Cover
Title page
Copyright page
Contributors
Preface
1 The Demography of Aging
1. 1.1 Introduction
2. 1.2 Demographic trends
3. 1.3 Impact of aging
4. 1.4 Policy responses
5. 1.5 Conclusion
6. References
2 The Omics of Aging: Insights from Genomes upon Stress
1. 2.1 Introduction
2. 2.2 Safeguarding the nuclear genome
3. 2.3 NER progerias and their connection to lifespan regulatory mechanisms
4. 2.4 Triggering a survival response in the absence of a DNA repair defect
5. 2.5 The omics connection between progeria and longevity
6. 2.6 Triggering of systemic versus cell-autonomous features of the survival response
7. 2.7 The omics connection between NER progeria, transcription, and longevity
8. 2.8 Future perspectives
9. References
3 Protein Quality Control Coming of Age
1. 3.1 Introduction
2. 3.2 The aging molecular chaperone network
3. 3.3 Protein degradation pathways in aging
4. 3.4 Compartment-specific protein quality control
5. 3.5 Conclusion
6. References
4 Telomerase Function in Aging
1. 4.1 Telomeres
2. 4.2 Telomerase
3. 4.3 Telomeres and human disease
4. 4.4 Telomeres biology, aging, and longevity
5. 4.5 Conclusion
6. References
5 The Cellular Senescence Program
1. 5.1 Cellular senescence and evidence of senescence in a cell
2. 5.2 Conditions associated with cellular senescence
3. 5.3 Mechanisms/pathways of senescence induction
4. 5.4 Cellular senescence in aging and age-related diseases of the lungs
5. 5.5 Conclusion
6. References
6 Signaling Networks Controlling Cellular Senescence
1. 6.1 Introduction
2. 6.2 Classification of cellular senescence
3. 6.3 Cross talk of signaling pathways
4. 6.4 Conclusion
5. References
7 Immune Senescence
1. 7.1 Introduction
2. 7.2 Barrier defenses and innate immunity in older adults
3. 7.3 Adaptive immune responses
4. 7.4 Consequences of immune senescence
5. 7.5 Conclusion
6. References
8 Developmental and Physiological Aging of the Lung
1. 8.1 Introduction
2. 8.2 The aging lung
3. 8.3 An animal model of the aging lung: The rat
4. 8.4 Conclusion
5. Acknowledgments
6. References
9 Mouse Models to Explore the Aging Lung
1. 9.1 Pulmonary changes during aging
2. 9.2 Key findings from mouse models of aging
3. 9.3 Age is a risk factor for obstructive pulmonary diseases
4. 9.4 Challenges ahead
5. 9.5 Conclusion
6. Acknowledgments
7. References
10 Evidence for Premature Lung Aging of the Injured Neonatal Lung as Exemplified by Bronchopulmonary Dysplasia
1. 10.1 Introducing bronchopulmonary dysplasia
2. 10.2 Altered pulmonary function in infants with BPD
3. 10.3 Response to injury
4. 10.4 Prenatal and genetic predisposition
5. 10.5 Conclusion
6. References
11 Remodeling of the Extracellular Matrix in the Aging Lung
1. 11.1 Introduction
2. 11.2 The aging lung
3. 11.3 Activation of tissue remodeling in the senescent lung
4. 11.4 The aging lung fibroblast
5. 11.5 Potential role of oxidant stress in triggering remodeling in the aging lung
6. 11.6 Implications for remodeling of the lung extracellular matrix in the aged lung
7. 11.7 Conclusions
8. Acknowledgments
9. References
12 Aging Mesenchymal Stem Cellsin Lung Disease
1. 12.1 Aging and lung diseases
2. 12.2 Mesenchymal stem cells (MSCs)
3. 12.3 Impact of aging on mesenchymal stem cells
4. 12.4 B-MSCs in disease
5. 12.5 B-MSCs in therapy
6. 12.6 Conclusion
7. Acknowledgments
8. References
13 COPD as a Disease of Premature Aging
1. 13.1 Introduction
2. 13.2 Senescent cells contribute to the pathogenesis of COPD
3. 13.3 Lung dysfunction and the general process of premature aging in COPD
4. 13.4 Conclusion
5. References
14 Lung Infections and Aging
1. 14.1 Introduction
2. 14.2 Aging and immunosenescence
3. 14.3 Inflamm-aging and susceptibility to infection
4. 14.4 Respiratory infection and regulation of host responses
5. 14.5 Preventing respiratory infection
6. 14.6 Summary and conclusions
7. References
Index
Eula

List of Tables

Chapter 08
1. Table 8.1 Age-related structural changes in the chest wall, diaphragm, and lung.
2. Table 8.2 Physiological changes in lung function in the elderly. Adapted from Green and Pinkerton (2004) and Sharma and Goodwin (2006).
3. Table 8.3 Changes in bronchoalveolar lavage fluid in healthy aged individuals. Adapted from Meyer (2001) and Green and Pinkerton (2004).
4. Table 8.4 Volume density of epithelial cell of tracheobronchial airways of male Fischer 344 rats.
5. Table 8.5 Alveolar tissue volumes (cm3/both lungs) in the aging Fischer 344 rats. Adapted from Pinkerton et al. (1982).
6. Table 8.6 Morphometric characteristics of the major parenchymal cells in the aging Fisher 344 rats. Adapted from Pinkerton et al. (1982).
Chapter 09
1. Table 9.1 List of genetically modified mice that could be used to establish age-dependent cellular and molecular changes and pathogenesis of age-associated pulmonary diseases.
2. Table 9.2 Factors to be considered while selecting mice for studying aging lung.
Chapter 12
1. Table 12.1 Age-related molecular changes in B-MSCs.
Chapter 14
1. Table 14.1 Age-associated changes that may increase susceptibility of the elderly to lung infections and dysregulated inflammatory responses.

List of Illustrations

Chapter 01
1. Figure 1.1 Increasing share of 60+ and 80+ population.
Chapter 02
1. Figure 2.1 Programmed and stochastic events during aging. Stochastic macromolecular damage drives the functional decline with advancing age; however, evolutionarily conserved mechanisms may promote longevity by counteracting damage through, for example, DNA repair pathways or setting the pace on how rapidly damage builds up and function is lost through, for example, the regulation of hormonal pathways and antioxidant responses.
2. Figure 2.2 Components and instigators of the survival response in mammals. (a) The survival response represents a preservative metabolic strategy that aims at removing free radicals, toxins, damaged organelles, and membranes; delays age-related genomic decay and in the meantime suppresses growth and reproduction; and decreases inflammatory responses. In mammals, the various components of this conserved response result in smaller body size, delayed puberty, and decreased reproduction. (b) Shown are the major instigators that are presently known to trigger a generalized evolutionary survival strategy against a multitude of adverse physiological threats. However, there might be more cues involved in triggering the battery of physiological responses favoring longevity.
Chapter 03
1. Figure 3.1 Imbalanced proteostasis upon aging. While the proteostasis network is well balanced in young cells due to proper chaperone-mediated protein refolding or protein degradation via the autophagosome or proteasome pathways, this balance is tipped in favor of protein damage and proteotoxic protein aggregation in aging cells due to impaired chaperone networks and protein degradation pathways.
Chapter 04
1. Figure 4.1 (a) Telomeres are ribonucleoprotein structures at the ends of linear chromosomes and can be detected by fluorescence in situ hybridization (FISH, yellow bright signals) and the extremities of each chromatide of the chromosomes (blue structures) during metaphase. (b) Schematically, telomeres are composed of hundreds to thousands of TTAGGG hexameric DNA repeats coated by specialized proteins collectively termed shelterin, forming a lariat at the very end of the molecule (T-loop). (c) Telomeres shorten with human aging. The graphic represents the lengths of telomeres of peripheral blood leukocytes from birth to 100 years in healthy volunteers. Telomeres are measured in kilobases (kb) and each circle represents one individual.
2. Figure 4.2 The telomerase holoenzyme is composed of the catalytic unit, TERT, its RNA component (TERC) that serves as a template for telomere elongation, and associated proteins (dyskerin, GAR, NOP10, and NHP2). The complex attaches to the 3´ end of the telomeric DNA and adds hexameric repeats. The inset shows a method to evaluate telomerase activity. Telomerase enzymatic activity may be measured in vitro by PCR amplification of telomerase products that are run in a gel. Each band represents the telomerase product and is separated by six nucleotides.
Chapter 06
1. Figure 6.1 Signaling networks regulating cellular senescence. Senescence programs may be triggered by intrinsic or extrinsic mechanisms that converge on downstream signaling cascades that mediate stable cellular growth arrest. ARF, protein that is transcribed from an alternate reading frame of the INK4a/ARF locus; Cyc E, cyclin E; Cdk 2, cyclin-dependent kinase 2; Cyc D: cyclin D; Cdk4,6, cyclin-dependent kinase 4 and 6; miRNA, microRNA; p16-INK4A, a cell cycle regulatory protein that is encoded by the CDKN2a gene; p19-ARF (mouse) or the human equivalent p14-ARF, alternative products of the CDKN2a gene; pRb, retinoblastoma protein.
Chapter 07
1. Figure 7.1 Alterations of innate immunity in the aged. Reprinted from Ref. [10] with permission from Elsevier.
2. Figure 7.2 Age-dependent decline in thymic output (measured as TCR excision circles (TRECs)) (a) and TCR β-chain diversity in naïve (b) and memory (c) CD4+ T cells in different age groups. With permission from Ref. [31]. Copyright 2005, The American Association of Immunologists, Inc.
Chapter 08
1. Figure 8.1 Total air space volume (cm3) in the glutaraldehyde-fixed lungs of male and female Fischer 344 rats. Each point represents the mean (±SD) of four animals. Asterisks indicate significant changes between consecutive age groups (p < 0.05). (Reproduced with permission from [69].)
Chapter 10
1. Figure 10.1 Summary of mechanisms that mediate characteristic changes to the neonatal lung following injury and a brief overview of the possible consequences.
Chapter 11
1. Figure 11.1 Hypothetical impact of transitional remodeling to tissue repair after injury. The young lung, with its natural extracellular matrix composition, is capable of repair after injury, leading to reestablishment of the original lung architecture and function after an insult, A (adaptive repair). However, severe and/or long-lasting insults may lead to permanent damage, B. During aging, the senescent lung undergoes transitional remodeling that alters the relative composition of the extracellular matrix, C. This does not have significant implications for lung structure and function at baseline. However, since lung resident and incoming cells interact with matrices through integrins and other receptors, these cells recognize this new matrix and, in response, engage in exuberant repair responses after an insult, leading to maladaptive repair and permanent tissue damage, D.
2. Figure 11.2 Extracellular matrix remodeling in senescent lungs. It is speculated that oxidant stress and chronic inflammation trigger the expression of growth factors and other mediators capable of activating tissue remodeling in the senescent lung. This results in altered phenotype in lung fibroblasts and perhaps other cells as well as increased expression and degradation of matrix proteins, leading to changes in the relative composition of the extracellular matrix. At baseline, this transitional remodeling may not cause major changes to tissue function. However, they may render the host susceptible to disrepair after injury, leading to permanent tissue damage.
Chapter 12
1. Figure 12.1 Comparison of the mechanisms of response in young and aged individuals. In the normal alveolus (left), there is normal fluid movement from the vascular to the interstitial space, with normal architecture of the epithelium and the endothelium, and production of surfactant. The panel in the middle shows an injured alveolus. Injury activates macrophages, which secrete a battery of proinflammatory cytokines and chemokines that leak into the bloodstream. Among these cytokines, IL-8 is responsible for the recruitment of neutrophils into the injured alveolus. ROS and proteases released by the activated neutrophils damage the alveolar epithelium and endothelium, and as a result, there is an increase in the permeability and in the influx of protein-rich edema. Another characteristic during injury is the increased levels of surfactant protein D by type II alveolar epithelial cells. The top right panel shows the representation of a restored alveolus including recruitment of healthy B-MSC. MSCs themselves produce and stimulate the production of IL-10 by macrophages, which attenuates their inflammatory cascade. The secretion of angiopoietin 1 and the transfer of mitochondria to the epithelial cells by B-MSC together with the production of KGF contribute to restoring the epithelium and endothelium. This results in improved alveolar fluid clearance and decreased permeability. The bottom right panel shows a defective senescent B-MSC with a decrease in their ability to respond to activation and mobilization, resulting in lung disrepair and fibrosis.
Chapter 13
1. Figure 13.1 Diagram illustrating potential mechanisms linking cell senescence and development of lung alterations at the origin of COPD and systemic manifestations of the disease.

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Library of Congress Cataloging-in-Publication Data

Molecular aspects of aging : understanding lung aging / edited by Mauricio Rojas, Silke Meiners,
Claude Jourdan Le Saux.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-118-39624-7 (cloth)
I. Rojas, Mauricio, 1963- editor of compilation. II. Meiners, Silke, editor of compilation.
III. Le Saux, Claude Jourdan, editor of compilation.
[DNLM: 1. Aging–physiology. 2. Lung–physiology. 3. Age Factors. 4. Lung Diseases–metabolism.
5. Lung Diseases–physiopathology. WF 600]
QP1837.3.A34
612.6′7–dc23

2014000056

Serge Adnot
INSERM U955 and Département
de Physiologie-Explorations
Fonctionnelles, Hôpital Henri Mondor,
Université Paris Est, Paris, France

David E. Bloom
Department of Global Health and
Population, Harvard School of Public
Health, Boston, Massachusetts, USA

Jorge Boczkowski
INSERM U955 and Département de
Physiologie-Explorations Fonctionnelles,
Hôpital Henri Mondor, Université Paris Est,
Paris, France

Laurent Boyer
INSERM U955 and Département de
Physiologie-Explorations Fonctionnelles,
Hôpital Henri Mondor, Université
Paris Est, Paris, France

Rodrigo T. Calado
University of São Paulo at Ribeirão,
Preto Medical School, São Paulo, Brazil

Leena P. Desai
Division of Pulmonary, Allergy, and
Critical Care Medicine, Department
of Medicine, University of Alabama
Birmingham, Birmingham,
Alabama, USA

Deepak A. Deshpande
Pulmonary and Critical Care Medicine
Division, University of Maryland
School of Medicine, Baltimore,
Maryland, USA

George A. Garinis
Institute of Molecular Biology and
Biotechnology, Foundation for Research
and Technology-Hellas and Department of
Biology, University of Crete, Crete, Greece

Francis H.Y. Green
University of Calgary, Calgary, Alberta, Canada

Kevin P. High
Section on Infectious Diseases, Wake
Forest School of Medicine, Winston-Salem,
North Carolina, USA

Anne Hilgendorff
Comprehensive Pneumology Center (CPC),
University Hospital, Ludwig-Maximilians
University, Helmholtz Zentrum München;
Member of the German Center for Lung
Research (DZL); Dr. von Haunersches
Children’s Hospital, Munich, Germany

Anna Ioannidou
Institute of Molecular Biology and
Biotechnology, Foundation for Research
and Technology-Hellas and Department of
Biology, University of Crete, Crete, Greece

Maria G. Kapetanaki
Dorothy P. and Richard P. Simmons Center
for Interstitial Lung Diseases, Division of
Pulmonary, Allergy and Critical Care
Medicine, University of Pittsburgh School
of Medicine, Pittsburgh, Pennsylvania, USA

Ismene Karakasilioti
Institute of Molecular Biology and
Biotechnology, Foundation for Research
and Technology-Hellas and Department of
Biology, University of Crete, Crete, Greece

Jacqueline M. Kruser
Department of Medicine, University of
Wisconsin School of Medicine and Public
Health, Madison, Wisconsin, USA

Claude Jourdan Le Saux
University of Texas Health Science Center,
Division of Cardiology and Pulmonary and
Critical Care, San Antonio, Texas, USA

Silke Meiners
Comprehensive Pneumology Center (CPC),
University Hospital, Ludwig-Maximilians-
University, Helmholtz Zentrum München;
Member of the German Center for Lung
Research (DZL), Munich, Germany

Keith C. Meyer
Department of Medicine, University of
Wisconsin School of Medicine and Public
Health, Madison, Wisconsin, USA

Ana L. Mora
Division of Pulmonary, Allergy and Critical
Care Medicine, University of Pittsburgh
School of Medicine, Pittsburgh,
Pennsylvania, USA

Kent E. Pinkerton
Center for Health and the Environment,
University of California Davis,
Davis, California, USA

Mauricio Rojas
Dorothy P. and Richard P. Simmons Center
for Interstitial Lung Diseases; Division of
Pulmonary, Allergy and Critical Care
Medicine; McGowan Institute for
Regenerative Medicine, University of
Pittsburgh School of Medicine, Pittsburgh,
Pennsylvania, USA

Jesse Roman
Department of Medicine, Division of
Pulmonary, Critical Care and Sleep
Disorders, Department of Pharmacology &
Toxicology, Robley Rex Veterans
Affairs Medical Center and University
of Louisville, Kentucky, USA

Yan Y. Sanders
Division of Pulmonary, Allergy, and
Critical Care Medicine, Department of
Medicine, University of Alabama
Birmingham, Birmingham, Alabama, USA

Sinead Shannon
Department of Health and Children,
Dublin, Ireland

Pooja Shivshankar
University of Texas Health Science Center,
Division of Cardiology and Pulmonary and
Critical Care, San Antonio, Texas, USA

Suzette M. Smiley-Jewell
Center for Health and the Environment,
University of California Davis,
Davis, California, USA

Victor J. Thannickal
Division of Pulmonary, Allergy, and
Critical Care Medicine, Department of
Medicine, University of Alabama
Birmingham, Birmingham, Alabama, USA

Lei Wang
Center for Health and the Environment,
University of California Davis,
Davis, California, USA

Mingyi Wang
Intramural Research Program, National
Institute on Aging, Baltimore, Maryland,
USA

Jingyi Xu
Center for Health and the Environment,
University of California Davis,
Davis, California, USA; Affiliated
Zhongshon Hospital of Dalian
University, Dalian, China

Preface

Aging is the inevitable fate of life. It is a natural process characterized by progressive functional impairment and reduced capacity to respond adaptively to environmental stimuli. The aging process, among other factors, determines the life span of an organism, whereas age-associated abnormalities account for the health status of a given individual. Aging is associated with increased susceptibility to a variety of chronic diseases, including type 2 diabetes mellitus, cancer, and neurological diseases. Lung pathologies are no exception, and the incidence and prevalence of chronic lung diseases has been found to increase considerably with age.

Aging has various faces, and most importantly, it has no purpose. Age-related pathologies are believed to result from the accumulation of molecular and cellular damage that cannot be repaired by aged cells due to limited performance of somatic maintenance and repair mechanisms. Two major hypotheses provide a conceptual framework for aging. According to the antagonistic pleiotropy hypothesis by Williams (Evolution, 1957), natural selection favors genes that are beneficial early in life for the cost that they may promote aging later in life. The disposable soma theory put forward by Kirkwood (Nature, 1977) proposes that the organism optimally allocates its metabolic resources, chiefly energy, to maximize reproduction, fitness, and survival. This comes at the cost of limited resources for somatic maintenance and repair causing accumulation of molecular and cellular damage. This concept supports the observation that the aging process is stochastic in nature and that there is individual plasticity.

The objectives of this book are to increase our awareness and knowledge of the physiological and accelerated mechanisms of the aging lungs given the expected increase in the aging population in the coming years. We would like to stimulate research on the molecular aspects of lung aging by combining chapters on the general hallmarks of aging with chapters on how to analyze lung aging by experimental approaches and chapters on the molecular and clinical knowledge on physiological and premature aging in lung disease.

As outlined in Chapter 1, the aging population will be more and more vulnerable to developing pathological conditions due to age-associated morbidities. Chapters 2–7 summarize characteristic cell-autonomous and systemic hallmarks of aging. While Chapter 2 gives an overview on the transcriptomic signatures of the aging organism, Chapters 3 and 4 introduce loss of proteostasis and the molecular details of telomere dysfunction, respectively. In Chapters 5 and 6, cellular senescence – the cell-autonomous aging program – is outlined in detail, and cellular signaling pathways that control senescence are elucidated. Chapter 7 provides an overview on the age-related changes of the immune system. Chapters 8–14 focus on the aging lung and age-related pathologies of the lung. Chapter 8 introduces the physiological aging process of the lung which is characterized by senile lung emphysema and the age-related decline in lung function in the elderly. Mouse models to explore the molecular nature of age-related lung pathologies are summarized in Chapter 9. Early damage of the immature lung as observed in neonates contributes to premature lung aging as outlined in Chapter 10. The aging lungs present featured changes of the extracellular matrix (Chapter 11) and of the mesenchymal stem cell compartment (Chapter 12). While age-related changes in tissue repair such as altered matrix remodeling and stem cell recruitment add to fibrotic pulmonary diseases, telomere dysfunction and cellular senescence are hallmarks of premature aging in chronic obstructive pulmonary disease (Chapter 13). Immunosenescence and inflamm-aging both promote impaired host responses to respiratory infections in the elderly as outlined in Chapter 14.

We hope that this book will attract basic and clinical scientists to study the mechanisms of aging in general and of the lung in particular. We are confident that the book will contribute to our understanding of age-related lung diseases, and we wish you pleasure reading this book!

Molecular Aspects of Aging

Understanding Lung Aging

Contributors

Preface