Telomeres and Telomerase in Ageing, Disease, and Cancer: Molecular Mechanisms of Adult Stem Cell Ageing

331 Pages·2008·4.84 MB·English

by  Andrew Dillin

Telomeres and Telomerase in Ageing,
Disease, and Cancer
Molecular Mechanisms of Adult Stem Cell Ageing
K. Lenhard Rudolph
Editor
Telomeres and Telomerase
in Ageing, Disease,
and Cancer
Molecular Mechanisms
of Adult Stem Cell Ageing
Dr. K. Lenhard Rudolph
Institute of Molecular Medicine and Max-Planck-Research-Group
on Stem Cell Aging
University of Ulm
Albert-Einstein-Allee 11, 89081 Ulm
Germany
[email protected]
ISBN 978-3-540-73708-7 e-ISBN 978-3-540-73709-4
Library of Congress Control Number: 2007931191
© 2008 Springer-Verlag Berlin Heidelberg
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Contents
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
Part I Telomere Shortening and Ageing
1. Cellular versus Organismal Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Andrew Dillin and Jan Karlseder
2. Telomere-Induced Senescence of Primary Cells . . . . . . . . . . . . . . . . . 23
Richard Allsopp
3. Telomeres, Senescence, Oxidative Stress, and Heterogeneity. . . . . . . 43
João F. Passos, Glyn Nelson, and Thomas von Zglinicki
4. Initiation of Genomic Instability, Cellular Senescence, and
Organismal Aging by Dysfunctional Telomeres. . . . . . . . . . . . . . . . . . 57
Sandy Chang
5. Telomerase Mutations and Premature Ageing in Humans. . . . . . . . . 77
Hong-Yan Du, Monica Bessler, and Philip J. Mason
Part II Telomerase, Telomeres, and Stem Cell Aging
6. Mechanisms of Stem Cell Ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Amanda Waterstrat, Erin Oakley, Alison Miller, Carol Swiderski,
Ying Liang, and Gary Van Zant
7. Senescence Signatures of Human Hematopoietic Stem Cells. . . . . . . 141
Stefan Zimmermann and Uwe M Martens
v
vi Contents
8. Telomere Shortening Induces Cell Intrinsic Checkpoints
and Environmental Alterations Limiting Adult
Stem Cell Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Luis Guachalla Gutierrez and Zhenyu Ju
9. p16INK4a and Stem Cell Ageing: A Telomere-Independent
Process? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Norman E. Sharpless
10. Telomerase as a Potential Regulator of Tissue
Progenitor Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Steven E. Artandi
Part III Telomeres, DNA Damage and Cancer
11. Telomere Shortening and Telomerase Activation during
Cancer Formation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
K. Lenhard Rudolph
12. Telomere Binding Proteins and Disease . . . . . . . . . . . . . . . . . . . . . . . . 229
Maria A. Blasco
Part IV Therapeutic Targets
13. Targeting Telomerase: Therapeutic Options for
Cancer Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
W. Nicol Keith and Alan E. Bilsland
14. Werner Syndrome, Telomeres, and Stress Signaling:
Implications for Future Therapies? . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
Terence Davis and David Kipling
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Contributors
Richard Allsopp
University of Hawaii, Institute for Biogenesis Research, John A Burns School
of Medicine, Honolulu, Hawaii, United States, [email protected]
Steven E. Artandi,
Department of Medicine, Cancer Biology Program, Stanford, California, United
States, [email protected]
Monica Bessler
Department of Internal Medicine, Washington University School of Medicine,
St. Louis, Missouri, United States
Alan E. Bilsland
Centre for Oncology and Applied Pharmacology, University of Glasgow,
Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road,
Bearsden, Glasgow G61 1BD, United Kingdom, [email protected]
María A. Blasco
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish
National Cancer Centre (CNIO), 3 Melchor Fernández Almagro, Madrid
E-28029, Spain, [email protected]
Sandy Chang
Department of Cancer Genetics and Hematopathology, The M.D. Anderson Cancer
Center, Houston, Texas, United States, [email protected]
Terence Davis
Department of Pathology, School of Medicine, Cardiff University, Heath Park,
Cardiff CF14 4XN, United Kingdom
Andrew Dillin
The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla,
California, United States, [email protected]
Hong-Yan Du
Department of Internal medicine, Washington University School of Medicine,
660 S. Euclid Ave., St. Louis, Missouri, United States
vii
viii Contributors
Luis Guachalla Gutierrez
Institute of Moleculare Medicine and Max-Planck-Research-Group on Stem Cell
Aging, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany
Zhenyu Ju
Institute of Moleculare Medicine and Max-Planck-Research-Group on Stem Cell
Aging, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany,
[email protected]
Jan Karlseder
The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla,
California, United States, [email protected]
W. Nicol Keith
Centre for Oncology and Applied Pharmacology, University of Glasgow,
Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road,
Bearsden, Glasgow, United Kingdom, [email protected]
David Kipling
Department of Pathology, School of Medicine, Cardiff University, Heath Park,
Cardiff, CF14 4XN, United Kingdom, [email protected]
Ying Liang
Departments of Internal Medicine and Physiology, Markey Cancer Center,
University of Kentucky, Lexington, Kentucky, United States
Uwe M. Martens
Medical University Center Freiburg, Department of Hematology/Oncology,
D-79106, Freiburg, Germany, [email protected]
Philip J. Mason
Department of Internal Medicine, Washington University School of Medicine,
6620 S Euclid Avenue, St. Louis, Missouri, United States
Alison Miller
Departments of Internal Medicine and Physiology, Markey Cancer Center,
University of Kentucky, Lexington, Kentucky, United States, [email protected]
Glyn Nelson
Henry Wellcome Laboratory for Biogerontology Research, Institute for Ageing
and Health, Center for Integrated Systems Biology of Ageing and Nutrition,
University of Newcastle upon Tyne, NE4 6BE, United Kingdom
Erin Oakley
Departments of Internal Medicine and Physiology, Markey Cancer Center,
University of Kentucky, Lexington, Kentucky, United States, [email protected]
Contributors ix
João F. Passos
Henry Wellcome Laboratory for Biogerontology Research, Institute
for Ageing and Health, Center for Integrated Systems Biology of Ageing
and Nutrition, University of Newcastle upon Tyne, NE4 6BE, United Kingdom,
[email protected]
K. Lenhard Rudolph
Institute of Moleculare Medicine and Max-Planck-Research-Group on Stem Cell
Aging, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany,
[email protected]
Norman E. Sharpless
Department of Medicine and Genetics, The Lineberger Comprehensive Cancer
Center, The University of North Carolina, Chapel Hill, North Carolina, United
States, [email protected]
Jerry Shay
Department of Cell Biology, University of Texas, Southwestern, Medical Center
at Dallas, Texas, United States, [email protected]
Carol Swiderski
Departments of Internal Medicine and Physiology, Markey, Cancer Center,
University of Kentucky, Lexington, Kentucky, United States
Gary Van Zant
Departments of Internal Medicine and Physiology, Markey Cancer Center,
University of Kentucky, Lexington, Kentucky, United States, [email protected]
Thomas Von Zglinicki
Henry Wellcome Laboratory for Biogerontology Research, Institute for Ageing
and Health, Center for Integrated Systems Biology of Ageing and Nutrition,
University of Newcastle upon Tyne, NE4 6BE, United Kingdom,
[email protected]
Amanda Waterstrat
Departments of Internal Medicine and Physiology, Markey Cancer Center, University
of Kentucky, Lexington, Kentucky, United States, [email protected]
Stefan Zimmerman
Medical University Center Freiburg, Department of Hematology/Oncology,
D-79106, Freiburg, Germany, [email protected]
Introduction
Twenty-five years after the disclosure of the telomeric DNA sequence and 22 years
after the discovery of telomerase, it has become clear that telomeres and telomerase
influence disease of human ageing including cancer. This book summarizes our
current knowledge on the role of telomeres and telomerase in ageing, regeneration,
and cancer with a special focus on ageing stem cells. Moreover, the book reviews
c urrent efforts to target telomeres and telomerase for anticancer treatment or regen-
erative therapies.
1.1 Ageing
The molecular analysis of ageing is an emerging research field that will have great
impact on patients care, lifestyle, and on disease prevention in the human population
worldwide. Major molecular mechanisms that influence the ageing process
include (1) the accumulation of molecular damage affecting DNA and pro-
teins, (2) alterations in gene expression, including alterations in checkpoint
responses, metabolic pathways, and developmental pathways, and (3) the decline in
adult stem cell function. All these mechanisms lead to a decrease in organ mainte-
nance and function, thus representing a major factor limiting the quality of life dur-
ing ageing. Moreover, the accumulation of molecular damage increases genetic
alterations and the cancer risk during ageing. Indeed, increased age is the leading
cause of cancer. Understanding the molecular basis of ageing will ultimately point
to targets for novel therapies aiming to improve the function of cells and organs in
the ageing organism, thus allowing increased vitality or what we think of as
“healthy ageing.”
In this book, Andrew Dillin and Jan Karlseder provide an overview on different
model organisms that are currently used to study ageing on the cellular and organ-
ismal levels. The authors discuss how different molecular mechanisms (telomere
shortening, insulin signaling, caloric restriction, mitochondrial function) may differen-
tially impact ageing of mitotically active versus postmitotic cells. Richard Allsopp
summarizes the influence of progressive telomere shortening and checkpoints
induced by dysfunctional telomeres on cellular ageing. When telomeres lose
xi
xii Introduction
capping function, a DNA damage response is induced, and the resultant telomere
shortening is one of the factors that leads to an accumulation of unrepaired DNA
damage during ageing, which causes cellular growth arrest. Similarly, DNA dam-
age checkpoints have been demonstrated for telomere-based replicative ageing as
well. There is now convincing evidence for progressive telomere shortening in
various human tissues during ageing, including stem cell compartments. It remains
an open debate as to what extent replicative senescence occurs during human age-
ing in vivo. Sandy Chang summarizes the consequences of telomere dysfunction on
ageing in mouse models. He describes evidence that telomere shortening can
cooperate with other pathways that are involved in DNA damage accumulation and
premature ageing (Werner Syndrome).
Oxidative damage is another factor that is responsible for the accumulation of
DNA damage during ageing. João F. Passos and colleagues summarize experimental
data indicating that oxidative damage and telomere dysfunction are interconnected
and cooperate to induce cellular ageing. It will be interesting to see whether similar
cooperation occurs during human ageing, which could then explain the exponential
accumulation of DNA damage in late life, when telomeres get short. Hong-Yan Du,
Monica Bessler, and Philip Mason conclude the first part of the book on telomeres
and ageing by summarizing disease states associated with telomerase mutations and
telomere shortening in humans. There is a growing number of human disease syn-
dromes that are associated with organ failure and that are caused by mutations in one
allele of genes encoding for telomerase (hTERT or hTR). It is notable that mutation
in only one allele of human telomerase leads to impaired organ homeostasis and pre-
mature death of these patients, sometimes at an age of 30–50 years. These findings
demonstrate that telomere reserves in humans are rather limited and that a reduction
in telomerase gene dosage has severe consequences that affect the ability to live a
“full” human lifespan. These findings provide strong evidence that telomere shorten-
ing can also influence normal ageing in humans without telomerase mutations.
2.1 Stem Cells
Although the molecular mechanisms of impaired organ maintenance during ageing
are largely unknown, it has been recognized that impaired organ maintenance corre-
lates with impaired function of adult stem cells during ageing. An understanding of
molecular mechanisms that are responsible for adult stem cell ageing is of utmost
importance to develop new therapies aiming to improve organ maintenance and func-
tion during ageing. The second part of this book focuses on adult stem cell ageing.
Garry Van Zant and coworkers provide a summary of our current knowledge of age-
ing of hematopoietic stem cells. The authors describe age associated changes in stem
cell number and function, and describe molecular pathways involved in stem cell
ageing. Their chapter shows that both cell i ntrinsic checkpoints and environmental
alterations represent major determinants limiting stem cell function during ageing.
Stefan Zimmermann and Uwe Martens also focus on hematopoietic stem cell ageing.