Molecular Aspects of Aging – Understanding Lung Aging

<p>Contributors xi</p>
<p>Preface xiii</p>
<p>1 The Demography of Aging 1<br /> David E. Bloom and Sinead Shannon</p>
<p>1.1 Introduction 1</p>
<p>1.2 Demographic trends 1</p>
<p>1.2.1 Fertility rates 2</p>
<p>1.2.2 Mortality rates and life expectancy 2</p>
<p>1.2.3 Proportion of older people 3</p>
<p>1.3 Impact of aging 4</p>
<p>1.3.1 Noncommunicable disease trends 4</p>
<p>1.3.2 Risk factors 5</p>
<p>1.3.3 Impact of NCDs on health and disability 6</p>
<p>1.3.4 Increase in multimorbidities 7</p>
<p>1.3.5 Impact on expenditure 7</p>
<p>1.4 Policy responses 8</p>
<p>1.4.1 Preventing and managing NCDs 8</p>
<p>1.4.2 Promoting exercise 9</p>
<p>1.4.3 Monitoring health–risk behaviors (and chronic health conditions) 9</p>
<p>1.5 Conclusion 9</p>
<p>References 10</p>
<p>2 The Omics of Aging: Insights from Genomes upon Stress 13<br /> Ismene Karakasilioti, Anna Ioannidou, and George A. Garinis</p>
<p>2.1 Introduction 13</p>
<p>2.2 Safeguarding the nuclear genome 14</p>
<p>2.3 NER progerias and their connection to lifespan regulatory mechanisms 15</p>
<p>2.4 Triggering a survival response in the absence of a DNA repair defect 16</p>
<p>2.5 The omics connection between progeria and longevity 19</p>
<p>2.6 Triggering of systemic versus cell–autonomous features of the survival response 20</p>
<p>2.7 The omics connection between NER progeria, transcription, and longevity 21</p>
<p>2.8 Future perspectives 22</p>
<p>References 22</p>
<p>3 Protein Quality Control Coming of Age 27<br /> Silke Meiners</p>
<p>3.1 Introduction 27</p>
<p>3.2 The aging molecular chaperone network 29</p>
<p>3.3 Protein degradation pathways in aging 30</p>
<p>3.3.1 Lysosomal autophagy pathway 30</p>
<p>3.3.2 Ubiquitin proteasome system 32</p>
<p>3.4 Compartment–specific protein quality control 34</p>
<p>3.4.1 The aging ER stress response 34</p>
<p>3.5 Conclusion 35</p>
<p>References 35</p>
<p>4 Telomerase Function in Aging 41<br /> Rodrigo T. Calado</p>
<p>4.1 Telomeres 41</p>
<p>4.2 Telomerase 43</p>
<p>4.3 Telomeres and human disease 45</p>
<p>4.3.1 Telomere dysfunction in the lungs 46</p>
<p>4.4 Telomeres biology, aging, and longevity 47</p>
<p>4.5 Conclusion 48</p>
<p>References 48</p>
<p>5 The Cellular Senescence Program 53<br /> Pooja Shivshankar and Claude Jourdan Le Saux</p>
<p>5.1 Cellular senescence and evidence of senescence in a cell 53</p>
<p>5.1.1 Characteristics of senescent cells and the inflammatory microenvironment 53</p>
<p>5.1.2 Detection of senescent cells in vitro and in vivo 54</p>
<p>5.2 Conditions associated with cellular senescence 55</p>
<p>5.2.1 Oxidative stress 55</p>
<p>5.2.2 DNA damage 55</p>
<p>5.2.3 Cell cycle arrest and senescence 56</p>
<p>5.3 Mechanisms/pathways of senescence induction 56</p>
<p>5.3.1 The p53/p21 pathway 56</p>
<p>5.3.2 The p16/pRB pathway 57</p>
<p>5.3.3 Convergence/coactivation of p53/p21 and p16/pRB pathways 57</p>
<p>5.3.4 Induction of senescence via molecular signaling 57</p>
<p>5.4 Cellular senescence in aging and age–related diseases of the lungs 58</p>
<p>5.4.1 Normal aging 59</p>
<p>5.4.2 Pneumonia 59</p>
<p>5.4.3 Chronic obstructive pulmonary disease 60</p>
<p>5.4.4 Idiopathic pulmonary fibrosis 60</p>
<p>5.5 Conclusion 61</p>
<p>References 61</p>
<p>6 Signaling Networks Controlling Cellular Senescence 67<br /> Leena P. Desai, Yan Y. Sanders, and Victor J. Thannickal</p>
<p>6.1 Introduction 67</p>
<p>6.2 Classification of cellular senescence 69</p>
<p>6.2.1 Intrinsic pathway 69</p>
<p>6.2.2 Extrinsic pathway 69</p>
<p>6.2.3 Reversibility of cellular senescence 70</p>
<p>6.3 Cross talk of signaling pathways 70</p>
<p>6.3.1 Protein kinases 70</p>
<p>6.3.2 Metabolic pathways 71</p>
<p>6.3.3 Mitochondria and reactive oxygen species 71</p>
<p>6.3.4 Integrin and focal adhesion signaling 72</p>
<p>6.3.5 Transforming growth factor– 1 73</p>
<p>6.3.6 Epigenetic mechanisms 73</p>
<p>6.4 Conclusion 76</p>
<p>References 77</p>
<p>7 Immune Senescence 85<br /> Kevin P. High</p>
<p>7.1 Introduction 85</p>
<p>7.2 Barrier defenses and innate immunity in older adults 86</p>
<p>7.2.1 Barrier defenses 86</p>
<p>7.2.2 Innate immunity 86</p>
<p>7.3 Adaptive immune responses 88</p>
<p>7.3.1 B cell number and function 88</p>
<p>7.3.2 T cell number, subtypes, and function 89</p>
<p>7.3.3 T cell activation, differentiation, exhaustion, and senescence 90</p>
<p>7.4 Consequences of immune senescence 91</p>
<p>7.4.1 Impaired vaccine responses, increased risk of infection, and age–related illness 91</p>
<p>7.4.2 Immune senescence: A cause of aging itself 93</p>
<p>7.5 Conclusion 94</p>
<p>References 95</p>
<p>8 Developmental and Physiological Aging of the Lung 99<br /> Kent E. Pinkerton, Lei Wang, Suzette M. Smiley–Jewell, Jingyi Xu, and Francis H.Y. Green</p>
<p>8.1 Introduction 99</p>
<p>8.2 The aging lung 99</p>
<p>8.2.1 Alterations in lung function and anatomy 99</p>
<p>8.2.2 Oxidative stress and lung antioxidant defenses 101</p>
<p>8.2.3 Immune system changes with aging 101</p>
<p>8.2.4 Body mass 102</p>
<p>8.2.5 Airway receptor and endocrine changes with aging 103</p>
<p>8.3 An animal model of the aging lung: The rat 104</p>
<p>8.3.1 The tracheobronchial tree and epithelium of the aging rat 104</p>
<p>8.3.2 Parenchymal lung structure in the aging rat 105</p>
<p>8.3.3 Alveolar tissue compartments 106</p>
<p>8.4 Conclusion 110</p>
<p>Acknowledgments 110</p>
<p>References 111</p>
<p>9 Mouse Models to Explore the Aging Lung 117<br /> Mingyi Wang and Deepak A. Deshpande</p>
<p>9.1 Pulmonary changes during aging 117</p>
<p>9.1.1 Advantages of mouse models for studying physiological lung changes 118</p>
<p>9.2 Key findings from mouse models of aging 119</p>
<p>9.2.1 Longevity and lung function in mice 120</p>
<p>9.2.2 Different strains of mice have different alterations in lung mechanics 120</p>
<p>9.2.3 Transgenic mouse model to study aging in the lungs 121</p>
<p>9.3 Age is a risk factor for obstructive pulmonary diseases 123</p>
<p>9.4 Challenges ahead 124</p>
<p>9.5 Conclusion 125</p>
<p>Acknowledgments 126</p>
<p>References 126</p>
<p>10 Evidence for Premature Lung Aging of the Injured Neonatal Lung as Exemplified by Bronchopulmonary Dysplasia 131<br /> Anne Hilgendorff</p>
<p>10.1 Introducing bronchopulmonary dysplasia 131</p>
<p>10.2 Altered pulmonary function in infants with BPD 132</p>
<p>10.3 Response to injury 133</p>
<p>10.3.1 Oxidative stress response 134</p>
<p>10.3.2 Extracellular matrix remodeling 136</p>
<p>10.3.3 Inflammation 136</p>
<p>10.3.4 Morphogenetic response 137</p>
<p>10.4 Prenatal and genetic predisposition 137</p>
<p>10.5 Conclusion 138</p>
<p>References 138</p>
<p>11 Remodeling of the Extracellular Matrix in the Aging Lung 145<br /> Jesse Roman</p>
<p>11.1 Introduction 145</p>
<p>11.2 The aging lung 145</p>
<p>11.3 Activation of tissue remodeling in the senescent lung 146</p>
<p>11.4 The aging lung fibroblast 148</p>
<p>11.5 Potential role of oxidant stress in triggering remodeling in the aging lung 149</p>
<p>11.6 Implications for remodeling of the lung extracellular matrix in the aged lung 150</p>
<p>11.7 Conclusions 152</p>
<p>Acknowledgments 154</p>
<p>References 154</p>
<p>12 Aging Mesenchymal Stem Cells in Lung Disease 159<br /> Maria G. Kapetanaki, Ana L. Mora, and Mauricio Rojas</p>
<p>12.1 Aging and lung diseases 159</p>
<p>12.2 Mesenchymal stem cells (MSCs) 160</p>
<p>12.2.1 Description of MSCs 160</p>
<p>12.2.2 Characterization of MSCs 160</p>
<p>12.2.3 Functional properties of MSCs 161</p>
<p>12.3 Impact of aging on mesenchymal stem cells 162</p>
<p>12.3.1 In vitro aging of MSCs 162</p>
<p>12.3.2 Age–related changes in B–MSCs 163</p>
<p>12.3.3 Aging of B–MSCs versus aging of the organism 163</p>
<p>12.4 B–MSCs in disease 164</p>
<p>12.5 B–MSCs in therapy 166</p>
<p>12.5.1 Ex vivo expansion 166</p>
<p>12.5.2 Conditions affecting the expansion 167</p>
<p>12.5.3 Autologous versus allogeneic B–MSCs 167</p>
<p>12.5.4 Combination of cell preparations 167</p>
<p>12.5.5 Delivery and targeting 167</p>
<p>12.6 Conclusion 167</p>
<p>Acknowledgments 168</p>
<p>References 168</p>
<p>13 COPD as a Disease of Premature Aging 173<br /> Laurent Boyer, Jorge Boczkowski, and Serge Adnot</p>
<p>13.1 Introduction 173</p>
<p>13.2 Senescent cells contribute to the pathogenesis of COPD 174</p>
<p>13.2.1 Accumulation of senescent cells in COPD lungs 174</p>
<p>13.2.2 Inflammation and lung–cell senescence in COPD 175</p>
<p>13.2.3 Emphysema and lung–cell senescence in COPD 176</p>
<p>13.2.4 Pulmonary hypertension and cell senescence in COPD 177</p>
<p>13.3 Lung dysfunction and the general process of premature aging in COPD 179</p>
<p>13.3.1 Clinical manifestations of premature aging in COPD patients 179</p>
<p>13.3.2 Role for lung alterations in systemic premature aging during COPD 180</p>
<p>13.4 Conclusion 181</p>
<p>References 181</p>
<p>14 Lung Infections and Aging 185<br /> Jacqueline M. Kruser and Keith C. Meyer</p>
<p>14.1 Introduction 185</p>
<p>14.2 Aging and immunosenescence 185</p>
<p>14.2.1 Innate immunity 187</p>
<p>14.2.2 Adaptive immunity 188</p>
<p>14.2.3 Autoimmunity 189</p>
<p>14.2.4 Lung–specific changes in immunity with aging 190</p>
<p>14.3 Inflamm–aging and susceptibility to infection 190</p>
<p>14.4 Respiratory infection and regulation of host responses 192</p>
<p>14.5 Preventing respiratory infection 194</p>
<p>14.6 Summary and conclusions 195</p>
<p>References 195</p>
<p>Index 201</p>