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A Review and Appraisal of the DNA Damage Theory of Ageing
Mutation Research 728 (2011) 12–22 Contents lists available at ScienceDirect Mutation Research/Reviews in Mutation Research jo urnal homepage: www.elsevier.com/locate/reviewsmr Co mmunity address: www.elsevier.com/locate/mutres Review A review and appraisal of the DNA damage theory of ageing a,b a, Alex A. Freitas , Joa˜o Pedro de Magalha˜es * a Integrative Genomics of Ageing Group, Institute of Integrative Biology, University of Liverpool, Biosciences Building, Crown Street, Liverpool, L69 7ZB, UK b School of Computing and Centre for BioMedical Informatics, University of Kent, Canterbury, CT2 7NF, UK A R T I C L E I N F O A B S T R A C T Article history: Given the central role of DNA in life, and how ageing can be seen as the gradual and irreversible Received 10 February 2011 breakdown of living systems, the idea that damage to the DNA is the crucial cause of ageing remains a Received in revised form 2 May 2011 powerful one. DNA damage and mutations of different types clearly accumulate with age in mammalian Accepted 3 May 2011 tissues. Human progeroid syndromes resulting in what appears to be accelerated ageing have been Available online 10 May 2011 linked to defects in DNA repair or processing, suggesting that elevated levels of DNA damage can accelerate physiological decline and the development of age-related diseases not limited to cancer. Keywords: Higher DNA damage may trigger cellular signalling pathways, such as apoptosis, that result in a faster Ageing depletion of stem cells, which in turn contributes to accelerated ageing. -
Human Cell and Organism Aging: Are There Limits? Interrupted Case Study on Cell Aging
Human Cell and Organism Aging: Are there Limits? Interrupted Case study on Cell Aging Teresa Gonya Department of Biological Sciences University of Wisconsin-Fox Valley Menasha, WI The search for the fountain of youth persists in advertising, and individuals are constantly bombarded with messages about diet, exercise, vitamins and minerals that can help prolong one’s life. The biological basis of aging is often not mentioned in the anti-aging promotions. Is it possible that a diet rich in protein, or fruits and vegetables can add years to your life? Is it possible that a vitamin or mineral ‘tonic’ can promote tissue repair and extend life? Is it possible that a vitamin drink can extend your normal life expectancy? Even clinical medicine focuses on developing new treatments that are based on preventing aging and maintaining organ longevity. We are told to exercise to keep our heart healthy and to stop smoking to prevent damage to body tissues, especially the lungs and blood vessels. The new field of regenerative medicine is based on the premise that stem cells may one day be able to repair tissue and return function to damaged organs. There are real limits to longevity that are based on genetics, lifestyle, medical history and sociology. (1) At the foundation of organism longevity is cell longevity. All organisms are composed of cells. Four different types of tissue cells form the basis of all organs that are found in any animal organism. Each type of tissue cell has a different ability to undergo mitosis and replace itself, should it become damaged or injured. -
From Here to Immortality: Anti-Aging Medicine
FromFrom HereHere toto Immortality:Immortaalitty: AAnti-AgingAnnntti-AAgging MMedicineedicine Anti-aging medicine is a $5 billion industry. Despite its critics, researchers are discovering that inter ventions designed to turn back time may prove to be more science than fiction. By Trudie Mitschang 14 BioSupply Trends Quarterly • October 2013 he symptoms are disturbing. Weight gain, muscle Shifting Attitudes Fuel a Booming Industry aches, fatigue and joint stiffness. Some experience The notion that aging requires treatment is based on a belief Thear ing loss and diminished eyesight. In time, both that becoming old is both undesirable and unattractive. In the memory and libido will lapse, while sagging skin and inconti - last several decades, aging has become synonymous with nence may also become problematic. It is a malady that begins dete rioration, while youth is increasingly revered and in one’s late 40 s, and currently 100 percent of baby boomers admired. Anti-aging medicine is a relatively new but thriving suffer from it. No one is immune and left untreated ; it always field driven by a baby- boomer generation fighting to preserve leads to death. A frightening new disease, virus or plague? No , its “forever young” façade. According to the market research it’s simply a fact of life , and it’s called aging. firm Global Industry Analysts, the boomer-fueled consumer The mythical fountain of youth has long been the subject of base will push the U.S. market for anti-aging products from folklore, and although it is both natural and inevitable, human about $80 billion now to more than $114 billion by 2015. -
“This Is Getting Really Old . . . ” the Genetics of Aging
“This is getting really old . ” The Genetics of Aging Prof. Mike Kuchka Department of Biological Sciences OBJECTIVES • Explain how mutations in genes can increase lifespan in various organisms (METHUSELAH gene of Drosophila) • Relate chromosome length with aging (TELOMERE SHORTENING) • Understand how alteration of intracelluar signaling pathway impacts aging (INSULIN-LIKE GROWTH FACTOR) • Relate caloric restriction with aging (Role of SIRTUIN proteins) • Describe accelerated aging disorders in humans (WERNER’S SYNDROME, HUTCHINSON-GILFORD PROGERIA) Aging – the decline in survival and fecundity with advancing age, caused by the accumulation of damage to macromolecules, intracellular organelles, cells, tissues, organs. SOME INTRODUCTORY POINTS • Natural selection does not select for genes that cause aging or determine lifespan. Rather, aging occurs as a result of the pleiotropic effects of genes that specify other processes [Christensen et al. (2006)]. • Genes that influence longevity are involved in stress response and nutrient sensing, generally, intracellular signaling pathways. • In the past century, mean life expectancy in Western countries increased from ~50 to 75 – 80. • Twin studies (human) suggest that 25% of variation in lifespan is caused by genetic differences. • Manipulation of >100 genes in experimental animal models increases longevity. • Most of these genes are also present in the human genome. • Gene manipulations that increase longevity also postpone age-related diseases. Nematode Worm (C. elegans) as a Model Experimental Organism For the Study of Aging OLD YOUNG MUTANT 2 weeks old 2 days old 2 weeks old From: Hopkin, K. (2004) Scientific American, 14: 12 – 17. Mouse (Mus musculus) as a Model Experimental Organism For the Study of Aging From: Hampton, K. -
Telomeres and Telomerase
Oncogene (2010) 29, 1561–1565 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 $32.00 www.nature.com/onc GUEST EDITORIAL 2009 Nobel Prize in Physiology or Medicine: telomeres and telomerase Oncogene (2010) 29, 1561–1565; doi:10.1038/onc.2010.15 sate for the chromosomal shortening produced asso- ciated with cell division, suggesting that progressive telomere shortening may be a key factor to limit the Elizabeth H Blackburn, Carol W Greider and Jack W number of cell divisions. James D Watson (Nobel Prize Szostak were acknowledged with this year’s Nobel Prize 1962) also recognized that the unidirectional nature of in Physiology or Medicine for their discoveries on how DNA replication was a problem for the complete copy chromosomes are protected by telomeres and the of chromosomal ends (Watson, 1972). This was called enzyme telomerase. the ‘end-replication problem’. In this manner, during In the first half of the twentieth century, classic studies each cycle of cell division, a small fragment of telomeric by Hermann Mu¨ller (Nobel Prize 1945) working with DNA is lost from the end. After several rounds of the fruit fly (Drosophila melanogaster) and by Barbara division, telomeres eventually reach a critically short McClintock (Nobel Prize 1983) studying maize (Zea length, which activates the pathways for senescence and Mays) proposed the existence of a special structure at cell death (Hermann et al., 2001; Samper et al., 2001). the chromosome ends (Mu¨ller, 1938; McClintock, 1939). Uncovering the solution to the end-replication pro- This structure would have the essential role of protect- blem took several years of intense research. -
Calorie Restriction and Sirtuins Revisited
Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Calorie restriction and sirtuins revisited Leonard Guarente1 Department of Biology, Glenn Laboratory for the Science of Aging, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA Calorie or dietary restriction (CR) has attracted attention Toward the resolution of discordances because it is the oldest and most robust way to extend rodent life span. The idea that the nutrient sensors, termed Sirtuins and aging sirtuins, might mediate effects of CR was proposed 13 years Perhaps the greatest challenge to the idea that sirtuins ago and has been challenged in the intervening years. This mediate effects of CR was a study describing the failure to review addresses these challenges and draws from a great observe extension of life span in worms or flies transgenic body of new data in the sirtuin field that shows a systematic for the corresponding SIR2 orthologs after controlling for redirection of mammalian physiology in response to diet by genetic background (Burnett et al. 2011). These findings sirtuins. The prospects for drugs that can deliver at least contradicted other, earlier studies that showed extension a subset of the benefits of CR seems very real. of life span in transgenic worms (Tissenbaum and Guarente 2001; Viswanathan et al. 2005; Berdichevsky et al. 2006) A review published previously in Genes & Development and flies (Rogina and Helfand 2004; Wood et al. 2004; (Guarente 2000) stated the hypothesis that calorie re- Bauer et al. 2009). In fact, a subset of these earlier studies striction (CR) slowed aging and the accompanying de- did control for genetic background (e.g., Bauer et al. -
“This Is Getting Really Old . . . ” the Genetics of Aging
“This is getting really old . ” The Genetics of Aging Prof. Mike Kuchka Department of Biological Sciences OBJECTIVES • Explain how mutations in genes can increase lifespan in various organisms (METHUSELAH gene of Drosophila) • Relate chromosome length with aging (TELOMERE SHORTENING) • Understand how alteration of intracellular signaling pathway impacts aging (INSULIN-LIKE GROWTH FACTOR) • Relate caloric restriction with aging (Role of SIRTUIN proteins) • Describe accelerated aging disorders in humans (WERNER’S SYNDROME, HUTCHINSON-GILFORD PROGERIA) Aging – the decline in survival and fecundity with advancing age, caused by the accumulation of damage to macromolecules, intracellular organelles, cells, tissues, organs. SOME INTRODUCTORY POINTS • Natural selection does not select for genes that cause aging or determine lifespan. Rather, aging occurs as a result of the pleiotropic effects of genes that specify other processes [Christensen et al. (2006)]. • Genes that influence longevity are involved in stress response and nutrient sensing, generally, intracellular signaling pathways. • In the past century, mean life expectancy in Western countries increased from ~50 to 75 – 80. • Twin studies (human) suggest that 25% of variation in lifespan is caused by genetic differences. • Manipulation of >100 genes in experimental animal models increases longevity. • Most of these genes are also present in the human genome. • Gene manipulations that increase longevity also postpone age-related diseases. Nematode Worm (C. elegans) as a Model Experimental Organism For the Study of Aging OLD YOUNG MUTANT 2 weeks old 2 days old 2 weeks old From: Hopkin, K. (2004) Scientific American, 14: 12 – 17. Mouse (Mus musculus) as a Model Experimental Organism For the Study of Aging From: Hampton, K. -
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. -
Longevity, Genes, and Aging: a View Provided by a Genetic Model System1
Experimental Gerontology, Vol. 34, No. 1, pp. 1–6, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0531-5565/99 $–see front matter PII S0531-5565(98)00053-9 LONGEVITY, GENES, AND AGING: A VIEW PROVIDED BY A GENETIC MODEL SYSTEM1 1 S. MICHAL JAZWINSKI Department of Biochemistry and Molecular Biology, Louisiana State University Medical Center, Box P7-2, 1901 Perdido Street, New Orleans, Louisiana 70112 Abstract—The genetic analysis of aging in the yeast Saccharomyces cerevisiae has revealed the importance of metabolic capacity, resistance to stress, integrity of gene regulation, and genetic stability for longevity. A balance between these life maintenance processes is sustained by the RAS2 gene, which channels cellular resources among them. This gene cooperates with mitochondria and PHB1 in metabolic adjustments important for longevity. It also modulates stress responses. Transcriptional silencing of heterochromatic regions of the genome is lost during aging, suggesting that gene dysregulation accompanies the aging process. There is evidence that this age change plays a causal role. Aging possesses features of a nonlinear process, and it is likely that application of nonlinear system methodology to aging will be productive. © 1999 Elsevier Science Inc. All rights reserved. Key words: metabolism, stress responses, gene dysregulation, nonlinear system INTRODUCTION IF WE WERE to design an organism, we would endow it with sufficient lifetime metabolic capacity, stress resistance, integrity of gene regulation, and genetic stability. Given a limit to the resources available, we would need to strike a balance between these processes and reproduc- tion. Genetic analysis of the aging process has confirmed the soundness of these engineering principles (Jazwinski, 1996). -
Controversy 2
Controversy 2 WHY DO OUR BODIES GROW OLD? liver Wendell Holmes (1858/1891), in his poem “The Wonderful One-Hoss Shay,” invokes a memorable image of longevity and mortality, the example of a wooden Ohorse cart or shay that was designed to be long-lasting: Have you heard of the wonderful one-hoss shay, That was built in such a logical way, It ran a hundred years to a day . ? This wonderful “one-hoss shay,” we learn, was carefully built so that every part of it “aged” at the same rate and didn’t wear out until the whole thing fell apart all at once. Exactly a century after the carriage was produced, the village parson was driving this marvelous machine down the street, when What do you think the parson found, When he got up and stared around? The poor old chaise in a heap or mound, As if it had been to the mill and ground! You see, of course, if you’re not a dunce, How it went to pieces all at once, All at once, and nothing first, Just as bubbles do when they burst. The wonderful one-horse shay is the perfect image of an optimistic hope about aging: a long, healthy existence followed by an abrupt end of life, with no decline. The one-horse shay image also suggests that life has a built-in “warranty expiration” date. But where does this limit on longevity come from? Is it possible to extend life beyond what we know? The living organism with the longest individual life span is the bristlecone pine tree found in California, more than 4,500 years old, with no end in sight. -
Skeletal Muscle in Aged Mice Reveals Extensive Transformation of Muscle
Lin et al. BMC Genetics (2018) 19:55 https://doi.org/10.1186/s12863-018-0660-5 RESEARCHARTICLE Open Access Skeletal muscle in aged mice reveals extensive transformation of muscle gene expression I-Hsuan Lin1†, Junn-Liang Chang3†, Kate Hua1, Wan-Chen Huang4, Ming-Ta Hsu2 and Yi-Fan Chen4* Abstract Background: Aging leads to decreased skeletal muscle function in mammals and is associated with a progressive loss of muscle mass, quality and strength. Age-related muscle loss (sarcopenia) is an important health problem associated with the aged population. Results: We investigated the alteration of genome-wide transcription in mouse skeletal muscle tissue (rectus femoris muscle) during aging using a high-throughput sequencing technique. Analysis revealed significant transcriptional changes between skeletal muscles of mice at 3 (young group) and 24 (old group) months of age. Specifically, genes associated with energy metabolism, cell proliferation, muscle myosin isoforms, as well as immune functions were found to be altered. We observed several interesting gene expression changes in the elderly, many of which have not been reported before. Conclusions: Those data expand our understanding of the various compensatory mechanisms that can occur with age, and further will assist in the development of methods to prevent and attenuate adverse outcomes of aging. Keywords: Aging, Skeletal muscle, Cardiac-related genes, RNA sequencing analysis, Muscle fibers, Defects on differentiation Background SIRT1 reduces the oxidative stress and inflammation Aging is a process whereby various changes were accu- associated with ameliorating diseases, such as vascular mulated over time, resulting in dysfunction in mole- endothelial disorders, neurodegenerative diseases, as cules, cells, tissues and organs. -
Longevidad Y Envejecimiento En El Tercer Milenio: Nuevas Perspectivas
LONGEVIDAD Y ENVEJECIMIENTO EN EL TERCER MILENIO: NUEVAS PERSPECTIVAS JOSÉ MIGUEL RODRÍGUEZ-PARDO DEL CASTILLO ANTONIO LÓPEZ FARRÉ LONGEVIDAD Y ENVEJECIMIENTO EN EL TERCER MILENIO: NUEVAS PERSPECTIVAS José Miguel Rodríguez-Pardo del Castillo Profesor del Máster en Ciencias Actuariales y Financieras Universidad Carlos III, Madrid Antonio López Farré Profesor de la Facultad de Medicina. Departamento de Medicina. Codirector del Aula AINTEC Universidad Complutense de Madrid Fundación MAPFRE no se hace responsable del contenido de esta obra, ni el hecho de publicarla implica conformidad o identificación con las opiniones vertidas en ella. Reservados todos los derechos. Está prohibido reproducir o transmitir esta publicación, total o parcialmente, por cualquier medio, sin la autorización expresa de los editores, bajo las sanciones establecidas en las leyes. Imágenes de cubierta e interiores: ThinkStock Maquetación e impresión: Edipack Gráfico © De los textos: sus autores © De esta edición: 2017, Fundación MAPFRE Paseo de Recoletos, 23 28004 Madrid www.fundacionmapfre.org ISBN: 978-84-9844-648-7 Depósito Legal: M-18221-2017 «Los hombres son como los vinos: la edad agria los malos y mejora los buenos». Marco Tulio Cicerón «Solo la alegría es señal de salud y longevidad». Santiago Ramón y Cajal «No anheléis la inmortalidad, pero agotad el límite de lo posible». Píndaro Agradecimiento: Los autores quieren agradecer a Begoña Larrea Cruz su excelente y dedicada labor en la edición de esta obra, sin cuya ayuda no hubiera sido nunca finalizada. PRESENTACIÓN Desde 1975 Fundación MAPFRE desarrolla actividades de interés general para la sociedad en distintos ámbitos profesionales y culturales, así como ac- ciones destinadas a la mejora de las condiciones económicas y sociales de las personas y de los sectores menos favorecidos de la sociedad.