The Epigenetics of Aging and Longevity

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (31 October 2017) | Viewed by 49999

Special Issue Editors

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10021, USA
Interests: chromatin assembly; histone modifications; chromatin remodeling; DNA double strand break repair; replicative aging
Special Issues, Collections and Topics in MDPI journals
Orentreich Foundation for the Advancement of Science, Cold Spring, NY 10516, USA
Interests: methionine restriction, chronological lifespan, Saccharomyces cerevisiae, budding yeast, aging, healthspan, longevity, senescence, autophagy

Special Issue Information

Dear Colleagues,

A growing body of evidence demonstrates that both genetic and epigenetic alterations contribute to aging. In contrast to genetic changes, the reversible nature of epigenetic mechanisms makes these pathways promising avenues for the development of regimens against age-related decline and disease.

With the advent of techniques for genome-wide analysis of histone modifications and DNA methylation, we are now learning that aging is accompanied by a wealth of changes to the epigenetic information. These age-associated changes in the epigenetic information alter the chromatin structure over time, in turn causing transcriptional changes, genomic instability and activation of transposons that drive the aging process. Furthermore, small molecules are being utilized to alter the epigenetic information in order to counter the aging process in model organisms. The best-characterized pathway connecting the environment to the epigenome is nutrient signaling. Exciting progress is being made in understanding how nutrients influence aging and how nutrients, including altered diets, can be utilized to promote longevity.

In this Special Issue, we would like to invite submissions of original research or review articles on topics relevant to “the epigenetics of aging and longevity”. We hope to gather together knowledge to empower efforts towards the effective and safe extension of lifespan and health span in humans. We look forward to receiving your contributions.

Prof. Dr. Jessica Tyler
Dr. Jay E. Johnson
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • replicative lifespan
  • chronological lifespan
  • longevity
  • aging
  • health span
  • dietary restriction
  • methionine restriction
  • autophagy
  • epigenome
  • epigenetics

Published Papers (7 papers)

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Research

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15 pages, 357 KiB  
Article
DNA Methylation and All-Cause Mortality in Middle-Aged and Elderly Danish Twins
by Anne Marie Svane, Mette Soerensen, Jesper Lund, Qihua Tan, Juulia Jylhävä, Yunzhang Wang, Nancy L. Pedersen, Sara Hägg, Birgit Debrabant, Ian J. Deary, Kaare Christensen, Lene Christiansen and Jacob B. Hjelmborg
Genes 2018, 9(2), 78; https://doi.org/10.3390/genes9020078 - 08 Feb 2018
Cited by 23 | Viewed by 4812
Abstract
Several studies have linked DNA methylation at individual CpG sites to aging and various diseases. Recent studies have also identified single CpGs whose methylation levels are associated with all-cause mortality. In this study, we perform an epigenome-wide study of the association between CpG [...] Read more.
Several studies have linked DNA methylation at individual CpG sites to aging and various diseases. Recent studies have also identified single CpGs whose methylation levels are associated with all-cause mortality. In this study, we perform an epigenome-wide study of the association between CpG methylation and mortality in a population of 435 monozygotic twin pairs from three Danish twin studies. The participants were aged 55–90 at the time of blood sampling and were followed for up to 20 years. We validated our results by comparison with results from a British and a Swedish cohort, as well as results from the literature. We identified 2806 CpG sites associated with mortality (false discovery rate ( FDR ) < 0.05 ), of which 24 had an association p-value below 10 7 . This was confirmed by intra-pair comparison controlling for confounding effects. Eight of the 24 top sites could be validated in independent datasets or confirmed by previous studies. For all these eight sites, hypomethylation was associated with poor survival prognosis, and seven showed monozygotic correlations above 35%, indicating a potential moderate to strong heritability, but leaving room for substantial shared or unique environmental effects. We also set up a predictor for mortality using least absolute shrinkage and selection operator (LASSO) regression. The predictor showed good performance on the Danish data under cross-validation, but did not perform very well in independent samples. Full article
(This article belongs to the Special Issue The Epigenetics of Aging and Longevity)
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19 pages, 5126 KiB  
Article
Linking DNA Damage and Age-Related Promoter DNA Hyper-Methylation in the Intestine
by Torsten Thalheim, Maria Herberg and Joerg Galle
Genes 2018, 9(1), 17; https://doi.org/10.3390/genes9010017 - 05 Jan 2018
Cited by 12 | Viewed by 4574
Abstract
Aberrant DNA methylation in stem cells is a hallmark of aging and tumor development. Here, we explore whether and how DNA damage repair might impact on these time-dependent changes, in particular in proliferative intestinal stem cells. We introduce a 3D multiscale computer model [...] Read more.
Aberrant DNA methylation in stem cells is a hallmark of aging and tumor development. Here, we explore whether and how DNA damage repair might impact on these time-dependent changes, in particular in proliferative intestinal stem cells. We introduce a 3D multiscale computer model of intestinal crypts enabling simulation of aberrant DNA and histone methylation of gene promoters during aging. We assume histone state-dependent activity of de novo DNA methyltransferases (DNMTs) and methylation-dependent binding of maintenance DNMTs to CpGs. We simulate aging with and without repeated DNA repair. Motivated by recent findings on the histone demethylase KDM2b, we consider that DNA repair is associated with chromatin opening and improved recruitment of de novo DNMTs. Our results suggest that methylation-dependent binding of maintenance DNMTs to CpGs, establishing bistable DNA methylation states, is a prerequisite to promoter hyper-methylation following DNA repair. With this, the transient increase in de novo DNMT activity during repair can induce switches from low to high methylation states. These states remain stable after repair, leading to an epigenetic drift. The switches are most frequent in genes with H3K27me3 modified promoters. Our model provides a mechanistic explanation on how even successful DNA repair might confer long term changes of the epigenome. Full article
(This article belongs to the Special Issue The Epigenetics of Aging and Longevity)
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Review

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17 pages, 2405 KiB  
Review
Chromatin Architectural Changes during Cellular Senescence and Aging
by Luyang Sun, Ruofan Yu and Weiwei Dang
Genes 2018, 9(4), 211; https://doi.org/10.3390/genes9040211 - 16 Apr 2018
Cited by 49 | Viewed by 10362
Abstract
Chromatin 3D structure is highly dynamic and associated with many biological processes, such as cell cycle progression, cellular differentiation, cell fate reprogramming, cancer development, cellular senescence, and aging. Recently, by using chromosome conformation capture technologies, tremendous findings have been reported about the dynamics [...] Read more.
Chromatin 3D structure is highly dynamic and associated with many biological processes, such as cell cycle progression, cellular differentiation, cell fate reprogramming, cancer development, cellular senescence, and aging. Recently, by using chromosome conformation capture technologies, tremendous findings have been reported about the dynamics of genome architecture, their associated proteins, and the underlying mechanisms involved in regulating chromatin spatial organization and gene expression. Cellular senescence and aging, which involve multiple cellular and molecular functional declines, also undergo significant chromatin structural changes, including alternations of heterochromatin and disruption of higher-order chromatin structure. In this review, we summarize recent findings related to genome architecture, factors regulating chromatin spatial organization, and how they change during cellular senescence and aging. Full article
(This article belongs to the Special Issue The Epigenetics of Aging and Longevity)
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27 pages, 1551 KiB  
Review
Epigenetic Mechanisms Impacting Aging: A Focus on Histone Levels and Telomeres
by Shufei Song and F. Brad Johnson
Genes 2018, 9(4), 201; https://doi.org/10.3390/genes9040201 - 09 Apr 2018
Cited by 44 | Viewed by 9161
Abstract
Aging and age-related diseases pose some of the most significant and difficult challenges to modern society as well as to the scientific and medical communities. Biological aging is a complex, and, under normal circumstances, seemingly irreversible collection of processes that involves numerous underlying [...] Read more.
Aging and age-related diseases pose some of the most significant and difficult challenges to modern society as well as to the scientific and medical communities. Biological aging is a complex, and, under normal circumstances, seemingly irreversible collection of processes that involves numerous underlying mechanisms. Among these, chromatin-based processes have emerged as major regulators of cellular and organismal aging. These include DNA methylation, histone modifications, nucleosome positioning, and telomere regulation, including how these are influenced by environmental factors such as diet. Here we focus on two interconnected categories of chromatin-based mechanisms impacting aging: those involving changes in the levels of histones or in the functions of telomeres. Full article
(This article belongs to the Special Issue The Epigenetics of Aging and Longevity)
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14 pages, 647 KiB  
Review
Age-Related Epigenetic Derangement upon Reprogramming and Differentiation of Cells from the Elderly
by Francesco Ravaioli, Maria G. Bacalini, Claudio Franceschi and Paolo Garagnani
Genes 2018, 9(1), 39; https://doi.org/10.3390/genes9010039 - 16 Jan 2018
Cited by 10 | Viewed by 4572
Abstract
Aging is a complex multi-layered phenomenon. The study of aging in humans is based on the use of biological material from hard-to-gather tissues and highly specific cohorts. The introduction of cell reprogramming techniques posed promising features for medical practice and basic research. Recently, [...] Read more.
Aging is a complex multi-layered phenomenon. The study of aging in humans is based on the use of biological material from hard-to-gather tissues and highly specific cohorts. The introduction of cell reprogramming techniques posed promising features for medical practice and basic research. Recently, a growing number of studies have been describing the generation of induced pluripotent stem cells (iPSCs) from old or centenarian biologic material. Nonetheless, Reprogramming techniques determine a profound remodelling on cell epigenetic architecture whose extent is still largely debated. Given that cell epigenetic profile changes with age, the study of cell-fate manipulation approaches on cells deriving from old donors or centenarians may provide new insights not only on regenerative features and physiology of these cells, but also on reprogramming-associated and age-related epigenetic derangement. Full article
(This article belongs to the Special Issue The Epigenetics of Aging and Longevity)
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1077 KiB  
Review
Histone MacroH2A1: A Chromatin Point of Intersection between Fasting, Senescence and Cellular Regeneration
by Oriana Lo Re and Manlio Vinciguerra
Genes 2017, 8(12), 367; https://doi.org/10.3390/genes8120367 - 05 Dec 2017
Cited by 27 | Viewed by 6123
Abstract
Histone variants confer chromatin unique properties. They have specific genomic distribution, regulated by specific deposition and removal machineries. Histone variants, mostly of canonical histones H2A, H2B and H3, have important roles in early embryonic development, in lineage commitment of stem cells, in the [...] Read more.
Histone variants confer chromatin unique properties. They have specific genomic distribution, regulated by specific deposition and removal machineries. Histone variants, mostly of canonical histones H2A, H2B and H3, have important roles in early embryonic development, in lineage commitment of stem cells, in the converse process of somatic cell reprogramming to pluripotency and, in some cases, in the modulation of animal aging and life span. MacroH2A1 is a variant of histone H2A, present in two alternatively exon-spliced isoforms macroH2A1.1 and macroH2A1.2, regulating cell plasticity and proliferation, during pluripotency and tumorigenesis. Furthermore, macroH2A1 participates in the formation of senescence-associated heterochromatic foci (SAHF) in senescent cells, and multiple lines of evidence in genetically modified mice suggest that macroH2A1 integrates nutritional cues from the extracellular environment to transcriptional programs. Here, we review current molecular evidence based on next generation sequencing data, cell assays and in vivo models supporting different mechanisms that could mediate the function of macroH2A1 in health span and life span. We will further discuss context-dependent and isoform-specific functions. The aim of this review is to provide guidance to assess histone variant macroH2A1 potential as a therapeutic intervention point. Full article
(This article belongs to the Special Issue The Epigenetics of Aging and Longevity)
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579 KiB  
Review
Epigenetic Basis of Cellular Senescence and Its Implications in Aging
by Timothy Nacarelli, Pingyu Liu and Rugang Zhang
Genes 2017, 8(12), 343; https://doi.org/10.3390/genes8120343 - 24 Nov 2017
Cited by 37 | Viewed by 9530
Abstract
Cellular senescence is a tumor suppressive response that has become recognized as a major contributor of tissue aging. Senescent cells undergo a stable proliferative arrest that protects against neoplastic transformation, but acquire a secretory phenotype that has long-term deleterious effects. Studies are still [...] Read more.
Cellular senescence is a tumor suppressive response that has become recognized as a major contributor of tissue aging. Senescent cells undergo a stable proliferative arrest that protects against neoplastic transformation, but acquire a secretory phenotype that has long-term deleterious effects. Studies are still unraveling the effector mechanisms that underlie these senescence responses with the goal to identify therapeutic interventions. Such effector mechanisms have been linked to the dramatic remodeling in the epigenetic and chromatin landscape that accompany cellular senescence. We discuss these senescence-associated epigenetic changes and their impact on the senescence phenotypes, notably the proliferative arrest and senescence associated secretory phenotype (SASP). We also explore possible epigenetic targets to suppress the deleterious effects of senescent cells that contribute towards aging. Full article
(This article belongs to the Special Issue The Epigenetics of Aging and Longevity)
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