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Naked mole rats seem almost entirely protected from developing cancer, and this can now, at least in part, be explained by the production of a unique high-molecular-mass form of hyaluronan, a component of the extracellular matrix; together with an increased sensitivity of naked mole-rat cells to hyaluronan signalling, this form protects its cells from oncogenic transformation. The giant molecule that keeps naked mole rat cancer-free Naked mole rats are remarkable in combining extreme longevity with virtually complete resistance to cancer. Now a novel glycosaminoglycan variant that may have evolved to provide the creatures with the tough, flexible skin needed for a subterranean lifestyle has been identified as a key contributor to their cancer resistance. Hyaluronan, or hyaluronic acid, is a ubiquitous component of the extracellular matrix. Xiao Tian et al. observed that the culture media of naked mole-rat fibroblasts becomes viscous owing to the accumulation of a thick 'gooey' substance and identified it as a high-molecular-mass hyaluronan (HMM-HA), more than five times larger than mouse and human equivalents. It accumulates in naked mole-rat tissues owing to low hyaluronidase activity and a unique form of hyaluronan synthase 2. HMM-HA acts through the CD44 receptor and removal of HMM-HA makes naked mole-rat cells more susceptible to transformation. This unusual model of cancer protection suggests potential new avenues of research into anticancer and life-extension strategies. The naked mole rat (Heterocephalus glaber) displays exceptional longevity, with a maximum lifespan exceeding 30 years.sup.1,2,3. This is the longest reported lifespan for a rodent species and is especially striking considering the small body mass of the naked mole rat. In comparison, a similarly sized house mouse has a maximum lifespan of 4 years.sup.4,5. In addition to their longevity, naked mole rats show an unusual resistance to cancer. Multi-year observations of large naked mole-rat colonies did not detect a single incidence of cancer.sup.2,6. Here we identify a mechanism responsible for the naked mole rat's cancer resistance. We found that naked mole-rat fibroblasts secrete extremely high-molecular-mass hyaluronan (HA), which is over five times larger than human or mouse HA. This high-molecular-mass HA accumulates abundantly in naked mole-rat tissues owing to the decreased activity of HA-degrading enzymes and a unique sequence of hyaluronan synthase 2 (HAS2). Furthermore, the naked mole-rat cells are more sensitive to HA signalling, as they have a higher affinity to HA compared with mouse or human cells. Perturbation of the signalling pathways sufficient for malignant transformation of mouse fibroblasts fails to transform naked mole-rat cells. However, once high-molecular-mass HA is removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme, HYAL2, naked mole-rat cells become susceptible to malignant transformation and readily form tumours in mice. We speculate that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide cancer resistance and longevity to this species., Author(s): Xiao Tian [sup.1] , Jorge Azpurua [sup.1] , Christopher Hine [sup.1] [sup.5] , Amita Vaidya [sup.1] , Max Myakishev-Rempel [sup.1] , Julia Ablaeva [sup.1] , Zhiyong Mao [sup.1] [sup.2] [...]

Descriptions of karyotypes of many animal species are currently available. In addition, there has been a significant increase in the number of sequenced genomes and an ever-improving quality of genome assembly. To close the gap between genomic and cytogenetic data we applied fluorescent in situ hybridization (FISH) and Hi-C technology to make the first full chromosome-level genome comparison of the guinea pig (Cavia porcellus), naked mole-rat (Heterocephalus glaber), and human. Comparative chromosome maps obtained by FISH with chromosome-specific probes link genomic scaffolds to individual chromosomes and orient them relative to centromeres and heterochromatic blocks. Hi-C assembly made it possible to close all gaps on the comparative maps and to reveal additional rearrangements that distinguish the karyotypes of the three species. As a result, we integrated the bioinformatic and cytogenetic data and adjusted the previous comparative maps and genome assemblies of the guinea pig, naked mole-rat, and human. Syntenic associations in the two hystricomorphs indicate features of their putative ancestral karyotype. We postulate that the two approaches applied in this study complement one another and provide complete information about the organization of these genomes at the chromosome level., (© 2023. The Author(s).)

Maximal lifespan of mammalian species, even if closely related, may differ more than 10-fold, however the nature of the mechanisms that determine this variability is unresolved. Here, we assess the relationship between maximal lifespan duration and concentrations of more than 20,000 lipid compounds, measured in 669 tissue samples from 6 tissues of 35 species representing three mammalian clades: primates, rodents and bats. We identify lipids associated with species' longevity across the three clades, uncoupled from other parameters, such as basal metabolic rate, body size, or body temperature. These lipids clustered in specific lipid classes and pathways, and enzymes linked to them display signatures of greater stabilizing selection in long-living species, and cluster in functional groups related to signaling and protein-modification processes. These findings point towards the existence of defined molecular mechanisms underlying variation in maximal lifespan among mammals.