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Epigenetic aging of the demographically non-aging naked mole-rat [RRBS]

ABSTRACT: The naked mole-rat (NMR) is an exceptionally long-lived rodent that does not show increased mortality with age, uniquely defining NMR as a demographically non-aging mammal. Here, we performed bisulfite sequencing on over one hundred NMR blood samples differing in age, assessing more than 3 million common CpG sites. We observed an information loss of the NMR methylome during aging suggesting that NMR ages. Unsupervised clustering based on the 758 CpG sites whose methylation level strongly correlate with age suggests an age-related shift of the NMR methylome. We also developed an epigenetic aging clock that accurately predicts the NMR age spread across the genome. Based on the clock, NMRs age much slower than mice and much faster than humans, consistent with their known maximum lifespans. We further found that patterns of age-related methylation changes of aging clock sites in Tert and Prpf19 showed differences between NMRs and mice. Together, the data indicate that NMRs, like other mammals, epigenetically age even in the absence of demographic aging of this species.

ORGANISM(S): Heterocephalus glaber

PROVIDER: GSE179039 | GEO | 2021/12/19

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.

Project description:Background Chronological aging-associated changes in the human DNA methylome are studied by multiple epigenome-wide association studies (EWAS); however, the aging-associated DNAmet changes identified among different age groups and tissues vary and especially the rates of aging-associated alterations in the epigenome during adulthood remain unclear. Here, we further explore and characterize CpG-sites where DNA methylation levels alter at a constant rate during adulthood and are also independent of blood cell type heterogeneity. Results In the study, we observed 1,202 aging-associated CpG-sites (a-CpGs), of which 48% were hypermethylated with advancing age in whole blood with an especially narrow age range (40 - 49 years). Repeatedly reported a-CpGs in ELOVL2, FHL2, PENK and KLF14 were also identified. Regions with aging-associated hypermethylation were enriched to several gene ontology terms (especially on the cluster of developmental processes), while hypomethylated sites showed no enrichment. The genes with a higher number of a-CpG hits were more often hypermethylated. Of the 1,202 aging-associated CpG-sites in the present study, 987 were identified in previous study (Vitality 90+) as differentially methylated also between nonagenarians and young adults in a previous study, and importantly, the directions of changes were identical in the previous and in the present study. Conclusions The set of 987 replicated a-CpGs presented here are altered in strong association with chronological aging in the whole range of adulthood. Consequently, future studies should note the variability of the types of a-CpGs, and the a-CpGs presented here should be dissociated from the environmental-sensitive CpG-sites or from regions that are associated with aging in a non-linear manner due to the accumulation of senescence-related features. This report offers detailed and verified pool of a-CpGs in which DNAmet levels associate linearly with chronological age and of which are different from the non-linearly changing ones.

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Epigenetic aging of the demographically non-aging naked mole-rat [RRBS]

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