Erosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals

Abstract

Short-title: Epigenetic noise and cell identity loss during agingOne Sentence Summary: The act of repairing DNA breaks induces chromatin reorganization and a loss of cell identity that may contribute to mammalian aging 1 SUMMARY All living things experience entropy, manifested as a loss of inherited genetic and epigenetic information over time. As budding yeast cells age, epigenetic changes result in a loss of cell identity and sterility, both hallmarks of yeast aging. In mammals, epigenetic information is also lost over time, but what causes it to be lost and whether it is a cause or a consequence of aging is not known. Here we show that the transient induction of genomic instability, in the form of a low number of non-mutagenic DNA breaks, accelerates many of the chromatin and tissue changes seen during aging, including the erosion of the epigenetic landscape, a loss of cellular identity, advancement of the DNA methylation clock and cellular senescence. These data support a model in which a loss of epigenetic information is a cause of aging in mammals.2

The aging DNA methylome reveals environment-by-aging interactions in a model teleost

“…In contrast, epigenetic clocks rely on non-random changes to the DNA methylome over time, suggestive of a process independent of epigenetic drift (36). Recent work demonstrates that DNA damage, namely the induction of DNA double stranded breaks (DSBs), plays an important role in the acceleration of epigenetic age (37). Induction of DSBs in mice accelerates epigenetic aging via the relocalization of chromatin modifiers (RCM) which are recruited to aid in DSB repair (37).…”

“…Given that evolutionary theories of aging, such as antagonistic pleiotropy, emphasize the importance of maximizing fitness during early life(50,51), understanding the role of the environment in determining rates of epigenetic aging at different life stages stands to better inform our understanding of the mechanisms driving adaptive plasticity in life histories. Studies examining how epigenetic aging trajectories, both in a quantitative (e.g., rate) and qualitative (e.g., variable subsets of loci acquiring age-associated patterns) sense, are affected in early life are clearly needed to advance our understanding regarding both the origins of epigenetic-to-chronological age discordance and the potential adaptive roles it might play in nature.Double stranded DNA breaks have recently been shown to accelerate epigenetic aging in mice(37), and based on these findings, we hypothesized that chronic IR exposure, a known source ofDSBs (52), might also result in accelerated aging. Previous research in humans has demonstrated a relationship between radiation treatment in breast cancer patients and increased epigenetic age (53).…”

Methylation of histone H3 lysine 4 is required for maintenance of beta cell function in adult mice

“…Reduction of H3K4 methylation did not prompt canonical dedifferentiation 33 of β-cells to a precursor-like state, however, the cells displayed some features of immaturity like elevated transcriptional entropy 43 , in vivo replication 58 , reduced expression of mature β-cell transcription factors, and reduced glucose-responsiveness 59 . Dilution of epigenetic complexity characterizing Dpy30 -KO cells is thematically similar to so-called “smoothening” of the epigenomic landscape which is proposed to cause loss of cellular identity and increase entropy during epigenetic aging 60 . In that model, both active and repressive chromatin modifications show reduced intensity at regions where they are most enriched.…”

Structural clusters of histone H3 and H4 residues regulate chronological lifespan in Saccharomyces cerevisiae

“…It was shown that transgenic mice, where a limited number of double strand breaks (DSBs) were made in the genome by induction of I-PpoI, displayed many features associated with old age at 10 months post treatment, including loss of visual acuity, muscle mass and neurological changes, when compared to an untreated control group 21 . Mouse embryonic fibroblasts derived from the same transgenic mouse line, displayed decreased H3K27ac, and H3K56ac, and increased H3K122ac levels in response to induced DSBs 22 . It was proposed that the repetitive repair of the DSBs causes a redistribution of histone modification marks, triggering the misregulation of a subset of genes that results in accelerated chronological aging 21,22 .…”

“…Mouse embryonic fibroblasts derived from the same transgenic mouse line, displayed decreased H3K27ac, and H3K56ac, and increased H3K122ac levels in response to induced DSBs 22 . It was proposed that the repetitive repair of the DSBs causes a redistribution of histone modification marks, triggering the misregulation of a subset of genes that results in accelerated chronological aging 21,22 .…”