Molecular Aspects of Aging

Dr. Mauricio Rojas is an Assistant Professor in the Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh. Silke Meiners, PhD is a Research Group Leader from the Comprehensive Pneumology Center in Munich.Claude Jourdan Le Saux, PhD is an Assistant Professor in the Department of Medicine Division of Cardiology/Pulmonary and Critical Care, University of Texas Health Science Center at San Antonio, San Antonio, Texas, as well as a faculty member of the Barshop Institute for Longevity and Aging Studies Nathan Shock Aging Center of Excellence and Department of Cellular and Structural Biology.

• Contributors xiPreface xiii1 The Demography of Aging 1David E. Bloom and Sinead Shannon1.1 Introduction 11.2 Demographic trends 11.2.1 Fertility rates 21.2.2 Mortality rates and life expectancy 21.2.3 Proportion of older people 31.3 Impact of aging 41.3.1 Noncommunicable disease trends 41.3.2 Risk factors 51.3.3 Impact of NCDs on health and disability 61.3.4 Increase in multimorbidities 71.3.5 Impact on expenditure 71.4 Policy responses 81.4.1 Preventing and managing NCDs 81.4.2 Promoting exercise 91.4.3 Monitoring health-risk behaviors (and chronic health conditions) 91.5 Conclusion 9References 102 The Omics of Aging: Insights from Genomes upon Stress 13Ismene Karakasilioti, Anna Ioannidou, and George A. Garinis2.1 Introduction 132.2 Safeguarding the nuclear genome 142.3 NER progerias and their connection to lifespan regulatory mechanisms 152.4 Triggering a survival response in the absence of a DNA repair defect 162.5 The omics connection between progeria and longevity 192.6 Triggering of systemic versus cell-autonomous features of the survival response 202.7 The omics connection between NER progeria, transcription, and longevity 212.8 Future perspectives 22References 223 Protein Quality Control Coming of Age 27Silke Meiners3.1 Introduction 273.2 The aging molecular chaperone network 293.3 Protein degradation pathways in aging 303.3.1 Lysosomal autophagy pathway 303.3.2 Ubiquitin–proteasome system 323.4 Compartment-specific protein quality control 343.4.1 The aging ER stress response 343.5 Conclusion 35References 354 Telomerase Function in Aging 41Rodrigo T. Calado4.1 Telomeres 414.2 Telomerase 434.3 Telomeres and human disease 454.3.1 Telomere dysfunction in the lungs 464.4 Telomeres biology, aging, and longevity 474.5 Conclusion 48References 485 The Cellular Senescence Program 53Pooja Shivshankar and Claude Jourdan Le Saux5.1 Cellular senescence and evidence of senescence in a cell 535.1.1 Characteristics of senescent cells and the inflammatory microenvironment 535.1.2 Detection of senescent cells in vitro and in vivo 545.2 Conditions associated with cellular senescence 555.2.1 Oxidative stress 555.2.2 DNA damage 555.2.3 Cell cycle arrest and senescence 565.3 Mechanisms/pathways of senescence induction 565.3.1 The p53/p21 pathway 565.3.2 The p16/pRB pathway 575.3.3 Convergence/coactivation of p53/p21 and p16/pRB pathways 575.3.4 Induction of senescence via molecular signaling 575.4 Cellular senescence in aging and age-related diseases of the lungs 585.4.1 Normal aging 595.4.2 Pneumonia 595.4.3 Chronic obstructive pulmonary disease 605.4.4 Idiopathic pulmonary fibrosis 605.5 Conclusion 61References 616 Signaling Networks Controlling Cellular Senescence 67Leena P. Desai, Yan Y. Sanders, and Victor J. Thannickal6.1 Introduction 676.2 Classification of cellular senescence 696.2.1 Intrinsic pathway 696.2.2 Extrinsic pathway 696.2.3 Reversibility of cellular senescence 706.3 Cross talk of signaling pathways 706.3.1 Protein kinases 706.3.2 Metabolic pathways 716.3.3 Mitochondria and reactive oxygen species 716.3.4 Integrin and focal adhesion signaling 726.3.5 Transforming growth factor-β1 736.3.6 Epigenetic mechanisms 736.4 Conclusion 76References 777 Immune Senescence 85Kevin P. High7.1 Introduction 857.2 Barrier defenses and innate immunity in older adults 867.2.1 Barrier defenses 867.2.2 Innate immunity 867.3 Adaptive immune responses 887.3.1 B cell number and function 887.3.2 T cell number, subtypes, and function 897.3.3 T cell activation, differentiation, exhaustion, and senescence 907.4 Consequences of immune senescence 917.4.1 Impaired vaccine responses, increased risk of infection, and age-related illness 917.4.2 Immune senescence: A cause of aging itself 937.5 Conclusion 94References 958 Developmental and Physiological Aging of the Lung 99Kent E. Pinkerton, Lei Wang, Suzette M. Smiley-Jewell, Jingyi Xu, and Francis H.Y. Green8.1 Introduction 998.2 The aging lung 998.2.1 Alterations in lung function and anatomy 998.2.2 Oxidative stress and lung antioxidant defenses 1018.2.3 Immune system changes with aging 1018.2.4 Body mass 1028.2.5 Airway receptor and endocrine changes with aging 1038.3 An animal model of the aging lung: The rat 1048.3.1 The tracheobronchial tree and epithelium of the aging rat 1048.3.2 Parenchymal lung structure in the aging rat 1058.3.3 Alveolar tissue compartments 1068.4 Conclusion 110Acknowledgments 110References 1119 Mouse Models to Explore the Aging Lung 117Mingyi Wang and Deepak A. Deshpande9.1 Pulmonary changes during aging 1179.1.1 Advantages of mouse models for studying physiological lung changes 1189.2 Key findings from mouse models of aging 1199.2.1 Longevity and lung function in mice 1209.2.2 Different strains of mice have different alterations in lung mechanics 1209.2.3 Transgenic mouse model to study aging in the lungs 1219.3 Age is a risk factor for obstructive pulmonary diseases 1239.4 Challenges ahead 1249.5 Conclusion 125Acknowledgments 126References 12610 Evidence for Premature Lung Aging of the Injured Neonatal Lung as Exemplified by Bronchopulmonary Dysplasia 131Anne Hilgendorff10.1 Introducing bronchopulmonary dysplasia 13110.2 Altered pulmonary function in infants with BPD 13210.3 Response to injury 13310.3.1 Oxidative stress response 13410.3.2 Extracellular matrix remodeling 13610.3.3 Inflammation 13610.3.4 Morphogenetic response 13710.4 Prenatal and genetic predisposition 13710.5 Conclusion 138References 13811 Remodeling of the Extracellular Matrix in the Aging Lung 145Jesse Roman11.1 Introduction 14511.2 The aging lung 14511.3 Activation of tissue remodeling in the senescent lung 14611.4 The aging lung fibroblast 14811.5 Potential role of oxidant stress in triggering remodeling in the aging lung 14911.6 Implications for remodeling of the lung extracellular matrix in the aged lung 15011.7 Conclusions 152Acknowledgments 154References 15412 Aging Mesenchymal Stem Cells in Lung Disease 159Maria G. Kapetanaki, Ana L. Mora, and Mauricio Rojas12.1 Aging and lung diseases 15912.2 Mesenchymal stem cells (MSCs) 16012.2.1 Description of MSCs 16012.2.2 Characterization of MSCs 16012.2.3 Functional properties of MSCs 16112.3 Impact of aging on mesenchymal stem cells 16212.3.1 In vitro aging of MSCs 16212.3.2 Age-related changes in B-MSCs 16312.3.3 Aging of B-MSCs versus aging of the organism 16312.4 B-MSCs in disease 16412.5 B-MSCs in therapy 16612.5.1 Ex vivo expansion 16612.5.2 Conditions affecting the expansion 16712.5.3 Autologous versus allogeneic B-MSCs 16712.5.4 Combination of cell preparations 16712.5.5 Delivery and targeting 16712.6 Conclusion 167Acknowledgments 168References 16813 COPD as a Disease of Premature Aging 173Laurent Boyer, Jorge Boczkowski, and Serge Adnot13.1 Introduction 17313.2 Senescent cells contribute to the pathogenesis of COPD 17413.2.1 Accumulation of senescent cells in COPD lungs 17413.2.2 Inflammation and lung-cell senescence in COPD 17513.2.3 Emphysema and lung-cell senescence in COPD 17613.2.4 Pulmonary hypertension and cell senescence in COPD 17713.3 Lung dysfunction and the general process of premature aging in COPD 17913.3.1 Clinical manifestations of premature aging in COPD patients 17913.3.2 Role for lung alterations in systemic premature aging during COPD 18013.4 Conclusion 181References 18114 Lung Infections and Aging 185Jacqueline M. Kruser and Keith C. Meyer14.1 Introduction 18514.2 Aging and immunosenescence 18514.2.1 Innate immunity 18714.2.2 Adaptive immunity 18814.2.3 Autoimmunity 18914.2.4 Lung-specific changes in immunity with aging 19014.3 Inflamm-aging and susceptibility to infection 19014.4 Respiratory infection and regulation of host responses 19214.5 Preventing respiratory infection 19414.6 Summary and conclusions 195References 195Index 201