Aging: From Fundamental Biology to Societal Impact

Front Cover
Aging
Copyright Page
Contents
List of contributors
Foreword
Preface
1 The societal burden of aging
1 Global aging and health determinants in a changing world
1.1 Introduction
1.2 The geographies of a global trend
1.2.1 Global patterns and projections
1.2.2 Multiscale intraregional variations of the aging process
1.3 Environmental health in later life
1.3.1 From successful aging to the role of place and inequities
1.3.2 How environment affects physical health in old age
1.3.3 The subjective experience of place: place attachment and residential normalcy
1.4 Global stressors in a changing world
1.4.1 Welfare state and neoliberalism
1.4.2 Climate change and health in old age
1.4.3 Migrations and health in old age
1.4.4 Discrimination as a health issue for older persons
1.5 Conclusion
Acknowledgments
References
2 Flagship initiatives for healthy living and active aging in Europe: the European Innovation Partnership on Active and Hea...
2.1 Demographic changes and aging
2.2 The European Innovation Partnership on Active and Healthy Ageing
2.2.1 European Innovation Partnership on Active and Healthy Ageing cross-cutting initiatives
2.3 Reference sites—case studies
2.3.1 Ageing@Coimbra Reference Site
2.3.2 The Healthy Ageing Network Northern Netherlands
2.3.3 Valencia region Reference Site
2.3.4 Andalusia Reference Site
2.3.5 The Lodz4Generations Reference Site
2.3.6 Campania Reference Site (ProMIS network)
2.3.7 MACVIA-France Reference Site
2.4 Reference Site Collaborative Network
2.5 Transition from Horizon 2020 to Horizon Europe—the role of IN-4-Active and Healthy Ageing
2.6 Future perspectives
Acknowledgment
References
3 Aging in Africa, challenges and opportunities—the particular case of Cabo Verde
3.1 Aging in Africa and West African Region
3.2 Geography and climate of Cabo Verde
3.3 Cabo Verde, the historical healthy islands
3.4 Epidemiology of slave society
3.5 Cabo Verde Famines
3.6 Cabo Verdean population genetics
3.7 Age pyramid of Cabo Verdean population
3.8 Urbanization of Cabo Verdean population
3.9 Aging and the emergence of a new demographic model
3.10 Elderly in Cabo Verde
3.11 Health and national health service—philosophy, structures, and budget
3.12 Healthy and active aging policies
3.13 Aging and poverty
3.14 Aging and gender
3.15 To a healthy living and active aging in Cabo Verde—the future
References
4 Flagship initiatives to prevent and treat diabetes as a burden of western societies
4.1 Introduction
4.1.1 Demographics of diabetes and prediabetes
4.1.2 Healthcare literacy and numeracy
4.1.3 Food insecurity and dietary quality
4.1.4 Community engagement
4.2 Impact of research: prediabetes
4.2.1 The diabetes prevention program study
4.2.2 The finnish diabetes prevention study
4.3 Lifestyle interventions
4.3.1 The national diabetes prevention program
4.3.2 Exercise
4.3.3 Pharmacologic therapy in prediabetes
4.4 Impact of research: diabetes
4.4.1 Diabetes self-management education
4.5 Summary and conclusions
References
5 Determining factors on active aging in Asia and Oceania: a systematic review
5.1 Introduction
5.2 Methodology
5.2.1 Population aging in Asia and Oceania
5.2.2 Data sources and search strategies
5.2.3 Study selection
5.2.4 Bias assessment
5.2.5 Data extraction
5.3 Results
5.3.1 Exergaming/active video games
5.3.2 Health wearables and activity trackers
5.3.3 Smartphones
5.3.4 Web-based programs
5.4 Discussion and concluding remarks
References
6 Healthy living and active aging in Latin America and the Caribbean countries: biological, demographic, and epidemiologica...
6.1 Introduction
6.2 Demographic and epidemiological changes in the Latin America and the Caribbean countries
6.3 Age-related biological changes and diseases in the context of Latin America and the Caribbean countries
6.3.1 Immunosenescence and infectious diseases
6.3.2 Age-related intestinal microbiota changes: the role in neurodegenerative and metabolic diseases
6.3.3 Common age-related diseases: cancer, vascular diseases, diabetes and neurodegenerative disorders
6.3.3.1 Cancer
6.3.3.2 Cardiovascular diseases
6.3.3.3 Diabetes mellitus
6.3.3.4 Neurodegenerative disorders
6.4 Health and social initiatives for the promotion of healthy living and active aging
6.4.1 Age-friendly initiatives
6.4.2 Labor force participation and active aging
6.5 Selected health issues among older people: evidence from long-term cohorts in Latin America
6.6 Conclusion
References
2 The biology of aging
7 Identification of metrics of molecular and cellular resilience in humans and animal models
7.1 Biomedicine is focused on disease, not health
7.2 Comorbidities are the prevailing characteristic of older age
7.3 Chronological versus physiological age
7.4 Linking aging to disease: geroscience principles
7.5 A common thread: improvement of resilience
7.6 Defining resilience at the molecular level
7.7 Measuring molecular resilience
7.8 We need to develop resilience metrics in animal models
7.9 Translation of resilience measurements to humans
7.10 Conclusions
References
8 A metabolic and mitochondrial angle on aging
Abbreviations
8.1 Aging and longevity: revisiting the evolutionary perspectives and controversies
8.2 Aging and longevity: challenging the traditional views for mitochondrial-derived oxidative stress
8.3 Changes of mitochondrial function and structure associated with aging
8.3.1 Oxidative phosphorylation and aging
8.3.2 Mitochondrial morphology and dynamics in aging
8.4 A metabolic angle on aging
8.4.1 Carbohydrate metabolism and aging
8.4.2 Lipid metabolism and aging
8.4.3 Protein metabolism and aging
8.4.4 Nutrient metabolism and caloric restriction
8.5 Oxidative stress and aging
8.5.1 Reactive oxygen species and their reactions
8.5.2 Reactive oxygen species as the cause of aging
8.5.3 Antioxidant defense in aging
8.5.4 Mitochondrial free radical theory of aging
8.5.5 Accumulation of reactive oxygen species-induced damage with aging
8.5.6 Age-related oxidative modifications of mitochondria
8.6 Potential strategies against aging to increase longevity
8.6.1 Metabolic control-related approaches
8.6.1.1 Caloric/dietary restriction
8.6.1.2 Melatonin
8.6.1.3 Sirtuins activators
8.6.1.3.1 Resveratrol showed cytotoxicity against several cancers (namely leukemia, skin and prostate cancer)
8.6.1.3.2 Food nutrients
8.6.1.3.3 Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), a diarylheptanoid derived from the rhizom...
8.6.1.4 Sirtuin inhibitors
8.6.1.5 Mitochondrial uncoupling
8.6.1.5.1 UCP1 was first identified in the 1970s and is the most well-known member of UCPs
8.6.1.5.2 UCP2, UCP3 and UCP4
8.6.1.5.3 2,4-dinitrophenol (DNP) and carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) are well-studied pharmac...
8.6.1.6 Physical activity
8.6.2 Mitochondria-related antioxidant approaches
8.6.2.1 What can we learn from the “eternal youth” of the naked mole rat?
8.6.2.2 Mitochondria-targeted antioxidants in delayed aging
8.6.2.2.1 MitoQ
8.6.2.2.2 SkQ1
8.6.2.2.3 AntiOxBEN2 and AntiOxCIN4
8.6.2.2.4 Other mitochondrially-targeted antioxidants
8.6.2.2.4.1 TEMPO and Mito-TEMPO
8.6.2.2.4.2 Szeto-Schiller (SS) peptides
8.7 Conclusions
Acknowledgments
References
9 Intercellular communication and aging
9.1 Importance of intercellular communication
9.2 The defining features of senescence
9.3 The mechanisms responsible for the induction of cellular senescence
9.4 Senescence associated secretory phenotype
9.5 Intercellular communication mediated by gap junctions and connexin channels
9.6 Intercellular communication mediated by tunneling nanotubes
9.7 Intercellular communication mediated by extracellular vesicles
9.8 Concluding remarks
Acknowledgments
References
10 Genomic instability and aging
10.1 Introduction
10.2 DNA strand breakage-induced genomic instability
10.3 Replication-induced genomic instability
10.3.1 Replication stress
10.3.2 Translesion DNA synthesis
10.3.3 Mismatch repair
10.4 Transcription-induced genomic instability
10.4.1 Transcription-coupled repair
10.4.2 Transcription-replication conflicts
10.5 Nucleotide pools
10.6 Mitochondrial functions in genomic integrity
10.6.1 Mitochondrial oxidative stress
10.6.2 FOXO in oxidative DNA damage response
10.6.3 Mitochondrial genome maintenance
10.6.4 Mitochondrial dysfunction
10.6.5 Mitophagy
10.7 Genomic instability in health and disease
10.7.1 Longevity
10.7.2 Progeroid syndromes
10.7.3 Cancer
10.7.4 Neurodegeneration
10.8 Aging interventions activating DNA repair
10.8.1 Exercise
10.8.2 Dietary restriction
10.8.3 Nicotinamide adenine dinucleotide
10.9 Conclusion and future perspectives
Acknowledgments
References
11 Telomeres and cell homeostasis in aging
11.1 What is cellular senescence
11.2 Link between cell senescence and telomeres
11.3 Critically short telomeres activate a DNA damage response and senescence
11.4 Telomere dysfunction can occur in a length-independent manner
11.5 Mechanisms by which stress accelerates telomere dysfunction
11.6 Telomere-associated DNA damage response foci accumulate during aging and disease
References
12 Cellular senescence during aging
12.1 Cell senescence is a complex stress response
12.2 The building blocks of the senescent phenotype
12.2.1 Telomeres and the DNA damage response
12.2.2 Senescence-associated secretory phenotype
12.2.3 Senescence-associated mitochondrial dysfunction
12.2.4 Nutrient signaling
12.2.5 Autophagy/mitophagy
12.2.6 Epigenetic reprogramming
12.3 Senescence during aging in vivo
12.3.1 Senescence in postmitotic cells
12.3.2 Senescent cell bystander effects
12.4 Senolytics and senostatics as anti-aging interventions
12.4.1 Senolytics
12.4.2 Senostatics
12.5 Conclusion
References
13 The epigenetics of aging
13.1 Introduction
13.2 Epigenetic alterations and aging
13.2.1 Histone depletion
13.2.2 Non-canonical histone variants
13.2.3 Histone acetylation
13.2.4 Histone methylation
13.2.5 ATP-dependent chromatin remodeling
13.2.6 DNA methylation
13.2.7 Non-coding RNA molecules
13.3 Epigenetic alterations and age-related diseases
13.3.1 Cancer and epigenetics
13.3.2 Neuronal diseases and epigenetics
13.3.3 Cardiovascular disease and epigenetics
13.4 Conclusions
Acknowledgment
Conflict of interest
References
14 Disrupted cellular quality control mechanisms in aging
14.1 Aging: is it a programmed fate and/or an error accumulation?
14.2 Autophagy: an evolutionarily conserved process
14.3 Role of autophagy in aging: what can go wrong?
14.4 The chase for “eternal youth”: can autophagy-directed interventions be the much-desired youth elixir?
14.5 Going down the rabbit hole: how lysosomes modulate longevity pathways
14.6 Partners in crime: mitochondria and lysosomes need each other
References
15 Stem cells, fitness, and aging
15.1 Introduction
15.2 Cell fitness and cell competition
15.3 Senescent mesenchymal stem cell phenotype
15.4 The functionality changes in senescent mesenchymal stem cells
15.5 The role of factors associated with aging
15.5.1 Oxidative stress
15.6 Genetic and epigenetic aspects
15.7 Senescence-associated secretory phenotype and the microenvironment
15.8 Therapeutic strategies to rejuvenate and increase fitness
15.9 Conclusion
Acknowledgments
References
16 Programming of early aging
16.1 Epidemiology of early life environment and adult aging—developmental origins of health, disease, and aging?
16.2 Early life nutrition and programming of adult aging and lifespan
16.2.1 Prenatal malnutrition, longevity, and aging
16.2.2 Can lactation and early life nutrition contribute to early aging?
16.3 Mechanisms underlying early programming of aging
16.3.1 Metabolic programming
16.3.2 Early cellular miscommunication and cellular senescence
16.3.3 Programming of genomic aging and epigenetic alterations
16.4 Early programming of aging-related diseases
16.4.1 Inflammaging
16.4.2 Cognitive decline and dementia
16.4.3 Aging-related neoplasia
16.4.4 Cardiovascular aging
16.4.5 Physical frailty
16.5 Transgenerational passage of the aging clock—reproductive cell plasticity and selection
16.6 Life interventions to “Re-set the Clock”
16.6.1 Nutrigenomics as a strategy to revert early life programming
16.6.2 Running against aging—exercise as anti-aging “medicine”
16.7 Conclusion
References
3 Aging-related physiology, disease and prevention of aging-related diseases
17 Polypharmacy and medication adherence
17.1 Adherence to therapy and medication management
17.1.1 Definition and classification
17.1.2 Assessment methodologies
17.1.3 Interventions in medication nonadherence
17.1.3.1 Patient education
17.1.3.2 Supporting materials
17.1.3.3 Medication regimen optimization
17.1.3.4 Medication organizing systems
17.1.3.5 New technologies
17.2 Concept of polypharmacy
17.2.1 Potentially inappropriate medication in the elderly
17.2.2 Pharmacokinetic and pharmacodynamic changes in older people
17.3 Inappropriate polypharmacy management
17.3.1 Implicit tools
17.3.2 Explicit tools
17.3.2.1 Indicators for preventable drug-related morbidity
17.3.2.2 Beers criteria
17.3.2.3 STOPP/START criteria
17.3.2.4 EU(7)-PIM list
17.3.2.5 EURO-FORTA list
17.3.2.6 Selecting an explicit tool
17.4 Epilogue
References
18 How molecular imaging studies can disentangle disease mechanisms in age-related neurodegenerative disorders
18.1 Introduction
18.2 Molecular imaging of neuroinflammation
18.3 Molecular imaging of mitochondria dysfunction and oxidative stress
18.4 Molecular imaging of misfolded proteins
18.4.1 Molecular tracers of amyloid and tau in vivo PET imaging
18.5 In vivo imaging of brain metabolic processes and activity
18.5.1 Molecular imaging of cerebral hypometabolism
18.5.2 Molecular imaging of brain functional connectivity
18.6 Imaging of iron accumulation
18.7 Emerging mechanisms of neurodegeneration
18.7.1 Glymphatic system
18.7.2 O-GLcNAc
18.8 Translational use of molecular imaging in neurodegenerative diseases
18.9 Conclusions
References
19 Physical frailty
Abbreviations
19.1 The concept of frailty
19.1.1 Frailty as a biological syndrome
19.1.2 Frailty as cumulative deficits
19.2 Frailty assessment
19.2.1 Frailty measurement tools
19.2.1.1 The performed frailty tools
19.2.1.2 The self-reported tools
19.2.2 A two-step frailty measurement
19.3 The biology of frailty
19.3.1 Chronic inflammation
19.3.2 Hypothalamic-pituitary axis stress response dysfunction
19.3.3 Endocrine dysregulation (dysfunctional hormone regulation)
19.3.4 Metabolic imbalance
19.3.5 Oxidative stress and mitochondrial dysfunction
19.3.6 Genomic factors
19.3.7 Metabolomic markers
19.4 Animal models of frailty
19.5 Interventions to attenuate frailty
19.5.1 Pharmacological interventions
19.5.2 Nonpharmacological interventions
19.6 Conclusion
References
20 The extracellular matrix in cardiovascular aging
Abbreviations
20.1 Introduction
20.2 Physiological alterations of the aged heart
20.2.1 Aging induces functional and morphologic cardiac alterations
20.3 Young cardiac extracellular matrix
20.3.1 Collagens
20.3.2 Elastin
20.3.3 Matricellular proteins: secreted protein, acidic and rich in cysteine and thrombospondin
20.3.4 Glycosaminoglycans and proteoglycans
20.3.5 Adhesive proteins: fibronectin and laminin
20.3.6 Basement membrane
20.4 Aged cardiac extracellular matrix
20.4.1 Collagen matrix—synthesis, deposition and modification with age
20.4.1.1 Age-related alterations in myocardial collagen content
20.4.1.2 Age-related alterations in myocardial collagen types
20.4.1.3 Age-related alterations in myocardial collagen cross-linking
20.4.2 Alterations on glycosaminoglycans and proteoglycans in the aged heart
20.4.3 Alterations on matrix adhesive proteins with aging
20.5 How does the aged heart respond to disease?
20.5.1 Age-associated extracellular matrix remodeling in MI
20.5.2 Age-associated cardiac extracellular matrix remodeling in heart failure
20.6 Conclusions and perspectives
Acknowledgments
References
21 Aging-related neoplasia
21.1 Introduction
21.2 Aging and the risk of cancer
21.3 Cellular senescence and carcinogenesis
21.4 Oxidative stress and carcinogenesis in aging
21.5 The hallmarks of aging and neoplasia
21.5.1 Cell signaling
21.5.2 Telomeres and telomerase
21.5.3 Genomic instability
21.5.4 Epigenetic aging and neoplasia
21.5.5 Proteostasis
21.5.6 Metabolism deregulation
21.5.7 Immune system dysfunction
21.5.8 Persistent viral infection
21.5.9 Stem cells
21.6 Neoplasias and aging
21.6.1 Aging-related neoplasias
21.6.2 Cancer therapeutics and aging
21.7 Conclusion
References
22 Multidimensional frailty as an outcome of biological aging: immunosenescence and inflammaging in the life course perspective
22.1 Introduction
22.2 Relevance of mechanisms of aging for medicine in the 21st century
22.3 Two facets of immunosenescence and inflammaging
22.4 Pathophysiological relevance of immunosenescence and inflammaging in the context of frailty: relevance for COVID-19
22.5 Concluding remarks and research outlook
References
Further reading
23 Geroscience: a unifying view on aging as a risk factor
23.1 Centenarians: a growing population
23.2 Morbidity compression in centenarians
23.3 Limits of human longevity
23.4 Exceptional aging “must-haves”
23.4.1 Low-grade inflammation
23.4.2 Genetic signature
23.4.3 Fine-tuned apoptosis
23.4.4 Stem cell pluripotency
23.4.5 Healthy lifestyle
23.5 Exceptional homeostasis in exceptional aging
23.6 Centenarians beyond 120?
References
4 The future and innovation in aging
24 Aging support with socially assistive robots
24.1 Introduction
24.1.1 Social robotics tools for demanding societies
24.1.2 Where are we in social robotics?
24.2 Where is social robotics heading?
24.2.1 Social robots for aging societies
24.2.2 User behaviors under uncertainty—the bayesian user model
24.2.3 Online knowledge integration using learning
24.3 Results with a team of robots
24.4 User’s attributes from distributed, asynchronous data
24.5 Collectively cluster users into distinguishable profiles
24.6 Discussion
Acknowledgments
References
25 Machine learning in the context of better healthcare in aging
25.1 Introduction
25.2 Machine learning overview
25.3 A review of machine learning applications for aging research
25.4 Telemonitoring data mining for hearth failure management
25.4.1 Heart failure condition
25.4.1.1 myHeart study
25.4.2 Algorithms for heart failure management
25.4.2.1 Diagnosis of heart failure arrhythmias
25.4.2.1.1 Preprocessing
25.4.2.1.2 Feature extraction
25.4.2.1.3 Classification
25.4.2.2 Prognosis of heart failure decompensation
25.4.2.2.1 Time series clustering
25.4.2.2.2 Prediction approach
25.4.3 Experimental results
25.4.3.1 Diagnosis of heart failure arrhythmias
25.4.3.1.1 Segmentation
25.4.3.1.2 Premature ventricular contractions and atrial fibrillation episodes
25.4.3.2 Prognosis of heart failure decompensation
25.4.4 Discussion
25.5 Machine learning for the English Longitudinal Study of Ageing
25.5.1 A brief overview of random forest classifiers
25.5.2 Preparing the English Longitudinal Study of Ageing-nurse data for the classification task
25.5.2.1 Data-driven missing value replacement
25.5.2.2 Adapting the random forest algorithm to longitudinal data
25.5.3 Computational results
25.5.3.1 Predictive performance results
25.6 Feature importance analysis
25.7 Conclusion
References
26 The future of integrated care in aged individuals
26.1 Introduction
26.2 The current model is more and more inadequate
26.3 The avoidable suffering
26.4 An integrated care approach
26.4.1 Healthy aging and disease prevention
26.4.2 Patient-centeredness and multimorbidity
26.4.3 Dementia
26.4.4 Palliative, end life, and bereavement care
26.5 Key messages
References
27 Moving from reactive to preventive medicine
27.1 Introduction
27.2 Aging and major chronic diseases
27.3 The mechanistic interplay between aging and age-related diseases. In the search of evidence for preventive medicine
27.3.1 Immunosenescence and age-related chronic diseases
27.3.2 Epigenetic drift and age-related chronic diseases
27.4 Age-related diseases—prevention initiatives are in order
27.5 Do we have preventive strategies for ameliorating age-related diseases?
27.5.1 Non-pharmacological approaches
27.5.2 Pharmacological interventions
27.6 Cardiovascular disease: the success of prevention
27.6.1 Hypertension: the most prevalent cardiovascular risk factor
27.7 Low-density lipoproteins-cholesterol lowering: the lower, the better
27.7.1 The need to control the obesity pandemic
27.7.2 Primordial prevention: the sooner, the better
27.8 Concluding remarks
References
28 Personalized medicine: will it work for decreasing age-related morbidities?
28.1 Introduction
28.2 Historical perspective
28.3 Slowing aging with GeroScience
28.3.1 The biological hallmarks of aging
28.3.2 A case for personalized aging
28.4 Personalized medicine for optimal longevity
28.5 Emerging predictors of “biological aging”
28.5.1 Epigenetic clocks
28.5.2 Transcriptomics
28.5.3 Metabolomics and proteomics
28.5.4 The gut microbiome
28.6 Applying personalized medicine to GeroScience
28.6.1 Personalized nutrition
28.7 Challenges and barriers to implementing personalized aging
28.7.1 Minimizing the risk-benefit ratio
28.7.2 Increasing diversity in clinical research
28.7.3 Improving adherence and accessibility
28.7.4 Innovation in clinical trial design
28.7.5 Ethical and policy concerns
28.7.6 Cross-disciplinary innovation
28.8 Conclusion
References
29 Interventions that target fundamental aging mechanisms: myths and realities
29.1 Introduction
29.2 Pillars of aging
29.3 Genomic instability
29.3.1 Telomere attrition
29.3.2 Epigenetic alterations
29.3.3 Loss of proteostasis
29.3.4 Deregulated nutrient sensing
29.3.5 Mitochondrial dysfunction
29.3.6 Cellular senescence
29.3.7 Stem cell exhaustion
29.3.8 Altered intercellular communication
29.4 Unitary theory of fundamental aging processes
29.5 Health span versus lifespan
29.6 Myths and realities
29.6.1 Senolytics
29.6.2 Other pharmacological interventions
29.6.2.1 Metformin
29.6.2.2 Rapamycin
29.6.2.3 Resveratrol
29.6.2.4 NAD+/NMN and inhibitors of CD38
29.6.2.5 17-α-Estradiol
29.6.2.6 Ketogenic agents
29.6.3 Behavioral/dietary interventions
29.6.3.1 Caloric restriction/fasting/food clocking
29.6.3.2 Exercise
29.7 Clinical trials and treating disease
29.7.1 Safety; risk/benefit ratio
29.7.2 Combining or sequencing therapies
29.7.3 Translational geroscience network
29.8 Conclusion
Conflict of interest disclosure
References
30 Being a frail older person at a time of the COVID-19 pandemic
30.1 Introduction
30.1.1 A minority of community-dwelling older adults are frail
30.1.2 Frailty in the time of a pandemic: the “measured” versus the “lived”
30.2 The community perspective
30.2.1 COVID-19-related challenges in community-dwelling frail older people
30.2.2 A glimpse of hope
30.3 The hospital perspective
30.3.1 Atypical presentations
30.3.2 Biological heterogeneity of the population of hospitalized older people
30.3.3 Ethical considerations
30.3.4 Optimization of the hospital environment and opportunities for in-hospital rehabilitation
30.3.5 Hospital-associated deconditioning and post-COVID-19 fatigue
30.4 The nursing home perspective
30.5 Research on COVID-19 treatments and service development perspectives
30.6 Conclusions
Competing interest
Funding
References
31 Aging: an illustrated adventure
Index
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