Identifying the epigenetic drivers of an accelerated aging process

Abstract

Aging impacts many important attributes of human beings such as the onset of diseases and the length of lifespans. Previous research demonstrated that DNA methylation based epigenetic clocks can be used to estimate biological age in both humans and mice. Interestingly, an accelerated aging process was observed in a short‐lived laboratory mouse strain (AKR/J, median lifespan = 288 days). By comparison, the more common laboratory mouse strain C57BL/6J lives substantially longer (median lifespan = 901 days). To elucidate the underlying mechanisms linking the accelerated aging process to a shortened lifespan, we used reduced representation bisulfite sequencing (RRBS) to profile DNA methylation in the cortex and the hippocampus extracted from these two strains, respectively (4 biological replicates per brain region for the C57BL/6J strain, 6 biological replicates per brain region for the AKR/J strain). At a 5X read depth cutoff, we detected 2,376,777 ± 195,194 unique CpG sites in the C57BL/6J strain samples and 2,288,300 ± 137,243 unique CpG sites in the AKR/J strain samples. Samples from the same brain region of the same strain clustered tightly based on their distinctive DNA methylation patterns. Using a publication‐supported R package, “DSS”, to compare between the two strains, we identified 14,625 differentially methylated cytosines (DMCs, Benjamini‐Hochberg FDR <0.05; methylation difference ≥0.15) and 257 differentially methylation regions (DMRs, p<0.05; methylation difference ≥0.15) from the cortex samples. Similarly, we found 14,215 DMCs (Benjamini‐Hochberg FDR <0.05; methylation difference ≥0.15) and 304 DMRs (p<0.05; methylation difference ≥0.15) from the hippocampus samples. Subsequent annotation of the DMRs from both sample groups revealed that 106 genes had significantly different methylation levels in their promoter regions. Pathway analysis demonstrated differential promoter methylation of genes (for example, Psat1, Smarca5, Rnf152 and Hspg2) enriched in the regulation of chromatin remodeling, cellular development, and metabolism. Importantly, Rnf152 and Hspg2 are associated with mouse aging. In summary, our study discovered potential epigenetic features involved in the accelerated aging process of a short‐lived mouse model. Future work should focus on the detailed functions of the identified genes and further understand their link to altered mice lifespans, eventually leading to strategies for improved healthcare in human lives.