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Cells
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Epigenetic Mechanisms of Longevity and Aging
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Epigenetic Mechanisms of Longevity and Aging

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 59927

Special Issue Editors

Prof. Dr. Gil Atzmon

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Guest Editor
Department of Biology, Faculty of Natural Sciences, University of Haifa, Mount Carmel, Haifa 31905, Israel
Interests: longevity; gene; genome; epigenetic; epigenome; aging
Special Issues, Collections and Topics in MDPI journals
Dr. Michael Klutstein

E-Mail Website
Guest Editor
Chromatin and Aging Research Laboratory, Institute of Biomedical and Oral Sciences, Hebrew University of Jerusalem, Jerusalem, Israel
Interests: epigenetics; aging; histone modifications; DNA methylation; fertility; long-term starvation; evolutionary adaptation
Special Issues, Collections and Topics in MDPI journals
Dr. Yitzhak Reizel

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Guest Editor
Department of Genetics and Institute for Diabetes Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-5156, USA
Interests: epigenetics; DNA methylation; pioneer factors; digestive system

Special Issue Information

Dear Colleagues,

Epigenetics, defined as heritable changes in gene function or phenotype, in the absence of DNA sequence changes, plays central roles in controlling gene expression in various fields. This is an especially important topic in aging, where epigenetic changes have been recognized as one of the molecular hallmarks of aging. Aging is associated with numerous molecular changes, such as altered metabolism, differential gene expression, and accumulated DNA damage. These changes are considered a general cause of aging, frailty and decreased life span.  While some mechanisms of the interplay between aging and epigenetics have been extensively studied in the last decade, the full understating of such processes is far from completion. In this Special Issue, we will consider state-of-the-art, innovative, and up-to-date studies that are in accordance with the exploration of roles of epigenetics in aging, using humans or other model organisms or substrates that will shed some light on this complex interaction. We invite you to contribute your thoughts, research articles and reviews of existing literature to this exciting new Special Issue.

Prof. Dr. Gil Atzmon
Dr. Michael Klutstein
Dr. Yitzhak Reizel
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 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

  • epigenetics
  • longevity aging
  • DNA methylation
  • histone
  • modifications
  • cancer
  • neurodegenerative
  • disease
  • reproduction
  • metabolism
  • gene expression

Published Papers (7 papers)

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Research

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21 pages, 6881 KiB  
Article
Pseudotime Analysis Reveals Exponential Trends in DNA Methylation Aging with Mortality Associated Timescales
by Kalsuda Lapborisuth, Colin Farrell and Matteo Pellegrini
Cells 2022, 11(5), 767; https://doi.org/10.3390/cells11050767 - 22 Feb 2022
Cited by 1 | Viewed by 2634
Abstract
The epigenetic trajectory of DNA methylation profiles has a nonlinear relationship with time, reflecting rapid changes in DNA methylation early in life that progressively slow with age. In this study, we use pseudotime analysis to determine the functional form of these trajectories. Unlike [...] Read more.
The epigenetic trajectory of DNA methylation profiles has a nonlinear relationship with time, reflecting rapid changes in DNA methylation early in life that progressively slow with age. In this study, we use pseudotime analysis to determine the functional form of these trajectories. Unlike epigenetic clocks that constrain the functional form of methylation changes with time, pseudotime analysis orders samples along a path, based on similarities in a latent dimension, to provide an unbiased trajectory. We show that pseudotime analysis can be applied to DNA methylation in human blood and brain tissue and find that it is highly correlated with the epigenetic states described by the Epigenetic Pacemaker. Moreover, we show that the pseudotime trajectory can be modeled with respect to time, using a sum of two exponentials, with coefficients that are close to the timescales of human age-associated mortality. Thus, for the first time, we can identify age-associated molecular changes that appear to track the exponential dynamics of mortality risk. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms of Longevity and Aging)
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13 pages, 3205 KiB  
Article
MicroRNA-Mediated Downregulation of HMGB2 Contributes to Cellular Senescence in Microvascular Endothelial Cells
by Hye-Ram Jo and Jae-Hoon Jeong
Cells 2022, 11(3), 584; https://doi.org/10.3390/cells11030584 - 08 Feb 2022
Cited by 6 | Viewed by 2315
Abstract
High mobility group box 2 (HMGB2) is a non-histone chromosomal protein involved in various biological processes, including cellular senescence. However, its role in cellular senescence has not been evaluated extensively. To determine the regulatory role and mechanism of HMGB2 in cellular senescence, we [...] Read more.
High mobility group box 2 (HMGB2) is a non-histone chromosomal protein involved in various biological processes, including cellular senescence. However, its role in cellular senescence has not been evaluated extensively. To determine the regulatory role and mechanism of HMGB2 in cellular senescence, we performed gene expression analysis, senescence staining, and tube formation assays using young and senescent microvascular endothelial cells (MVECs) after small RNA treatment or HMGB2 overexpression. HMGB2 expression decreased with age and was regulated at the transcriptional level. siRNA-mediated downregulation inhibited cell proliferation and accelerated cellular senescence. In contrast, ectopic overexpression delayed senescence and maintained relatively higher tube-forming activity. To determine the HMGB2 downregulation mechanism, we screened miRNAs that were significantly upregulated in senescent MVECs and selected HMGB2-targeting miRNAs. Six miRNAs, miR-23a-3p, 23b-3p, -181a-5p, -181b-5p, -221-3p, and -222-3p, were overexpressed in senescent MVECs. Ectopic introduction of miR-23a-3p, -23b-3p, -181a-5p, -181b-5p, and -221-3p, with the exception of miR-222-3p, led to the downregulation of HMGB2, upregulation of senescence-associated markers, and decreased tube formation activity. Inhibition of miR-23a-3p, -181a-5p, -181b-5p, and -221-3p delayed cellular senescence. Restoration of HMGB2 expression using miRNA inhibitors represents a potential strategy to overcome the detrimental effects of cellular senescence in endothelial cells. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms of Longevity and Aging)
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11 pages, 1371 KiB  
Article
Leukocyte Telomere Length Correlates with Extended Female Fertility
by Jennia Michaeli, Riham Smoom, Noa Serruya, Hosniyah El Ayoubi, Keren Rotshenker-Olshinka, Naama Srebnik, Ofir Michaeli, Talia Eldar-Geva and Yehuda Tzfati
Cells 2022, 11(3), 513; https://doi.org/10.3390/cells11030513 - 02 Feb 2022
Cited by 11 | Viewed by 2735
Abstract
Current social trends of delayed reproduction to the fourth and fifth decade of life call for a better understanding of reproductive aging. Demographic studies correlated late reproduction with general health and longevity. Telomeres, the protective ends of eukaryotic chromosomes, were implicated in various [...] Read more.
Current social trends of delayed reproduction to the fourth and fifth decade of life call for a better understanding of reproductive aging. Demographic studies correlated late reproduction with general health and longevity. Telomeres, the protective ends of eukaryotic chromosomes, were implicated in various aging-associated pathologies and longevity. To examine whether telomeres are also associated with reproductive aging, we measured by Southern analysis the terminal restriction fragments (TRF) in leukocytes of women delivering a healthy infant following a spontaneous pregnancy at 43–48 years of age. We compared them to age-matched previously fertile women who failed to conceive above age 41. The average TRF length in the extended fertility group (9350 bp) was significantly longer than in the normal fertility group (8850 bp; p-value = 0.03). Strikingly, excluding women with nine or more children increased the difference between the groups to over 1000 bp (9920 and 8880 bp; p-value = 0.0009). Nevertheless, we observed no apparent effects of pregnancy, delivery, or parity on telomere length. We propose that longer leukocyte telomere length reflects higher oocyte quality, which can compensate for other limiting physiological and behavioral factors and enable successful reproduction. Leukocyte telomere length should be further explored as a novel biomarker of oocyte quality for assessing reproductive potential and integrating family planning with demanding women’s careers. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms of Longevity and Aging)
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Review

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34 pages, 2165 KiB  
Review
A Mechanistic Theory of Development-Aging Continuity in Humans and Other Mammals
by Richard F. Walker
Cells 2022, 11(5), 917; https://doi.org/10.3390/cells11050917 - 07 Mar 2022
Cited by 3 | Viewed by 7607
Abstract
There is consensus among biogerontologists that aging occurs either as the result of a purposeful genome-based, evolved program or due to spontaneous, randomly occurring, maladaptive events. Neither concept has yet identified a specific mechanism to explain aging’s emergence and acceleration during mid-life and [...] Read more.
There is consensus among biogerontologists that aging occurs either as the result of a purposeful genome-based, evolved program or due to spontaneous, randomly occurring, maladaptive events. Neither concept has yet identified a specific mechanism to explain aging’s emergence and acceleration during mid-life and beyond. Presented herein is a novel, unifying mechanism with empirical evidence that describes how aging becomes continuous with development. It assumes that aging emerges from deterioration of a regulatory process that directs morphogenesis and morphostasis. The regulatory system consists of a genome-wide “backbone” within which its specific genes are differentially expressed by the local epigenetic landscapes of cells and tissues within which they reside, thereby explaining its holistic nature. Morphostasis evolved in humans to ensure the nurturing of dependent offspring during the first decade of young adulthood when peak parental vitality prevails in the absence of aging. The strict redundancy of each morphostasis regulatory cycle requires sensitive dependence upon initial conditions to avoid initiating deterministic chaos behavior. However, when natural selection declines as midlife approaches, persistent, progressive, and specific DNA damage and misrepair changes the initial conditions of the regulatory process, thereby compromising morphostasis regulatory redundancy, instigating chaos, initiating senescence, and accelerating aging thereafter. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms of Longevity and Aging)
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40 pages, 3331 KiB  
Review
How to Slow down the Ticking Clock: Age-Associated Epigenetic Alterations and Related Interventions to Extend Life Span
by Anne-Marie Galow and Shahaf Peleg
Cells 2022, 11(3), 468; https://doi.org/10.3390/cells11030468 - 29 Jan 2022
Cited by 24 | Viewed by 32167
Abstract
Epigenetic alterations pose one major hallmark of organismal aging. Here, we provide an overview on recent findings describing the epigenetic changes that arise during aging and in related maladies such as neurodegeneration and cancer. Specifically, we focus on alterations of histone modifications and [...] Read more.
Epigenetic alterations pose one major hallmark of organismal aging. Here, we provide an overview on recent findings describing the epigenetic changes that arise during aging and in related maladies such as neurodegeneration and cancer. Specifically, we focus on alterations of histone modifications and DNA methylation and illustrate the link with metabolic pathways. Age-related epigenetic, transcriptional and metabolic deregulations are highly interconnected, which renders dissociating cause and effect complicated. However, growing amounts of evidence support the notion that aging is not only accompanied by epigenetic alterations, but also at least in part induced by those. DNA methylation clocks emerged as a tool to objectively determine biological aging and turned out as a valuable source in search of factors positively and negatively impacting human life span. Moreover, specific epigenetic signatures can be used as biomarkers for age-associated disorders or even as targets for therapeutic approaches, as will be covered in this review. Finally, we summarize recent potential intervention strategies that target epigenetic mechanisms to extend healthy life span and provide an outlook on future developments in the field of longevity research. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms of Longevity and Aging)
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15 pages, 852 KiB  
Review
Epigenetic Mechanisms of Senescence in Plants
by Matin Miryeganeh
Cells 2022, 11(2), 251; https://doi.org/10.3390/cells11020251 - 12 Jan 2022
Cited by 10 | Viewed by 4007
Abstract
Senescence is a major developmental transition in plants that requires a massive reprogramming of gene expression and includes various layers of regulations. Senescence is either an age-dependent or a stress-induced process, and is under the control of complex regulatory networks that interact with [...] Read more.
Senescence is a major developmental transition in plants that requires a massive reprogramming of gene expression and includes various layers of regulations. Senescence is either an age-dependent or a stress-induced process, and is under the control of complex regulatory networks that interact with each other. It has been shown that besides genetic reprogramming, which is an important aspect of plant senescence, transcription factors and higher-level mechanisms, such as epigenetic and small RNA-mediated regulators, are also key factors of senescence-related genes. Epigenetic mechanisms are an important layer of this multilevel regulatory system that change the activity of transcription factors (TFs) and play an important role in modulating the expression of senescence-related gene. They include chromatin remodeling, DNA methylation, histone modification, and the RNA-mediated control of transcription factors and genes. This review provides an overview of the known epigenetic regulation of plant senescence, which has mostly been studied in the form of leaf senescence, and it also covers what has been reported about whole-plant senescence. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms of Longevity and Aging)
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29 pages, 3204 KiB  
Review
Overview of Polyamines as Nutrients for Human Healthy Long Life and Effect of Increased Polyamine Intake on DNA Methylation
by Kuniyasu Soda
Cells 2022, 11(1), 164; https://doi.org/10.3390/cells11010164 - 04 Jan 2022
Cited by 28 | Viewed by 6184
Abstract
Polyamines, spermidine and spermine, are synthesized in every living cell and are therefore contained in foods, especially in those that are thought to contribute to health and longevity. They have many physiological activities similar to those of antioxidant and anti-inflammatory substances such as [...] Read more.
Polyamines, spermidine and spermine, are synthesized in every living cell and are therefore contained in foods, especially in those that are thought to contribute to health and longevity. They have many physiological activities similar to those of antioxidant and anti-inflammatory substances such as polyphenols. These include antioxidant and anti-inflammatory properties, cell and gene protection, and autophagy activation. We have first reported that increased polyamine intake (spermidine much more so than spermine) over a long period increased blood spermine levels and inhibited aging-associated pathologies and pro-inflammatory status in humans and mice and extended life span of mice. However, it is unlikely that the life-extending effect of polyamines is exerted by the same bioactivity as polyphenols because most studies using polyphenols and antioxidants have failed to demonstrate their life-extending effects. Recent investigations revealed that aging-associated pathologies and lifespan are closely associated with DNA methylation, a regulatory mechanism of gene expression. There is a close relationship between polyamine metabolism and DNA methylation. We have shown that the changes in polyamine metabolism affect the concentrations of substances and enzyme activities involved in DNA methylation. I consider that the increased capability of regulation of DNA methylation by spermine is a key of healthy long life of humans. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms of Longevity and Aging)
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