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      Epigenetic regulation of ageing: linking environmental inputs to genomic stability

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          Preface

          Ageing is affected by both genetic and non-genetic factors. Here, we review the chromatin-based epigenetic changes that occur during ageing, the role of chromatin modifiers in modulating lifespan and the importance of epigenetic signatures as biomarkers of ageing. We also discuss how epigenome remodeling by environmental stimuli impacts several aspects of transcription and genomic stability, with important consequences on longevity, and outline epigenetic differences between the ‘mortal soma’ and the ‘immortal germline’. Finally, we discuss the inheritance of ageing characteristics and potential chromatin-based strategies to delay or reverse hallmarks of ageing or age-related diseases.

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          DNA methylation age of blood predicts all-cause mortality in later life

          Riccardo E Marioni, Sonia Shah, Allan McRae … (2015)
          Background DNA methylation levels change with age. Recent studies have identified biomarkers of chronological age based on DNA methylation levels. It is not yet known whether DNA methylation age captures aspects of biological age. Results Here we test whether differences between people’s chronological ages and estimated ages, DNA methylation age, predict all-cause mortality in later life. The difference between DNA methylation age and chronological age (Δage) was calculated in four longitudinal cohorts of older people. Meta-analysis of proportional hazards models from the four cohorts was used to determine the association between Δage and mortality. A 5-year higher Δage is associated with a 21% higher mortality risk, adjusting for age and sex. After further adjustments for childhood IQ, education, social class, hypertension, diabetes, cardiovascular disease, and APOE e4 status, there is a 16% increased mortality risk for those with a 5-year higher Δage. A pedigree-based heritability analysis of Δage was conducted in a separate cohort. The heritability of Δage was 0.43. Conclusions DNA methylation-derived measures of accelerated aging are heritable traits that predict mortality independently of health status, lifestyle factors, and known genetic factors. Electronic supplementary material The online version of this article (doi:10.1186/s13059-015-0584-6) contains supplementary material, which is available to authorized users.
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            The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis.

            Ali Shilatifard (2012)
            The Saccharomyces cerevisiae Set1/COMPASS was the first histone H3 lysine 4 (H3K4) methylase identified over 10 years ago. Since then, it has been demonstrated that Set1/COMPASS and its enzymatic product, H3K4 methylation, is highly conserved across the evolutionary tree. Although there is only one COMPASS in yeast, Drosophila possesses three and humans bear six COMPASS family members, each capable of methylating H3K4 with nonredundant functions. In yeast, the histone H2B monoubiquitinase Rad6/Bre1 is required for proper H3K4 and H3K79 trimethylations. The machineries involved in this process are also highly conserved from yeast to human. In this review, the process of histone H2B monoubiquitination-dependent and -independent histone H3K4 methylation as a mark of active transcription, enhancer signatures, and developmentally poised genes is discussed. The misregulation of histone H2B monoubiquitination and H3K4 methylation result in the pathogenesis of human diseases, including cancer. Recent findings in this regard are also examined.
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              Aging of blood can be tracked by DNA methylation changes at just three CpG sites

              Carola Weidner, Qiong Lin, Carmen Koch … (2014)
              Background Human aging is associated with DNA methylation changes at specific sites in the genome. These epigenetic modifications may be used to track donor age for forensic analysis or to estimate biological age. Results We perform a comprehensive analysis of methylation profiles to narrow down 102 age-related CpG sites in blood. We demonstrate that most of these age-associated methylation changes are reversed in induced pluripotent stem cells (iPSCs). Methylation levels at three age-related CpGs - located in the genes ITGA2B, ASPA and PDE4C - were subsequently analyzed by bisulfite pyrosequencing of 151 blood samples. This epigenetic aging signature facilitates age predictions with a mean absolute deviation from chronological age of less than 5 years. This precision is higher than age predictions based on telomere length. Variation of age predictions correlates moderately with clinical and lifestyle parameters supporting the notion that age-associated methylation changes are associated more with biological age than with chronological age. Furthermore, patients with acquired aplastic anemia or dyskeratosis congenita - two diseases associated with progressive bone marrow failure and severe telomere attrition - are predicted to be prematurely aged. Conclusions Our epigenetic aging signature provides a simple biomarker to estimate the state of aging in blood. Age-associated DNA methylation changes are counteracted in iPSCs. On the other hand, over-estimation of chronological age in bone marrow failure syndromes is indicative for exhaustion of the hematopoietic cell pool. Thus, epigenetic changes upon aging seem to reflect biological aging of blood.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100962782
                Journal ID (pubmed-jr-id): 22271
                Journal ID (nlm-ta): Nat Rev Mol Cell Biol
                Journal ID (iso-abbrev): Nat. Rev. Mol. Cell Biol.
                Title: Nature reviews. Molecular cell biology
                ISSN (Print): 1471-0072
                ISSN (Electronic): 1471-0080
                Publication date Nihms-submitted: 30 January 2016
                Publication date (Electronic): 16 September 2015
                Publication date (Print): October 2015
                Publication date PMC-release: 01 October 2016
                Volume: 16
                Issue: 10
                Pages: 593-610
                Affiliations
                [1 ]Department of Genetics, Stanford University, Stanford CA 94305, USA
                [2 ]Paul F. Glenn Laboratories for the Biology of Ageing, Stanford University, Stanford CA 94305, USA
                [3 ]Cancer Biology Program, Stanford University, Stanford CA 94305, USA
                Author notes
                [4 ]Correspondence: Anne Brunet, anne.brunet@ 123456stanford.edu
                [*]

                Equal contribution

                Article
                Accession ID: PMC4736728 Pmcid ID: PMC4736728 Pmc-uid ID: 4736728 Manuscript ID: nihpa751698
                DOI: 10.1038/nrm4048
                PMC ID: 4736728
                PubMed ID: 26373265
                SO-VID: f2056548-99b5-4c24-a6b1-6f1189fb2b23
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