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 xi

Preface xiii

1 The Demography of Aging 1
David E. Bloom and Sinead Shannon

1.1 Introduction 1

1.2 Demographic trends 1

1.2.1 Fertility rates 2

1.2.2 Mortality rates and life expectancy 2

1.2.3 Proportion of older people 3

1.3 Impact of aging 4

1.3.1 Noncommunicable disease trends 4

1.3.2 Risk factors 5

1.3.3 Impact of NCDs on health and disability 6

1.3.4 Increase in multimorbidities 7

1.3.5 Impact on expenditure 7

1.4 Policy responses 8

1.4.1 Preventing and managing NCDs 8

1.4.2 Promoting exercise 9

1.4.3 Monitoring health-risk behaviors (and chronic health conditions) 9

1.5 Conclusion 9

References 10

2 The Omics of Aging: Insights from Genomes upon Stress 13
Ismene Karakasilioti, Anna Ioannidou, and George A. Garinis

2.1 Introduction 13

2.2 Safeguarding the nuclear genome 14

2.3 NER progerias and their connection to lifespan regulatory mechanisms 15

2.4 Triggering a survival response in the absence of a DNA repair defect 16

2.5 The omics connection between progeria and longevity 19

2.6 Triggering of systemic versus cell-autonomous features of the survival response 20

2.7 The omics connection between NER progeria, transcription, and longevity 21

2.8 Future perspectives 22

References 22

3 Protein Quality Control Coming of Age 27
Silke Meiners

3.1 Introduction 27

3.2 The aging molecular chaperone network 29

3.3 Protein degradation pathways in aging 30

3.3.1 Lysosomal autophagy pathway 30

3.3.2 Ubiquitin–proteasome system 32

3.4 Compartment-specific protein quality control 34

3.4.1 The aging ER stress response 34

3.5 Conclusion 35

References 35

4 Telomerase Function in Aging 41
Rodrigo T. Calado

4.1 Telomeres 41

4.2 Telomerase 43

4.3 Telomeres and human disease 45

4.3.1 Telomere dysfunction in the lungs 46

4.4 Telomeres biology, aging, and longevity 47

4.5 Conclusion 48

References 48

5 The Cellular Senescence Program 53
Pooja Shivshankar and Claude Jourdan Le Saux

5.1 Cellular senescence and evidence of senescence in a cell 53

5.1.1 Characteristics of senescent cells and the inflammatory microenvironment 53

5.1.2 Detection of senescent cells in vitro and in vivo 54

5.2 Conditions associated with cellular senescence 55

5.2.1 Oxidative stress 55

5.2.2 DNA damage 55

5.2.3 Cell cycle arrest and senescence 56

5.3 Mechanisms/pathways of senescence induction 56

5.3.1 The p53/p21 pathway 56

5.3.2 The p16/pRB pathway 57

5.3.3 Convergence/coactivation of p53/p21 and p16/pRB pathways 57

5.3.4 Induction of senescence via molecular signaling 57

5.4 Cellular senescence in aging and age-related diseases of the lungs 58

5.4.1 Normal aging 59

5.4.2 Pneumonia 59

5.4.3 Chronic obstructive pulmonary disease 60

5.4.4 Idiopathic pulmonary fibrosis 60

5.5 Conclusion 61

References 61

6 Signaling Networks Controlling Cellular Senescence 67
Leena P. Desai, Yan Y. Sanders, and Victor J. Thannickal

6.1 Introduction 67

6.2 Classification of cellular senescence 69

6.2.1 Intrinsic pathway 69

6.2.2 Extrinsic pathway 69

6.2.3 Reversibility of cellular senescence 70

6.3 Cross talk of signaling pathways 70

6.3.1 Protein kinases 70

6.3.2 Metabolic pathways 71

6.3.3 Mitochondria and reactive oxygen species 71

6.3.4 Integrin and focal adhesion signaling 72

6.3.5 Transforming growth factor-β1 73

6.3.6 Epigenetic mechanisms 73

6.4 Conclusion 76

References 77

7 Immune Senescence 85
Kevin P. High

7.1 Introduction 85

7.2 Barrier defenses and innate immunity in older adults 86

7.2.1 Barrier defenses 86

7.2.2 Innate immunity 86

7.3 Adaptive immune responses 88

7.3.1 B cell number and function 88

7.3.2 T cell number, subtypes, and function 89

7.3.3 T cell activation, differentiation, exhaustion, and senescence 90

7.4 Consequences of immune senescence 91

7.4.1 Impaired vaccine responses, increased risk of infection, and age-related illness 91

7.4.2 Immune senescence: A cause of aging itself 93

7.5 Conclusion 94

References 95

8 Developmental and Physiological Aging of the Lung 99
Kent E. Pinkerton, Lei Wang, Suzette M. Smiley-Jewell, Jingyi Xu, and Francis H.Y. Green

8.1 Introduction 99

8.2 The aging lung 99

8.2.1 Alterations in lung function and anatomy 99

8.2.2 Oxidative stress and lung antioxidant defenses 101

8.2.3 Immune system changes with aging 101

8.2.4 Body mass 102

8.2.5 Airway receptor and endocrine changes with aging 103

8.3 An animal model of the aging lung: The rat 104

8.3.1 The tracheobronchial tree and epithelium of the aging rat 104

8.3.2 Parenchymal lung structure in the aging rat 105

8.3.3 Alveolar tissue compartments 106

8.4 Conclusion 110

Acknowledgments 110

References 111

9 Mouse Models to Explore the Aging Lung 117
Mingyi Wang and Deepak A. Deshpande

9.1 Pulmonary changes during aging 117

9.1.1 Advantages of mouse models for studying physiological lung changes 118

9.2 Key findings from mouse models of aging 119

9.2.1 Longevity and lung function in mice 120

9.2.2 Different strains of mice have different alterations in lung mechanics 120

9.2.3 Transgenic mouse model to study aging in the lungs 121

9.3 Age is a risk factor for obstructive pulmonary diseases 123

9.4 Challenges ahead 124

9.5 Conclusion 125

Acknowledgments 126

References 126

10 Evidence for Premature Lung Aging of the Injured Neonatal Lung as Exemplified by Bronchopulmonary Dysplasia 131
Anne Hilgendorff

10.1 Introducing bronchopulmonary dysplasia 131

10.2 Altered pulmonary function in infants with BPD 132

10.3 Response to injury 133

10.3.1 Oxidative stress response 134

10.3.2 Extracellular matrix remodeling 136

10.3.3 Inflammation 136

10.3.4 Morphogenetic response 137

10.4 Prenatal and genetic predisposition 137

10.5 Conclusion 138

References 138

11 Remodeling of the Extracellular Matrix in the Aging Lung 145
Jesse Roman

11.1 Introduction 145

11.2 The aging lung 145

11.3 Activation of tissue remodeling in the senescent lung 146

11.4 The aging lung fibroblast 148

11.5 Potential role of oxidant stress in triggering remodeling in the aging lung 149

11.6 Implications for remodeling of the lung extracellular matrix in the aged lung 150

11.7 Conclusions 152

Acknowledgments 154

References 154

12 Aging Mesenchymal Stem Cells in Lung Disease 159
Maria G. Kapetanaki, Ana L. Mora, and Mauricio Rojas

12.1 Aging and lung diseases 159

12.2 Mesenchymal stem cells (MSCs) 160

12.2.1 Description of MSCs 160

12.2.2 Characterization of MSCs 160

12.2.3 Functional properties of MSCs 161

12.3 Impact of aging on mesenchymal stem cells 162

12.3.1 In vitro aging of MSCs 162

12.3.2 Age-related changes in B-MSCs 163

12.3.3 Aging of B-MSCs versus aging of the organism 163

12.4 B-MSCs in disease 164

12.5 B-MSCs in therapy 166

12.5.1 Ex vivo expansion 166

12.5.2 Conditions affecting the expansion 167

12.5.3 Autologous versus allogeneic B-MSCs 167

12.5.4 Combination of cell preparations 167

12.5.5 Delivery and targeting 167

12.6 Conclusion 167

Acknowledgments 168

References 168

13 COPD as a Disease of Premature Aging 173
Laurent Boyer, Jorge Boczkowski, and Serge Adnot

13.1 Introduction 173

13.2 Senescent cells contribute to the pathogenesis of COPD 174

13.2.1 Accumulation of senescent cells in COPD lungs 174

13.2.2 Inflammation and lung-cell senescence in COPD 175

13.2.3 Emphysema and lung-cell senescence in COPD 176

13.2.4 Pulmonary hypertension and cell senescence in COPD 177

13.3 Lung dysfunction and the general process of premature aging in COPD 179

13.3.1 Clinical manifestations of premature aging in COPD patients 179

13.3.2 Role for lung alterations in systemic premature aging during COPD 180

13.4 Conclusion 181

References 181

14 Lung Infections and Aging 185
Jacqueline M. Kruser and Keith C. Meyer

14.1 Introduction 185

14.2 Aging and immunosenescence 185

14.2.1 Innate immunity 187

14.2.2 Adaptive immunity 188

14.2.3 Autoimmunity 189

14.2.4 Lung-specific changes in immunity with aging 190

14.3 Inflamm-aging and susceptibility to infection 190

14.4 Respiratory infection and regulation of host responses 192

14.5 Preventing respiratory infection 194

14.6 Summary and conclusions 195

References 195

Index 201