Chen, 2003 Chen I. Hungry for science. Science of Aging Knowledge Environment 2003;2003(1):NF18January.
Critser, 2010 Critser G. Eternitysoup:InsidethequesttoendagingNewYork:Crown Publishing 2010.
Masoro, 2009 Masoro EJ. Caloric restriction-induced life extension of rats and mice: A critique of proposedmechanisms. BiochimicaetBiophysicaActa.2009;10:1040–1048.
Department of Biochemistry and Physiology, Yong Loo School Lin School of Medicine, National University ofSingapore,Singapore,Singapore CentreforHealthyLongevity,NationalUniversityHealthSystem,Singapore,Singapore SingaporeInstituteforClinicalSciences,A*STAR,Singapore,Singapore
JungKiKim, DavisSchoolofGerontology,UniversityofSouthernCalifornia,LosAngeles,CA,United States
Laura J.Niedernhofer, InstituteontheBiologyofAgingandMetabolism,Departmentof Biochemistry,MolecularBiologyandBiophysics,UniversityofMinnesota,Minneapolis,MN,UnitedStates
MirandaE. Orr
Sticht Center for Healthy Aging and Alzheimer’s Prevention, Internal Medicine – Gerontology and GeriatricMedicine,WakeForestSchoolofMedicine(WFSM),Winston-Salem,NC,UnitedStates W.G.HefnerVeteransAffairsMedicalCenter,Salisbury,NC,UnitedStates
JuanPabloPalavicini
Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio,SanAntonio,Texas,UnitedStates
Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, SanAntonio,Texas,UnitedStates
BarshopInstituteforLongevityandAgingStudies,UTHealth,SanAntonio,TX,UnitedStates DepartmentofMolecularMedicine,UTHealth,SanAntonio,TX,UnitedStates Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University ofAlabamaatBirmingham,Birmingham,AL,UnitedStates DepartmentofNeurobiology,TheUniversityofAlabamaatBirmingham,Birmingham,AL,UnitedStates
Peter S.Rabinovitch, DepartmentofLaboratoryMedicineandPathology,UniversityofWashington, Seattle,WA,UnitedStates
Dr. Nicolas Musi is a tenured Professor of Medicine (Division of Geriatrics and Gerontology and Division of Diabetes) and Director of the Barshop Institute for Longevity and Aging Studies and the San Antonio Claude D. Pepper Older Americans Independence Center. He is also Associate Director for Research of the San Antonio Geriatric Research, Education and Clinical Center He is an active educator and research mentor, and supervises clinical and research fellows, residents, and graduate students. In thisrole,healsofunctionsasDirectorofaT32TrainingGrantontheBiologyofAging.
Dr. Peter J. Hornsby obtained a PhD in Cell Biology at the Institute of Cancer Research of the University of London. He has held faculty positions at the University of California San Diego, the Medical College of Georgia, and Baylor College of Medicine. Currently he is Professor in the Department of Physiology and Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center,SanAntonio
Since the inaugural publication of the HandbooksofAgingin 1976, the series has played a key role in promoting and guiding gerontological science. By preserving foundational knowledge and illuminating emerging areas, the series has served as a core resource for established researchers and an inspiration for students of gerontology. From its inception, gerontological science has been cross-disciplinary. The three-volume series has played a key role in maintaining cohesion in a science that spans dozens of disciplines.
The need to understand aging only increases in importance over time. The global population has now passed an important tipping point, moving from a world where children predominate to one in which there are more older people than youth. This reshaping of the age distribution in the population demandsgrandinvestmentsinthescienceofaging.
Thankfully, the science of aging is also growing faster than ever across social and biological sciences. Along with phenomenal advances in the understanding of the biology of aging as well as genetic influences on aging trajectories, and susceptibility to age-related diseases has come the awareness of the critical importance of the physical and social environments in which people age and the psychologicalfactorsthatmodulateandsometimesaltergeneticpredispositions.
The HandbooksofAgingseries, comprised of the HandbookoftheBiologyofAging, the Handbookof thePsychologyofAging, and the HandbookofAgingandtheSocialSciences, is now in its ninth edition. TheHandbookofAgingandtheSocialSciencesand theHandbookofthePsychologyofAginghave long provided conceptual anchors and frameworks to the social and behavioral sciences while also addressing emerging topics that did not exist decades ago, such as the fluidity of race and gender, groundbreaking insights into the role of sleep in cognitive aging, and the ways that smartphones, robots, and social media can modify the experience of aging. The handbooks also provide cutting-edge updates to the understanding of genetics, built environments, and intergenerational commitments. The 9th edition of the HandbookoftheBiologyofAgingintroduces geroscience, a discipline that did not exist 10 years ago and is now among the most vibrant in all of science. This edition also provides updates on the exciting advances in the genetics and integrative genomics of aging and longevity as wellasthebiologyandtherapeuticopportunitiesaffordedbythestudiesofcellularsenescence.
What has not changed over the editions is the superb synthesis of the field. The editors of the 9th edition extend a long tradition of giants in the field giving generously of their time and knowledge to produce consistently excellent volumes. Their thoughtful selection of topics and recruitment of deeply knowledgeable authors is reflected throughout the series. We are most grateful to Nicolas Musi and Peter J. Hornsby, editors of the HandbookoftheBiologyofAging, Kenneth F. Ferraro and Deborah S. Carr, editors of the HandbookofAgingandtheSocialSciences, and K. Warner Schaie and Sherry Lynn Willis,editorsoftheHandbookofthePsychologyofAging
We also express our deep appreciation to our publishers at Elsevier, whose profound interest and dedication to the topic has facilitated the publication of the Handbooks through many editions. We remain eternally grateful to James Birren, for establishing the series and shepherding it through the first six editions that played a profound role in establishing the tradition of multidisciplinary science in the fieldofaging.
Preface
NicolasMusiand PeterJ.Hornsby
As this series of volumes enters its 9th edition, it may well be said that the field of the biology of aging hasreacheditsmaturity.Thereareseveralthemesthatarereflectedinthecontentsofthisvolume.
1.1. In the past—now in reality the distant past—the biology of aging was a separate field of research, relatively unconnected to the mainstream of biological investigation. This has changed radically. Aging is now incorporated into a broad range of related fields, including cancer, diabetes and other metabolic diseases, immunology, and more. This has changed the way research in aging is viewed in many ways, and the benefits have been mutual on both sides. Research in aging has benefited from the input from these related areas, while those related areas have benefited from concepts developed in the biology of aging. Just one example is cellular senescence. Once considered a topic of narrow interest to a small group of investigators in technical aspects of cell culture, it has now been incorporated into multiple other areas, includingcancerandmetabolicdiseases,aswellasagingitself.
2.2. The second development reflected in the chapters in this volume is the degree to which the biology of aging has been incorporated into the basic biology of each organ system. For example, the basic biology of bone and the musculoskeletal system is incomplete without a consideration of the changes that take place in aging. Those include changes in the endocrine system, as well as stem cell biology. No account of the complete biology of any organ system is validunlessitincorporatesthebiologyofagingasanintegralpart.
3.3.The third significant development is the merging of translational and clinical research with basic biology. As the field has matured, it has become possible to apply biological findings to human patients, either in clinical trials or clinical practice. Translational research has also assumed a much greater prominence. Basic biology has benefited from these clinical and translational investigations. As results have emerged from those studies, they have stimulated new avenues of investigation in basic biology. For example, studies on interventions that may increase rodent life span have already had a major impact on clinical and translational investigation, and in turn those studies have impacted new research in basic biology. mTOR inhibitors and senolytics are examples of pharmacological interventions that increase rodent life span and have already been translated to the clinic. Findings from clinical and translational studies have in turn stimulated newavenuesinbasicbiology.Wecanexpectthistrendtocontinueinthefuture.
One of the more unfortunate consequences of these exciting developments is that it becomes impossible to produce a volume in the HandbookoftheBiologyofAgingseries that comprehensively covers all aspects of the topic. The selection of topics offered in the current volume is an attempt to sample many of these exciting areas with contributions from leading scientists in their fields. But we also offer in advance our apologies to readers whose particular areas of interest we had to omit. Omission does not indicate that we felt the area of less importance, but we simply face the reality of an incrediblyexpandingandincreasinglyexcitingfield.
PART I
Basic mechanisms, underlying physiological changes, model organisms and interventions
Aging is influenced by many intrinsic and extrinsic factors including genetic background, epigenetics, diet, and environment. Both our ability to develop a complete model of the aging process and accurately predict outcomes designed to extend lifespan or treat age-associated pathology require the identification of the range of factors capable of influence aging and an understanding of how these factors interact. In this chapter we discuss longevity and other phenotypes related to aging as complex genetic traits. We first review past and ongoing efforts to comprehensively catalog genetic and nongenetic factors that impact lifespan in invertebrate and mammalian model systems and conclude by discussing emerging tools that will help the aging-researchcommunityencompassthecomplexitiesoftheagingprocess.
Complex traits are phenotypic characteristics that result from the integration of many genetic loci and environmental factors. Longevity, along with the age-dependent decline in cellular and physiological processes that define aging, is quintessentially a complex genetic trait. A complete understanding of a complex trait requires both defining the range of factors that contribute to the trait and developing models for how the various factors interact. In the past several decades, hundreds of genes have been identified that are capable of influencing longevity or other age-associated phenotypes across a range of model systems. The majority of these genes can be broadly assigned to one or more of the following genetic pathways: (1) protein homeostasis, (2) insulin/IGF-1-like signaling (IIS), (3) mitochondrial metabolism, (4) sirtuins, (5) chemosensory function, or (6) dietary restriction. Pharmacologic agents targeting several of these pathways have been shown to increase lifespan and improve outcomes in age-associated disease in model systems and are either in use or in clinical trials for treatment of specific ailments. These include the mechanistic target of rapamycin (mTOR)-inhibitor rapamycin, the sirtuin activator resveratrol, and the glucose production suppressor metformin, and are discussed in greater detail in other chapters. Extragenetic but organism-intrinsic factors, such as tissue-specific gene expression,parentallyinheritedmolecules,andepigeneticscanalsocontributetoagingphenotypes.
Many environmental factors have been identified that impact longevity and age-associated disease. These include the abundance and composition of diet, exposure to various forms of stress, environmental temperature, social interaction, and even the presence or absence of a magnetic field. Among these, dietary restriction is by far the most widely studied. Reduction in total dietary intake or a change in the composition in the diet can have a profound impact on longevity in model systems. Shortterm exposure to thermal, oxidative, endoplasmic reticulum (ER), or other forms of stress is sufficient to increase lifespan. In both worms and fruit flies, adjusting the culture temperature can dramatically influencelifespan.Ineachcase,genes havebeenidentifiedthatmediatetheorganism’sresponsetothe environmentalstimuli.
This chapter examines aging as a complex trait. The following sections review past and ongoing efforts to define the scope of genetic, extragenetic, and environmental factors that influence aging, outline strategies for building interaction models, and discuss emerging tools that are furthering our abilitytoencompassthecomplexitiesofaging.
Defining the aging gene-space
A primary task in understanding the genetic complexity underlying any highly integrative phenotype is to identify the range of genes capable of impacting that phenotype. Three approaches are commonly employed to uncover novel aging factors. In models where targeted genome-scale genetic manipulation is possible and lifespan can be measured in a moderate- to high-throughput manner, screens have been carried out to identify single-gene manipulations capable of enhancing longevity. In longer-lived models and those less amenable to high-throughput targeted genetics, genetic mapping strategies are used to identify genetic loci at which natural variation is associated with differences in lifespan. A third approach is to leverage a secondary phenotype, such as stress resistance, that correlates with longevity but can be more rapidly screened to narrow the candidate gene list, and only screen genes that pass the primarythresholdforlongevity
Direct screens for genetic longevity determinants
Among models commonly used in aging research, the nematode Caenorhabditis elegans and the budding yeast Saccharomycescerevisiaepossess three characteristics allowing for large-scale genetic screening for longevity: (1) genetic tools allowing for targeted genome-scale manipulation of individual genes, (2) relatively short lifespans, and (3) techniques to rapidly and inexpensively culture large populations in the laboratory Complete genome sequences are available for both organisms (C.elegans SequencingConsortium,1998;Goffeauetal.,1996) and standardized lifespan assays can be completed in a matter of weeks (Murakami & Kaeberlein, 2009; Steffen, Kennedy, & Kaeberlein, 2009; Sutphin & Kaeberlein, 2009). Both models have been used in genome-scale screens for single-gene manipulations capable of increasing lifespan. In Drosophilamelanogaster, while targeted gene-modification is not
available at the genome-scale, random mutagenesis screens are used to identify novel longevity determinants and lifespan assays can similarly be completed in a matter of months (Linford, Bilgir, Ro, & Pletcher,2013).
RNA interferencescreensinnematodes
In C.elegans, targeted gene knockdown by RNA interference (RNAi) can be accomplished by feeding animals bacteria expressing double-stranded RNA containing the target sequence (Timmons & Fire, 1998). Two RNAi feeding libraries targeting individual genes throughout the C.elegansgenome have been constructed and are commercially available. The original Ahringer library contains 16,256 unique clones constructed by cloning genomic fragments targeting specific genes between two inverted T7 promoters (Fraser et al., 2000; Kamath et al., 2003). This library has recently been supplemented with an additional 3507 clones. The complete Ahringer library is commercially available through Source Bioscience (RNAi Resources | Source BioScience, n.d.). The Vidal library contains 11,511 clones produced using a full-length open reading frames (ORFs) gateway cloned into a double T7 vector (Rual et al., 2004) and is commercially available through either Source Bioscience (RNAi Resources | Source BioScience, n.d.) or Dharmacon Inc. (C.elegans| Dharmacon, 2019). Combined, these libraries provide single-gene clones targeting more than 20,000 unique sequences covering approximately 90% of knownORFsinC.elegans.
In total, more than 300 C.elegansgenes have been identified for which reducing expression results in prolonged lifespan (Braeckman & Vanfleteren, 2007; Smith et al., 2008), the majority in longevity screens using the RNAi feeding libraries (reviewed by Yanos, Bennett, & Kaeberlein, 2012) or random mutagenesis screens (de Castro, Hegi de Castro, & Johnson, 2004; Muñoz & Riddle, 2003) (Table 1.1). These include three genome-wide screens using the Ahringer RNAi feeding library (Hamilton et al., 2005; Hansen, Hsu, Dillin, & Kenyon, 2005; Samuelson, Klimczak, Thompson, Carr, & Ruvkun, 2007), two partial screens targeting genes on specific chromosomes (Dillin et al., 2002; Lee et al., 2003), five screens of RNAi clones or mutant sets selected in a preliminary screen for a secondary longevityassociated phenotype, such as arrested development, upregulation of the mitochondrial unfolded protein response, or resistance to thermal or oxidative stress (Bennett et al., 2017; Chen, Pan, Palter, & Kapahi, 2007; Curran & Ruvkun, 2007; de Castro et al., 2004; Kim & Sun, 2007; Muñoz & Riddle, 2003), and one recent screen of C.elegansorthologs of human genes differentially expressed at different ages in human whole blood (Sutphin et al., 2017). Combined, these studies have identified aging factors in a range of biological processes including mitochondrial metabolism, mitochondrial unfolded protein response, cell structure, cell surface proteins, cell signaling, protein homeostasis, RNA processing, and chromatinbinding.
Table1.1
Invertebratelongevityscreens Study
Wormlifespan
Dillin et al. (2002)
Chr. I, Ahringer RNAiLibrary
Lee et al. (2003)
Chr. I & II, Ahringer RNAi Library
daf-2, daf-16
mitochondrial metabolism
b daf-16 Mitochondrial function, metabolism, gene expression, protein homeostasis, signal transduction, stressresponse
Hamilton et al.(2005)
Whole genome, Ahringer RNAi Library
Hansen et al. (2005)
Whole genome, Ahringer RNAi Library
Samuelson et al.(2007)
Whole genome, Ahringer RNAi Library
89 daf-16, sir-2.1
Metabolism, signal transduction, protein homeostasis, gene expression
29
daf-2, daf-12, daf16, eat-2, glp-1
Signal transduction, stress response, gene expression, mitochondrial metabolism
