Ageing: Lessons from C. elegans

433 Pages·2017·9.622 MB·English

by  Anders Olsen, Matthew S. Gill (eds.)

Healthy Ageing and Longevity 5
Series Editor: Suresh I.S. Rattan
Anders Olsen
Matthew S. Gill Editors
Ageing:
Lessons from
C. elegans
Healthy Ageing and Longevity
Volume 5
Series editor
Suresh I.S. Rattan, Aarhus, Denmark
More information about this series at http://www.springer.com/series/13277
Anders Olsen • Matthew S. Gill
Editors
Ageing: Lessons from
C. elegans
Editors
Anders Olsen Matthew S. Gill
Department of Molecular Biology Department of Metabolism & Aging
and Genetics The Scripps Research Institute
Aarhus University Jupiter, FL, USA
Aarhus, Denmark
ISSN 2199-9007 ISSN 2199-9015 (electronic)
Healthy Ageing and Longevity
ISBN 978-3-319-44701-8 ISBN 978-3-319-44703-2 (eBook)
DOI 10.1007/978-3-319-44703-2
Library of Congress Control Number: 2016957399
© Springer International Publishing Switzerland 2017
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Contents
1 Introduction ............................................................................................. 1
Anders Olsen and Matthew S. Gill
2 Effects of Ageing on the Basic Biology and Anatomy
of C. elegans ............................................................................................. 9
Laura A. Herndon, Catherine A. Wolkow, Monica Driscoll,
and David H. Hall
3 Dauer Formation and Ageing................................................................. 41
Pedro Reis-Rodrigues, Kailiang Jia, and Matthew S. Gill
4 Longevity Regulation by Insulin/IGF-1 Signalling .............................. 63
Seon Woo A. An, Murat Artan, Sangsoon Park, Ozlem Altintas,
and Seung-Jae V. Lee
5 Mitochondrial Longevity Pathways ...................................................... 83
Alfonso Schiavi and Natascia Ventura
6 Influences of Germline Cells on Organismal Lifespan
and Healthspan........................................................................................ 109
Francis R.G. Amrit and Arjumand Ghazi
7 Reproductive Ageing ............................................................................... 137
Cheng Shi and Coleen T. Murphy
8 Nervous System Ageing .......................................................................... 163
Claire Bénard and Maria Doitsidou
9 Stress Response Pathways ...................................................................... 191
Dana L. Miller, Joseph Horsman, and Frazer I. Heinis
10 Oxidative Stress ....................................................................................... 219
Bart P. Braeckman, Patricia Back, and Filip Matthijssens
11 Genome Stability and Ageing ................................................................. 245
Aditi U. Gurkar, Matthew S. Gill, and Laura J. Niedernhofer
v
vi Contents
12 Protein Homeostasis and Ageing in C. elegans ..................................... 265
Silvestre Alavez
13 Translational Control of Longevity ....................................................... 285
Jarod Rollins and Aric Rogers
14 Lipid Metabolism, Lipid Signalling and Longevity ............................. 307
Jonathon Duffy, Ayse Sena Mutlu, and Meng C. Wang
15 Autophagy and Ageing ............................................................................ 331
Malene Hansen
16 Dietary Restriction in C. elegans ........................................................... 355
Yue Zhang and William B. Mair
17 Integration of Metabolic Signals ............................................................ 393
Dana A. Lynn and Sean P. Curran
18 Microbiota, Probiotic Bacteria and Ageing .......................................... 411
Katrine V. Christensen, Maria G. Morch, Tine H. Morthorst,
Simon Lykkemark, and Anders Olsen
19 The Future of Worm Ageing .................................................................. 431
Gordon J. Lithgow
Index ................................................................................................................. 437
Chapter 1
Introduction
Anders Olsen and Matthew S. Gill
Abstract Advances in healthcare over the last century have led to an increase in
global life expectancy. In 2015, the fraction of the world population over the age of
65 was estimated at 8.5 % and is predicted to rise to 16.7 % by 2050 [1]. Unfortunately,
with every advancing decade of life the probability of developing one or more of the
chronic debilitating conditions that we associate with ageing increases dramatically.
This in turn leads to an extended period of late life morbidity and a deteriorating
quality of life that will have huge consequences for individuals and their families.
Ageing is the primary risk factor for a number of diseases and chronic condi-
tions. Therefore, slowing the rate of ageing would be an effective approach to com-
press the period of late life morbidity and increase the healthy years of life. This
would also provide an opportunity to simultaneously prevent or delay all age-
associated chronic conditions.
The pursuit of interventions that slow the rate of ageing is not new to modern
science. However, the last 40 years have seen a revolution in the field of ageing
research and we are much closer to the goal of improving human healthspan [2]. We
now realize that ageing is not an inevitable, intractable problem but rather it is mal-
leable and the rate of ageing can be manipulated genetically, environmentally as
well as chemically. Some of the dramatic advances in our understanding of the age-
ing process stem from seminal discoveries in the nematode C. elegans
(C. elegans).
Keywords C. elegans • Ageing • Longevity • Healthspan • Intervention
A. Olsen (*)
Department of Molecular Biology and Genetics, Aarhus University,
Gustav Wieds Vej 10C, 8000-DK, Aarhus, Denmark
e-mail: [email protected]
M.S. Gill (*)
Department of Metabolism & Aging, The Scripps Research Institute, Jupiter, FL, USA
e-mail: [email protected]
© Springer International Publishing Switzerland 2017 1
A. Olsen, M.S. Gill (eds.), Ageing: Lessons from C. elegans, Healthy Ageing
and Longevity 5, DOI 10.1007/978-3-319-44703-2_1
2 A. Olsen and M.S. Gill
1.1 C. elegans: A Most Excellent Model Organism
It was the work of Sydney Brenner at the University of Cambridge in the late 1960s
and early 1970s that laid the groundwork for establishing C. elegans as a powerful
genetic model system. Brenner was looking for an organism which could be used to
study how genes specify organismal development, particularly development of the
nervous system. In a landmark paper in 1974, he described how genetic screens
could be used to identify mutants with visible phenotypes, and how genetic analysis
could map these traits to single genes [3]. In the years that followed, C. elegans
developed into a powerful and tractable genetic model system, alongside the well-
established fly and yeast models.
As Brenner’s former postdocs and trainees established their own independent
laboratories, the C. elegans field diversified to examine other phenotypes including
apoptosis [4], sex determination [5] and germ line biology [6, 7]. The complete
embryonic and larval cell lineage for both hermaphrodites and males provided the
blueprint for C. elegans development [8–10] and in the late 1990s C. elegans became
the first multicellular organism to have its genome sequenced [11]. Other techno-
logical advances, such as the use of green fluorescent protein (GFP) to detect gene
expression and protein localization in vivo [12] and the discovery of RNA interfer-
ence (RNAi) as a means of knocking down gene function [13], continued to add to
the utility of the worm as a model system. Indeed, in the last 20 years four Nobel
Prizes have been awarded for discoveries that stemmed from the use of C. elegans.
1.2 C. elegans as Model Organism for Studying Ageing
The short lifespan and tractable genetics of C. elegans also made it an attractive
system in which to investigate the environmental and genetic basis of lifespan. In
the late 1970s, Michael Klass demonstrated that lifespan could be manipulated by
changing the temperature of cultivation and that dietary restriction could lead to
increased longevity [14]. He was also the first person to publish a genetic screen to
identify long-lived worms that he called Age mutants [15]. This initial screen identi-
fied a number of mutants that were surmised to extend lifespan via dietary restric-
tion, based upon their inability to take up an appropriate amount of food. Another
mutant, age-1 appeared wild type in terms of development and fertility and did not
appear to be dietary restricted. In parallel, other researchers started using C. elegans
to identify genes involved in ageing. The discovery in 1993 that the dauer constitu-
tive mutant daf-2 was long-lived [16] indicated that longevity mutants could be
identified using surrogate phenotypes and that epistasis approaches could be used to
define longevity pathways. In the years that followed, a number of other long-lived
mutants were identified via a number of different approaches ([17–20]).
In the late 1990s, cloning of C. elegans longevity genes revealed that some of the
long-lived C. elegans mutants had defects in an insulin/insulin-like growth factor
signalling (IIS) pathway [21, 22]. In a short space of time it was subsequently
1 Introduction 3
discovered that mouse and fly mutants that affected the IIS pathway also showed
increased longevity, illustrating the evolutionary conservation of pathways that
affect ageing. This moved C. elegans ageing research from a niche area of nematode
biology into the broader scientific community.
The sequencing of the C. elegans genome [11] and the development of RNAi by
feeding [23] heralded a new era of reverse genetic approaches that greatly facilitated
the identification of longevity genes. It was not long after the development of the
first whole genome RNAi library by the Ahringer Lab [24, 25] that large scale
reverse genetic screens for ageing genes began to appear [26, 27], dramatically
increasing the number of genes involved with lifespan determination.
1.2.1 Measurement of Ageing in C. elegans
At the time of publication of this book over a 1000 C. elegans genes have been
reported to influence lifespan via loss of function or over-expression [28] and many
more have been implicated through gene expression studies. Lifespan of wild type
worms grown at 20 °C is typically 20–25 days and many of the early interventions
lead to a doubling or tripling of lifespan. Null mutations in age-1 confer the largest
increase in lifespan for single gene mutants, with maximum lifespans of more than
250 days [29]. Combinations of multiple longevity mutants can also lead to extreme
longevity [18, 20, 30, 31]. Many other interventions have much more modest effects
on lifespan, often in the region of 20–40 %. It is also important to note that despite
the fact that lifespan is measured in isogenic populations under controlled environ-
mental conditions, there is substantial variation in C. elegans lifespan both within a
population and between biological replicates. It is therefore critical that replicate
lifespan studies are performed.
Most C. elegans ageing studies have used and continue to use survival as the
primary measurement outcome. This metric simply measures the fraction of a syn-
chronized sample population that is alive on any given day. It is important to note
that increased survival does not necessarily equate to changes in the rate of ageing.
Early studies of C. elegans ageing took advantage of the ease of growing large num-
bers of worms to carry out mortality rate analyses [32]. However, in recent years
there has been a trend away from this approach. The development of automated
methods of lifespan assessment [33] provides a new opportunity to carry out such
analyses but will require widespread implementation throughout the C. elegans age-
ing research community.
In parallel, there has been a move towards developing other measures of ageing
in the worm that are not focused solely on survival. These measurements attempt to
provide a metric of the health of the animals and include movement [34, 35], pha-
ryngeal pumping [36] and autofluorescence [37]. The use of these metrics has con-
tributed to the realization that increased lifespan is not always paralleled by
increased health and, conversely, some interventions increase healthspan without
extending lifespan.