Early life DNA methylation profiles are indicative of age-related transcriptome changes

Abstract

Alterations to cellular and molecular programs with brain aging result in cognitive impairment and susceptibility to neurodegenerative disease. Changes in DNA methylation patterns, an epigenetic modification required for various CNS functions, are observed with aging and can be prevented by anti-aging interventions, but the functional outcomes of altered methylation on transcriptome profiles are poorly understood with brain aging.Integrated analysis of the hippocampal methylome and transcriptome with aging of male and female mice demonstrates that age-related differences in methylation and gene expression are anti-correlated within gene bodies and enhancers, but not promoters. Methylation levels at young age of genes altered with aging are positively associated with age-related expression changes even in the absence of significant changes to methylation with aging, a finding also observed in mouse Alzheimer's models. DNA methylation patterns established in youth, in combination with other epigenetic marks, are able to predict changes in transcript trajectories with aging. These findings are consistent with the developmental origins of disease hypothesis and indicate that epigenetic variability in early life may explain differences in age-related disease.

Molecular basis of ageing in chronic metabolic diseases

“…Epigenetic changes are crucial processes behind these trajectories of alternative ageing [ 10 , 142 ]. Indeed, age-related dysregulation of epigenetic control is a common aetiological factor for ARDs ranging from T2D to neurodegenerative diseases [ 143 ]. Moreover, many effective lifespan-extending interventions act through epigenetic pathways [ 142 ].…”

“…These changes include DNA methylation, chromatin remodelling, histone modifications, and non-coding RNA transcription [ 89 , 142 – 144 ]. Although each of these mechanisms is functionally relevant, geroscience research has best characterized the role of DNA methylation dynamics during ageing and their involvement in cellular senescence [ 142 , 143 ]. DNA methylation mainly occurs at the 5′ position of the cytosine residues of cytidine-guanine dinucleotides (CpGs) and may be associated with either transcriptional repression or activation, depending on the site where it occurs.…”

“…Paired methylome and transcriptome analyses in ageing cells and tissues from both mice and humans have revealed an inverse correlation between age-related differences in gene expression and DNA methylation [ 143 , 147 ]. Quantitative measurements of these differences between young and old mammals show that they are in the range of 5–25% at susceptible genes [ 148 ].…”

“…Quantitative measurements of these differences between young and old mammals show that they are in the range of 5–25% at susceptible genes [ 148 ]. Notably, these genes are enriched in pathways dysregulated during ageing such as senescence, inflammation, and the insulin-signalling pathway [ 143 ].…”

Epigenetic age-predictions in mice using pyrosequencing, droplet digital PCR or barcoded bisulfite amplicon sequencing

“…Advantages of this approach are the very high coverage and the relatively long target regions (up to 500 base pairs), which may cover more neighboring CpGs than pyrosequencing or ddPCR (Franzen et al, 2017 Altered promoter methylation with aging was found to be generally unrelated to altered gene expression, also in mice (Hadad, Masser, Blanco-Berdugo, Stanford, & Freeman, 2019). There is evidence, that the epigenetic drift by stochastic DNAm changes in promoters results in degradation of coherent transcriptional networks during aging (Hernando-Herraez et al, 2019).…”