DNA methylation and healthy human aging Jones, Meaghan J.; Goodman, Sarah J.; Kobor, Michael S.
Aging cell,
December 2015, Letnik:
14, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Summary
The process of aging results in a host of changes at the cellular and molecular levels, which include senescence, telomere shortening, and changes in gene expression. Epigenetic patterns also ...change over the lifespan, suggesting that epigenetic changes may constitute an important component of the aging process. The epigenetic mark that has been most highly studied is DNA methylation, the presence of methyl groups at CpG dinucleotides. These dinucleotides are often located near gene promoters and associate with gene expression levels. Early studies indicated that global levels of DNA methylation increase over the first few years of life and then decrease beginning in late adulthood. Recently, with the advent of microarray and next‐generation sequencing technologies, increases in variability of DNA methylation with age have been observed, and a number of site‐specific patterns have been identified. It has also been shown that certain CpG sites are highly associated with age, to the extent that prediction models using a small number of these sites can accurately predict the chronological age of the donor. Together, these observations point to the existence of two phenomena that both contribute to age‐related DNA methylation changes: epigenetic drift and the epigenetic clock. In this review, we focus on healthy human aging throughout the lifetime and discuss the dynamics of DNA methylation as well as how interactions between the genome, environment, and the epigenome influence aging rates. We also discuss the impact of determining ‘epigenetic age’ for human health and outline some important caveats to existing and future studies.
Epigenetic biomarkers of aging (the "epigenetic clock") have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women ...consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors.
We analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue.
Epigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women.
DNA methylation is an epigenetic mark thought to be robust to environmental perturbations on a short time scale. Here, we challenge that view by demonstrating that the infection of human dendritic ...cells (DCs) with a live pathogenic bacteria is associated with rapid and active demethylation at thousands of loci, independent of cell division. We performed an integrated analysis of data on genome-wide DNA methylation, histone mark patterns, chromatin accessibility, and gene expression, before and after infection. We found that infection-induced demethylation rarely occurs at promoter regions and instead localizes to distal enhancer elements, including those that regulate the activation of key immune transcription factors. Active demethylation is associated with extensive epigenetic remodeling, including the gain of histone activation marks and increased chromatin accessibility, and is strongly predictive of changes in the expression levels of nearby genes. Collectively, our observations show that active, rapid changes in DNA methylation in enhancers play a previously unappreciated role in regulating the transcriptional response to infection, even in nonproliferating cells.
Epigenetic “clocks” can now surpass chronological age in accuracy for estimating biological age. Here, we use four such age estimators to show that epigenetic aging can be reversed in humans. Using a ...protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age‐related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (−2.5‐year change compared to no treatment at the end of the study). The rate of epigenetic aging reversal relative to chronological age accelerated from −1.6 year/year from 0–9 month to −6.5 year/year from 9–12 month. The GrimAge predictor of human morbidity and mortality showed a 2‐year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment. This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention.
Epigenetic aging—an accurate measure of biological aging in humans—can run in reverse. A thymus regeneration protocol has enabled estimated biological age to decrease in healthy 51‐ to 65‐year‐old men by 1.5 years after 1 year of treatment (or by 2.5 years compared to chronological age). This significantly exceeds the heretofore theoretical concept of “longevity escape velocity,” wherein biological age is reduced by 1 year for every 1 year of chronological age.
Biological embedding of experience Aristizabal, Maria J.; Anreiter, Ina; Halldorsdottir, Thorhildur ...
Proceedings of the National Academy of Sciences,
09/2020, Letnik:
117, Številka:
38
Journal Article
Recenzirano
Odprti dostop
Biological embedding occurs when life experience alters biological processes to affect later life health and well-being. Although extensive correlative data exist supporting the notion that ...epigenetic mechanisms such as DNA methylation underlie biological embedding, causal data are lacking. We describe specific epigenetic mechanisms and their potential roles in the biological embedding of experience. We also consider the nuanced relationships between the genome, the epigenome, and gene expression. Our ability to connect biological embedding to the epigenetic landscape in its complexity is challenging and complicated by the influence of multiple factors. These include cell type, age, the timing of experience, sex, and DNA sequence. Recent advances in molecular profiling and epigenome editing, combined with the use of comparative animal and human longitudinal studies, should enable this field to transition from correlative to causal analyses.
Infection of macrophages by the intracellular protozoan Leishmania leads to down-regulation of a number of macrophage innate host defense mechanisms, thereby allowing parasite survival and ...replication. The underlying molecular mechanisms involved remain largely unknown. In this study, we assessed epigenetic changes in macrophage DNA methylation in response to infection with L. donovani as a possible mechanism for Leishmania driven deactivation of host defense. We quantified and detected genome-wide changes of cytosine methylation status in the macrophage genome resulting from L. donovani infection. A high confidence set of 443 CpG sites was identified with changes in methylation that correlated with live L. donovani infection. These epigenetic changes affected genes that play a critical role in host defense such as the JAK/STAT signaling pathway and the MAPK signaling pathway. These results provide strong support for a new paradigm in host-pathogen responses, where upon infection the pathogen induces epigenetic changes in the host cell genome resulting in downregulation of innate immunity thereby enabling pathogen survival and replication. We therefore propose a model whereby Leishmania induced epigenetic changes result in permanent down regulation of host defense mechanisms to protect intracellular replication and survival of parasitic cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Allergic disease affects 30% to 40% of the world's population, and its development is determined by the interplay between environmental and inherited factors. Air pollution, primarily ...consisting of diesel exhaust emissions, has increased at a similar rate to allergic disease. Exposure to diesel exhaust may play a role in the development and progression of allergic disease, in particular allergic respiratory disease. One potential mechanism underlying the connection between air pollution and increased allergic disease incidence is DNA methylation, an epigenetic process with the capacity to integrate gene-environment interactions. Objective We sought to investigate the effect of allergen and diesel exhaust exposure on bronchial epithelial DNA methylation. Methods We performed a randomized crossover-controlled exposure study to allergen and diesel exhaust in humans, and measured single-site (CpG) resolution global DNA methylation in bronchial epithelial cells. Results Exposure to allergen alone, diesel exhaust alone, or allergen and diesel exhaust together (coexposure) led to significant changes in 7 CpG sites at 48 hours. However, when the same lung was exposed to allergen and diesel exhaust but separated by approximately 4 weeks, significant changes in more than 500 sites were observed. Furthermore, sites of differential methylation differed depending on which exposure was experienced first. Functional analysis of differentially methylated CpG sites found genes involved in transcription factor activity, protein metabolism, cell adhesion, and vascular development, among others. Conclusions These findings suggest that specific exposures can prime the lung for changes in DNA methylation induced by a subsequent insult.
Parkinson's disease (PD) is a neurodegenerative disorder with a complex etiology and increasing prevalence worldwide. As PD is influenced by a combination of genetic and environment/lifestyle factors ...in approximately 90% of cases, there is increasing interest in identification of the interindividual mechanisms underlying the development of PD as well as actionable lifestyle factors that can influence risk. This narrative review presents an outline of the genetic and environmental factors contributing to PD risk and explores the possible roles of cytosine methylation and hydroxymethylation in the etiology and/or as early-stage biomarkers of PD, with an emphasis on epigenome-wide association studies (EWAS) of PD conducted over the past decade. Specifically, we focused on variants in the
gene, exposure to pesticides, and physical activity as key contributors to PD risk. Current research indicates that these factors individually impact the epigenome, particularly at the level of CpG methylation. There is also emerging evidence for interaction effects between genetic and environmental contributions to PD risk, possibly acting across multiple omics layers. We speculated that this may be one reason for the poor replicability of the results of EWAS for PD reported to date. Our goal is to provide direction for future epigenetics studies of PD to build upon existing foundations and leverage large datasets, new technologies, and relevant statistical approaches to further elucidate the etiology of this disease.
DNA:RNA hybrid formation is emerging as a significant cause of genome instability in biological systems ranging from bacteria to mammals. Here we describe the genome-wide distribution of DNA:RNA ...hybrid prone loci in Saccharomyces cerevisiae by DNA:RNA immunoprecipitation (DRIP) followed by hybridization on tiling microarray. These profiles show that DNA:RNA hybrids preferentially accumulated at rDNA, Ty1 and Ty2 transposons, telomeric repeat regions and a subset of open reading frames (ORFs). The latter are generally highly transcribed and have high GC content. Interestingly, significant DNA:RNA hybrid enrichment was also detected at genes associated with antisense transcripts. The expression of antisense-associated genes was also significantly altered upon overexpression of RNase H, which degrades the RNA in hybrids. Finally, we uncover mutant-specific differences in the DRIP profiles of a Sen1 helicase mutant, RNase H deletion mutant and Hpr1 THO complex mutant compared to wild type, suggesting different roles for these proteins in DNA:RNA hybrid biology. Our profiles of DNA:RNA hybrid prone loci provide a resource for understanding the properties of hybrid-forming regions in vivo, extend our knowledge of hybrid-mitigating enzymes, and contribute to models of antisense-mediated gene regulation. A summary of this paper was presented at the 26th International Conference on Yeast Genetics and Molecular Biology, August 2013.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Across a variety of adverse life circumstances, such as social isolation and low socioeconomic status, mammalian immune cells have been found to show a conserved transcriptional response to adversity ...(CTRA) involving increased expression of proinflammatory genes. The present study examines whether such effects might stem in part from the selective up-regulation of a subpopulation of immature proinflammatory monocytes (Ly-6c ʰⁱᵍʰ in mice, CD16 ⁻ in humans) within the circulating leukocyte pool. Transcriptome representation analyses showed relative expansion of the immature proinflammatory monocyte transcriptome in peripheral blood mononuclear cells from people subject to chronic social stress (low socioeconomic status) and mice subject to repeated social defeat. Cellular dissection of the mouse peripheral blood mononuclear cell transcriptome confirmed these results, and promoter-based bioinformatic analyses indicated increased activity of transcription factors involved in early myeloid lineage differentiation and proinflammatory effector function (PU.1, NF-κB, EGR1, MZF1, NRF2). Analysis of bone marrow hematopoiesis confirmed increased myelopoietic output of Ly-6c ʰⁱᵍʰ monocytes and Ly-6c ⁱⁿᵗᵉʳᵐᵉᵈⁱᵃᵗᵉ granulocytes in mice subject to repeated social defeat, and these effects were blocked by pharmacologic antagonists of β-adrenoreceptors and the myelopoietic growth factor GM-CSF. These results suggest that sympathetic nervous system-induced up-regulation of myelopoiesis mediates the proinflammatory component of the leukocyte CTRA dynamic and may contribute to the increased risk of inflammation-related disease associated with adverse social conditions.
PDF
