Naked Mole-rat Heterocephalus Glaber Research Articles

Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles

The naked mole-rat Heterocephalus glaber is a eusocial mammal exhibiting extreme longevity (37-year lifespan), extraordinary resistance to hypoxia and absence of cardiovascular disease. To identify the mechanisms behind these exceptional traits, metabolomics and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and C57/BL6 mouse). We identify metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1α is observed while downstream hypoxia responsive-genes are down-regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts show reduced succinate levels during ischemia compared to C57/BL6 mouse and negligible tissue damage following ischemia-reperfusion injury. These evolutionary traits reflect adaptation to a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span.

E skin of the naked mole-rat and its resilience against aging and cancer

The naked mole-rat (NMR) Heterocephalus glaber (from the Greek/latin words ἕτερος, heteros = divergent, κεφαλή, kephalē = head and glabra = hairless) was first described by Rüppell (Fig.1) and belongs to the Hystricognath (from the Greek words ὕστριξ, hystrix = porcupine and Γνάθος, gnathos = jaw) as a suborder of rodents. NMR are characterized by the highest longevity among rodents and reveal a profound cancer resistance. Details of its skin-specific protective and resistance mechanisms against aging and carcinogenesis have so far not been adequately characterized. Recently, our knowledge of NMR skin biology was complemented and expanded by published data using state-of-the art histological and molecular techniques.Here we review and integrate novel published data regarding skin morphology and histology of the aging NMR and the underlying mechanisms at the cellular and molecular level. We relate this data to the longevity of the NMR and its resistance to neoplastic transformation and discuss further open questions to understand its extraordinary longevity. In addition, we will address the exposome, defined as “the total of all non-genetic, endogenous and exogenous environmental influences” on the skin, respiratory tract, stomach, and intestine. Finally, we will discuss in perspective further intriguing possibilities arising from the interaction of skin with other organs.

Mechanisms of Aging from a Genetic, Molecular and Lifestyle Perspective.

Aging is an evitable part of the lives of every organism. However, many organisms are capable of bending the rules and experience an increased longevity. Among these are turtles, elephants, whales and most importantly – humans. Definition for the discussion of anti-aging and longevity is presented alongside a historic analysis of the reasons for this venture. An examination of the adaptations of both short-lived, such as the mayfly, and long-lived organisms like turtles, the naked mole rat Heterocephalus glaber and the American lobster Homarus americanus for their possible human applications. Several studies on the genetics and molecular basis of longevity are presented and debated upon. Finally, there is an examination of possible cultural lifestyle effects on longevity, such as one’s environmental stresses, diet and nutrition, and physical activity. Overall, showing that a combination of genetic, molecular and lifestyle factors strongly affect and allow one to surpass the typical life expectancy.

Bodyweight, locomotion, and behavioral responses of the naked mole rat (Heterocephalus glaber) to lipopolysaccharide administration

The naked mole rat has unique biologic characteristics that include atypical inflammatory responses. Lipopolysaccharide induces inflammation which triggers brain centers controlling feeding, and behavior to result in “sick animal behavior”. We characterized the bodyweight, locomotor, and other behavioral responses of this rodent to lipopolysaccharide administration. Lipopolysaccharide caused weight losses, which were not prevented by TAK 242. In the open field test, lipopolysaccharide did not depress locomotion, while urination, defecation, and activity freezing were rare. The animals exhibited walling but not rearing and fast backward movements that were unaffected by lipopolysaccharide. Failure to depress locomotion suggests either a unique immunity-brain crosstalk or motor responses/centers that tolerate depressive effects of inflammation. The absence of activity freezing and rarity of urination and defecation suggests that novel environments or lipopolysaccharide do not induce anxiety, or that anxiety is expressed differently in the animal. The absence of rearing could be due to the design of the animal’s locomotor apparatus while fast backward movement could be a mechanism for quick escape from threats in the tunnels of their habitat. Our results elucidate the unique biology of this rodent, which elicits interest in the animal as a model for inflammatory research, although the findings require mechanistic corroborations.

Motor Activity and "Neotenic" Sleep in the Naked Mole Rat (Heterocephalus glaber) under Isolation.

For the first time, continuous registration of motor activity and electroencephalogram for 40 days was carried out in four individuals of the naked mole rat (Heterocephalus glaber) in isolated conditions in the laboratory. A clear circadian rhythm of motor activity was found, with a gradual decrease during the night and an increase during the day, which remained both in the 12L/12D mode and in conditions of complete darkness. The rest states occupied, on average, about half the time of the day. There were both typical and atypical sleep periods, in which REM sleep episodes preceded NREM sleep periods. REM sleep percentage was unusually high (up to 50% of the total sleep time). During REM sleep episodes, a synchronized two-phase high-amplitude rhythm with a frequency of 12-16 Hz was recorded in the EEG. In addition, there were hard-to-identify periods of sleep, combining elements of both NREM and REM sleep. The sleep structure of naked mole rats resembles that of evolutionarily ancient species, as well as the "disorganized" sleep characteristic of the early stages of ontogenesis in altricial mammals.

DNA methylation clocks as a predictor for ageing and age estimation in naked mole-rats, Heterocephalus glaber.

The naked mole-rat, Heterocephalus glaber (NMR), the longest-lived rodent, is of significance and interest in the study of biomarkers for ageing. Recent breakthroughs in this field have revealed ‘epigenetic clocks’ that are based on the temporal accumulation of DNA methylation at specific genomic sites. Here, we validate the hypothesis of an epigenetic clock in NMRs based on changes in methylation of targeted CpG sites. We initially analysed 51 CpGs in NMR livers spanning an age range of 39-1,144 weeks and found 23 to be significantly associated with age (p<0.05). We then built a predictor of age using these sites. To test the accuracy of this model, we analysed an additional set of liver samples, and were successfully able to predict their age with a root mean squared error of 166 weeks. We also profiled skin samples with the same age range, finding a striking correlation between their predicted age versus their actual age (R=0.93), but which was lower when compared to the liver, suggesting that skin ages slower than the liver in NMRs. Our model will enable the prediction of age in wild-caught and captive NMRs of unknown age, and will be invaluable for further mechanistic studies of mammalian ageing.

Preliminary Data on Phylogeography of the Naked Mole-Rat Heterocephalus glaber (Rodentia: Heterocephalidae)

The naked mole-rat Heterocephalus glaber is widespread in arid and semiarid areas of northeast Africa. It is endemic to the Somali-Masai biome and has a number of unique characteristics of its biology. Obviously, this could affect the structure of the genetic diversity of the species, which is insufficiently studied. For the first time, we conducted a comparative analysis of two complete mitochondrial genes (cytochrome b and control region) of the species from a significant part of its range. Our results showed that H. glaber has a strong phylogeographic structure. There are probably several deeply divergent lineages of H. glaber, whose taxonomic status is not resolved.

Abstract 137: The Role of TNNI3K in Adult Mammalian Heart Regeneration

Adult mammalian heart regenerative capacity is thought to be extremely limited. All fetal and newborn mouse cardiomyocytes are mononuclear and diploid, and most become polyploid during the first postnatal week. Our lab showed that mononucleated diploid cardiomyocytes (MNDCMs) retain regenerative capacity, and that the percentage of this subpopulation in the adult mouse heart is variable across strains and correlated with the regeneration capacity of mouse heart. We reported cardiac troponin I-interacting kinase (TNNI3K), a novel cardiac specific gene, to be a key regulator of MNDCM frequency. Nonetheless, a detailed mechanism of how Tnni3k regulates MNDCM frequency is still lacking. TNNI3K is a MAPKKK by sequence, but no change in MAPK signaling pathways (p38, ERK1/2, JNK) occurs in Tnni3k knock-out mice. To distinguish whether Tnni3k plays a kinase role, we created a mouse line harboring the kinase-dead mutant of Tnni3k (Tnni3k-k489r) , which recapitulates the high MNCM frequency of Tnni3k knock-out mice. Engineered Tnni3k truncations in mice yield no stable protein, and these mice also show a high MNCM frequency. Interestingly, we found that naked mole-rat ( Heterocephalus glaber ) has a Tnni3k truncation mutation, doesn't express a stable TNNI3K protein, and has a high level of MNCM frequency and cardiomyocyte polyploidy. These results indicate that Tnni3k may influence cardiomyocyte karyokinesis and cytokinesis across mammalian species. We also found that several human TNNI3K polymorphisms compromise kinase activity, which may influence variation in MNDCM frequency and heart regenerative capacity in the human population.

Is the Mole Rat Vomeronasal Organ Functional?

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, growth-associated 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. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc. Anat Rec, 303:318-329, 2020. © 2019 American Association for Anatomy.

Overview of African naked mole-rat Heterocephalus glaber for bioprospecting, and access and benefit sharing in Ethiopia

Biodiversity in developing countries such as Ethiopia has been accessed for a long time, for various purposes, by outside researchers and private companies with little or no returns to conservation activities and with no equitable sharing of the benefits resulting from the commercial use of genetic resources. Ethiopia now aims to conserve, sustainably use and share the benefits from bioprospecting of its richer biodiversity by developing legislations which practically put in place the contents of basic principles of the international treaties such as the Convention on Biological Diversity and the Nagoya Protocol. Bioprospecting of potentially valuable genetic resources from the country’s biodiversity-rich regions can bring monetary and non-monetary benefits from users, bioprospectors and investors. This review also aims to have an overview of the really bizarre looking, little explored and economically important rodent animal, the East African naked mole-rat, Heterocephalus glaber, from the Horn of Africa, for Bioprospecting and Access and Benefit Sharing in Ethiopia. It reveals that this animal has lots of peculiar morphological, physiological, ecological and environmental adaptations, which attract the attention of outside researchers to conduct analgesic, anti-cancer and anti-aging and various other innovative scientific researches, or invite bioprospectors to undergo medicinal, pharmaceutical and industrial bioprospecting on the animal genetic resource. However, any research and development studies related with animal bioprospecting in Ethiopia should be complemented by the conservation, sustainable utilization of biodiversity, and the access and benefit sharing of this animal genetic resource.

Overview of African naked mole-rat Heterocephalus glaber for bioprospecting, and access and benefit sharing in Ethiopia

Overview of African naked mole-rat Heterocephalus glaber for bioprospecting, and access and benefit sharing in Ethiopia

The novel cathelicidin of naked mole rats, Hg-CATH, showed potent antimicrobial activity and low cytotoxicity

We performed the in silico genome-wide identification of antimicrobial peptides against the available genome sequence of the naked mole rat Heterocephalus glaber (H. glaber). Our results showed the presence of Hg-CATH, the single cathelicidin containing the antimicrobial domain in H. glaber. We chemically synthesized a 25 amino-acid peptide (ΔHg-CATH) corresponding to the predicted antimicrobial-active core region of Hg-CATH, and evaluated its antibacterial activity against seven bacterial strains. The ΔHg-CATH peptide exhibited strong bactericidal activity against gram-negative bacteria, including a multi-drug resistant strain, while showing low toxicity towards mammalian cells, including erythrocytes. Scanning electron microscopy images of bacterial cells treated with ΔHg-CATH showed disruption of their membranes due to the formation of toroidal pores. Identifying novel antimicrobial peptides, such as Hg-CATH, may be important for identifying candidate peptides for the control of multi-drug resistant bacteria.

Поддержание стабильности генома у Heterocephalus glaber

The naked mole-rat (Heterocephalus glaber) is one of the most promising models used to study genome maintenance systems, including the effective repair of damage to DNA. The naked mole-rat is the longest lived rodent species, which is extraordinarily resistant to cancer and has a number of other unique phenotypic traits. For at least 80% of its lifespan, this animal shows no signs of aging or any increased likelihood of death and retains the ability to reproduce. The naked mole-rat draws the heightened attention of researchers who study the molecular basis of lengthy lifespan and cancer resistance. Despite the fact that the naked mole-rat lives under genotoxic stress conditions (oxidative, etc.), the main characteristics of its genome and proteome are a high stability and effective functioning. Replicative senescence in the somatic cells of naked mole-rats is missing, while an additional p53/pRb-dependent mechanism of early contact inhibition has been revealed in its fibroblasts, which controls cell proliferation and its mechanism of arf-dependent aging. The unique traits of phenotypic and molecular adaptations found in the naked mole-rat speak to a high stability and effective functioning of the molecular machinery that counteract damage accumulation in its genome. This review analyzes existing results in the study of the molecular basis of longevity and high cancer resistance in naked mole-rats.

Naked mole-rats maintain healthy skeletal muscle and Complex IV mitochondrial enzyme function into old age.

The naked mole-rat (NMR) Heterocephalus glaber is an exceptionally long-lived rodent, living up to 32 years in captivity. This extended lifespan is accompanied by a phenotype of negligible senescence, a phenomenon of very slow changes in the expected physiological characteristics with age. One of the many consequences of normal aging in mammals is the devastating and progressive loss of skeletal muscle, termed sarcopenia, caused in part by respiratory enzyme dysfunction within the mitochondria of skeletal muscle fibers. Here we report that NMRs avoid sarcopenia for decades. Muscle fiber integrity and mitochondrial ultrastructure are largely maintained in aged animals. While mitochondrial Complex IV expression and activity remains stable, Complex I expression is significantly decreased. We show that aged naked mole-rat skeletal muscle tissue contains some mitochondrial DNA rearrangements, although the common mitochondrial DNA deletions associated with aging in human and other rodent skeletal muscles are not present. Interestingly, NMR skeletal muscle fibers demonstrate a significant increase in mitochondrial DNA copy number. These results have intriguing implications for the role of mitochondria in aging, suggesting Complex IV, but not Complex I, function is maintained in the long-lived naked mole rat, where sarcopenia is avoided and healthy muscle function is maintained for decades.

Sequence analysis of serum paraoxonase 1 of bathyergidae family specific rats

Initially characterized as an organophosphate hydrolase, paraoxonase (PON) was seen to catalyses the hydrolysis of paraoxon organophosphate insecticides and sarin nerve gases as well as other similar compounds. The paraoxonase gene cluster contains three adjacent gene members, PON1, PON2, and PON3. Emerging from the same lactonase precursor (fungus), all of the PON genes share profound level of sequence identity and a very similar β propeller protein structure. Formerly a study on the structural characterization of arylesterase (paraoxonase) of Ancylostoma duodenale was done to understand their structural improvements. The objective of this study was to determination of protein sequence level characteristics of PON1 of bathyergidae family specific rats (naked mole rat (Heterocephalus glaber) and Damaraland mole rat (Fukomys damarensis) with the help of different bioinformatical tools. The present study clearly demonstrates that protein evolution occurred within the bathyergidae family specific rats i.e., in naked mole rat and Damaraland mole-rat.

Leveraging Naked Mole Rat (Heterocephalus glaber) Comparative Genomics to Identify Canine Genes Modulating Susceptibility to Tumorigenesis and Cancer Phenotypes

We utilized a comparative genomics approach to analyze a core set of tumorigenesis orthologs among human, mouse, dog and naked mole rat. The analysis identified cancer orthologs that are both conserved and divergent between dog and the cancer resistant species naked mole rat. These tumorigenesis orthologous are associated with phenotypes that modulate cancer susceptibility, cardiac development, craniofacial development, brain development, skeletal development, and immune function, to name a few. This bioinformatics approach employed a variety of literature mining tools to further uncover relationships between the tumorigenesis orthologs. Together, these results shed light on the relationship between breed formations, breed associated morphological traits and breed associated susceptibility to tumorigenesis. These findings support the use of a comparative genomic analysis between species with dramatically different disease phenotypes as a gene discovery tool. A total of 146 proteins coding SNPs were identified in these tumorigenesis orthologs representing missense variations, frame shift variations and nonsense variations. The genes identified in this study can serve as a list of candidates for subsequent laboratory and clinical study. Furthermore, the identification of SNPs impacting the primary structure of the tumorigenesis orthologs may provide clues about the basis of cancer susceptibility between dog breeds.

Milk composition and lactation strategy of a eusocial mammal, the naked mole‐rat

The reproductive female, or queen, in a eusocial colony must allocate sufficient nutrients to reproduction to maintain a high rate of reproductive output. In mammals, the energetic costs of lactation greatly exceed those of pregnancy, and thus, lactation should be exceptionally costly for a eusocial queen, such as the naked mole-rat Heterocephalus glaber. We predicted that naked mole-rat milk would be energy- and nutrient-dense. Naked mole-rat milk averaged 17.2% dry matter, 4.5% fat, 4.8% protein, 5.7% sugar and 1.1% ash; and per gram contained 3.0 mg calcium, 1.1 mg phosphorus, 0.44 mg magnesium and 0.54 mg potassium. Other than elevated protein and low sugar in colostrum, the composition of milk did not change over the course of lactation. Naked mole-rats not only had the lowest energy content of milk (3.9 kJ g −1 ) reported for any rodent but also appeared to be an outlier from a trend for milk dry matter, fat and energy concentrations to be inversely related to body mass in rodents. The dilute nature of naked mole-rat milk indicates that an unusually large amount of milk (equivalent to about half of body mass) must be produced daily to sustain the energy needs of an average litter (12 young). Sustaining high water throughput during lactation may be necessary to meet expected water needs of the offspring but may limit the queen to foods that are high in moisture. The concentrations of macrominerals in milk were within the range described for other rodents, except that the Ca : P ratio of milk (2.8:1) was unusually high. Given a lifespan that can exceed 30 years, large average litter size and several litters per year, the lifetime lactation output of a mole-rat queen must be phenomenal and warrants further study.

Transkriptom-Sequenzierung in der Alternsforschung

With the advent of next-generation sequencing technologies transcriptome sequencing (RNA-seq) became widely used to study the genetic background of ageing processes and related diseases. We describe the power of this method in the study of two novel age research model organisms, the short-lived killifish Nothobranchius furzeri and the long-lived naked mole rat Heterocephalus glaber. A third example illustrates the utility of RNA-seq in a multispecies approach elucidating the role of mild stress in healthy ageing.

Comments on Point:Counterpoint: High altitude is/is not for the birds!

TO THE EDITOR: The debate between Scott et al. (6) and Llanos et al. (4) highlights the remarkable ability of birds and mammals to adapt and survive at high altitudes and cope with reduced oxygen (O2) availability. Scott and colleagues (6) make a compelling argument that birds are far superior to mammals at adapting and thriving in hypoxic environments, both at rest and during exercise. While their argument is supported by comparisons between birds and terrestrial mammals, it ignores marine mammals. Marine mammals such as seals are routinely exposed to and tolerate long bouts of hypoxia during breath-hold diving. For example, elephant seals may dive to depths of nearly 1,600 m and occasionally remain submerged for 2 h (3). Moreover, marine mammals can be exposed to partial pressures of arterial oxygen (PaO2) as low as 12 mmHg during free dives (5), which is less than the 20 mmHg observed in the bar-headed goose (6). Interestingly, a PaO2 of 12 mmHg observed in elephant seals corresponds to arterial saturations and O2 content of only 8% and 2.7 ml O2/dl (5). Thus marine mammals such as the elephant seal demonstrate a remarkable hypoxia tolerance. The integration of several key physiological adaptations including 1) substantially greater myoglobin concentrations compared to other mammals, 2) reductions in metabolism, 3) a greater reliance on aerobic metabolism (i.e., less lactate production), 4) a host of dramatic acute cardiovascular adjustments; and 5) an increased intrinsic cerebral hypoxia tolerance allow marine mammals to thrive in hypoxic environments and enable long deep dives (1–3).

Expression pattern of cadherins in naked mole rat (Heterocephalus glaber) suggests innate cortical diversification of the cerebrum

Expression pattern of cadherins in naked mole rat (Heterocephalus glaber) suggests innate cortical diversification of the cerebrum