Immunosenescence is a hallmark of aging and manifests as increased susceptibility to infection, autoimmunity, and cancer in the elderly. One component of immunosenescence is thymic involution, age-associated shrinkage of the thymus, observed in all vertebrates studied to date. The naked mole rat (Heterocephalus glaber) has become an attractive animal model in aging research due to its extreme longevity and resistance to disease. Here, we show that naked mole rats display no thymic involution up to 11 years of age. Furthermore, we found large ectopic cervical thymi in addition to the canonical thoracic thymus, both being identical in their cell composition. The developmental landscape in naked mole rat thymi revealed overt differences from the murine T-cell compartment, most notably a decrease of CD4+ /CD8+ double-positive cells and lower abundance of cytotoxic effector T cells. Our observations suggest that naked mole rats display a delayed immunosenescence. Therapeutic interventions aimed at reversing thymic aging remain limited, underscoring the importance of understanding the cellular and molecular mechanisms behind a sustained immune function in the naked mole rat.

Long-lived rodents have become an attractive model for the studies on aging. To understand evolutionary paths to long life, we prepare chromosome-level genome assemblies of the two longest-lived rodents, Canadian beaver (Castor canadensis) and naked mole rat (NMR, Heterocephalus glaber), which were scaffolded with in vitro proximity ligation and chromosome conformation capture data and complemented with long-read sequencing. Our comparative genomic analyses reveal that amino acid substitutions at \"disease-causing\" sites are widespread in the rodent genomes and that identical substitutions in long-lived rodents are associated with common adaptive phenotypes, e.g., enhanced resistance to DNA damage and cellular stress. By employing a newly developed substitution model and likelihood ratio test, we find that energy and fatty acid metabolism pathways are enriched for signals of positive selection in both long-lived rodents. Thus, the high-quality genome resource of long-lived rodents can assist in the discovery of genetic factors that control longevity and adaptive evolution.

Mouse and rats are staple model organisms that have been traditionally used for oncological studies; however, their short lifespan and highly prone to cancers limit their utilizationsin understanding the mechanisms of cancer resistance. In recent years, several studies of the non-standard long-lived mammalian species like naked mole rat (NMR) have provided new insights of mechanisms in natural anti-cancer. How long-lived species genetically maintain longevity and cancer-resistance remains largely elusive. To better understand the underlying anti-cancer mechanisms in long-lived mammals, we genome widely identified long noncoding RNA (lncRNA) transcripts of two longevous mammals, bowhead whale (BW, Balaena mysticetus) and Brandt\'s bat (BB, Myotis brandtii) and featured their sequence traits, expression patterns, and their correlations with cancer-resistance. Similar with naked mole rat (NMR, Heterocephalus glaber), the most long-lived rodent, BW and BB lncRNAs show low sequence conservation and dynamic expressions among tissues and physiological stages. By utilizing k-mers clustering, 75-136 of BW, BB and NMR lncRNAs were found in close relation (Pearson\'s r ≥0.9, p < 0.01) with human ageing diseases related lncRNAs (HAR-Lncs). In addition, we observed thousands of BB and BW lncRNAs strongly co-expressed (r > 0.8 or r <-0.8, p < 0.01) with potential tumour suppressors, indicating that lncRNAs are potentially involved in anti-cancer regulation in long-lived mammals. Our study provides the basis for lncRNA researches in perspectives of evolution and anti-cancer studies. Abbreviations: BW: bowhead whale; BB: Brandt\'s bat; NMR: naked mole rat; LLM: long-lived mammal; HTS: human tumour-suppressors; PTS: potential tumour suppressor; ARD: ageing related diseases; HAR-Lncs: lncRNAs that related with human ageing diseases; Kmer-lncs: lncRNAs in long-lived mammal species that corelated (Pearson\'sr ≥0.9, p < 0.01) with the 10 HAR-Lncs by k-mers clustering; All-lncs: all the lncRNAs in long-lived mammal species; SDE-lncs: significant differentially expressed lncRNAs.

Neurodevelopmental duration plays a central role in the evolution of the retina and neocortex in mammals. In the diurnal primate eye and retina, it is necessary to scale the number of cones versus the number of rods with different exponents to defend their respective functions of spatial acuity and sensitivity in eyes of different sizes. The order of photoreceptor precursor specification, cones specified first, rods second, couples their respective cell numbers at maturity to the kinetics of embryonic stem cell proliferation. Different durations of retinogenesis change the ratio of rods to cones produced so as to defend both functions over a range of eye diameters. In the evolution of nocturnality, the same coupling of photoreceptor specification to neurogenesis is altered to fewer cones and many more rods in nocturnal eyes, by delaying the onset of retinogenesis. Similarly, the neocortex also shows coupling of the specification of laminar position with duration of neurogenesis. Overall, duration of neurogenesis directly predicts neocortex volume in most mammalian clades. In larger brains with longer neocortical neurogenesis, its organization changes progressively, differentiating the frontal pole from the occipital pole in volume of connectivity and number of neurons per unit column. This permits greater, hierarchically organized information abstraction with increasing neocortex volume. Exceptions do exist, however, in species of three separate taxa, marsupials, naked mole rats, and bats, which break the correlation of neurodevelopmental duration and brain size. Naked mole rats and bats both have small brains and unusual longevity, coupled with neurodevelopmental periods characteristic of much bigger-brained animals, raising the possibility that developmental duration and lifespan have some genetic or mechanistic control in common. The role of duration of development in mediating between the mechanistic levels of construction of retinal and cortical organization, and the different life histories associated with larger brains, such as duration of parental care, learning and overall longevity are discussed.

OBJECTIVE: Naked mole rats (NMRs) spend their lives in burrow systems containing very low levels of oxygen, indicating long-term hypoxic exposure, and suggesting that pathological changes caused by hypoxia are attenuated or absent in this hypoxia-tolerant species. The mechanisms underlying NMRs hypoxia tolerance remain poorly understood. In this study, we explored whether hypoxia inducible factor 1α (HIF-1α), and vascular endothelial growth factor A (VEGFA) play a role in NMRs adaption to hypoxia.
METHODS: Primary hepatic stellate cells (HSCs) isolated from NMRs and mice were treated with 50 μM YC-1, 50 μM KC7F2 or VEGFA siRNA. HIF-1α or VEGFA expression was detected by Western blot and real-time PCR. Apoptosis was determined by flow cytometry. The expression of autophagy markers (LC3 and p62) was detected by Western blot.
RESULTS: Our results showed that HIF-1α and VEGFA expression in NMRs was significantly higher than in hypoxia-sensitive mice. Inhibition of HIF-1α expression induced apoptosis in both NMR and mouse HSCs following hypoxia. However, blocking VEGFA transcription results in a significant increase of apoptosis in both NMR and mouse HSCs before and after hypoxia. In addition, NMR HSCs displayed higher levels of autophagy (ratio of LC3ΙΙ/LC3Ι = 9.6) than mouse HSCs (relative ratio of LC3ΙΙ/ LC3Ι = 4.9) under hypoxic conditions.
CONCLUSIONS: We conclude that HIF-1α activation may be an important mechanism for hypoxia adaption. However, high expression of VEGFA follows HIF-1α activation in NMRs.

The naked mole rat (NMR; Heterocephalus glaber) is a small rodent species found in regions of Kenya, Ethiopia and Somalia. It has a high tolerance for hypoxia and is thus considered one of the most important natural models for studying hypoxia tolerance mechanisms. The various mechanisms underlying the NMR\'s hypoxia tolerance are beginning to be understood at different levels of organization, and next-generation sequencing methods promise to expand this understanding to the level of gene expression. In this study, we examined the sequence and transcript abundance data of the muscle transcriptome of NMRs exposed to hypoxia using the Illumina HiSeq 2500 system to clarify the possible genomic adaptive responses to the hypoxic underground surroundings. The RNA-seq raw FastQ data were mapped against the NMR genome. We identified 2337 differentially expressed genes (DEGs) by comparison of the hypoxic and control groups. Functional annotation of the DEGs by gene ontology (GO) analysis revealed enrichment of hypoxia stress-related GO categories, including \'biological regulation\', \'cellular process\', \'ion transport\' and \'cell-cell signaling\'. Enrichment of DEGs in signaling pathways was analyzed against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database to identify possible interactions between DEGs. The results revealed significant enrichment of DEGs in focal adhesion, the mitogen-activated protein kinase (MAPK) signaling pathway and the glycine, serine and threonine metabolism pathway. Furthermore, inhibition of DEGs (STMN1, MAPK8IP1 and MAPK10) expression induced apoptosis and arrested cell growth in NMR fibroblasts following hypoxia. Thus, this global transcriptome analysis of NMRs can provide an important genetic resource for the study of hypoxia tolerance in mammals. Furthermore, the identified DEGs may provide important molecular targets for biomedical research into therapeutic strategies for stroke and cardiovascular diseases.

Naked mole rat (NMR) is a valuable model for aging and cancer research due to its exceptional longevity and cancer resistance. We observed that the reprogramming efficiency of NMR fibroblasts in response to OSKM was drastically lower than that of mouse fibroblasts. Expression of SV40 LargeT antigen (LT) dramatically improved reprogramming of NMR fibroblasts. Inactivation of Rb alone, but not p53, was sufficient to improve reprogramming efficiency, suggesting that NMR chromatin may be refractory to reprogramming. Analysis of the global histone landscape revealed that NMR had higher levels of repressive H3K27 methylation marks and lower levels of activating H3K27 acetylation marks than mouse. ATAC-seq revealed that in NMR, promoters of reprogramming genes were more closed than mouse promoters, while expression of LT led to massive opening of the NMR promoters. These results suggest that NMR displays a more stable epigenome that resists de-differentiation, contributing to the cancer resistance and longevity of this species.

Long noncoding RNAs (lncRNAs) are a class of ubiquitous noncoding RNAs and have been found to act as tumor suppressors or oncogenes, which dramatically altered our understanding of cancer. Naked mole rat (NMR, Heterocephalus glaber) is an exceptionally long-lived and cancer-resistant rodent; however, whether lncRNAs play roles in cancer resistance in this seductive species remains unknown.
In this study, we developed a pipeline and identified a total of 4422 lncRNAs across the NMR genome based on 12 published transcriptomes. Systematic analysis revealed that NMR lncRNAs share many common characteristics with other vertebrate species, such as tissue specificity and low expression. BLASTN against with 1057 human cancer-related lncRNAs showed that only 5 NMR lncRNAs displayed homology, demonstrating the low sequence conservation between NMR lncRNAs and human cancer-related lncRNAs. Further correlation analysis of lncRNAs and protein-coding genes indicated that a total of 1295 lncRNAs were intensively coexpressed (r ≥ 0.9 or r ≤ -0.9, cP value ≤ 0.01) with potential tumor-suppressor genes in NMR, and 194 lncRNAs exhibited strong correlation (r ≥ 0.8 or r ≤ -0.8, cP value ≤ 0.01) with four high-molecular-mass hyaluronan related genes that were previously identified to play key roles in cancer resistance of NMR.
In this study, we provide the first comprehensive genome-wide analysis of NMR lncRNAs and their possible associations with cancer resistance. Our results suggest that lncRNAs may have important effects on anticancer mechanism in NMR.

BACKGROUND: The naked mole rat (NMR, Heterocephalus glaber) is a long-lived rodent model with multiple extraordinary traits. They live underground and have been known to live for up to thirty years, much longer than similar-sized mice. Moreover, congenital cancer or experimentally induced cancer genesis could not been observed in this rodent so far. Such unique biochemical and physiological characteristics lead them to become a popular model for cancer research.
RESULTS: In this paper, a genome-wide comparative analysis was conducted based on the genomes of NMR and several other mammals. First, all the annotated proteins of NMR were searched against 11 selected mammalian genomes to verify their occurrence in these organisms. Among them, 66 NMR genes were not detected in other 11 mammals, almost all of which present alkalinity isoelectric points. In contrast, a total of 89 genes that are present in all of the 11 organisms could not be found in NMR genome. Among them, 3 genes are known to be related to cancer development. Finally, we identified NMR-specific single amino acid change (SAAC) events for the proteins that are present in both NMR and other mammals. KEGG pathway database was also used to investigate the metabolic processes in which these SAAC proteins may be involved. These genes were significantly enriched in two known cancer pathways, \"Pathways in cancer\" and \"Pancreatic cancer\". In the \"Pancreatic cancer\" pathway, 3 out of 6 paths leading to DNA duplication appeared to be affected by direct connection to the SAAC genes in NMR. In addition, a significant number of other SAAC genes enriched in several cancer-related pathways have been known to be associated with a variety of cancers, implying that many of them may be also related to tumor genesis in mammals.
CONCLUSIONS: Overall, our results not only can be used to find possible genes involved in physiological mechanism of NMR but also provide new clues for the anti-cancer mechanism of NMR.