Handbook of the Biology of Aging

Nicolas Musi, Peter Hornsby

• Publisher: Academic Press
• Year: 2015
• ISBN:
  9780124116207
• Edition: 8
• Topic: Medicine
• Subtopic: Geriatrics

Handbook of the Biology of Aging, Eighth Edition, provides readers with an update on the rapid progress in the research of aging. It is a comprehensive synthesis and review of the latest and most important advances and themes in modern biogerontology, and focuses on the trend of 'big data' approaches in the biological sciences, presenting new strategies to analyze, interpret, and understand the enormous amounts of information being generated through DNA sequencing, transcriptomic, proteomic, and the metabolomics methodologies applied to aging related problems.

The book includes discussions on longevity pathways and interventions that modulate aging, innovative new tools that facilitate systems-level approaches to aging research, the mTOR pathway and its importance in age-related phenotypes, new strategies to pharmacologically modulate the mTOR pathway to delay aging, the importance of sirtuins and the hypoxic response in aging, and how various pathways interact within the context of aging as a complex genetic trait, amongst others.

• Covers the key areas in biological gerontology research in one volume, with an 80% update from the previous edition
• Edited by Matt Kaeberlein and George Martin, highly respected voices and researchers within the biology of aging discipline
• Assists basic researchers in keeping abreast of research and clinical findings outside their subdiscipline
• Presents information that will help medical, behavioral, and social gerontologists in understanding what basic scientists and clinicians are discovering
• New chapters on genetics, evolutionary biology, bone aging, and epigenetic control
• Provides a close examination of the diverse research being conducted today in the study of the biology of aging, detailing recent breakthroughs and potential new directions

Part I

Basic Mechanisms of Aging: Models and Systems

Outline

Chapter 1 Longevity as a Complex Genetic Trait

Chapter 2 The mTOR Pathway and Aging

Chapter 3 Sirtuins, Healthspan, and Longevity in Mammals

Chapter 4 The Hypoxic Response and Aging

Chapter 5 The Role of Neurosensory Systems in the Modulation of Aging

Chapter 6 The Naked Mole-Rat: A Resilient Rodent Model of Aging, Longevity, and Healthspan

Chapter 7 Contributions of Telomere Biology to Human Age-Related Disease

Chapter 8 Systems Approaches to Understanding Aging

Chapter 9 Integrative Genomics of Aging

Chapter 10 NIA Interventions Testing Program: A Collaborative Approach for Investigating Interventions to Promote Healthy Aging

Chapter 11 Comparative Biology of Aging: Insights from Long-Lived Rodent Species

Chapter 1

Longevity as a Complex Genetic Trait

George L. Sutphin and Ron Korstanje, The Jackson Laboratory, Bar Harbor, ME, USA

Aging is influenced by many intrinsic and extrinsic factors including genetic background, epigenetics, diet, and environment. Our ability to develop a complete model of the aging process and accurately predict outcomes designed to extend lifespan or treat age-associated pathology requires 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 non-genetic factors that impact lifespan in invertebrate and mammalian model systems and conclude by discussing emerging tools that will help the aging-research community encompass the complexities of the aging process.

Keywords

Longevity; complex trait; gene mapping; QTL; GWAS; genomics

Outline

Introduction 4

Defining the Aging Gene-Space 4

Direct Screens for Genetic Longevity Determinants 5

RNAi Screens in Nematodes 5

Knockout Screens in Budding Yeast 8

Overexpression Screens in Fruit Flies 9

Leveraging Genetic Diversity to Identify Aging Loci 10

Mapping Longevity Genes in Human Populations 10

Mapping Longevity Genes in Mouse Populations 16

Mouse–Human Concordance 19

Age-Associated Gene Expression Studies 19

Non-Genetic Sources of Complexity 21

Tissue-Specific Aging 21

Tissue-Specific Age-Related DNA Methylation 21

Telomere Shortening and Telomerase 22

Tissue-Specific Responses of Aging Pathways 23

Gene–Environment Interaction 24

Genetic Response to DR 24

DR: Quantity, Composition, and Timing 26

Environmental Temperature 28

Environmental Oxygen and the Hypoxic Response 29

Other Environmental Factors That Influence Aging 30

Emerging Tools for Studying Aging as a Complex Genetic Trait 31

High-Throughput Lifespan Assays in Yeast and Worms 31

Genome-Scale Mouse Knockout Collection 34

Collaborative Cross and Diversity Outbred Mice 34

Expression QTLs 39

Aging Biomarkers 40

Conclusions 42

References 43

Introduction

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 (DR) (Fontana et al., 2010; Kenyon, 2010). 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 target of rapamycin (TOR)-inhibitor rapamycin, the sirtuin activator resveratrol, and the antidiabetic drug metformin (Kaeberlein, 2010), and are discussed in greater detail in Chapters 2, 3, and 10. Extragenetic, but organism-intrinsic, factors such as tissue-specific gene expression, parentally inherited molecules, and epigenetics can also contribute to aging phenotypes.

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, DR 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 (Masoro, 2005; Omodei and Fontana, 2011). Short-term exposure to thermal, oxidative, endoplasmic reticulum (ER), or other forms of stress is sufficient to increase lifespan (Cypser et al., 2006; Mattson, 2008). In both worms and fruit flies, adjusting the culture temperature can dramatically influence lifespan (Hosono et al., 1982; Loeb and Northrop, 1917; Miquel et al., 1976). In each case, genes have been identified that mediate the organism’s response to the environmental stimuli.

This chapter will examine 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 ability to comprehend the complexities of aging.

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 examine longevity for genes that pass a specified threshold for the secondary phenotype.

Direct Screens for Genetic Longevity Determinants

Among models commonly used in aging research, the nematode Caenorhabditis elegans and the budding yeast Saccharomyces cerevisiae possess 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 (Consortium, 1998; Goffeau et al., 1996) and standardized lifespan assays can be completed in a matter of weeks (Murakami and Kaeberlein, 2009; Steffen et al., 2009; Sutphin and Kaeberlein, 2009). Both models have been used in genome-scale screens for single-gene manipulations capable of increasing lifespan. In Drosophila melanogaster, while targeted gene-modification is not available at the genome-scale, random mutagenesis screens are used to identify novel longevity determinants.

RNAi Screens in Nematodes

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 and Fire, 1998). Two RNAi feeding libraries targeting individual genes throughout the C. elegans genome 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 (2013). The Vidal library contains 11,511 clones produced using full-length open reading frames (ORFs) gateway cloned into a double T7 vector (Rual et al., 2004) and is commercially available through Thermo Scientific (2013). Combin...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Foreword
• Preface
• About the Editors
• List of Contributors
• Part I: Basic Mechanisms of Aging: Models and Systems
• Part II: The Pathobiology of Human Aging
• Author Index
• Subject Index