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Increased hyaluronan by naked mole-rat HAS2 extends healthspan in mice

ABSTRACT: Abundant high molecular weight hyaluronic acid (HMW-HA) contributes to cancer resistance and possibly longevity of the longest-lived rodent, the naked mole-rat1,2. To study whether the benefits of increased HMW-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHAS2). nmrHAS2 mice showed increase in hyaluronan levels in several tissues, and lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHAS2 mice shifted towards that of longer-lived species. The most striking change observed in nmrHAS2 mice was attenuated inflammation across multiple tissues. HMW-HA reduced inflammation via several pathways including direct immunoregulatory effect on immune cells, protection from oxidative stress, and improved gut barrier function during aging. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exploited to other species, and open new avenues for using HMW-HA to improve lifespan and healthspan.

ORGANISM(S): Mus musculus

PROVIDER: GSE234563 | GEO | 2023/08/10

REPOSITORIES: GEO

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Project description:The naked mole-rat, Heterocephalus glaber (NMR), the longest-lived rodent with a maximum possible lifespan exceeding 33 years, is emerging as an important non-model organism for the study of longevity and healthspan. As such it is of significance and interest in the study of biomarkers for ageing in mammals. Recent breakthroughs in this field have indicated that ‘epigenetic clocks’ based on the temporal accumulation of DNA methylation at specific genomic sites can enable accurate age estimates for tissues across the lifespan of an individual. Here, we validate the hypothesis of an epigenetic clock in NMRs, and create a method for predicting the age of naked mole-rats based on changes in methylation of targeted CpG sites in regions known as ageing-associated differentially methylated positions (aDMPs). In the discovery phase, we performed a targeted analysis of 51 different CpGs in 24 different NMR livers spanning an age range from 39 weeks to 1,144 weeks. Of these 51 different sites, 23 were found to be significantly associated with age (p < 0.05). We then built a predictor of age using the 23 sites that showed an association with age. To test the accuracy of this model, we predicted age in an additional test set of 19 different livers spanning an age range 43 to 1,196 weeks. Our model was able to successfully predict age in the test with a root mean squared error (RMSE) of 166.11 weeks. We also profiled a 20 skin samples with the same age range and found a striking correlation between the predicted age of these samples versus their actual age (R=0.93). However, this correlation when compared to the liver samples showed a lower predicted age than actual age, suggesting that skin tissue ages slower than the liver in NMRs. Finally, we have produced freely available software tool that will take in raw sequencing data and produce an age prediction for new NMR samples. Our model will enable the prediction of age in wild caught naked mole-rats and captive animals of unknown age, and will be invaluable for further mechanistic studies of mammalian ageing.

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Increased hyaluronan by naked mole-rat HAS2 extends healthspan in mice

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