Table Of ContentPergamon studies in neuroscience No 8
Series editor Or William Winlow, Dept of Physiology, University of Leeds, LS2
9NQ, UK
Neuroscience is one of the major growth areas in the biological sciences and
draws both techniques and ideas from many other scientific disciplines.
Pergamon studies in neuroscience presents both monographs and multi-author
volumes drawn from the whole range of the subject and brings together the
subdisciplines that have arisen from the recent explosive development of the
neurosciences.
Pergamon studies in neuroscience includes contributions from molecular and
cellular neurobiology, developmental neuroscience (including tissue culture),
neural networks and systems research (both clinical and basic) and behavioural
neuroscience (including ethology). The series is designed to appeal to research
workers in clinical and basic neuroscience, their graduate students and advanced
undergraduates with an interest in the subject.
1. Function and dysfunction in the basal ganglia ed. A. J. Franks, J. W.
Ironside, R. H. S. Mindham, R. J. Smith, E. G. S. Spokes and
W. Winlow
2. Comparative aspects of neuropeptide function ed. Ernst Florey and
George B. Stefano
3. Neuromuscular transmission: basic and applied aspects ed. Angela
Vincent and Dennis Wray
4. Neurobiology of motor programme selection: new approaches to the
study of behavioural choose ed. Jenny Kien, Catherine R. McCrohan and
William Winlow
5. lnterleukin-1 in the brain ed. Nancy J. Rothwell and Robert D. Dantzer
New in 1993
A theory of the striatum J. Wickens
Glycobiology and the brain ed. M. Nicolini and P. F. Zatta
Neural modeling and neural networks ed. F. Ventriglia
Neurophysiology of Ingestion ed. D. A. Booth
Neuroregulatory mechanisms in aging ed. Maynard H. Makman and
George B. Stefano
Thalamic networks for relay and modulation ed. Diego Minciacchi,
Marco Molinari, Giorgio Macchi and Edward G. Jones
Neuroregulatory Mechanisms
in Aging
edited by
Maynard H. Makman and George B. Stefano
PERGAMON PRESS
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First edition 1993
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A catalogue record for this book is available from the
Library of Congress
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the
British Library
ISBN 0 08 041989 5
In order to make this volume available as
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List of Contributors
S. BHATNAGAR
Aging Research Program, McGill University-Douglas Hospital
Research Center, Departments of Psychiatry, Neurology and
Neurosurgery and Experimental Medicine, McGill University,
Montreal, Canada
T. V. BILFINGER
Department of Surgery, Health Science Center, University Hospital,
SUNY at Stony Brook, Stony Brook, NY 11794, USA
P. BLANCO
Departamento de Biologia Molecular (CSIC-UAM), Universidad
Autonoma, Canto Blanco, 28049 Madrid, Spain
R. J. BODNAR
Department of Psychology, Queens College, Flushing, New York, USA
S. R. BODNOFF
Aging Research Program, McGill University-Douglas Hospital
Research Center, Departments of Psychiatry, Neurology and
Neurosurgery and Experimental Medicine, McGill University,
Montreal, Canada
E. BOGONEZ
Departamento de Biologia Molecular (CSIC-UAM), Universidad
Autonoma, Canto Blanco, 28049 Madrid, Spain
D. O. CARPENTER
Wadsworth Center for Laboratories and Research, New York State
Department of Health and School of Public Health, Albany, New York
12201-0509, USA
E. E. EL-FAKAHANY
Department of Pharmacology and Toxicology, University of Maryland,
School of Pharmacy, Baltimore, MD 21201, USA
vii
viii List of Contributors
G. L. FRICCHIONE
Brigham's Womens Hospital, Division of Psychiatry, Harvard Medical
School, Boston, Mass., USA
I. HIROTSU
Laboratory of Experimental Pharmacology, Suntory Institute for
Biomedical Research, 1-1-1, Wakayamadai, Shimamoto-Cho, Mishima-
Gun, Osaka 618, Japan
N. HORI
Wadsworth Center for Laboratories and Research, New York State
Department of Health and School of Public Health, Albany, New York
12201-0509, USA and Department of Pharmacology, Faculty of
Dentistry, Kyushu University, 1-1-3, Maidashi, Higashi-Ku, Fukuoka
812, Japan
C. JANSE
Department of Biology, Vrije Universiteit, 1007 MC, Amsterdam, The
Netherlands
J.A.JOSEPH
Molecular Physiology and Genetics Section, Gerontology Research
Center/NIA, Baltimore, MD 21224, USA
N. KATSUDA
Department of Pharmacology, Faculty of Dentistry, Kyushu
University, 1-1-3, Maidashi, Higashi-Ku, Fukuoka 812, Japan
M. H. MAKMAN
Departments of Biochemistry and Molecular Pharmacology, Albert
Einstein College of Medicine, Bronx, New York 10461, USA
L. MALLOZZI
Multidisciplinary Center for the Study of Aging, State University of
New York/College at Old Westbury, Old Westbury, New York 11568,
USA
A. MARTINEZ-SERRANO
Departamento de Biologia Molecular (CSIC-UAM), Universidad
Autonoma, Canto Blanco, 28049 Madrid, Spain
List of Contributors ix
M.J.MEANEY
Aging Research Program, McGill University-Douglas Hospital
Research Center, Departments of Psychiatry, Neurology and
Neurosurgery and Experimental Medicine, McGill University,
Montreal, Canada
D. O'DONNELL
Aging Research Program, McGill University-Douglas Hospital
Research Center, Departments of Psychiatry, Neurology and
Neurosurgery and Experimental Medicine, McGill University,
Montreal, Canada
G. W. PASTERNAK
The George C. Cotias Laboratory of Neuro-Oncology, Memorial Sloan-
Kettering Cancer Center and Department of Neurology and
Neuroscience, Department of Pharmacology, Cornell University
Medical College, New York 10021, USA
J. POIRIER
Aging Research Program, McGill University-Douglas Hospital
Research Center, Departments of Psychiatry, Neurology and
Neurosurgery and Experimental Medicine, McGill University,
Montreal, Canada
S. PRYOR
Multidisciplinary Center for the Study of Aging, State University of
New York/College at Old Westbury, Old Westbury, New York 11568,
USA
P. G. PUERTAS
Departamento de Biologia Molecular (CSIC-UAM), Universidad
Autonoma, Canto Blanco, 28049 Madrid, Spain
J. SATRUSTEGUI
Departamento de Biologia Molecular (CSIC-UAM), Universidad
Autonoma, Canto Blanco, 28049 Madrid, Spain
G. B. STEFANO
Old Westbury Neuroscience Institute and Multidisciplinary Center for
the Study of Aging, State University of New York/College at Old
Westbury, New York 11568-0210, USA
x List of Contributors
M. VILLALBA
Departamento de Biologia Molecular (CSIC-UAM), Universidad
Autonoma, Canto Blanco, 28049 Madrid, Spain
S. A. WELNER
Aging Research Program, McGill University-Douglas Hospital
Research Center, Departments of Psychiatry, Neurology and
Neurosurgery and Experimental Medicine, McGill University,
Montreal, Canada
Introduction and Perspectives on the
Neurobiology of Aging
MAYNARD H. MAKMAISM and GEORGE B. STEFANO2
1 Departments of Biochemistry and Molecular Pharmacology, Albert Einstein
College of Medicine, Bronx, New York 10461, USA
2 Old Westbury Neuroscience Institute and Multidisciplinary Center for the
Study of Aging, State University of New York/ College at Old Westbury, New York
11568-0210, USA
Studies of aging have generally been concerned with determinants of
life span and cause of death, decreases in proliferative capacity of
different cell types, and functional impairments associated with old
age. An additional major consideration, of particular relevance to aging
of the nervous system, is the existence of and interaction between
"normal" aging and specific disease states that are more likely to occur
with increased age. The nature and extent of changes that occur with
increasing age may differ considerably in different species and also in
the various organs or tissues of a given species. Functionally important
age-related changes may or may not also be important causes of death
of the animal. In addition, a particular age-related pathological process
may be unique to one species or to a group of animal species. On the
other hand, important features of senescence may be shared by
different animals, and indeed there may be aspects of aging that are
shared by both vertebrate and invertebrate species.
There may be certain animals that do not appear to age, e.g., certain
paramecia and bivalve molluscs. However, it is possible that even
those animals age, but they also have an extremely long natural life
span. We may not see each individual organism age simply because of
the occurrence of accidental death. The concept of negative pleiotropy
has been employed to account for biological senescence. Indeed,
cumulative and unavoidable events or reactions may eventually lead
to decrements in function and/or death of an organism. Hence,
oxygen-free radicals, advanced glycosylation endproducts, protein
adducts, damage occurring with genetic repair, etc., may accumulate to
critical levels at which normal functions are compromised.
1
2 M. H. Makman and G. B. Stefano
Furthermore, the causative factor may even be a once useful process
now occurring in excess. Over time molecular alterations may pyramid
into cellular, tissue, organ and organismal modifications
/compensations whereby an individual will exhibit a general decline
in function and reactive capacity. Such age-associated modifications, at
least certain of them, are essentially inevitable. Also, by such processes
alterations that continue to occur may eventually allow the organism to
succumb to an environmental assault which at an earlier time posed no
threat. Thus, the aging process may insure for enhanced vulnerability
and death of a particular organism, thereby allowing for turnover of
the population and the possibility for incorporation of useful
mutations into the population.
In the human population there is evidence of age-related decrements
in central nervous system (CNS) function, including behavioral
impairment and altered response to CNS drugs. Certain of these
decrements may apply to the general human population and be due to
selective age-related alterations in neurotransmitter systems that also
occur with aging in other mammalian species. However, there may be
no close counterpart in other species to senile dementia of the
Alzheimer's type, a human disease associated with, and possibly
caused by, loss of certain central cholinergic neurons. It is often
difficult to be certain in studies of human aging whether or not
particular age-related changes represent "normal" aging due to factors
intrinsic to the organism or unavoidable interactions with the
environment, or to specific disease processes that may be as yet
undefined. However, it appears likely, based on animal studies, that
age-associated changes in CNS neurotransmitter systems indeed occur
independent of any specific disease process. These changes may be
manifest in altered function per se, altered functional "reserves" and/or
altered predisposition to or severity of pathological processes.
Not all functional components or neuronal cell types are affected
similarly by the aging process. Probably in most instances the
underlying cause(s) for a particular change is (are) not known. The
degree of plasticity of the adult nervous system is only now beginning
to be appreciated. Also, the possible regenerative capacity in some
situations remains to be evaluated. Additionally, changes in these
parameters with aging remain to be investigated.
The chapters in this book present studies of neuronal aging in a
variety of species. Also, a variety of approaches are utilized in order to
gain insight into the nature and significance of age-related changes.
The overall intent is to present some indication of the wide scope of
these studies, to give some idea of the present state of knowledge of
the neurobiology of aging in selected areas, and to include
Neurobiology of aging 3
representative examples of approaches and "model systems" for such
studies. We believe the comparative biological aspect to be of
particular importance. The comparative study of neuronal aging
greatly enhances our knowledge of the functioning of animal species
that may be quite different from one another, yet contain nervous
systems with many similarities with respect to their transmitter
systems as well as the basic sensory, motor and integrative functions.
These studies reveal surprising similarities in the integrative processes
regulating function and the life cycle in mammals and invertebrates.
Comparative studies of neuronal aging may also serve to focus
attention on those aspects of neuronal processes and adaptive
mechanisms that are necessary for survival and propagation of the
organism. For these reasons, such studies have a general relevance to
our understanding of life cycle events and the aging process in all
living organisms.
Since molecular biology has not yet provided the means for
intervention in the aging process, at present we are left with the
pharmacological approach to alleviate some of the effects of aging and
to restore age-associated alterations of normal function. Given the vast
amount of information that has been accumulated concerning the
pharmacology of the nervous system, it becomes important to attempt
to use this information to intervene appropriately in the aging process.
Also, age-related changes in the responses of humans to CNS-active
drugs have provided significant clues to the possible underlying
changes in the nervous system that occur with age. For these reasons,
neuropharmacological studies have provided a major focus for this
book.
Clearly, the nervous system plays a central role in the integrative
dynamic responsiveness of the organism. At the cellular and molecular
levels, modifications associated with damage or aging can be masked
by a host of compensatory mechanisms. However, once the utilization
of a particular compensatory mechanism reaches a point at which no
further change in the mechanism is possible or at which no further
response of the organism to that mechanism is possible, then the
functioning of the organism is compromised. A characteristic feature of
aging appears to be an altered, generally decreased, intrinsic or
adaptive response, including decreased reliability of homeostatic
regulation. In this regard, the role of the nervous system is particularly
important since it may be the first system to "signal" a decrease in the
dynamic capacity to respond.
The integrative functions of the nervous system include not only the
obvious hard wiring, including direct innervation of peripheral tissues,
but also a sort of soft wiring that allows for bidirectional
