title: Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions.
abstract: Age-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 Prop1df/dfmutation, calorie restriction and rapamycin.
  
  
  
  In 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.
  
  
  
  Age-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.
authors.affiliation: Beatson Institute for Cancer Research and University of Glasgow, Garscube Estate, G61 1BD, UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Cole
authors.affiliation: Beatson Institute for Cancer Research and University of Glasgow, Garscube Estate, G61 1BD, UK.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Robertson
authors.affiliation: Beatson Institute for Cancer Research and University of Glasgow, Garscube Estate, G61 1BD, UK.
authors.forename: Mohammed Iqbal
authors.initials: MI
authors.lastname: Rather
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh, UK.
authors.forename: John P
authors.initials: JP
authors.lastname: Thomson
authors.affiliation: Beatson Institute for Cancer Research and University of Glasgow, Garscube Estate, G61 1BD, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: McBryan
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh, UK.|Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh, UK.
authors.forename: Duncan
authors.initials: D
authors.lastname: Sproul
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Wang
authors.affiliation: Beatson Institute for Cancer Research and University of Glasgow, Garscube Estate, G61 1BD, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Brock
authors.affiliation: Beatson Institute for Cancer Research and University of Glasgow, Garscube Estate, G61 1BD, UK.
authors.forename: William
authors.initials: W
authors.lastname: Clark
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh, UK.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Meehan
authors.affiliation: Department of Pathology and Glenn Center for the Biology of Aging, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.affiliation: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, 58203, USA. holly.brown.borg@med.und.edu.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Brown-Borg
authors.affiliation: Beatson Institute for Cancer Research and University of Glasgow, Garscube Estate, G61 1BD, UK. p.adams@beatson.gla.ac.uk.|Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA. p.adams@beatson.gla.ac.uk.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Adams
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D004392:Dwarfism / Q000235:genetics; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation; D008099:Liver / Q000378:metabolism; D008136:Longevity / Q000235:genetics*; D008297:Male; D051379:Mice; D009928:Organ Specificity / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid