Aging and Rejuvenation -A Modular Epigenome Model
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Epigenetic Clocks
Cognitive Vitality Reports® are reports written by neuroscientists at the Alzheimer’s Drug Discovery Foundation (ADDF). These scientific reports include analysis of drugs, drugs-in- development, drug targets, supplements, nutraceuticals, food/drink, non-pharmacologic interventions, and risk factors. Neuroscientists evaluate the potential benefit (or harm) for brain health, as well as for age-related health concerns that can affect brain health (e.g., cardiovascular diseases, cancers, diabetes/metabolic syndrome). In addition, these reports include evaluation of safety data, from clinical trials if available, and from preclinical models. Epigenetic Clocks Evidence Summary Horvath and Hannum epigenetic clocks are highly correlative of age and time to death in population studies; however, it is unclear how valuable these clocks will be as a measure in individuals. Neuroprotective Benefit: There is no evidence that blood epigenetic clocks correlate with Alzheimer’s disease. Aging and related health concerns: Evidence suggests that epigenetic clocks correlate with mortality and several disease states in population studies. Safety: N/A 1 What is it? DNA methylation (DNAm) is one of three primary epigenetic mechanisms that control gene expression (the other two being histone tail modifications and microRNA regulation of mRNA). A methyl group (CH3) is attached to a cytosine DNA base pair, usually located next to a guanine base pair (a CpG site), which modifies the packaging of the DNA and changes gene expression. Three DNA methyltransferases: DNMT1, DNMT3a and DNMT3b, primarily mediate DNAm. DNMT1 has a maintenance role – during DNA replication, it copies the methylation pattern of the original strand. DNMT3a and DNMT3b add methyl groups to new CpG sites (Sen et al, 2016). -
Supercentenarians Landscape Overview
Supercentenarians Landscape Overview Top-100 Living Top-100 Longest-Lived Top-25 Socially and Professionally Active Executive and Infographic Summary GERONTOLOGY RESEARCH GROUP www.aginganalytics.com www.grg.org Supercentenarians Landscape Overview Foreword 3 Top-100 Living Supercentenarians Overview 44 Preface. How Long Can Humans Live and 4 Ages of Oldest Living Supercentenarians by Country 46 the Importance of Age Validation Top-100 Living Supercentenarians Continental Executive Summary 10 47 Distribution by Gender Introduction. 26 Top-100 Living Supercentenarians Distribution by Age 50 All Validated Supercentenarians Сhapter III. Top-25 Socially and Professionally Active All Supercentenarians Region Distribution by Gender 29 52 Living Centenarians Top-25 Socially and Professionally Active Centenarians All Supercentenarians Distribution by Nations 30 53 Overview Top-25 Socially and Professionally Active Centenarians Longest-Lived Supercentenarians Distribution by Country 31 54 Distribution by Nation Top-25 Socially and Professionally Active Centenarians All Supercentenarians Distribution by Gender and Age 32 55 Gender Distribution Top-25 Socially and Professionally Active Centenarians Сhapter I. Top-100 Longest-Lived Supercentenarians 35 56 Distribution by Type of Activity Chapter IV. Profiles of Top-100 Longest-Lived Top-100 Longest-Lived Supercentenarians Overview 36 57 Supercentenarians Top-100 Longest-Lived Supercentenarians Regional 38 Chapter V. Profiles of Top-100 Living Supercentenarians 158 Distribution by Gender Top-100 Longest-Lived Supercentenarians Distribution by Chapter VI. Profiles of Top-25 Socially and Professionally 40 259 Age Active Living Centenarians and Nonagenarians Сhapter II. Top-100 Living Supercentenarians 43 Disclaimer 285 Executive Summary There have always been human beings who have lived well beyond normal life expectancy, these ‘supercentenarians’ who lived past 110 years of age. -
Increased Epigenetic Age in Normal Breast Tissue from Luminal Breast Cancer Patients Erin W
Hofstatter et al. Clinical Epigenetics (2018) 10:112 https://doi.org/10.1186/s13148-018-0534-8 RESEARCH Open Access Increased epigenetic age in normal breast tissue from luminal breast cancer patients Erin W. Hofstatter1*† , Steve Horvath2,3†, Disha Dalela4, Piyush Gupta5, Anees B. Chagpar6, Vikram B. Wali1, Veerle Bossuyt7, Anna Maria Storniolo8, Christos Hatzis1, Gauri Patwardhan1, Marie-Kristin Von Wahlde1,9, Meghan Butler4, Lianne Epstein1, Karen Stavris4, Tracy Sturrock4, Alexander Au4,10, Stephanie Kwei4 and Lajos Pusztai1 Abstract Background: Age is one of the most important risk factors for developing breast cancer. However, age-related changes in normal breast tissue that potentially lead to breast cancer are incompletely understood. Quantifying tissue-level DNA methylation can contribute to understanding these processes. We hypothesized that occurrence of breast cancer should be associated with an acceleration of epigenetic aging in normal breast tissue. Results: Ninety-six normal breast tissue samples were obtained from 88 subjects (breast cancer = 35 subjects/40 samples, unaffected = 53 subjects/53 samples). Normal tissue samples from breast cancer patients were obtained from distant non-tumor sites of primary mastectomy specimens, while samples from unaffected women were obtained from the Komen Tissue Bank (n = 25) and from non-cancer-related breast surgery specimens (n = 28). Patients were further stratified into four cohorts: age < 50 years with and without breast cancer and age ≥ 50 with and without breast cancer. The Illumina HumanMethylation450k BeadChip microarray was used to generate methylation profiles from extracted DNA samples. Data was analyzed using the “Epigenetic Clock,” a published biomarker of aging based on a defined set of 353 CpGs in the human genome. -
An Epigenetic Clock Controls Aging
An epigenetic clock controls aging The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Mitteldorf, Josh. “An Epigenetic Clock Controls Aging.” Biogerontology 17.1 (2016): 257–265. As Published http://dx.doi.org/10.1007/s10522-015-9617-5 Publisher Springer Netherlands Version Author's final manuscript Citable link http://hdl.handle.net/1721.1/105831 Terms of Use Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. Biogerontology (2016) 17:257–265 DOI 10.1007/s10522-015-9617-5 OPINION ARTICLE An epigenetic clock controls aging Josh Mitteldorf Received: 25 December 2014 / Accepted: 7 October 2015 / Published online: 25 November 2015 Ó Springer Science+Business Media Dordrecht 2015 Abstract We are accustomed to treating aging as a Introduction set of things that go wrong with the body. But for more than twenty years, there has been accumulating Reasons to believe that aging derives evidence that much of the process takes place under from a genetic program genetic control. We have seen that signaling chemistry can make dramatic differences in life span, and that Since the pioneering work of Medawar (1952) and single molecules can significantly affect longevity. Williams (1957), it has become customary to under- We are frequently confronted with puzzling choices stand the phenotypes of aging as failures of home- the body makes which benefit neither present health ostasis in the body. Where the body has clearly made nor fertility nor long-term survival. -
Epigenetic Aging Is Accelerated in Alcohol Use Disorder and Regulated by Genetic Variation in APOL2
www.nature.com/npp ARTICLE OPEN Epigenetic aging is accelerated in alcohol use disorder and regulated by genetic variation in APOL2 Audrey Luo1, Jeesun Jung1, Martha Longley1, Daniel B. Rosoff1, Katrin Charlet1,2, Christine Muench 1, Jisoo Lee1, Colin A. Hodgkinson3, David Goldman3, Steve Horvath4,5, Zachary A. Kaminsky6 and Falk W. Lohoff1 To investigate the potential role of alcohol use disorder (AUD) in aging processes, we employed Levine’s epigenetic clock (DNAm PhenoAge) to estimate DNA methylation age in 331 individuals with AUD and 201 healthy controls (HC). We evaluated the effects of heavy, chronic alcohol consumption on epigenetic age acceleration (EAA) using clinical biomarkers, including liver function test enzymes (LFTs) and clinical measures. To characterize potential underlying genetic variation contributing to EAA in AUD, we performed genome-wide association studies (GWAS) on EAA, including pathway analyses. We followed up on relevant top findings with in silico expression quantitative trait loci (eQTL) analyses for biological function using the BRAINEAC database. There was a 2.22-year age acceleration in AUD compared to controls after adjusting for gender and blood cell composition (p = 1.85 × 10−5). This association remained significant after adjusting for race, body mass index, and smoking status (1.38 years, p = 0.02). Secondary analyses showed more pronounced EAA in individuals with more severe AUD-associated phenotypes, including elevated gamma- glutamyl transferase (GGT) and alanine aminotransferase (ALT), and higher number of heavy drinking days (all ps < 0.05). The genome-wide meta-analysis of EAA in AUD revealed a significant single nucleotide polymorphism (SNP), rs916264 (p = 5.43 × 10−8), in apolipoprotein L2 (APOL2) at the genome-wide level. -
Living to 100”
The Likelihood and Consequences of “Living to 100” Leonard Hayflick, Ph.D. Professor of Anatomy, Department of Anatomy University of California, San Francisco, School of Medicine Phone: (707) 785-3181 Fax: (707) 785-3809 Email: [email protected] Presented at the Living to 100 Symposium Orlando, Fla. January 5-7, 2011 Copyright 2011 by the Society of Actuaries. All rights reserved by the Society of Actuaries. Permission is granted to make brief excerpts for a published review. Permission is also granted to make limited numbers of copies of items in this monograph for personal, internal, classroom or other instructional use, on condition that the foregoing copyright notice is used so as to give reasonable notice of the Society’s copyright. This consent for free limited copying without prior consent of the Society does not extend to making copies for general distribution, for advertising or promotional purposes, for inclusion in new collective works or for resale. Abstract There is a common belief that it would be a universal good to discover how to slow or stop the aging process in humans. It guides the research of many biogerontologists, the course of some health policy leaders and the hopes of a substantial fraction of humanity. Yet, the outcome of achieving this goal is rarely addressed despite the fact that it would have profound consequences that would affect virtually every human institution. In this essay, I discuss the impact on human life if a means were found to slow our aging process, thus permitting a life expectancy suggested by the title of this conference, “Living to 100.” It is my belief that most of the consequences would not benefit either the individual or society. -
Epigenetic Clocks Reveal a Rejuvenation Event During
bioRxiv preprint doi: https://doi.org/10.1101/2021.03.11.435028; this version posted March 12, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging Csaba Kerepesi, Bohan Zhang, Sang-Goo Lee, Alexandre Trapp, Vadim N. Gladyshev* Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA * Correspondence: [email protected] The notion that germline cells do not age goes back to the 19th century ideas of August Weismann. However, being in a metabolically active state, they accumulate damage and other age-related changes over time, i.e., they age. For new life to begin in the same young state, they must be rejuvenated in the offspring. Here, we developed a new multi-tissue epigenetic clock and applied it, together with other aging clocks, to track changes in biological age during mouse and human prenatal development. This analysis revealed a significant decrease in biological age, i.e. rejuvenation, during early stages of embryogenesis, followed by an increase in later stages. We further found that pluripotent stem cells do not age even after extensive passaging and that the examined epigenetic age dynamics is conserved across species. Overall, this study uncovers a natural rejuvenation event during embryogenesis and suggests that the minimal biological age (the ground zero) marks the beginning of organismal aging. -
51. Increased Epigenetic Age in Normal Breast Tissue from Luminal
Hofstatter et al. Clinical Epigenetics (2018) 10:112 https://doi.org/10.1186/s13148-018-0534-8 RESEARCH Open Access Increased epigenetic age in normal breast tissue from luminal breast cancer patients Erin W. Hofstatter1*† , Steve Horvath2,3†, Disha Dalela4, Piyush Gupta5, Anees B. Chagpar6, Vikram B. Wali1, Veerle Bossuyt7, Anna Maria Storniolo8, Christos Hatzis1, Gauri Patwardhan1, Marie-Kristin Von Wahlde1,9, Meghan Butler4, Lianne Epstein1, Karen Stavris4, Tracy Sturrock4, Alexander Au4,10, Stephanie Kwei4 and Lajos Pusztai1 Abstract Background: Age is one of the most important risk factors for developing breast cancer. However, age-related changes in normal breast tissue that potentially lead to breast cancer are incompletely understood. Quantifying tissue-level DNA methylation can contribute to understanding these processes. We hypothesized that occurrence of breast cancer should be associated with an acceleration of epigenetic aging in normal breast tissue. Results: Ninety-six normal breast tissue samples were obtained from 88 subjects (breast cancer = 35 subjects/40 samples, unaffected = 53 subjects/53 samples). Normal tissue samples from breast cancer patients were obtained from distant non-tumor sites of primary mastectomy specimens, while samples from unaffected women were obtained from the Komen Tissue Bank (n = 25) and from non-cancer-related breast surgery specimens (n = 28). Patients were further stratified into four cohorts: age < 50 years with and without breast cancer and age ≥ 50 with and without breast cancer. The Illumina HumanMethylation450k BeadChip microarray was used to generate methylation profiles from extracted DNA samples. Data was analyzed using the “Epigenetic Clock,” a published biomarker of aging based on a defined set of 353 CpGs in the human genome. -
Nebraska's 37 Supercentenarians Validated Among World's Longest-Lived
Nebraska’s 37 Supercentenarians Validated Among World’s Longest-Lived by E. A. Kral Updated Oct. 3, 2018 Since publication of the author's 44-page supplement "Nebraska's Centenarians Age 107 Or Above--1867 to 2001" in the April 24, 2002, Crete News and follow-up article on the state's supercentenarians published in the October 2, 2002, Crete News, more longevity claims have been validated for persons who have Nebraska connections by birth or by residence and have reached age 110 or above. For validation of longevity claims, three records are usually needed from the first 20 years of a person's life, including such sources as birth registration, baptismal record, census data, or marriage certificate. The author was able to validate--with assistance from Gerontology Research Group scholars and volunteers--all the individual supercentenarian reports that follow, along with a brief summary for each. Clara Herling Huhn (1887-2000) Born near Clarkson, Colfax County, she died at La Mesa, California at the age of 113 years and 327 days. She lived the first 51 years of her life in Colfax County, and is the longest-lived Nebraska native. To date, she is the oldest person in Nebraska history, and as of March 2012, she ranked among the top 100 oldest persons in world history, according to Gerontology Research Group based in Los Angeles. Ella Winkelmann Schuler (1897 - 2011) Born near Fontanelle, Washington County, Nebraska, she died at Topeka, Kansas at the age of 113 years and 244 days. She moved to Hooper, Dodge County in 1917, where she was married in 1923, then lived near Denver, Colorado and Page City, Thomas County, Kansas until 1934, when she relocated to Topeka. -
Castration Delays Epigenetic Aging and Feminizes DNA
RESEARCH ARTICLE Castration delays epigenetic aging and feminizes DNA methylation at androgen- regulated loci Victoria J Sugrue1, Joseph Alan Zoller2, Pritika Narayan3, Ake T Lu4, Oscar J Ortega-Recalde1, Matthew J Grant3, C Simon Bawden5, Skye R Rudiger5, Amin Haghani4, Donna M Bond1, Reuben R Hore6, Michael Garratt1, Karen E Sears7, Nan Wang8, Xiangdong William Yang8,9, Russell G Snell3, Timothy A Hore1†*, Steve Horvath4†* 1Department of Anatomy, University of Otago, Dunedin, New Zealand; 2Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, United States; 3Applied Translational Genetics Group, School of Biological Sciences, Centre for Brain Research, The University of Auckland, Auckland, New Zealand; 4Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; 5Livestock and Farming Systems, South Australian Research and Development Institute, Roseworthy, Australia; 6Blackstone Hill Station, Becks, RD2, Omakau, New Zealand; 7Department of Ecology and Evolutionary Biology, UCLA, Los Angeles, United States; 8Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, United States; 9Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, United States *For correspondence: Abstract In mammals, females generally live longer than males. Nevertheless, the mechanisms [email protected] (TAH); underpinning sex-dependent longevity are currently unclear. Epigenetic clocks are powerful [email protected] (SH) biological biomarkers capable of precisely estimating chronological age and identifying novel †These authors contributed factors influencing the aging rate using only DNA methylation data. In this study, we developed the equally to this work first epigenetic clock for domesticated sheep (Ovis aries), which can predict chronological age with a median absolute error of 5.1 months. -
Preliminary Autopsy Findings of Mr. George H. Johnson, 112 Yo Male
“Extreme Longevity: Secrets on the Oldest Old” by L. Stephen Coles, M.D., Ph.D., Director Supercentenarian Research Foundation UCLA Molecular Biology Institute 817 Levering Avenue, Suite 8 Los Angeles, CA 90024-2767; USA E-mails: [email protected]; [email protected]; URLs: www.grg.org; www.supercentenarian-research-foundation.org; Wednesday, June 8, 2011; [2:00 – 2:30] PM CDT OECD Conference Melia Reforma Hotel; Mexico City, DF; MEXICO June 8, 2011 Supercentenarians Slide 1. Blind Men Touching the Elephant Aging/Senescence – Energy (photons from the sun) Sexual Reproduction vs. Damage Repair (Reboot OS: “No babies are born old”) Nature‟s Objective Function: Minimize Species Extinction within an ecosystem s.t. Environmental Constraints (Entropy) (Antagonistic Pleiotropy)(Recessive/Dominant Genes) June 8, 2011 Supercentenarians Slide 2. Blind Men Theories of Aging • Evolutionary Theory -- Disposable Soma[Tom Kirkwood]/ Immortality of the Germ Line -- Sponges/Sea Anemonies • Genomic Drift {DNA Mutations: Deletions, Insertions, Substitutions, Double-Strand Breaks}Epigenomic Drift{CH3; C2H5} • Protein Misfolding- Chaperone Failure in Rough ER; Recycling • ROS; Oxidative Stress (Collagen Crosslinking; Glycation) SOD Zn/Mn; Glutathione; Catalase {2H2O2 2H2O + O2} CR • Mitochondrial Theory [sarcopenia; frailty] • Neurological (hypothalamic clocks {circadian [diurnal]; lunar [menstruation]; puberty/menopause/andropause}) • Endocrinological [ACTH, TSH, hGH, LH, FSH,…] • Immunological {thymic involution; autoimmunity; IL-x; inflammation; interstitial pneumonia; aspiration pneumonia} • Stem-Cell Depletion [telomere erosion; deafness/blindness] Extra Cellular Matrix (ECM); Trophic Factors; Cytokines • Lipofusin Accumulation and other undigestable garbage June 8, 2011 Supercentenarians Slide 3. Metaphor with Aging: Alchemy Chemistry (Periodic Table of the Elements) Goal: Transmutation of Base Metals into Gold or Silver Science June 8, 2011 Supercentenarians Slide 4. -
Epigenetics of the Estrogen Receptors in Women Healthy Aging
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2020 Epigenetic of the Estrogen Receptors in Women Healthy Aging Gardini, Elena Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-191763 Dissertation Originally published at: Gardini, Elena. Epigenetic of the Estrogen Receptors in Women Healthy Aging. 2020, University of Zurich, Faculty of Arts. Epigenetics of the Estrogen Receptors in Women Healthy Aging Thesis (cumulative thesis) presented to the Faculty of Arts and Social Sciences of the University of Zurich for the degree of Doctor of Philosophy by Elena Silvia Gardini Accepted in the fall semester 2020 on the recommendation of the doctoral committee composed of Prof. Dr. Ulrike Ehlert (main supervisor) Prof. Dr. Marta Manser Zurich, 2020 Table of Contents Acknowledgements .......................................................................................................... 6 Summary .......................................................................................................................... 7 Zusammenfassung ............................................................................................................ 8 Abbreviations ................................................................................................................. 10 1. General Introduction .................................................................................................. 11 1.1 Women healthy