The naked mole rat (NMR), Heterocephalus glaber, is known as the longest-lived rodent and is extraordinarily resistant to hypoxia and cancer. Here, both NMR embryonic fibroblasts (NEFs) and their mouse counterparts (MEFs) were subjected to anoxic conditions (0% O2, 5% CO2). A combination of comparative transcriptomics and proteomics was then employed to identify differentially expressed genes (DEGs). Notably, we observed distinct levels of histone H1.2 (encoded by HIST1H1C) accumulation between NEFs and MEFs. Subsequent mechanistic analyses showed that higher H1.2 expression in NEFs was associated with the lower expression of its inhibitor, PARP1. Additionally, we discovered that H1.2 can directly interact with HIF-1α PAS domains, thereby promoting the expression of HIF-1α through facilitating the dimerization with HIF-1β. The overexpression of H1.2 was also found to trigger autophagy and to suppress the migration of cancer cells, as well as the formation of xenograft tumors, via the NRF2/P62 signaling pathway. Moreover, an engineered H1.2 knock-in mouse model exhibited significantly extended survival in hypoxic conditions (4% O2) and showed a reduced rate of tumor formation. Collectively, our results indicate a potential mechanistic link between H1.2 and the dual phenomena of anoxic adaptation and cancer resistance.

Hyaluronic acid is a major component of extracellular matrix which plays an important role in development, cellular response to injury and inflammation, cell migration, and cancer. The naked mole-rat (Heterocephalus glaber) contains abundant high-molecular-mass hyaluronic acid in its tissues, which contributes to this species\' cancer resistance and possibly to its longevity. Here we report that abundant high-molecular-mass hyaluronic acid is found in a wide range of subterranean mammalian species, but not in phylogenetically related aboveground species. These subterranean mammalian species accumulate abundant high-molecular-mass hyaluronic acid by regulating the expression of genes involved in hyaluronic acid degradation and synthesis and contain unique mutations in these genes. The abundant high-molecular-mass hyaluronic acid may benefit the adaptation to subterranean environment by increasing skin elasticity and protecting from oxidative stress due to hypoxic conditions. Our work suggests that high-molecular-mass hyaluronic acid has evolved with subterranean lifestyle.

The naked mole rat (Heterocephalus glaber), bats (e.g., genus Myotis), and elephants (family Elephantidae) are known as long-lived mammals and are assumed to be excellent cancer antagonists. However, whether there are common genetic changes underpinning cancer resistance in these long-lived species is yet to be fully established. Here, we newly generated a high-quality chromosome-level Asian elephant (Elephas maximus) genome and identified that the expanded gene families in elephants are involved in Ras-associated and base excision repair pathways. Moreover, we performed comparative genomic analyses of 12 mammals and examined genes with signatures of positive selection in elephants, naked mole rat, and greater horseshoe bat. Residues at positively selected sites of CDR2L and ALDH6A1 in these long-lived mammals enhanced the inhibition of tumor cell migration compared to those in short-lived relatives. Overall, our study provides a new genome resource and a preliminary survey of common genetic changes in long-lived mammals.

Naked mole-rats (NMRs) (Heterocephalus glaber) are highly social and subterranean rodents with large communal colonies in burrows containing low oxygen levels. The inhibition of severe hypoxic conditions is of particular interest to this study. To understand the mechanisms that facilitate neuronal preservation during hypoxia, we investigated the proteins regulating hypoxia tolerance in NMR hippocampal neurons. Caveolin-1 (Cav-1), a transmembrane scaffolding protein, confers prosurvival signalling in the central nervous system. The present study aimed to investigate the role of Cav-1 in hypoxia-induced neuronal injury. Western blotting analysis and immunocytochemistry showed that Cav-1 expression was significantly upregulated in NMR hippocampal neurons under 8% O2 conditions for 8 h. Cav-1 alleviates apoptotic neuronal death from hypoxia. Downregulation of Cav-1 by lentiviral vectors suggested damage to NMR hippocampal neurons under hypoxic conditions in vitro and in vivo. Overexpression of Cav-1 by LV-Cav-1 enhanced hypoxic tolerance of NMR hippocampal neurons in vitro and in vivo. Mechanistically, the levels of hypoxia inducible factor-1α (HIF-1α) are also increased under hypoxic conditions. After inhibiting the binding of HIF-1α to hypoxia response elements in the DNA by echinomycin, Cav-1 levels were downregulated significantly. Furthermore, chromatin immunoprecipitation assays showed the direct role of HIF1α in regulating the expression levels of Cav-1 in NMR hippocampal neurons under hypoxic conditions. These findings suggest that Cav-1 plays a critical role in modulating the apoptosis of NMR hippocampal neurons and warrant further studies targeting Cav-1 to treat hypoxia-associated brain diseases.

OBJECTIVE: The naked mole rats (NMRs, Heterocephalus glaber) are subterranean rodents that belong to the family Bathyergidae. They gained the attention of the scientific community for their exceptionally long lifespan of up to 30 years and have become an animal model of biomedical research on neurodegenerative diseases, aging and cancer. NMRs dig and survive in a maze of underground tunnels and chambers and demarcate toilet chambers for defecation and urination. Due to their coprophagic behaviours, we believed that the toilet chamber might play a role in maintaining optimal health of the NMRs. A 16S rRNA gene amplicon sequencing was performed to characterize the bacterial microbiome of faecal samples collected from the toilet chamber of a laboratory NMR colony.
RESULTS: Four faecal samples were collected at different time points from the same toilet chamber of a laboratory NMR colony for analysis. The 16S rRNA gene amplicon sequencing revealed that bacterial phyla Firmicutes and Bacteroidetes were the dominant taxa in the bacterial microbiome of NMRs. The relative abundance of the bacterial taxa shifted substantially between time points, indicating a dynamic microbiome in the toilet chamber. The data provided an insight to the faecal microbiome of NMRs in the toilet chamber.

Naked mole-rats (Heterocephalus glaber, NMRs) and blind mole-rats (Spalax galili, BMRs) are representative subterranean rodents that have evolved many extraordinary traits, including hypoxia tolerance, longevity, and cancer resistance. Although multiple candidate loci responsible for these traits have been uncovered by genomic studies, many of them are limited to functional changes to amino acid sequence and little is known about the contributions of other genetic events. To address this issue, we focused on gene losses (unitary pseudogenes) and systematically analyzed gene losses in NMRs and BMRs, aiming to elucidate the potential roles of pseudogenes in their adaptation to subterranean lifestyle.
We obtained the pseudogene repertoires in NMRs and BMRs, as well as their respective aboveground relatives, guinea pigs and rats, on a genome-wide scale. As a result, 167, 139, 341, and 112 pseudogenes were identified in NMRs, BMRs, guinea pigs, and rats, respectively. Functional enrichment analysis identified 4 shared and 2 species-specific enriched functional groups (EFGs) in subterranean lineages. Notably, the pseudogenes in these EFGs might be associated with either regressive (e.g., visual system) or adaptive (e.g., altered DNA damage response) traits. In addition, several pseudogenes including TNNI3K and PDE5A might be associated with specific cardiac features observed in subterranean lineages. Interestingly, we observed 20 convergent gene losses in NMRs and BMRs. Given that the functional investigations of these genes are generally scarce, we provided functional evidence that independent loss of TRIM17 in NMRs and BMRs might be beneficial for neuronal survival under hypoxia, supporting the positive role of eliminating TRIM17 function in hypoxia adaptation. Our results also suggested that pseudogenes, together with positively selected genes, reinforced subterranean adaptations cooperatively.
Our study provides new insights into the molecular underpinnings of subterranean adaptations and highlights the importance of gene losses in mammalian evolution.

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.

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.

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