Abstract
Naked mole rats (NMRs) live an exceptionally long life, appear not to exhibit age-related decline in physiological capacity and are resistant to age-related diseases. However, it has been unknown whether NMRs also evade aging according to a primary hallmark of aging: epigenetic changes. To address this question, we profiled n = 385 samples from 11 tissue types at loci that are highly conserved between mammalian species using a custom array (HorvathMammalMethylChip40). We observed strong epigenetic aging effects and developed seven highly accurate epigenetic clocks for several tissues (pan-tissue, blood, kidney, liver, skin clocks) and two dual-species (human–NMR) clocks. The skin clock correctly estimated induced pluripotent stem cells derived from NMR fibroblasts to be of prenatal age. The NMR epigenetic clocks revealed that breeding NMR queens age more slowly than nonbreeders, a feature that is also observed in some eusocial insects. Our results show that despite a phenotype of negligible senescence, the NMR ages epigenetically.
Highlights
Direction of associationHypermethylated Hypomethylated Background0 50100150200250 0 100 200 300 0 100 200 300 02,5005,0007,50100,000 CpG count d0.5 R = –0.25, P = 0.054 R = 0.62, P = 6 × 10–8R = –0.38, P = 0.017R = 0.73, P = 1.1 × 10–7R = 0.0065, P = 0.96R = 0.77, P = 3 × 10–14 CpGislandNon–island Island Mean beta value
We obtained methylation profiles of 382 DNA samples derived from 11 number 2009-054 (NMR) tissues (Supplementary Table 1): adipose (n = 3), blood (n = 92), cerebellum (n = 5), cerebral cortex (n = 15), heart (n = 21), kidney (n = 33), liver (n = 68), lung (n = 19), muscle (n = 19), skin (n = 105) and spleen (n = 2), and induced pluripotent stem cells
These tissues were obtained from NMRs that ranged in age from 0 to 26 yr
Summary
Random forest predictors of tissue and sex. We obtained methylation profiles of 382 DNA samples derived from 11 NMR tissues (Supplementary Table 1): adipose (n = 3), blood (n = 92), cerebellum (n = 5), cerebral cortex (n = 15), heart (n = 21), kidney (n = 33), liver (n = 68), lung (n = 19), muscle (n = 19), skin (n = 105) and spleen (n = 2), and induced pluripotent stem cells. Strong age correlations were obtained with the human–NMR clock for relative age, regardless of whether the analysis was carried out with both species (R = 0.98, Fig. 1h) or only NMRs (R = 0.95, Fig. 1i) These results suggest that a subset of CpGs in both humans and NMRs undergo similar methylation changes during aging, allowing the derivation of highly accurate dual-species age-estimators. For a more robust identification of shared age-related CpGs, we limited this analysis to the three tissues (blood, skin and liver) for which there were more than 50 samples This identified 60 common loci in the NMR genome that have consistent age correlations in the three tissues (Fig. 2b). Seven genes (that is, ACSS2, ATP5L, CHTOP, EWSR1, F12, LRPPRC, TOE1) related to age according to all three data types: DNAm, transcription and protein levels
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