Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses

Abstract Aging is accompanied by the functional decline of tissues. However, a systematic study of epigenomic and transcriptomic changes across tissues during aging is missing. Here we generated chromatin maps and transcriptomes from 4 tissues and one cell type from young, middle-age, and old mice, yielding 143 high-quality datasets. We focused specifically on chromatin marks linked to gene expression regulation and cell identity: histone H3 trimethylation at lysine 4 (H3K4me3), a mark enriched at promoters, and histone H3 acetylation at lysine 27 (H3K27ac), a mark enriched at active enhancers. Epigenomic and transcriptomic landscapes could easily distinguish between ages, and machine learning analysis showed that specific epigenomic states could predict transcriptional changes during aging. Analysis of datasets from all tissues identified recurrent age-related chromatin and transcriptional changes in key processes, including the upregulation of immune system response pathways such as the interferon signaling pathway. The upregulation of interferon response pathway with age was accompanied by increased transcription of various endogenous retroviral sequences. Pathways deregulated during mouse aging across tissues, notably innate immune pathways, were also deregulated with aging in other vertebrate species – African turquoise killifish, rat, and humans – indicating common signatures of age across species. To date, our dataset represents the largest multi-tissue epigenomic and transcriptomic dataset for vertebrate aging. This resource identifies chromatin and transcriptional states that are characteristic of youthful tissues, which could be leveraged to restore aspects of youthful functionality to old tissues.