Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions

Abstract

BackgroundAge-associated epigenetic changes are implicated in aging. Notably, age-associated DNA methylation changes comprise a so-called aging “clock”, a robust biomarker of aging. However, while genetic, dietary and drug interventions can extend lifespan, their impact on the epigenome is uncharacterised. To fill this knowledge gap, we defined age-associated DNA methylation changes at the whole-genome, single-nucleotide level in mouse liver and tested the impact of longevity-promoting interventions, specifically the Ames dwarf Prop1 df/df mutation, calorie restriction and rapamycin.ResultsIn wild-type mice fed an unsupplemented ad libitum diet, age-associated hypomethylation was enriched at super-enhancers in highly expressed genes critical for liver function. Genes harbouring hypomethylated enhancers were enriched for genes that change expression with age. Hypermethylation was enriched at CpG islands marked with bivalent activating and repressing histone modifications and resembled hypermethylation in liver cancer. Age-associated methylation changes are suppressed in Ames dwarf and calorie restricted mice and more selectively and less specifically in rapamycin treated mice.ConclusionsAge-associated hypo- and hypermethylation events occur at distinct regulatory features of the genome. Distinct longevity-promoting interventions, specifically genetic, dietary and drug interventions, suppress some age-associated methylation changes, consistent with the idea that these interventions exert their beneficial effects, in part, by modulation of the epigenome. This study is a foundation to understand the epigenetic contribution to healthy aging and longevity and the molecular basis of the DNA methylation clock.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1185-3) contains supplementary material, which is available to authorized users.

Global remodeling of the mouse DNA methylome during aging and in response to calorie restriction

“…The data suggest that these sites initially change after the start of the intervention, but then the cumulative effect drives methylation back to the level of the control group. In addition, we examined 24 publicly available mouse samples (Cole et al., 2017; Hahn et al., 2017), which revealed similar trends in response to CR (Figure S11). …”

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

“…As the methylation arrays used in our analyses mainly interrogate genetic elements and do not include repeated DNA, which covers a substantial fraction of the genome and frequently loses DNA methylation in tumors and aged cells, the genome‐wide landscape may be different (Ehrlich, 2009). Nonetheless, epigenetic signatures have been successfully derived previously using array technology (Fernández et al., 2015; Rakyan et al., 2010; Teschendorff et al., 2010) and our results are in line with recent studies which report no global decreases in DNA hypomethylation with aging in diverse mouse tissues, such as liver (Cole et al., 2017; Hahn et al., 2017), hippocampus (Masser et al., 2017), or hematopoietic stem cells (Beerman et al., 2013; Sun et al., 2014), thus strengthening the validity of our observations.…”

“…Moreover, recent analyses mainly performed in mouse tissue have failed to confirm global hypomethylation during the aging process (Cole et al., 2017; Hahn et al., 2017; Masser et al., 2017) and, to date, no study has provided a back‐to‐back and systematic comparison of the epigenetic changes that occur in aging and cancer. To address this issue, here we have analyzed DNA methylation changes and their associated chromatin patterns in a total of more than 2,300 healthy and tumoral samples obtained from differentially aged individuals, using HumanMethylation450 BeadChip data generated by The Cancer Genome Atlas (TCGA) consortium and other datasets (Bormann et al., 2016; Guintivano, Aryee & Kaminsky, 2013; Hannum et al., 2013).…”

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

“…A parallel thyroxine treatment had no effect on lifespan (243,244,245) whereas thyroxine and GH combined treatment reduced maximal lifespan in only female Ames mice (246). (iii) Extensive work by Brown-Borg and colleagues have described epigenetic signatures in DNA methylation patterns in Ames mice compared to their WT littermates (247,248). This indicates that a tissue-and sex-specific systematic interrogation of the epigenetic landscape in in GHRKO mice as well as in Israeli and Ecuadorian cohorts of LS patients can be valuable.…”