WERNER' S SYNDROME AND HUMAN AGING

ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY

Editorial Board:

NATHAN BACK, State University oj New York at Bujjalo

NICHOLAS R. DI LUZIO, Tulane University School oj Medicine

EPHRAIM KATCHALSKI-KATZIR, The Weizmann Institute oj Science

DA VID KRITCHEVSKY, Wistar Institute

ABEL LAJTHA, Rockland Research Institute

RODOLFO PAOLETTI, University oj Milan

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WERNER'S SYNDROME ANDHUMAN AGING

Edited hy

Darrell Salk School of Medicine University of Washington Seattle, Washington

Y oshisada Fu jiwara Kobe University School of Medicine Kobe, Japan

and

George M. Martin School of Medicine University of Washington Seattle, Washington

PLENUM PRESS • NEW YORK AND LONDON

Library of Congress Cataloging-in-Publication Data

United States-Japan Cooperative Seminar on Werner's Syndrome and Human Aging (1982: Kobe-shi, Japan) Werner's Syndrome and Human Aging.

(Advances in experimental medicine and biology; v. 190) "Proceedings of a United States-Japan Cooperative Seminar on Werner's Syndrome

and Human Aging, held December 10-12,1982, in Kobe, Japan"-T.p. verso. Includes bibliographies and index. I. Werner's syndrome - Congresses. 2. Cells - Aging - Congresses.

3. Aging-Congresses. I. Salk, Darrell. II. Fujiwara, Yoshisada. III. Martin, George, 1927- IV. Title. V. Series. [DNLM: 1. Aging-congresses. 2. Werner's Syndrome-pathology-congresses. WI AD559 / QZ 45 U58w 1982) RC580.W47U55 1982 618.97 85-19426 ISBN 978-1-4684-7855-6 ISBN 978-1-4684-7853-2 (eBook) DOl 10.1007/978-1-4684-7853-2

Proceedings of a United States-Japan Cooperative Seminar on Werner's Syndrome and Human Aging, held December 10-12, 1982, in Kobe, Japan

©1985 Plenum Press, New York Softcover reprint of the hardcover 1 st edition 1985

A Division of Plenum Publishing Corporation 233 Spring Street, New York, N.Y. 10013

All rights reserved

No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher

PREFACE

In keeping with the traditions of deve1opmenta1 bio1ogy and geronto1ogy, there was a long incubation period before fu11 expres­sion of the plans for an International Conference on the Werner Syndrome and the pub1ication of the present monograph based upon the proceedings of that conference. The initial concept emerged at the Xlth International Congress. of Geronto1ogy, which took p1ace in Tokyo in 1978. Drs. G.M. Martin, Y. Fujiwara and Y. Mitsui met on that occasion to discuss ways of acce1erating the pace of research on this important disorder, inc1uding banking and sharing of ce11 cu1tures, establishment of patient registries, and p1anning of joint conferences and pub1ications.

In November 1979, under the auspices of the Geronto1ogica1 Society of America and a conference grant from the National Institute on Aging of the U.S. National Institutes of Hea1th, a group of Japanese investigators (Drs. Fujiwara, Mitsui, M. Goto, T. Ishii, K. Oota and ·T. Matsumura) met with Drs. Martin, D. Sa1k and W. Ted Brown to deve10p plans to implement the goals discussed at the initial Tokyo meeting. A workshop focused on the needs of ce11 banking and 1ed to an accumu1ation of research materials both in Japan (main1y under the leadership of T. Matsumura) and in the U.S.A. (with the cooperation of Dr. Arthur Greene of the Institute of Medica1 Research).

In 1981, Drs. Martin, Sa1k and Fujiwara deve10ped joint proposals to the U.S. National Science Foundation and the Japan Society for the Promotion of Sciences for a U.S.-Japan Cooperative Seminar on the Werner Syndrome. The conference took p1ace in Kobe, Japan in December, 1982. This was the first major confer­ence exc1usive1y devoted to a comprehensive examination of the natural history and experimental studies of the Werner syndrome. In the subsequent two years, the conference members participated in the preparation of this volume which brings together most of of what is known about the Werner syndrome, inc1uding pervious major reviews and the first Eng1ish translation of Otto Werner's original description. Unfortunate1y we seem to be a long way from e1ucidating the primary biochemica1 genetic defect, presum­ab1y an enzyme defic1ency. There is, therefore, tne promise

v

PREFACE

of future joint efforts to understand this experiment of nature. All of the conference participants were enthusiastic in agreeing to a second International Conference on the Werner Syndrome some years hence, perhaps in Germany, where Otto Werner first recognized and described the syndrome that bears his name.

We are grateful to the N.S.F. and the J.S.P.S. for having generously funded the conference. Additional support was provided by the Poncin Foundation, the Sanyo Electric Company Fund, the Naito Grant (1982), and several Japanese pharmaceutical companies. Colleagues and students in the Department of Radiation Biophysics, Kobe University School of Medicine provided invaluable assistance in organizational matters during the conference. Special thanks are due Kathy Hall for editorial and organizational assistance with the preparation of this book, and to Marie Walters for coordinating so much. Several other persons contributed to editing and manuscript preparation, and we express our appreciation: Allison Ross, Ginny Walters, Christy Cota, Suzanne Simmons, Linda Lawson and Ginny Wejak.

CONTENTS

HISTORICAL PERSPECTIVE

On Cataraet in Conjunetion with Seleroderma ••• • • • •• 1 Otto Werner (translated by Holger Hoehn)

Werner's Syndrome (Progeria of the Adult) and Rothmund's Syndrome: Two Types of Closely Related Heredofamilial Atrophie Dermatoses with Juvenile Cataraets and Endoerine Features; a Critieal Study with Five New Cases ••••••••• 15

S.J. Thannhauser

Werner's Syndrome: A Review of its Symptomatology, Natural History, Pathologie Features, Geneties and Relationship to the Natural Aging Proeess • • • •• 57

C.J. Epstein, G.M. Martin, A.L. Sehultz and A.G. Motulsky

Werner Syndrome: A Review of Reeent Research with an Analysis of Conneetive Tissue Metabolism, Growth Control of Cultured Cells, and Chromosomal Aberrations

D. Salk

CLINICAL, PATHOLOGICAL AND GENETIC ASPECTS OF THE WERNER SYNDROME AND NORMAL HUMAN AGING

Geneties and Aging: Werner's Syndrome as a

121

Segmental Progeroid Syndrome • • • • • • •• 161 G.M. Martin

viii

Clinieal, Endoerine and Metabolie Aspeets of the Werner Syndrome Compared with Those of

CONTENTS

Normal Aging • • • • • • • • • • • • • • • • • •• 171 H. Imura, Y. Nakao, H. Kuzuya, M. Okamoto,

M. Okamoto and K. Yamada

Pathology of the Werner Syndrome • • • • • • • • • • • • •• 187 T. Ishii, Y. Hosoda, Y. Hamada, S. Nakagawa,

G. Asano and Y. Horibe

Neuropathology of the Werner Syndrome • • • • • • • • • •• 215 S.M. Sumi

Werner's Syndrome and Aging: A Reappraisal ••••• • •• 219 C.J. Epstein

A Comparison of Adult and Childhood Progerias: Werner Syndrome and Hutehinson-Gilford Progeria Syndrome • • • • • • • • • • • • • • •• 229

W.T. Brown, F.J. Kieras, G.E. Houek, R. Dutkowski, E.C. Jenkins

Clinieal, Demographie and Genetie Aspeets of the Werner Syndrome in Japan • • • • • • • • • • •• 245

M. Goto, F. Takeuehi, K. Tanimoto, T. Miyamoto

Immunologieal Aspeets of the Werner's Syndrome: An Analysis of 17 Patients ••••••••

M. Goto, K. Tanimoto and T. Miyamoto

Clinieal and Metabolie Studies on the Werner's Syndrome: With Special Referenee to Disorders of Lipid and Liver Funetion • •

K. Murata and H. Nakashima

GROWTH CONTROL OF WERNER SYNDROME CELLS IN VITRO

Growth Charaeteristies of Werner Syndrome Cells in Vitro ••••••••••••

D. Salk, E. Bryant, H. Hoehn, P. Johnston and G.M. Martin

Studies of SV40-Infeeted Werner Syndrome Fibroblasts T. Matsumura, M. Nagata, R. Konishi and M. Goto

Experimental Studies on Werner's Syndrome Fibroblasts R. Holliday, K.V.A. Thompson, L.I. Husehtseha,

S.I.S. Rattan, S.G. Sedgwiek and A. Spanos

263

285

305

313

331

CONTENTS ix

Cell Fusion Studies in the Werner Syndrome • • • • • • • • • 341 K. Tanaka, K. Yamamura, K. Fukuehi, K. Kawai

and Y. Kumahara

Cell Fusion Studies and Bioehemieal Analysis of DNA Synthesis in Werner and Non-Werner Cultured Cells • • • • • •

W. Pendergrass, D. Salk and T. Norwood

MOLECULAR MECHANISMS OF CELLULAR SENESCENCE: DNA METABOLISM AND CHROMATIN CHANGE

Histone H1 in GI Arrested, Seneseent and Werner

353

Syndrome Fibroblasts • • • • • • • • • • • • • • 373 Y. Mitsui, H. Sakagami and M. Yamada

Genome Reorganization During Aging of Dividing Cells • • •• 391 A. Maeieira-Coelho and F. Puvion-Dutilleul

Cellular Meehanisms of Ageing in the Werner Syndrome • • •• 421 o. Nikaido, T. Nishida and A. Shima

Autoradiographie Studies of DNA Replieation in Werner's Syndrome Cells

F. Hanaoka, M. Yamada, F. Takeuehi, M. Goto, T. Miyamoto and T. Hori

Abnormal Fibroblast Aging and DNA Replieation in the Werner Syndrome • • • • • • • • • •

Y •. Fujiwara, Y. Kano, M. Iehihashi, Y. Nakao and T. Matsumura

Extraehromosomal Cireular DNA and Aging Cells • • C.K. Lumpkin, Jr., J.R. MeGill, K.T. Riabowol,

E.J. Moerman, R.J. Shmookler Reis and S. Goldstein

MOLECULAR MECHANISMS OF CELLULAR SENESCENCE: ERRORS IN PROTEIN SYNTHESIS

Protein Synthetie Fidelity in Aging Human Fibroblasts • • • • • • • • • • • • •

S. Goldstein, R.I. Wojtyk, C.B. Harley, J.W. Pollard, J.W. Chamberlain and C.P. Stanners

439

459

'479

495

x

Analysis of Cellular Senescence through Detection and Assessment of RNAs and Proteins Important to Gene Expression:

CONTENTS

Transfer RNAs and Autoimmune Antigens • • • • • • • •• 509 P.F. Agris, A. Boak, J.W. Basler, C.

Van Voorn, C. Smith and M. Reichlin

CYTOGENETICS OF THE WERNER SYNDROME

Cytogenetic Aspects of Werner Syndrome • • • • • • • •• 541 D. Salk, K. Au, H. Hoehn and G.M. Martin

A Population and Cytogenetic Study of the Werner Syndrome in Sardinia • • • • • • • • • •• 547

M. Fraccaro and S. Scappaticci and D. Cerimele

CONNECTIVE TISSUE METABOLISM AND DISTURBANCES IN THE WERNER SYNDROME

Proteoglycans in the Werner Syndrome and Aging: A Review and Perspective • • • • • • • • •• 553

E. Bryant, D. Salk and T. Wight

Cell Surface Changes in Senescent and Werner's Syndrome Fibroblasts: Their Role in Cell Proliferation

Y. Mitsui, K. Yamamoto, M. Yamamoto and K. Matuoka

. . . . . . . . .

Acidic Glycosaminoglycans in Werner's Syndrome: Studies on Levels in Tissue, Organ, Cell and Fluid • • • • • • • • •

K. Murata, R. Hiwatari and T. Matsumura

Acidic Glycosaminoglycans of SV40-Transformed Werner's Syndrome Cells •••••••••

K. Murata, M. Kudo and T. Matsumura

567

587

607

CONTENTS

Glycosaminoglycan Synthesis in Untransformed and Transformed \.ferner Syndrome

xi

Fibroblasts: A Preliminary Report • • • • • • •• 613 Y. Fujiwara and M. Icihashi

GENE ACTION, DEVELOPMENT AND AGING: NEW DIRECTIONS FOR RESEARCH IN THE WERNER SYNDROME

The Notion of Primordial Building Blocks in Construction of Genes and Transcriptional and Processing Errors due to Random Occurrence of Oligonucleotide Signal Sequences ••••••••••• 627

S. Ohno

Appearance of Albumin-Producing Cells in the Liver of Anabulminemic Rats on Aging and Administration of Mutagens ••••

H. Esumi, Y. Takahashi, R. Makino, S. Sato and T. Sugimura

INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . .

637

651

OPENING REMARKS

Kunio Oota

Director Emeritus, Tokyo Metropolitan Institute of Gerontology, Shiroyama 2-31-2, Bunkyo-ku, Tokyo 112, Japan

This morning, I have the honor to say a few words on behalf of the Committee on Aging Research, the parent committee of the Japanese organizer of this seminar, as apart of the government­supported national project of life-science studies in Japan, welcoming to Japan and to the City of Kobe all of you participating in the U.S.-Japan Seminar on Pathogenetic Mechanisms of Werner's syndrome.

As you are weil aware, not a great number of the world's scientists are deeply committed to aging research. It is not because gerontology is being regarded as unimportant, but because of difficulties in finding effective approaches to this most interesting problem. Mechanisms involved in the senescence of living bodies seem to be in a great big black box, the guarded wall of which has been penetrated only by so many theories and hypotheses. One expects, however, that if only a tiny hole could be dug deep enough, we might possibly insert glass-fiber optics and inspect the inside.

One of the most hopeful candidates of such pioneering attempts may be the elucidation of the mechanisms involved in the pathogenesis of human progeroids. As it happens, our colleagues here have been successful in collecting data from a number of cases with the Werner syndrome, now called segmental progeroid, and in analyzing them from various aspects. I congratulate the U.S. National Science Foundation and the Japan Society for Promotion of Sciences for selecting this subject as a topic of the U.S.-Japan Cooperative Research Project.

xm

xiv K.OOTA

To be very frank, we did not expect too much when the group was first formed in Japan a few years aga to study progeroid. We bad the very good luck to find enthusiastic scientists among the members and an extremely able leader in Professor Fujiwara, and now we are grateful to the members and proud of their accomplishments.

I am convinced that the fruits to be reaped from the preeminent gerontologists of the world during the three-day seminar will make a distinguished and valuable contribution, not only to the study of the Werner syndrome per se, but also to the basic knowledge of gerontology in general. I personally expect, especially, that the discussions will point out the future direction of the aging study. Some of us even expect to hear choice discussions on whether we could regard senescence as ~ biological expression of extended differentiation or as a sequence of stochastically occurring errors among the biological molecules.

I was born in Kobe some 70 years ago, and I may be allowed to add a few words concerning the history of the land on which we are now standing. The city was almost completely destroyed by bombing during World War 11. A very imaginative mayor with his background in technology proposed that the city be rebuilt with a new idea. His plan, as now realized, presents to you spacious lots of new land reclaimed from the sea. The work took over 30 years to complete. In completing it, the citizens of Kobe City moved earth from the mountains in the background into the sea, expanding the living and working spaces in both the background and the foreground of the city.

I hope you enjoy your seminar and also your stay in the City of Kobe, which is very beautiful.

Thank you.

Garl Wilhelm Otto Werner 1879 - 1936 (Kiel, 1904)