HJG@>PG<M =<NDN W N <BDIB @]bm^]�[r <eoZkh�HZ\b^bkZ*>h^eah)�H+?+)�?+N\+)�?+a+\+ M^l^Zk\a�?bk^\mhk� DIN@MH� Q^klZbee^l)�AkZg\^ First published 1995 by CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 Reissued 2018 by CRC Press © 1995 by Taylor & Francis CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. 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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. A Library of Congress record exists under LC control number: 95015170 Publisher’s Note The publisher has gone to great lengths to ensure the quality of this reprint but points out that some imperfections in the original copies may be apparent. Disclaimer The publisher has made every effort to trace copyright holders and welcomes correspondence from those they have been unable to contact. ISBN 13: 978-1-138-10600-0 (hbk) ISBN 13: 978-0-203-71130-9 (ebk) Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com T E he ditor Alvaro Macieira-Coelho, M.D., D.Sc., D.h.c., is Research Director at the French National Institute of Health (INSERM), Department of Immu­ nology, Medical School Pitié-Salpetrière, University of Paris VI. Dr. Macieira-Coelho obtained his M.D. at the University of Lisbon, Portugal and his D.Sc. from the University of Uppsala, Sweden. From 1958-1961 he was an intern at the Lisbon University Hospital and a research associate at the Wistar Institute of the University of Pennsylvania (1961-1964) and in the Department of Pathology of the University of Uppsala (1964-1967). He was head of the Department of Cell Pathology at the Institute of Cancerology and Immunogenetics, Villejuif, France (1967- 1986) and visiting professor at the Department of Cell Biology at the University of Linköping, Sweden (1987-1989). Dr. Macieira-Coelho currently teaches at the University of Paris. He has given over 100 invited lectures at international meetings and at vari­ ous institutes and universities, has published more than 100 research papers, and is the author of one book. He was the editor of one book on aging and is on the editorial board of four international gerontology journals. Dr. Macieira-Coelho received the Johananoff International Visiting Professorship from the Mario Negri Institute (Milan) in 1982, the Fritz- Verzaàr Prize for Gerontology from the University of Vienna in 1988, and a Dr. Honoris Causa from the University of Linköping, Sweden, in 1991. He is a member of the New York Academy of Sciences, American Society for Cell Biology, American Association for Cancer Research, and the Gerontological Society of America. His current research interests concern the role of cell replication in aging of the human organism, for which he received support from a grant from the Sandoz Foundation for Gerontological Research. C ontributors Paul S. Agutter, Ph.D. Siegfried Hoyer, M.D. Department of Biological Sciences Department of Pathochemistry and General Napier University Neurochemistry Edinburgh, Scotland University of Heidelberg Heidelberg, Germany Hervé Allain, M.D., Ph.D. Kenneth H. Johnson, M.D. Pharmacology Laboratory Department of Veterinary PathoBiology Faculty of Medicine College of Veterinary Medicine University of Rennes I University of Minnesota Rennes, France St. Paul, Minnesota Fiorenzo Battaini, Ph.D. M. S. Kanungo, Ph.D. Department of Experimental Medicine and Molecular Biology Laboratory Biochemical Sciences Department of Zoology University of Rome Tor Vergata Banaras Hindu University Rome, Italy Varanasi, India and Danièle Bentue-Ferrer, Ph.D. Institute of Life Sciences Bhaneswar, India Pharmacology Laboratory Faculty of Medicine Paul J. M. Klosen, Ph.D. University of Rennes I Laboratory of Cell Biology Rennes, France Catholic University of Louvain Louvain-la-Neuve, Belgium Philippe van den Bosch de Aguilar, J. Labat-Robert, Ph.D. Ph.D. Department of Cell Biology Laboratory of Cell Biology University of Paris VII Catholic University of Louvain Paris, France Louvain-la-Neuve, Belgium Hans U. Lutz, Ph.D. Ulf Brunk, Ph.D. Laboratory for Biochemistry Department of Pathology Swiss Federal Institute of Technology University of Linköping Zurich, Switzerland Linköping, Sweden Alvaro Macieira-Coelho, M.D., D.Sc., D.hc. James W. Gaubatz, Ph.D. Research Director, INSERM Department of Biochemistry and Molecular Versailles, France Biology College of Medicine Jaime Miquel, Ph.D. University of South Alabama Chief, Division of Applied Neuroscience Mobile, Alabama Institute of Neurosciences University School of Medicine Stefano Govoni, Ph.D. Alicante, Spain Institute of Pharmacological Sciences and University of Milan Institute of Molecular Medical Sciences Milan, Italy Palo Alto, California Werner E. G. Müller, Ph.D. George S. Roth, Ph.D. Department of Applied Molecular Biology Molecular Physiology and Genetics Section Institute of Physiological Chemistry Laboratory of Cellular and Molecular Biology Mainz, Germany Gerontology Research Center NIH, National Institute on Aging Atsushi Miyamoto, M.S., Ph.D. Baltimore, Maryland Department of Pharmacology Heinz C. Schröder, M.D., Ph.D. Sapporo Medical University School of Medicine Department of Applied Molecular Biology Sapporo, Japan Institute of Physiological Chemistry Mainz, Germany Hans Niedermüller, Ph.D. D. F. Swaab, M.D., Ph.D. Austrian Society for Geriatrics and Director, Graduate School Neurosciences Gerontology Netherlands Institute for Brain Research Institute of Physiology Amsterdam, The Netherlands and The Ludwig Boltzmann Institute of Marco Trabucchi, M.D. Experimental Gerontology Department of Experimental Medicine and Veterinary Medical University Biochemical Sciences Vienna, Austria University of Rome Tor Vergata Rome, Italy Suresh I. S. Rattan, Ph.D., D.Sc. Laboratory of Cellular Aging Per Westermark, M.D., Ph.D. Department of Chemistry Department of Pathology Aarhus University Linköping University Aarhus, Denmark Linköping, Sweden Ladislas Robert, M.D., Ph.D. Dazhong Yin, Ph.D. Department of Cell Biology Department of Pathology University of Paris VII Linköping University Paris, France Linköping, Sweden J. N. Zhou, M.D. Graduate School Neurosciences Netherlands Institute for Brain Research Amsterdam, The Netherlands and Ningxia Medical College Ningxia, China T C able of ontents Introduction....................................................................................................1 I. THE STORAGE OF INFORMATION Chapter 1 Reorganization of the Genome during Aging of Proliferative Cell Compartments..............................................................................................21 Alvaro Macieira-Coelho Chapter 2 Genomic Instability during Aging of Postmitotic Mammalian Cells...............71 James W. Gaubatz Chapter 3 DNA Repair during Aging...........................................................................137 Hans Niedermiiller Chapter 4 Changes in Gene Expression during Aging of Mammals.............................183 M. S. Kanungo Chapter 5 Role of Mitochondria in Cell Aging..............................................................219 Jaime Miquel II. THE FLOW OF INFORMATION Chapter 6 Modifications of the Cell Surface Leading to Cell Elimination......................237 Hans U. Lutz Chapter 7 Protein Kinase C Signal Transmission during Aging....................................269 Fiorenzo Battaini, Stefano Govoni, and Marco Trabucchi Chapter 8 Changes in Transmembrane Signaling Mechanisms during Aging: Cellular and Molecular Aspects...................................................................293 Atsushi Miyamoto and George S. Roth Chapter 9 Structural Changes Modifying the Intracellular Flow of Information..............................................................................................307 Alvaro Macieiro-Coelho Chapter 10 The Aging of the Neuronal Cytoskeleton......................................................327 Paul J. M. Klosen and Philippe van den Bosch de Aguilar Chapter 11 Transport of mRNA into the Cytoplasm......................................................353 Werner E. G. Mittler, Paul S. Agutter; and Heinz C. Schroder Chapter 12 Translational and Post-translational Modifications during Aging.................389 Suresh I. S. Rattan Chapter 13 Carbonyl Toxification Hypothesis of Biological Aging..................................421 Dazhong Yin and Ulf Brunk Chapter 14 Amyloidosis and Aging...............................................................................437 Per Westermark and Kenneth H. Johnson Chapter 15 Extracellular Matrix......................................................................................459 Ladislas Robert and J. Labat-Robert Chapter 16 Brain Metabolism during Aging...................................................................493 Siegfried Hoyer Chapter 17 Central Neurotransmission in the Elderly.....................................................511 Hervé Allain and Daniele Bentue-Ferrer Chapter 18 Age-Related Changes in Neuropeptidergic Neurons in the Human Hypothalamus.................................................................................527 J. N. Zhou and D. F. Swaab Index............................................................................................................533 I ntroduction Those without expertise in gerontology, but interested in understand­ ing the investigations carried out to elucidate the mechanisms of aging, face many difficulties. PROBLEMS ARISING FROM COMPARATIVE BIOLOGY AND PHYSIOPATHOLOGY One difficulty comes from the tendency that many gerontologists have of looking for a global view of the mechanisms of aging along the evolutionary scale, extrapolating data, and then seeking for universal explanations. Comparative biology has shown that the mechanisms of aging cannot be universal.1 This does not mean, however, that studies performed on lower organisms along the evolutionary scale are useless in understanding human aging. Some mechanisms may be conserved, but as an organism becomes more complex other regulatory mechanisms come into the picture, and as a result the homeostatic regulation of the life span also increases in complexity. Moreover, along the evolutionary road some mechanisms have remained preponderant in some species, while becom­ ing secondary in others. It is obvious that the mechanisms controlling the life span in Droso­ phila, for instance, where there is no cell turnover in the mature organism, cannot be the same as those in a mammal, where permanent renewal occurs throughout the life span in many cell compartments, and whose genome is more complex than that of a fly. Initial mortality rates are also extremely high in flies; as compared with humans, they are 1000 times higher.1 This illustrates fundamental developmental differences, showing that the mechanisms regulating the life span in Drosophila cannot be extrapolated to vertebrates. A disregard for comparative biology and physiopathology has led to shortcuts and misinterpretations that have retarded the advancement of gerontology and handicapped communications between gerontologists. We have limited this volume to experimental approaches performed with mammals but even among mammals striking differences appear, indicating that extrapolations should be carried out with restraint. 1