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

Abstract

(max 250 words)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 humansindicating common signatures of age across species. To date, our dataset represents the largest multitissue 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.

PIWI-piRNA pathway-mediated transposable element repression inHydrasomatic stem cells

“…Furthermore, we demonstrate direct targeting of TE RNAs by the pathway which is accompanied by the upregulation of genes involved in immune response. This suggests a model in which TE upregulation triggers an immune response in Hydra, similar to recent reports in mammals Simon et al 2019;Capone et al 2018;Benayoun et al 2018).…”

“…A prominent feature of somatic aging is the breakdown of heterochromatic domains and expression of transposable elements (TEs), which are typically repressed (López-Otín et al 2013;Cecco et al 2013;Benayoun et al 2018;Jones et al 2016;Li et al 2013;Patterson et al 2015;Hendrickson et al 2018;Sousa-Victor et al 2017). Although TE expression is likely a secondary effect of heterochromatin disruption, mounting evidence suggests that suppressing TE mobilization can extend lifespan Jones et al 2016;Wang et al 2011;Cecco et al 2019;Simon et al 2019).…”

Inhibition of Cdc42 activity extends lifespan and decreases circulating inflammatory cytokines in aged female C57BL/6 mice

“…Interestingly, a recent analysis of changes in the epigenome and transcriptome with aging across different tissues identified that the up‐regulation of the inflammatory response and gamma interferon pathways correlated best with aging both across tissues and species (Benayoun et al, 2019). Many age‐related diseases, such as obesity, metabolic syndrome, diabetes, cardiovascular diseases, cancer, depression, and Alzheimer's disease, share an inflammatory pathogenesis; moreover, the activation of inflammatory pathways appears to be involved in the pathophysiology of sarcopenia and frailty.…”

Modeling the human aging transcriptome across tissues, health status, and sex

“…These molecular changes can themselves be investigated to unveil what functions and processes are the most profoundly altered between different age classes (Valdes et al, 2013). For example, the laboratory of Anne Brunet analyzed transcriptomes to discover that innate immune pathways become dysregulated with age in mice, African turquoise killifish, rats, and humans (Benayoun et al, 2019). Recent work spearheaded by Tony Wyss‐Coray demonstrated that deleterious lipid‐droplet‐accumulating microglia build up with age in mouse and human brains.…”