows a remarkable tolerance to hypoxia, cancer-resistance and longevity. Unravelling the genomic basis of these adaptations will be important for biomedical applications. RNA-Seq gene expression data were obtained from normoxic and hypoxic Spalax and rat liver tissue. Hypoxic Spalax broadly downregulates genes from major liver function pathways. This energy-saving response is likely a crucial adaptation to low oxygen levels. In contrast, the hypoxia-sensitive rat shows massive upregulation of energy metabolism genes. Candidate genes with plausible connections to the mole rat's phenotype, such as important key genes related to hypoxia-tolerance, DNA damage repair, tumourigenesis and ageing, are substantially higher expressed in Spalax than in rat. Comparative liver transcriptomics highlights the importance of molecular adaptations at the gene regulatory level in Spalax and pinpoints a variety of starting points for subsequent functional studies.

Breeding and Rearing Naked Mole-Rats (Heterocephalus glaber) under Laboratory Conditions.

The unique biologic characteristics of naked mole-rats (NMR, Heterocephalus glaber) include longevity, cancer resistance, hypoxia tolerance, and pain insensitivity, making NMR an attractive model for biomedical research on aging, cancer, and neurobiology. However, breeding and rearing NMR in captivity is challenging. Here, we report a method for breeding NMR by using a closed-colony mating system. We selected sexually mature male and female NMR from different natal colonies and mated them 1:1. The 5 original colonies had an annual parity of 3.20 ± 0.84 (mean ± 1 SD), with 38.80 ± 9.50 pups born, 33.80 ± 8.32 pups weaned, and a survival rate of 87.19% ± 6.09% after weaning. The average annual parity of 22 N1 pairs (established from the progeny of the 5 original pairs) was 3.09 ± 0.81, with 34.86 ± 10.66 total pups born during the year, 30.14 ± 10.23 pups weaned, and a survival rate after weaning of 85.51% ± 6.60%. The average annual parity of 29 N2 pairs (that is, offspring of N1 pairs) was 3.04 ± 0.87, with 33.69 ± 11.42 pups born, 28.17 ± 10.43 pups weaned, and a survival rate after weaning of 83.66% ± 10.75%. None of these measures differed among the 3 generations, with average reproductive success exceeding 70% for each. In addition, the reproduction and growth of the N1 and N2 generations was similar to the original colonies. Our breeding method remarkably increases the production of NMR, thus representing a great potential to promote experimental NMR research and its applications.

O2 binding and CO2 sensitivity in haemoglobins of subterranean African mole rats.

Inhabiting deep and sealed subterranean burrows, mole rats exhibit a remarkable suite of specializations, including eusociality (living in colonies with single breeding queens), extraordinary longevity, cancer immunity and poikilothermy, and extreme tolerance of hypoxia and hypercapnia. With little information available on adjustments in haemoglobin (Hb) function that may mitigate the impact of exogenous and endogenous constraints on the uptake and internal transport of O2, we measured haematological characteristics, as well as Hb-O2 binding affinity and sensitivity to pH (Bohr effect), CO2, temperature and 2,3-diphosphoglycerate (DPG, the major allosteric modulator of Hb-O2 affinity in red blood cells) in four social and two solitary species of African mole rats (family Bathyergidae) originating from different biomes and soil types across Central and Southern Africa. We found no consistent patterns in haematocrit (Hct) and blood and red cell DPG and Hb concentrations or in intrinsic Hb-O2 affinity and its sensitivity to pH and DPG that correlate with burrowing, sociality and soil type. However, the results reveal low specific (pH independent) effects of CO2 on Hb-O2 affinity compared with humans that predictably safeguard pulmonary loading under hypoxic and hypercapnic burrow conditions. The O2 binding characteristics are discussed in relation to available information on the primary structure of Hbs from adult and developmental stages of mammals subjected to hypoxia and hypercapnia and the molecular mechanisms underlying functional variation in rodent Hbs.

Learning of nature: The curious case of the naked mole rat.

Naked mole rats (NMRs) are the longest-living rodents known, living up to approximately 30 years and showing sustained good health. Nowadays, NMRs are considered excellent models for aging and, additionally, for cancer research, due to the evidence of a remarkable cancer resistance demonstrated through thousands of necropsies performed with very few cases that describe this pathology, which is believed to be a disease that unavoidably accompanies aging. Since some years ago, several studies have tried to explain the possible mechanisms underlying longevity and cancer resistance in NMRs through different perspectives and directions, creating new knowledge that subsequently could be used for cancer prevention and delaying aging in humans. Thus, the purpose of this review is to summarize the recent knowledge on naked mole rats with a particular emphasis on the molecular mechanisms associated with their longevity and cancer resistance.