Kyoko Miura

Several exceptionally long-lived mammals show natural resistance to cancer. The longest-lived rodent, the naked mole-rat (NMR; Heterocephalus glaber) is renowned for its remarkable resistance to carcinogenesis; however, it is unclear whether other long-lived African mole-rat species are also cancer-resistant, and whether they exhibit similar responses to chemical carcinogens. Here, we demonstrate that a long-lived, close relative of the NMR, the Damaraland mole-rat (DMR; Fukomys damarensis), is also highly resistant to skin carcinogenesis induced by two different chemical carcinogens. Strikingly, DMRs developed no tumors over a period of more than 3 years. Despite sharing a cancer-resistant phenotype, the two species exhibit markedly different immune responses. After exposure to carcinogens, DMRs show robust immune cell infiltration, whereas NMRs exhibit only minimal immune cell infiltration. At the transcriptomic level, these differences were even more pronounced. DMRs upregulated genes associated with both T cell-mediated and innate immune responses, reflecting broad immune activation, while simultaneously upregulating immunosuppressive molecules that may restrain excessive inflammatory responses. By contrast, NMRs showed limited transcriptional changes, instead engaging the keratinization and p53-related stress pathways, consistent with attenuated inflammation and potentially reflecting a distinct tissue-protective strategy. Both species, however, showed low expression of Toll-like receptor genes and loss of necroptosis induction, which may mitigate cancer-promoting tissue inflammation. Together, these findings indicate that closely related cancer-resistant African mole-rat species can exhibit divergent immune responses despite similar life-history traits and shared evolutionary history, highlighting the diversity of biological pathways associated with cancer resistance in long-lived mammals. Graphical abstract

Naked mole-rats are extremely long-lived rodents with a lifespan of up to 40 years, during which cellular and tissue aging is rarely observed. In this study, we analyzed the extracellular matrix (ECM) of naked mole-rat skin at the molecular level to elucidate the molecules involved in anti-aging and their localization. Raman spectroscopy and Fourier transform infrared spectroscopy were applied to investigate the hierarchical structure of the ECM, showing that, whereas the epidermis of aged mice had thinned, the epidermis of naked mole-rats became thickened and hyaluronic acid (HA) was distributed under the basement membrane. Furthermore, naked mole-rat skin had a regular skin texture and flexibility, allowing the maintenance of a youthful appearance. Hyaluronic acid in naked mole-rats characteristically exists as clusters (chain HA) in skin tissue, where it is thought to permit moisture retention and maintain elasticity, contributing to the skin’s youthful appearance. These results suggested that not only the density of ECM but also its spatial distribution and topographic properties are important for skin anti-aging. Our findings may contribute to the elucidation of skin disease pathology, the development of therapeutic gel scaffolds, and the control of aging.

The naked mole rat (NMR, Heterocephalus glaber ) is a eusocial rodent that is native to northeastern Africa. NMRs exhibit extraordinary traits such as longevity, resistance to age-related decline, and remarkable hypoxia tolerance. Although the reference genome of this species has been determined because of its unique characteristics, the significance or role of intraspecific genomic variations remains unknown. In this study, we used PacBio long-read sequencing to generate a genome assembly of NMR reared in Japan. The assembled genome is 2.56 Gb. Benchmarking Universal Single–Copy Orthologs (BUSCO) revealed high completeness (95.2%). BRAKER3 estimated 26,714 protein-coding genes, and we successfully added functional annotations for 26,232 protein-coding genes using the functional annotation workflow. We identified 417 gene models that were previously undetectable in the reference genome of this species. We also identified structural and amino acid sequence variations between our assembly and the reference genome, suggesting the presence of intraspecific genomic variations. This new genomic resource could help uncover the molecular mechanisms underlying the behavioral and physiological traits of NMR.

The naked mole-rat is a subterranean rodent adapted to extreme hypoxia and low metabolic demands, with an exceptionally long lifespan relative to its small body size, while maintaining reproductive capacity. Using 16S rRNA gene sequencing of 24 samples and whole-metagenome sequencing of 11 samples from individuals up to 15 years of age, we characterized the gut microbiota and showed its complexity and distinctiveness compared with that of other rodents, including mice, squirrels, and rabbits. Although all animals were born and raised in a laboratory setting, the gut microbiota remained taxonomically stable across ages and retained key taxa previously reported in wild naked mole-rats (e.g., Treponema and Desulfovibrio ). Metagenome-assembled genomes revealed the presence of archaeal methanogens and termite-gut-associated bacteria (e.g., Methanobacteria within Euryarchaeota and Avelusimicrobium within Elusimicrobiota), together with genes involved in hydrogen metabolism and archaeal methanogenesis. Compared with mice, the naked mole-rat gut microbiota was enriched in carbohydrate-active enzymes targeting plant cell-wall polysaccharides, resembling those found in ruminants. We also detected evidence of flagellates, ciliates, and fungi, which may further contribute to polysaccharide degradation and fermentation, potentially within the enlarged cecum. Together, this comprehensive analysis provides distinctive gut microbial features of the naked mole-rat that may be associated with the naked mole-rat’s low metabolic rate and exceptional longevity.

Gene expression is co-regulated by the rates of RNA synthesis and degradation, and recent evidence has linked their imbalance to the onset of aging. The naked mole-rat (NMR) is a small rodent with an exceptionally long lifespan and markedly delayed aging, yet little is known about its RNA synthesis and degradation characteristics compared to other rodents that age more rapidly. Here, we investigate RNA synthesis and degradation in NMR and mouse skin fibroblasts by monitoring incorporation of a uridine analog, 4-thiouridine. Cross-species analysis showed that the NMR cells have higher overall rates of RNA synthesis and degradation. It further revealed higher RNA degradation rates in aging-related pathways, notably Mtorc1 signaling, likely contributing to reducing the overall expression. Although known aging-associated genes, including Xrcc5, Nudt1, Fen1 , and Aptx , were expressed at similar levels in NMR and mouse fibroblasts, the RNA turnover rates were largely altered. To uncover the underlying mechanism enabling differential control of RNA kinetics, we analyzed the transcript feature importance by machine learning and identified key features governing RNA degradation both common and unique in NMR and mouse fibroblasts. Our data highlight a potential role of RNA synthesis and degradation as hidden layers of gene regulation in NMR.

In highly organized animal societies, individual behavioral differences and close social relationships are crucial for group success and cohesion. However, in naked mole-rats, a eusocial mammal, these factors remain poorly understood because monitoring all colony members simultaneously is challenging. We developed an automated radio frequency identification (RFID) tracking system to continuously collect behavioral data from entire colonies, monitoring 102 individuals from five colonies for 30 days. Based on behavioral parameters, we statistically identified distinct behavioral phenotypes, comprising one cluster for breeders and six clusters for nonbreeders. Breeders formed strong social bonds, consistently remaining close in activity rhythm synchrony, spatial proximity, and directional following. In contrast, nonbreeders exhibited behavioral heterogeneity according to their cluster: One cluster avoided other active nonbreeders, whereas another cluster attracted frequent following. Our study highlights social complexity in this eusocial mammal and establishes a robust platform for further investigations into naked mole-rat social dynamics.

Naked mole-rats are extremely long-living rodents with a maximum lifespan of 37 years, and their cellular aging and tissue aging are almost nonexistent. Therefore, in this study, we aim to analyze the extracellular matrix of the temporomandibular joint (TMJ) of naked mole-rats at the molecular level and explore the molecules involved in anti-aging and their localization. Micro-computed tomography (CT) scans revealed increased mineral density and wear of the mandibular condyle in aged mice. Conversely, CT scans did not reveal wear of the mandibular condyle in naked mole-rats, and histological analysis did not reveal wear of the articular disk. Using various spectroscopies and artificial intelligence (AI), we found that the articular disk of naked mole-rats is composed of a cartilage-like layer with hyaluronic acid and collagen fibers with varying orientations, which is thought to have relieved mechanical stress and have protected the mandibular condyle. These results suggest that not only the amount, but also the spatial distribution of the extracellular matrix is important for the anti-aging properties of the TMJ, and may contribute to elucidating the pathology of TMJ disorders and other degenerative conditions and developing therapeutic drugs.

The naked mole rat (NMR, Heterocephalus glaber ) is a eusocial rodent that is native to northeastern Africa. NMRs exhibit extraordinary traits such as longevity, resistance to age-related decline, and remarkable hypoxia tolerance. Although the reference genome of this species has been determined because of its unique characteristics, the significance or role of intraspecific genomic variations remains unknown. In this study, we used PacBio long-read sequencing to generate a genome assembly of NMR reared in Japan. The assembled genome is 2.56 Gb. Benchmarking Universal Single–Copy Orthologs (BUSCO) revealed high completeness (95.2%). BRAKER3 estimated 26,714 protein-coding genes, and we successfully added functional annotations for 26,232 protein-coding genes using the functional annotation workflow. We identified 417 gene models that were previously undetectable in the reference genome of this species. We also identified structural and amino acid sequence variations between our assembly and the reference genome, suggesting the presence of intraspecific genomic variations. This new genomic resource could help uncover the molecular mechanisms underlying the behavioral and physiological traits of NMR.

Background: CD163 is a scavenger receptor predominantly expressed on the surfaces of macrophages in various mammalian species and is a marker of anti‐inflammatory (M2‐like) macrophages. High density of CD163‐positive tumor‐associated macrophages (TAMs) is associated with worse prognosis in various patient tumors. Interestingly, studies on mice have shown that CD163‐positive TAMs only infiltrate the margins of tumor tissues, not the center. Based on these observations, we hypothesized that circulating monocyte‐derived macrophages (MDMs), which are the origin of most TAMs, do not express CD163 in mice. Results: We examined CD163 expression in MDMs, differentiated from healthy animals in vitro, and in normal, pathogenic, and tumorigenic macrophages infiltrating various tumors and organs across multiple species including primates, rodents, cetartiodactylans, and carnivores. We found that MDMs, including TAMs, do not express CD163 in mice. Our findings also suggest that murine CD163‐positive macrophages likely originate from a specific subset of resident macrophages, namely fetal liver monocytes/macrophages, as indicated by fetal analysis. Furthermore, we revealed that the CD163‐negative expression pattern in MDMs is a trait shared by the rodent clade. Conclusions: Rodent MDMs do not express CD163, a phenotype not shared with MDMs of other mammals. Our findings caution against the extrapolation of rodent experimental results to other animal models.

The Damaraland mole-rat (DMR; Fukomys damarensis) is a long-lived (~ 20 years) Bathyergid rodent that diverged 26 million years ago from its close relative, the naked mole-rat (NMR). While the properties of NMR cultured fibroblasts have been extensively studied and have revealed several unusual features of this cancer-resistant, long-lived species, comparative DMR studies are extremely limited. We optimized conditions for successfully culturing primary DMR skin fibroblasts and also established immortalized DMR cells using simian virus 40 early region expression. Like NMRs, DMR fibroblasts are more resistant than mice to various cytotoxins including heavy metals, DNA-damaging agents, oxidative stressors, and proteasome inhibitors. DMR genome sequencing analyses revealed the presence of premature stop codons in the master regulator genes of necroptosis, an inflammatory programmed cell death—receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), although these mutations have different locations to those found in the NMR. DMR cells, like NMR cells, did not show significantly increased cell death in response to necroptosis induction. Our data suggest that both Bathyergid species require species-specific cell culture conditions for optimized growth, display similar resistance to cytotoxins, and show loss-of-function mutations abrogating the ability to employ necroptosis. These shared traits may contribute to their evolved adaptations to their subterranean lifestyle and prolonged longevity. These convergent insights and valuable resource may be pertinent to biomedical research.