INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 144
PRINCIPLES OF EVALUATING CHEMICAL EFFECT ON THE AGED
POPULATION
This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organisation, or the World Health Organization.
Published under the joint sponsorship of
the United Nations Environment Programme,
the International Labour Organisation,
and the World Health Organization
World Health Orgnization
Geneva, 1993
The International Programme on Chemical Safety (IPCS) is a
joint venture of the United Nations Environment Programme, the
International Labour Organisation, and the World Health
Organization. The main objective of the IPCS is to carry out and
disseminate evaluations of the effects of chemicals on human health
and the quality of the environment. Supporting activities include
the development of epidemiological, experimental laboratory, and
risk-assessment methods that could produce internationally
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toxicology. Other activities carried out by the IPCS include the
development of know-how for coping with chemical accidents,
coordination of laboratory testing and epidemiological studies, and
promotion of research on the mechanisms of the biological action of
chemicals.
WHO Library Cataloguing in Publication Data
Principles for evaluating chemical effects on the aged population.
(Environmental health criteria ; 144)
1.Aged 2.Aging 3.Environmental exposure 4.Environmental
pollutants - adverse effects 5.Hazardous substances - adverse
effects
I.Series
ISBN 92 4 157144 6 (NLM Classification: WT 104)
ISSN 0250-863X
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CONTENTS
PRINCIPLES FOR EVALUATING CHEMICAL EFFECTS ON THE AGED POPULATION
INTRODUCTION
1. SCOPE OF THE PROBLEM
1.1. Objectives
1.2. Definitions
1.2.1. Aging versus senescing
1.2.2. Aging of individuals and populations
1.2.3. Chemicals of concern
1.2.4. Time and dose of exposure
1.3. Chemical exposure
1.4. Aged population
1.4.1. Demographic consideration
1.4.2. Life expectancy
1.4.3. Life-style in aged populations
1.5. Theories of aging
2. STRUCTURAL AND PHYSIOLOGICAL CHANGES IN THE AGED
2.1. Changes in gene structure and function in aging
2.1.1. Chromatin structure
2.1.2. DNA repair
2.1.3. Transcription
2.1.4. Translation
2.2. Changes in tissues, organs and systems in aging
2.2.1. Nervous system
2.2.1.1 Structural changes
2.2.1.2 Biochemical changes
2.2.1.3 Functional changes
2.2.2. Sensory organs
2.2.2.1 Vision
2.2.2.2 Hearing
2.2.2.3 Olfaction
2.2.2.4 Taste
2.2.2.5 Somatic sensations
2.2.3. Endocrine system
2.2.3.1 The pituitary-thyroid axis and the
basal metabolism
2.2.3.2 The pituitary-adrenal axis
2.2.3.3 The endocrine pancreas and
carbohydrate metabolism
2.2.4. Reproductive system
2.2.4.1 Female aging
2.2.4.2 Male aging
2.2.5. Immune system
2.2.5.1 Aging of lymphoid organs
2.2.5.2 Aging of cellular constituents
2.2.5.3 Neuroendocrine-immune
2.2.6. Cardiovascular system
2.2.6.1 Heart
2.2.6.2 Blood vessels
2.2.6.3 Characteristics of atherosclerotic
lesions
2.2.6.4 Theories of atherosclerosis
2.2.7. Respiratory function
2.2.7.1 Gas-exchange organs
2.2.7.2 Erythropoietic activity
2.2.8. Kidney and body fluid distribution
2.2.8.1 Renal function
2.2.8.2 Lower urinary tract
2.2.9. Gastrointestinal function
2.2.9.1 Gastrointestinal tract
2.2.9.2 Pancreas
2.2.9.3 Liver
2.2.10. Musculo-skeletal system
2.2.10.1 Bones
2.2.10.2 Joints
2.2.10.3 Skeletal muscles
2.2.11. Skin
3. BASIS OF ALTERED SENSITIVITY TO ENVIRONMENTAL CHEMICALS
3.1. Pharmacokinetics
3.1.1. Absorption
3.1.2. Distribution
3.1.3. Metabolism
3.1.4. Excretion
3.2. Pharmacodynamics
3.2.1. Central nervous system
3.2.2. Endocrine system
3.2.2.1 Changes in hormonal availability
with age
3.2.2.2 Changes with age in the reception
of the signal by the target cells
3.2.2.3 Changes in the nature of the
hormonal message with age
3.2.3. Kidney
3.2.4. Immune system
3.2.5. Other tissues and systems
3.3. Modifying factors
3.3.1. Nutrition
3.3.2. Alcohol intake
3.3.3. Smoking
3.4. Interactions of chemicals and diseases
3.4.1. Cancer
3.4.2. Other diseases
4. APPROACHES TO EXAMINING THE EFFECTS OF CHEMICALS ON THE AGED
POPULATION
4.1. Experimental approaches
4.1.1. Principles for testing chemicals in
the aged population
4.1.2. Animal models
4.1.2.1 Animal species
4.1.2.2 Animal strain
4.1.2.3 Animal sex
4.1.2.4 Selection of age groups for
comparison
4.1.2.5 Underlying pathology of animals of
different ages
4.1.2.6 Transgenic animals
4.1.2.7 Animal husbandry
4.1.3. Chemical exposure
4.1.3.1 Dose level
4.1.3.2 Route of administration
4.1.3.3 Duration of exposure
4.1.4. Non-mammalian models
4.1.5. In vitro studies
4.1.6. Statistical considerations
4.1.7. Extrapolation of animal data to humans
4.2. Epidemiological and clinical approaches
4.2.1. Disease pattern of aged population
4.2.2. Assessment of effects of environmental
chemicals in the elderly population
4.2.3. Acute episodes
4.2.4. Concerns for the aged population
4.3. Biomarkers of aging
5. CONCLUSIONS
6. FURTHER RESEARCH
REFERENCES
APPENDIX 1
PARTICIPANTS IN THE PLANNING AND TASK GROUP MEETINGS ON PRINCIPLES
FOR EVALUATING CHEMICAL EFFECTS ON THE AGED POPULATION
Members
Dr V.N. Anisimov, N.N. Petrov Institute of Oncology, Ministry of
Health, St Petersburg, Russian Federationa,b,c,d
Dr L.S. Birnbaum, US Environmental Protection Agency, Research
Triangle Park, North Carolina, USAa,b,d
Dr G. Butenko, Institute of Gerontology, Kiev, Ukraineb
Dr R.L. Cooper, US Environmental Protection Agency, Research
Triangle Park, North Carolina, USAa,b,d
Dr V.M. Dilman, N.N. Petrov Research Institute of Oncology,
Ministry of Health, St Petersburg, Russian Federationa,c,d
Dr N. Fabris, Italian National Research Centre on Aging, Ancona,
Italyb,d
Dr N.S. Gradetskaya, Research Institute of Industrial Hygiene
and Occupational Diseases, Academy of Medical Sciences,
Moscow, Russian Federationa
Dr K. Kitani, Tokyo Metropolitan Institute of Gerontology, Tokyo,
Japanb
Dr J. Leaky, National Center for Toxicological Research,
Jefferson, Arkansas, USAb
Dr A.Y. Likhachev, N.N. Petrov Institute of Oncology, Ministry of
Health, St Petersburg, Russian Federationa,d
Dr S. Li, Chinese Academy of Preventive Medicine, Department of
Scientific Information, Beijing, Chinaa,b,d
Dr G.M. Martin, University of Washington, Department of Pathology,
Seattle, Washington, USAa,b*,c,d
Dr E. Masoro, The Texas University at San Antonio, San
Antonio, Texas, USAb
Dr N.P. Napalkov, N.N. Petrov Research Institute of Oncology,
Ministry of Health, St Petersburg, Russian Federationa
Dr G.I. Paramonova, Institute of Gerontology, Academy of Medical
Sciences, Kiev, Ukrainea
Dr J. Parizek, Czechoslovakia Academy of Sciences, Institute of
Nuclear Biology and Radiochemistry, Prague, Czechoslovakiaa
Dr P.K. Ray, Industrial Toxicology Research Centre, Council of
Scientific and Industrial Research, Lucknow, Indiaa,b*,d
Dr A. Richardson, Illinois State University, Normal, Illinois,
USAb*,d
Dr G.S. Roth, National Institute of Health, National Institute on
Aging, Baltimore, Maryland, USAb
Dr G.J.A. Speijers, National Institute for Public Health and
Environmental Protection (RIVM), Bilthoven, The
Netherlandsb,d
Dr K.T. Suzuki, National Institute for Environmental Studies,
Ibaraka, Japana,c
Dr J. Vijg, Medscand Ingeny, Leiden, The Netherlandsb
Dr J.R. Zhu, Zhong Shan Hospital, Shanghai Medical University,
Shanghai, Chinab,d
Observer
Dr E.I. Komarov, Central Research Institute of Roentgenology and
Radiology, Ministry of Health, St Petersburg, Russian
Federationa
Secretariat
Dr G.C. Becking, International Programme on Chemical Safety,
Interregional Research Unit, World Health Organization,
Research Triangle Park, North Carolina, USA (Secretary for the
Planning Meeting)a
Dr B.H. Chen, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland (Secretary
for the Task Group Meeting)b
Dr Z.P. Grigorevskaya, Centre for International Projects,
Moscow, Russian Federationa
Dr M.I. Gounar, Centre for International Projects, Moscow,
Russian Federationa
Dr H. Hermanova, Regional Office for Europe, World Health
Organization, Copenhagen, Denmarka*
Dr P.G. Jenkins, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerlandb
Dr M. Mercier, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerlandb
a Participant in Planning Meeting, St Petersburg, Russian
Federation, 5-9 September, 1988
b Participant in Task Group Meeting, Geneva, Switzerland,
9-13 December, 1991
c Submitted background information for planning meeting
d Prepared background paper for the preparation of the first
draft
* Invited but unable to attend
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
Every effort has been made to present information in the
criteria monographs as accurately as possible without unduly
delaying their publication. In the interest of all users of the
Environmental Health Criteria monographs, readers are kindly
requested to communicate any errors that may have occurred to the
Director of the International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland, in order that they may be
included in corrigenda.
INTRODUCTION
The aged population and the number of chemicals in the
environment have been increasing and will undoubtedly continue to
increase. It is estimated that there will be 612 millon people aged
60 years and over by the year 2000, and of these 61% will live in
developing countries. The numerous physiological and biochemical
changes occurring during aging can modify the pharmacokinetics and
pharmacodynamics of chemicals in the elderly, resulting in either
higher or lower levels of toxicity. It is expected that the adverse
effects of chemical exposure on the elderly will increase in
importance as a health care issue. IPCS has been active in the
development and validation of methodology for the assessment of
risks from exposure to chemicals. One area of concern has been the
evaluation of methodology appropriate for the assessment of risks in
"high-risk" groups. The fifth meeting of the IPCS Programme Advisory
Committee endorsed the need for an Environmental Health Criteria
monograph dealing with the effects of chemicals on the aged
population and the aging processes. This monograph integrates
relevant studies of toxicology and gerontology; toxicology examines
the potential health effects of exposure to chemicals, while
gerontology focuses on the scientific explanations for the phenomena
and mechanism of aging.
A planning meeting was held in St Petersburg from 5 to 9
September 1988 and was organized locally by the N.N. Petrov Research
Institute of Oncology, Ministry of Health, Russian Federation.
Financial support through the UNEP Country Projects was provided by
the Centre for International Projects (CIP), State Committee for the
Protection of the Environment, Moscow, Russian Federation. Dr M.I.
Gounar, CIP, formally opened the meeting, and Dr V. Anisimov, on
behalf of Dr N.P. Napalkov, former Director of the Petrov Research
Institute of Oncology, welcomed the participants. Dr G.C. Becking
welcomed the participants on behalf of the Executive Heads of the
three IPCS cooperating organizations (UNEP/ILO/WHO). Dr V. Anisimov
and Dr L. Birnbaum were Joint Chairmen and Dr P.K. Ray and Dr A.
Likhachev were Joint Rapporteurs.
After discussing the scientific issues relevant to both the
aged population and aging processes, the committee considered that
there was sufficient epidemiological, clinical and experimental data
to support the preparation of an Environmental Health Criteria
monograph to evaluate chemical effects on the aged population.
However, the differing views on the mechanisms of aging and how
chemical exposure might alter such mechanisms preclude at present
the preparation of an evaluation of the chemical effects on the
aging process. It was decided to prepare a monograph on principles
for evaluating chemical effects on the aged population, with only a
brief discussion of the present concept of aging. An outline of the
monograph together with a list of possible authors was produced.
Drs L. Birnbaum and V. Anisimov prepared the first draft of
this monograph based on 13 background papers written by various
authors (Appendix 1). Dr V. Anisimov prepared the second draft
incorporating comments received following the circulation of the
first draft to IPCS Contact Points for Environmental Health Criteria
monographs and to IPCS Participating Institutions. Dr L. Birnbaum
made a considerable contribution to the preparation of the final
text.
A WHO Task Group Meeting met from 9 to 13 December 1991 in
Geneva. Dr B.H. Chen, IPCS, opened the meeting and welcomed the
participants on behalf of the Director, IPCS, and the three IPCS
cooperating organizations. Dr J. Vijg and Dr K. Kitani were Chairman
and Vice-Chairman, respectively, and Drs L. Birnbaum and V. Anisimov
were Joint Rapporteurs.
The Task Group considered it likely that the aged population is
more susceptible to the harmful effects of environmental chemicals.
However, very few environmental chemicals have been tested for
toxicity in the elderly. Some age-associated diseases may lead to an
increased susceptibility to the harmful action of specific
environmental chemicals. The effects of environmental chemicals on
the process of aging remain to be evaluated. It was suggested that a
special scientific workshop be devoted to this topic.
Drs B.H. Chen (IPCS Central Unit) and G.C. Becking
(Interregional Research Unit) were responsible for the overall
scientific content, and Dr P.G. Jenkins (IPCS Central Unit) was
responsible for the technical editing.
The efforts of all who helped in the preparation and
finalization of the monograph are gratefully acknowledged.
ABBREVIATIONS
ACTH adrenocorticotrophic hormone
BMAA beta- N-methylamino-1-alanine
BOAA beta- N-oxalylamino-L-alanine
cDNA complementary DNA
CNS central nervous system
GABA gamma-aminobutyric acid
GH growth hormone
GI gastrointestinal
HDL high density lipoprotein
hnRNA heterogeneous nuclear RNA
LDL low density lipoprotein
LH luteinizing hormone
mRNA messenger RNA
SDAT senile dementia of Alzheimer type
T3 triiodothyronine
T4 thyroxine
TSH thyroid-stimulating hormone
UDP uridine diphosphate
UDPGA UDP-glucuronic acid
1. SCOPE OF THE PROBLEM
1.1 Objectives
The main objective of the Group involved in the preparation of
this report was to review present knowledge concerning the effects
of environmental chemicals on the aged population and to evaluate
available models for the assessment of these effects and the
consequent risk to human health in the aged population.
About ten million natural and synthetic chemicals have been
identified by the Chemical Abstract Service Registry and some eighty
to one hundred thousand have been identified as important to
commerce. The restricted knowledge of the toxicological properties
of the natural substances makes it difficult to give clear evidence
of whether the elderly population is at risk for this category of
compounds, but the impact of these natural toxins might be even
larger than that of most man-made toxicants. As the requirements for
more toxicological data on natural toxicants become more important
internationally, the possible effects on the elderly population
should also be included in the assessment.
The following relationships need to be considered: a) the
special response of the aged as compared to that of the young
following exposure to environmental chemicals; and b) the impact of
exposure to environmental chemicals on the processes of aging. This
report focuses on the first relationship, i.e. the elderly as a
population at special risk. The elderly are heterogeneous with
respect to aging processes, life-style and diseases. Indeed, in
most instances the deficit in the majority of the elderly relates
more to life-style and diseases than to the aging processes per se.
The Group recommended that the evaluation of the effects of
environmental chemicals on the process(es) of aging should be the
focus of a separate scientific workshop. This monograph will focus
on environmental chemicals as opposed to pharmaceuticals and food
additives, although information on these latter chemicals will be
used when necessary to support the issues.
The study of the effects of chemicals on the aged population
requires the integration of two disciplines, toxicology and
gerontology. Toxicology examines the potential health effects of
exposure to chemicals, while gerontology focuses on the scientific
explanations for the phenomena and mechanisms of aging. The lack of
a unified theory of aging, together with the inability at present to
distinguish intrinsic aging from natural disease and toxic response,
creates difficulties which make the objective of the Group only
partially attainable.
1.2 Definitions
1.2.1 Aging versus senescing
Plant biologists often sharply differentiate between these
terms (Leopold, 1975). They may use the word aging to refer to all
of the changes in structure and function in an organism throughout
the life course, including the period of development. They reserve
the term senescence for the deteriorative alterations in structure
and function that are the immediate precursors of tissue and
organismal death. Mammalian gerontologists, however, typically use
the terms aging and senescence (or, more properly, senescing)
interchangeably to describe the constellation of changes that occur
after the attainment of sexual maturity and the young adult stage of
life. This is not to deny the critical importance of developmental
events in setting the stage for subsequent patterns of senescence.
For example, a specific chemical, physical or infectious agent,
acting during a crucial period of ontogeny, could conceivably
deplete, but not ablate, a subset of stem cells or their partially
differentiated progeny without any phenotypic consequences until
additional depletion, related to some normative aging process,
reaches a clinically significant threshold.
1.2.2 Aging of individuals and populations
At the organismal level, endogenously and exogenously induced
injuries are more likely to occur as the organism ages. There is a
decreasing probability, as a function of chronological time, that
the organism will survive. Thus, there is an exponential increase in
the death rate over time. Although subject to important
environmental influences, the ages at which such exponential
increments of death rates begin and the kinetics of their
progression are subject to strong genetic influences in that they
are species-specific. The basic observations have been summarized by
the following equation (Gompertz, 1825):
Rm = R0.ealpha t
where Rm indicates the mortality rate at time t, R0 is a
parameter empirically determined by extrapolating an exponential
curve back to zero time (sometimes referred to as the "initial
vulnerability"), e is the natural logarithm, t is time and alpha is
a slope constant. Better fits to empirical data are obtained if a
second constant is added to the right hand side of the above
equation (the Gompertz-Makeham equation).
The Gompertz-Makeham equation is a satisfactory approximation
to the kinetics of specific mortality in human populations in the
age range 20-80 years. Correspondingly, the value of alpha
characterizes the rate of aging only within this interval. Although
some deviations of alpha within this interval in human populations
have been noted (Pakin & Hrisanov, 1984), the analysis of the
parameters of the Gompertz-Makeham equation permit one to make
objective estimations of the changes in the mortality in populations
(Sacher, 1977; Hirsch, 1982). It is important to note that the use of
this method for measuring the rate of aging in populations of
experimental animals is especially reliable when the external
conditions (e.g., the housing of animals) remain constant throughout
the whole period of a study.
1.2.3 Chemicals of concern
The first class of agents of concern would be those with a
special potential to injure elderly subjects because of their
unusual susceptibility. This sensitivity might be the result of
intrinsic biological aging, chronic exposure to deleterious
environmental agents, a high prevalence of various age-related
diseases, or a combination of all of these. A rational approach to
this problem requires detailed knowledge of the altered physiology,
biochemistry and special pathologies of older people (those over age
65) and, especially, of the very old (those over age 85). Examples
include the special vulnerability of many elderly subjects to air
pollutants, to certain pharmaceuticals and combinations of
pharmaceuticals, and even to injury from methane gas explosions. The
latter results from a high prevalence of atrophic change in the
olfactory network, with consequent marked reduction in the ability
of many older people to detect the low concentration of sulfide
contaminants that are deliberately added to household gas to warn of
leakage. It is apparent that, with respect to such classes of
agents, public health actions can be of immediate benefit to older
people.
The second class of chemicals of concern would be those that
might modulate the processes of aging. These could either accelerate
("gerontogens") or retard ("geroprotectors") the aging processes.
1.2.4 Time and dose of exposure
As indicated above, chemical agents that have the potential to
accelerate aspects of aging could act at any time during the life
course, from before birth to death. Strictly speaking, however,
agents that are most likely to closely mimic natural aging processes
are slow, insidious and progressive. Moreover, since the phenotypic
consequences of aging are often subtle and, for the human species,
develop over a period of decades, it would be difficult indeed to
establish a minimum effective dose for such putative chemicals. The
task is somewhat less difficult in the case of agents to which the
elderly have some special vulnerability, since acute and sub-acute
end-points are often involved. For example, the prevalence of
cardiopulmonary morbidity can be related to ambient concentrations
of specific urban pollutants.
1.3 Chemical exposure
The world is irrevocably dependent on man-made chemicals,
modern technology bringing a dramatic increase in their production
and consumption. More than 750 000 chemicals are known to be in our
environment and between 1000 and 2000 new ones enter the market each
year. A major proportion of these chemicals find use as components
of various consumer products, or they enter the environment as
industrial waste, posing health risks as well as benefits.
In present-day society, we use chemicals to boost our food
production, make our lives easier and protect our health. Many of
these chemicals are hazardous and great care must be taken during
their usage, storage and disposal. Their releases into the
environment, whether intentional or not, can have severe
consequences.
Billions of tons of hazardous industrial waste materials,
produced every year, may enter the environment through complex and
interrelated pathways (air, water, food, etc.), and could affect
humans. Pesticides, fertilizers and herbicides enter the environment
as a result of direct application; nitrogen oxides, sulfur oxides
and polycyclic aromatic hydrocarbons result from combustion
processes. Many manufacturing processes liberate unwanted
by-products and waterborne and airborne wastes, which are sometimes
more toxic than the raw materials. Incidents such as the
contamination of water by mercury, the widespread distribution of
industrial oils (e.g., polychlorinated biphenyls), and the
destruction of the ozone layer in the stratosphere due to the
release of aerosol propellants (chlorofluorocarbons) have made the
public aware of the ability of some chemicals to cause unexpected
results at some point far removed from where they were originally
introduced. Chemicals undergo transformation once they enter the
environment, and a relatively harmless chemical may become a toxic
by-product. It may further enter the food chain and accumulate in
living organisms, eventually reaching humans.
In both developed and developing countries there has been a
great impact of life-styles upon the quality of life and upon the
life span of the population concerned. Of particular interest are
the aged individuals, who, having lived longer in an environment
containing toxic agents, may suffer from their cumulative effects
even when exposure levels are relatively low. The multiple
life-long, though low-level, human exposure to chemicals is
difficult to assess adequately in terms of associated health risks
(Pines et al., 1987). It has been reported that some chronic low
level exposures to chemical or physical stressors have beneficial
effects on longevity (hormesis) (Sacher, 1977; Neafsey, 1990).
Among the chronic health effects of chemicals, cancer is of
major concern. Many substances have found in recent years to be
carcinogenic in one or more species of laboratory animals (WHO,
1983). In humans, cancer is seldom manifest until 10-40 years after
exposure to the carcinogenic agent (IARC, 1990). Thus, cancers
caused by chemicals are most often observed in the aged population.
However, it is not easy to identify the hazards unless past exposure
is known. Similar comments may be made about atherosclerosis, which
may also be related to chemical exposure (Penn et al., 1981).
In many cases, especially with respect to long-term effects,
the response to a chemical may vary, quantitatively or
qualitatively, in different groups of individuals depending on
predisposing conditions, such as nutritional status, disease status,
current infection, climatic extremes, and genetic features, sex and
age of the individuals. Understanding the response of such specific
risk groups is an important area of toxicology research today.
There is no biological basis for classifying substances
according to their environmental source (e.g., industry or
agricultural use), or use patterns (e.g., food additives). Chemical
substances with neurotoxic potential, for example, are found as
natural metabolites (e.g., quinolinate), biological poisons in
plants (e.g., gossypol) and animals (e.g., batrachotoxin), natural
components of food (e.g., beta-oxalylamino-L-alanine (BOAA)) and
beverages (e.g., ethanol), food contaminants (e.g., ergot),
synthetic food additives (e.g., aspartame), flavours and fragrances
(e.g., dinitromethoxybutyl toluene), pollutants of air (e.g., lead),
water (e.g., zinc pyridinethione) and industrial processes (e.g.,
carbon disulfide), and therapeutic drugs (e.g., phenothiazines). In
addition, numerous chemicals, if they have damaging actions, may
contribute to the aging phenotype.
Chemicals influencing the processes of aging and/or affecting
the aged population may be classified into several groups according
to their chemical properties and metabolic behaviours. Chemicals
that are poorly metabolized fall into two groups. The first are
absorbed and distributed into certain tissues according to their
partitioning behaviour, based on their physical/chemical properties.
For example, organochlorine compounds concentrate in adipose tissue.
During fasting, adipose tissue is mobilized and accumulated
chemicals are liberated into body fluids. Organo-chlorine compounds
are detectable in adipose tissue, blood and breast milk long after
cessation of exposure. The second group comprises chemicals that are
poorly excreted and accumulate in the body. Some of these chemicals
are detoxified by binding to specific proteins, resulting in
long-term storage. For example, cadmium, lead and mercury induce
specific proteins such as metallothionein which help in the
detoxification of heavy metals (Oh et al., 1978; Onasaka & Cherian,
1981). The appearance of cadmium toxicity among the population over
50 years of age may be related to the decreased capacity of
metallothionein synthesis with advancing age (Hunziker & Kagi,
1985).
Chemically and biologically active chemicals are readily
metabolized. Thus, they do not accumulate in the body. Continuous
exposure to these chemicals is of concern because these may be
metabolized to reactive intermediates that can interact and damage
cellular macromolecules. Such damage may be cumulative, resulting in
the aged population being more vulnerable. Other types of chemicals
which belong to this group (e.g., NOx, SO2) can also cause more
severe adverse effects on the aged whose defensive mechanisms are
weakened. It should be stressed that several chemicals can enter the
body at the same time, causing a more complex problem.
1.4 Aged population
1.4.1 Demographic consideration
The United Nations has defined people of 60 years and over as
the aged. In 1988, it was estimated that there were about 488
million people in the world fitting this criterion. The number is
expected to rise to 612 million by the year 2000, 61% of whom (i.e.
376 million) will be living in developing countries (Fig. 1) (WHO,
1990).
Many countries are, however, using 65 years and over as the
definition of the elderly. The corresponding numbers for this age
group are 327 million in the world in 1990 and 423 million by the
year 2000, of whom 250 million will be in developing countries (WHO,
1990). The increase in the elderly population will be particularly
marked in Asia, primarily as a result of the rapid growth expected
in the numbers of the aged in China and India. This trend is
illustrated in Fig. 2, which indicates the 20 countries with the
largest aged population in 1980 and the expected growth of the aged
population. By the year 2020, there will be an increase of 270
million elderly citizens in China and India. The size of the aged
population is expected to rise by more than 20 million in both
Brazil and Indonesia, and by roughly half that number in Mexico,
Nigeria and Pakistan (WHO, 1989).
On the other hand, a much smaller absolute increase in the
elderly population is anticipated for the European countries, where
population aging began much earlier. As a result, the developing
countries will gradually account for the largest elderly population
in the world. Indonesia, for example, is expected to move from tenth
place in 1980 to fifth in 2020 (Fig. 2), and Mexico is expected to
have the eighth largest elderly population, ahead of Italy, France,
and the United Kingdom (WHO, 1989).
The elderly population of the USA is growing much more rapidly
than the population as a whole. In the 1970s, the population aged 65
and over increased by 28% and the population aged 85 and over
increased by 59%, whereas the total population increased only by
11%. The population aged 85 and over is expected to triple between
1980 and 2020 and is the fastest growing of the four older age
groups (55-64, 65-74, 75-84, and 85 and over). Census projections
for 2050 indicate that the proportion of the population aged 65 and
over (22%) will be almost twice as great as it is today (12%). In
the last two decades alone, the 65-plus population has grown by 54%
while the under-65 population has increased by only 24%. At the
beginning of this century, less than one in eight Americans was age
55 and over. The increase in the numbers of elderly people is
expected to occur in two stages. Until the year 2000, the proportion
of the population age 55 and over is expected to remain relatively
stable at 22%. By 2010, because of the maturation of the post World
War II baby boom, more than a quarter of the total population of the
USA is expected to be at least 55 years old, and one in seven of the
population will be at least 65 years old. By 2050, one in three
persons is expected to be 55 years or older and one in five will be
over 65 (US Senate Special Committee on Aging, 1986).
It is commonly assumed that today's large percentage of elderly
people in the population is a result of increased longevity and
decreased birth rate. For example, in Japan the proportion of people
aged 65 or more had increased to 10.3% in 1985. At the same time,
the values were 15.1%, 14.5%, 12.4% and 16.9% in the United Kingdom,
Federal Republic of Germany, France and Sweden, respectively. Japan
is a new "aged-type" country with the greatest rate of increase in
the elderly in the world. By the year 2025, the proportion of the
Japanese population aged 65-plus will rise to 23.4% (Hosomi, 1990).
In China, the proportion of the population aged 60 and over was
7.3% of the total population in 1953. By 1984 it had increased to 9%
of the total population, and by the year 2000 the proportion of the
population 60 and over will be as high as 10.6%. The proportion is
predicted to increase to 26.2% by 2025 (Xiong, 1990).
At present, the aged population is growing more rapidly in
China than in countries of Europe and North America. According to
data from the US Bureau of the Census, it took 115 years (1865-1980)
for the proportion of people aged 65 or more in France to increase
from 7% to 14%, 85 years (1890-1975) in Sweden, 66 years (1944-2010)
in the USA, 45 years (1930-1975) in the United Kingdom, and 26 years
(1970-1996) in Japan. For China, the pattern of the growing number
of elderly is similar to Japan, i.e. the proportion of people aged
65 or more will be 7.4% in 2000, and by 2025 it will have increased
to 12.8% (Hosomi, 1990; Yao, 1990; Xiong, 1990).
1.4.2 Life expectancy
Life expectancy at birth is a statistical index calculated by
the use of a life table from the age-specific death rates of the
population. This illustrates the overall level of health in a
country or a region. Throughout this century, it has been evident
that, as a result of improvements in many aspects of health status,
an individual can expect to live longer. From 1960 to 1990, life
expectancy at birth for the total population had increased by 13.5
years. The life expectancy at birth for the period 1985-1990 was
estimated to be 63.9 years for the world as a whole, 74.0 years for
the more developed regions, and 61.4 years for the less developed
regions. The longest life expectancies are in Japan (78.3), Iceland
(77.5), Sweden (77.1), Switzerland (77.1), and the Netherlands
(76.9) (World Population Prospects, 1991).
The trend for life expectancy at birth in the USA showed an
increase from 1900 (46.4 for males and 49.4 for females) to 1950
(65.6 and 71, respectively) and in the year 2000 is expected to be
72.1 and 79.5 (for males and females). By 2050, it may have
increased to 73.6 for males and 81 for females (US Senate Special
Committee on Aging, 1986).
In China, the life expectancy at birth before 1949 was about 35
years of age, being one of the lowest in the world at that time. By
1957 it had increased to 57 years, from 1973 to 1975 it was 63.6
years for males and 66.3 years for females, and in 1981 it was 68
years. It is expected that the continued increase in the average
life expectancy of the people of China will be slow due to a high
death rate from cardiovascular diseases (Gu, 1986).
1.4.3 Life-style in aged populations
A basic issue in planning for the consequences of demographic
aging is whether elderly people should be considered a specific
target group for the development of services, or whether their needs
should be catered for within the context of planning for the
population as a whole. One approach to a rational policy for this
issue is to consider the nature of human aging. For this it is
necessary to view the physical, psychological and sociological
dimensions of aging as a whole.
Life-style influences the effects of chemicals on human health,
including that of the elderly, both quantitatively and
qualitatively. Environmental chemicals and their uses are diverse.
Specialized nutritional elements of the diet have become popular,
while in certain countries many people prefer predominantly
vegetarian diet. Others take supplements and additives which contain
pure preparations of vitamins, minerals, amino-acids and other
substances. Whether such substances have either adverse or
beneficial effects on the elderly and aging processes, has not
generally been fully evaluated. Another important source of human
exposure to chemicals comes from the intake of different kinds of
cosmetic agents and fragrances, such as shampoos, creams, perfumes,
oral deodorants, sunscreen and suntan lotions, and insect
repellents. These are often chemical mixtures whose components have
not been evaluated or tested beyond acute toxic potential.
Occupational status, indoor air quality, recreational
activities, exercise, eating and drinking habits, alcohol
consumption, and tobacco smoking can all affect the elderly and
aging processes to a certain degree. Elements of life-style can
strengthen or reduce the risk of developing aged-related
degenerative diseases. They can also accelerate or delay
physiological and anatomical changes. Typical examples are the
various age-related diseases caused by toxic chemicals in tobacco
smoke and the reduction of the risk of cardiovascular diseases
produced by regular exercise (Committee on Chemical Toxicity and
Aging, 1987).
As far as the possible influence of life-style factors on the
manifestations of aging is concerned, many studies have shown that
loneliness and physical and intellectual inactivity are common among
the elderly, especially widowed people. Several studies have
revealed that living conditions have an influence on health and
well-being, resulting in an increase in the demand for social care
and medical service. Marital status and living arrangements have
important significance for the unique life-style of the elderly.
There are striking differences between the proportions of elderly
males and females who are married: in many countries the proportion
of married males is twice that of married females. In general, the
proportion of widows is very high and that of widowers relatively
low (WHO, 1984).
Migration is also one of the life-style variables of the
elderly. In rural areas of Asia, many older women move to cities to
join their children after they have been widowed. Another common
type of move is the migration of the recently widowed or chronically
ill elderly from urban areas to their home towns or villages. For
many countries in Africa and Asia, the urban-rural migration is most
apparent among males, who return from urban to rural areas when they
are old. Worldwide, only a minority of elderly people live in urban
areas (WHO, 1984).
1.5 Theories of aging
During the last century, more than 100 various hypotheses
concerning the origin and mechanism of aging have been put forward.
All of them could be grouped generally into two broad categories:
those that invoke deterministic, or "programmed", alterations in
gene expression or gene structure; and those that invoke a variety
of stochastic, or "random", alterations in the structure and
function of macromolecules, cells, and organ systems. This
distinction, however, has some limitations, because stochastic
alterations in individual cells can lead to predictable phenomena in
the large populations of cells. The use of terminal differentiation
to explain the limited replicative life span of somatic cells
(Martin et al., 1974) could be an example of the blurring of the
stochastic and non-stochastic categories. For each individual cell,
differentiation is a random event; however, for a population of
cells, the process appears deterministic.
The mechanisms of aging are likely to be coupled to the
reproductive strategy of the organism. One example is the
synchronous, rapid physiological declines and mortalities that are
characteristic of species with single massive episodes of
reproduction (e.g., migrating Pacific salmon or soybean plants).
Placental mammals, however, have ample opportunity for a variety of
stochastic processes to take place during their long reproductive
and postreproductive phases. The associated patterns of structural
and functional decline can vary substantially, both qualitatively
and quantitatively, among individuals within a species and among
different related species. Evolutionary biologists in fact present
compelling arguments that aging did not evolve because of any
adaptive value to the individual or to the species, as would be
assumed by strictly programmed theories (reviewed in Rose, 1991).
Aging is thought to occur simply because of the decline in the force
of natural selection for gene action that is postreproductive. Such
gene action could be related to accumulations of late-acting
mutations in the constitutional genome or to selection for forms of
genes that have positive effects on reproductive fitness early in
the lifespan, but whose effects may be negative late in the lifespan
(the "antagonistic pleiotropy" theory of aging) (Rose, 1991).
It is beyond the scope of this monograph, however, to consider
the potentially large numbers of specific mechanisms that may be
modulated by such accumulated constitutional mutations or
pleiotropic genes. The reader is referred to recent reviews of the
many postulated theories of aging (Warner et al., 1987; Committee on
Chemical Toxicity and Aging, 1987; Finch, 1991; Cutler, 1991).
These can be classified in a variety of ways (Dilman, 1987;
Medvedev, 1990).
2. STRUCTURAL AND PHYSIOLOGICAL CHANGES IN THE AGED
2.1 Changes in gene structure and function in aging
Changes in gene expression are of critical importance to an
organism. Aging can potentially alter not only the structure of
genes, but the way in which they function. Changes in the DNA are
often thought to be integral to aging. It is clear that not only
mutations, but chromosomal rearrangements accumulate with age (Vijg,
1990). Repetitive sequence families may play a crucial role in the
processes of aging. In addition, the organization of DNA and protein
in chromatin is important structurally and functionally. Therefore,
changes in chromatin could play a major role in the age-related
change in the regulation of gene expression (Richardson et al.,
1983; Medvedev, 1984; Thakur, 1984; Richardson et al., 1985).
2.1.1 Chromatin structure
Chromatin changes may involve either proteins that interact
with DNA or the chemical structure of the DNA molecule itself.
Although no change in the stoichiometry of the major histones has
been observed with increasing age (Richardson et al., 1983;
Medvedev, 1984), several investigators have reported changes in the
subspecies of histone H1 (Medvedev, 1984; Mitsui et al., 1980;
Niedzwiecki et al., 1985). The acetylation of histones, which has
been proposed to alter histone-DNA interactions thereby making DNA
more accessible, decreases by 30% to 70% with increasing age
(O'Meara & Pochron, 1979).
With respect to age-related changes in DNA chemical structure,
there is now conclusive evidence for the "spontaneous" induction of
a variety of DNA lesions in different organs and tissues of both
humans and experimental animals (for a review, see Mullaart et al.,
1990). Most of these lesions seem to be repaired (see below), but
not all. For example, Cathcart et al. (1984) and Fraga et al. (1990)
estimated that in rats about 105 oxidative DNA lesions occur per
cell per day. Since the rate of repair does not entirely equal the
rate of induction of damage, there is a net increase of spontaneous
DNA lesions with age. Fraga et al. (1990) calculated for one
specific lesion, 8-hydroxy-deoxyguanosine, that about 80 residues
accumulate per rat cell per day.
Although some DNA lesions are repaired quickly, this is not the
case for all lesions. Indeed, after treating rats with low doses of
2-acetyl-aminofluorene (AAF), Mullaart et al. (1989) were still able
to detect about 30% of the major lesions induced as late as 21 days
after treatment. Such incomplete repair could be responsible for
accumulation of DNA lesions during continuous or frequent exposure to
genotoxic agents.
2.1.2 DNA repair
To preserve the DNA chemical structure, cells are equipped with
a battery of repair systems to remove damage. As yet the various
mechanisms of action of these DNA repair systems and their
interrelationships are incompletely understood (for a recent review,
see Lehmann et al., 1992). In general, repair systems can be divided
into three categories, i.e. direct repair, excision repair and
post-replication repair. In direct repair, the lesion itself is
removed without any further (transient) changes in the DNA
structure. Direct repair includes the enzymatic photo-reactivation
of UV-induced pyrimidine dimers and the removal of O6-alkyl
adducts by specific alkyl transferases.
DNA excision repair is brought about by a complex multi-enzyme
system, the components of which are involved in the various steps in
this repair process (Vijg & Knook, 1987). The third type of repair,
post-replication repair, does not actually remove the damage but
allows the replication system to bypass the damage. It is this
latter process especially that is considered to be associated with
nucleotide misincorporation (mutation).
Accurate assessment of an organism's capacity to repair
specific lesions is difficult and subject to error. In general, the
most reliable data can be obtained when the induction and
disappearance of the relevant lesions themselves are monitored in
the different organs and tissues of an experimental animal.
Unfortunately, in most studies on the possible existence of a
decline in DNA repair activities with age, assays were used which
measured the DNA synthesis phase of excision repair. The general
conclusion from these data, mostly obtained with cultured cells, is
that there is no age-related decline in the efficiency of DNA repair
systems (Tice & Setlow, 1985; Likhachev, 1985; Hanawalt, 1987). It
cannot be ruled out, however, that during aging DNA repair systems
become more error prone, leading to an accelerated induction of
mutations (Vijg & Knook, 1987). In any case, a certain degree of
imperfection is a general characteristic of DNA repair systems as
indicated by the actual accumulation of both DNA lesions and DNA
sequence changes (see above). The question that should be addressed
is what type of DNA alterations occur, how many exist, and at what
rate do they accumulate with age. Finally, their relevance in terms
of actual physiological decrements or the initiation of disease
should be assessed.
2.1.3 Transcription
Several review articles have been published in the past decade
that discuss the effect of age on transcription (Rothstein &
Seifert, 1981; Richardson et al., 1983; Richardson et al., 1985;
Richardson & Semsei, 1987; Slagboom & Vijg, 1989). A major problem
in this area has been the difficulty in accurately measuring the
rates of synthesis of specific RNA species and their intracellular
levels. With the major advances in recombinant DNA technology, this
problem has now been virtually eliminated and our knowledge of how
aging affects the expression of specific genes is rapidly growing.
At present, it appears that the overall transcriptional
activity of a cell declines as an organism ages. However, the level
of total RNA tends to remain constant suggesting a decline in the
rate of RNA turnover (Horbach et al., 1986).
The levels of some specific mRNA species using cDNA probes for
specific genes have been measured recently (Richardson & Semsei,
1987). In general, no consistent trend has emerged. The levels of
some mRNA species decrease with age; however, other mRNA species do
not change with age, and others actually increase (Slagboom & Vijg,
1989).
In most of the studies, a good correlation has been found
between the age-related changes in the level of an mRNA species and
the level of protein (or enzyme activity) specified by the mRNA
species. This has been demonstrated in rat liver for albumin
(Horbach et al., 1984), apha2u-globulin (Richardson et al., 1987),
and superoxide dismutase and catalase (Semsei et al., 1989), and in
rat kidney and small intestine for calbindin-D (Armbrecht et al.,
1989). The age-related decline in mitogen-induction of interleukin 2
(IL-2) (Wu et al., 1986; Nagel et al., 1988; Pahlavani et al., 1988)
and IL-3 (Li et al., 1988) mRNA in lymphocytes from rodents and
humans corresponded to the age-related decline in the biological
activities of these two interleukins. In contrast, Strong et al.
(1990) reported an uncoupling of tyrosine hydroxylase transcription
and translation in the adrenal glands of old rats.
Investigators usually assume that age-related changes in the
levels of a particular mRNA species arise from a change in
transcription. However, only a few studies have actually measured
the transcription of a specific gene as a function of age using
nuclear run-off assays. While an age-related decrease occurs in the
nuclear transcription of the alpha2u-globulin (Richardson et al.,
1987; Murty et al., 1988a), cytochrome P450(b+e) (Rath & Kanungo,
1989), and superoxide dismutase and catalase (Semsei et al., 1989)
genes, the nuclear transcription of tyrosine amino-transferase and
tryptophan oxygenase (Wellinger & Guigoz, 1986), albumin (Horbach
et al., 1988b) and the c-myc (Buckler et al., 1988) genes was
similar in young and old rodents. Studies are now underway to
explore in more detail age-changes in specified mRNA species in
terms of the transcription factors involved (Post et al. 1991).
One exciting development in the area of transcription and aging
has been the observation that dietary restriction, which enhances
the longevity of rodents, alters the expression of some genes at the
level of transcription (Richardson et al., 1987; Semsei et al.,
1989). However, the expression of all genes is not affected by
dietary restriction (Waggoner et al., 1990).
In addition to nuclear synthesis, post-transcriptional
processing of hnRNA plays an important role in the regulation of
gene expression. Müller et al. (1989) recently discussed various
views of how the post-transcriptional processing of hnRNA might
alter with age. At present, there is little evidence that major
changes occur with age in the size of the poly(A)-segment of mRNA
(Birchenall-Sparks et al., 1985). Interestingly, in the many studies
in which mRNA species have been analysed by Northern blot analysis,
there has been not a single report of a significant change in the
size of the mRNA species examined with increasing age (Richardson &
Semsei, 1987). Thus, there is very little direct evidence at present
to support the view that the processing and/or nuclear transport of
hnRNA is altered with age.
2.1.4 Translation
Increasing age generally results in a decrease in total protein
synthesis in plants, invertebrates, rodents and cultured cells
(Richardson & Birchenall-Sparks, 1983; Ward & Richardson, 1991).
Recent studies have focused on the influence of age on the
translation of mRNA into specific proteins and on the ability to
modulate age changes in protein synthesis. There is no evidence that
a decrease in the fidelity of protein synthesis occurs with
advancing age but technical limitations do not permit a definitive
conclusion (Rosenberger & Kirkwood, 1986). The influence of age on
protein synthesis differs from protein to protein and much more work
must be done in assessing the effect on key individual proteins.
Attempts to modulate protein synthesis have recently begun. The rate
of protein synthesis in the liver is higher after maturity for
dietary restricted than for ad libitum fed rats (Ward, 1988). In
an in vitro system, growth hormone increases protein synthesis in
muscles of old rats to the level found in muscles of young rats
(Sonntag et al., 1985). Much more study is required, focusing on
individual proteins, different tissues and different organisms.
2.2 Changes in tissues, organs and systems in aging
The progressive modification of body functions with age
involves alterations not only at the genetic, molecular and cellular
levels, but at the level of the tissues, organs, systems and entire
organism. It is important to attempt to differentiate between
age-related pathology and true physiological aging. This is often
difficult because the majority of age-related changes increase the
vulnerability of the aging organism to disease and ultimately death.
In the following, each organ or system will be discussed in
reference to age-related changes in its structure which might
predispose to alterations in function, not only inherently as part
of aging, but in response to environmental agents. The focus will be
on the healthy aged as opposed to the diseased.
2.2.1 Nervous system
The brain may undergo a progressive deterioration with age at
all levels of organization - structural, biochemical and functional.
CNS disorders, including Parkinson's and Alzheimer's diseases, are
common in the elderly.
2.2.1.1 Structural changes
Brain weight decreases slightly with aging. This is due to
atrophy of both grey and white matter (Creasey & Rapoport,1985). At
the cellular level, the major age-associated modification is in the
number of neurons, which are significantly diminished in discrete
areas of the brain (Brizzee, 1985), particularly in the basal
ganglia, cerebellum (probably related to decreased motor control),
locus ceruleus (associated with alterations in sleep patterns),
nucleus basalis of Meynert (associated with senile dementia of
Alzheimer type (SDAT) (Bondareff, 1986), and the spinal cord.
Neuronal loss, which is associated with an increase in the number of
glial cells, is relatively mild in the healthy aged, but is much
more severe in SDAT, Parkinson's disease and in the early aging
associated with Down's syndrome.
In addition to a reduced number of neurons, the aged brain is
characterized by a reduction in the number of dendrites and
dendritic spines, probably due to a slowing renewal process
(Scheibel & Tomiyasu, 1978). Synapse density declines in discrete
areas of the brain, but this is partially compensated by enlargement
of the remaining synapses (Bertoni-Freddari et al., 1990).
Intracellular changes include dilation and fragmentation of the
Golgi apparatus (Mervis, 1981), distortion of membranes and the
nucleus, and accumulation of lipofuscin, in both neurons and glial
cells within discrete brain areas. With advancing age, there is an
increase in neurofibrillary tangles (intracellular tangled masses of
paired helical filaments) (Terry, 1963), extracellular neuritic
plaques (a core of amyloid surrounded by material derived from
dystrophic neurites), and reactive glial and microglial cell
accumulation (Master et al., 1985). Again, these changes occur in
normal aging at a moderate level, but are much more frequent in SDAT
(Iqbal et al., 1982) and other dementias.
There are also age-related changes in the morphology of the
peripheral and autonomic nervous systems. These include reductions
in the number of sensory and motor neurons, increases in
demyelination, increases in connective tissue, and a mild loss of
myelinated fibres (Tomlinson & Irving, 1977; Spencer & Ochoa, 1981).
The central processes of dorsal root ganglion cells typically
undergo distal dystrophic and degenerative changes. Regressive
changes have been reported in the terminals of motor axons.
2.2.1.2 Biochemical changes
Besides the pathological changes, there are many age-related
alterations in brain chemistry required for cell-to-cell
communications (Rogers & Bloom, 1985; Finch, 1991). These include
changes in the concentration and/or turnover of the amines (e.g.,
acetylcholine, norepinephrine, epinephrine, dopamine, serotonin),
amino acids (e.g., glycine, glutamate and GABA) and peptides (e.g.,
enkephalin, substance P, thyrotropin-releasing hormone,
cholecystokinin, somatostatin). There are numerous studies showing
impairments of adrenergic, dopaminergic and serotonergic activity in
the senescent animal (Zhou et al., 1984; Roth & Joseph, 1988;
Telford et al., 1988). One of the underlying causes of these
alterations seems to be an overall loss of receptors (Weiss et al.,
1984; Roth & Joseph, 1988).
Synapses may utilize one or more neuromodulator (e.g.,
norepinephrine and neuropeptide). The multiple levels of control and
the regional diversification of different synapses in discrete brain
regions make it difficult to define the age-related alterations in
neurotransmitter/neuropeptide function. In fact, rather than a
uniform drop in the level of a specific neurotransmitter throughout
the nervous system, a "desynchronization" of signals may occur. For
example, while the brain content of norepinephrine and dopamine are
decreased in old age, that of serotonin is unchanged or even
increased, depending on specific brain areas. In some cases, the
greater the concentration of a neurotransmitter in a discrete brain
region, the higher the decrement with aging and vice versa (Timiras
et al., 1984). In fact, age-dependent alterations in different
neurotransmitter/neuropeptide concentrations do not always occur
simultaneously. Each neurotransmitter has its own timetable:
dopamine levels decrease in the cerebral hemispheres of rats from
the age of one year, whereas in the same areas serotonin levels
remain unaffected until three years of age (Timiras et al., 1984).
Aged-related changes in neurotransmitter receptor number and
function have also been reported (Greenberg & Weiss, 1983; Roth &
Joseph, 1988). Changes in binding affinity have not been frequently
detected. Beta-adrenergic receptor responsiveness is decreased in
the elderly (Vestal et al., 1979; Lakatta, 1980). This appears to be
due to uncoupling of the beta-receptor from the adenylate cyclase
complex which transmits the signal (Wood, 1985). In the rat pineal
gland, corpus striatum and cerebellum, a reduced responsiveness to
catecholamines is present due to a decrease in the affinity of
beta-adrenergic receptors to their ligand. However, there is no
change in receptor number (Greenberg & Weiss, 1978). This may be due
in part to a reduced ability to increase the number of
beta-adrenergic receptors after decreased noradrenergic input
(Greenberg & Weiss, 1979).
Changes in general biochemical properties of the cells occur in
the nervous system as they do elsewhere in the aging organism.
Lipid composition may change, resulting in altered membrane
viscosity. Protein synthesis decreases in discrete brain regions.
Lipofuscin accumulates, although the functional significance is
unclear, and there are alterations in electrolytes and trace
elements (Brizzee, 1985). For example, aluminium levels may increase
sharply in elderly people (Bjorksten et al., 1989). Decreases in
zinc may be important in the light of the zinc requirement of
various enzymes and growth factors, including nerve growth factor
(NGF) (Dunn et al., 1980). In addition, aging is accompanied by a
decreased brain water content (Meisami, 1988). Alterations in
vascular flow have also been reported (Katzman & Terry, 1983).
2.2.1.3 Functional changes
Despite the morphological and biochemical changes observed in
the aging brain, the functional efficiency of the nervous system
seems to be well maintained in most elderly people. However, CNS
disorders do occur in some individuals, though it may be difficult
to discriminate age-related pathology from physiological aging
phenomena. Perhaps the most ubiquitous and significant change
observed in the older organism is slowness of behaviour (Birren et
al., 1979). The slowing of behaviour with age not only appears in
motor responses and perceptual processing, but is also apparent for
the more complex processing of information associated with
short-term memory (Smith et al., 1980). Related cross-sectional
studies using global measures of intellectual function such as the
Wechsler Adult Intelligence Scale (WAIS) show evidence that some
performance abilities decline by the late 60s and early 70s, while
others (e.g., verbal abilities) appear to be maintained throughout
life in healthy individuals (Gallagher et al., 1980). The slowing of
reaction time may be associated with the age-associated slowing and
loss of coordination in motor tasks, such as those involved in
handwriting and other purposeful movements.
The age-related modification of biorhythms is exemplified by
the alterations of the sleep/wakefulness cycle, which is largely
dependent on the reticular system. Alterations of sleep patterns
with aging are qualitative rather than quantitative (Dement et al.,
1985) and affect primarily the "deep sleep" phases, as confirmed by
the alterations observed in the brain electrical activity (Müller &
Schwartz, 1978). Among neurotransmitters, serotonin seems to be
implicated.
Alterations in posture and locomotion in the elderly (Klawans &
Tanner, 1984) also depend on CNS impairment. Peripheral
modifications such as decreased nerve conduction velocity, reduced
muscle mass and increased rigidity occur. Autonomic system
dysfunction is also implicated in many pathophysiological changes
of age including hypotension, thermoregulation, gastrointestinal
function and urinary incontinence (Finch & Landfield, 1985). Other
changes in the autonomic system include changes in vascular and
cardiac reflexes, galvanic skin responses, and potency (Katzman &
Terry, 1983). Sympathetic hyperactivity is commonly present in the
aged and could interfere with cognitive functioning.
2.2.2 Sensory organs
All of the sensory organs are affected by aging, both those in
which the cells are continuously renewed (such as cutaneous sense
tissues) and those in which the cells are terminally differentiated
early in life (vision and hearing).
2.2.2.1 Vision
Both neural (retina) and optical (cornea, lens, pupil, aqueous
and vitreous humours) components of vision are affected by age. The
changes in the optical compartment are probably the primary cause of
visual impairment in the elderly (Sekuler et al., 1982). The most
common alterations are in the lens with increased hardness and
decreased transparency (Graham, 1985). The former results in reduced
refractive power (Marsh, 1980). The loss of transparency relates to
the following chemical changes in the lens: protein oxidation,
racemization, glycation, aggregation, polymerization and
precipitation (Taylor, 1989). These alterations are associated with
presbyopia and cataracts, respectively.
In the neuronal compartment, the retina undergoes progressive
loss of rods, while cones may be augmented. Morphometric analysis of
the retina demonstrates an increase in electron-dense plaques and a
decrease in the ground substance during aging. Such retinopathies
result in decreased light sensitivity and reduced colour vision
(Marsh, 1980).
Vision declines as a function of age (Weale, 1986) and can be
measured in several tests, such as the Humphrey Field Analyser
(Iwase et al., 1988), and retinal potentials (Trick, 1987). Visual
acuity is substantially decreased. The ability to detect light
gradually decreases (Sample et al., 1988) and light adaptation
declines (Katz & Robinson, 1987).
2.2.2.2 Hearing
Decrements in hearing are frequently observed in the elderly.
There is also a progressive loss of hearing in animals with age
(Willott, 1986). Both auditory structures and neuronal components
are involved. While the outer and middle ear show few modifications,
degenerative changes occur in the hair cells, which are the auditory
receptors, and in the mechano-electrical transducing organs
resulting in otosclerosis. This accounts for the preferential loss
of hearing of high frequency sounds (presbycusis) (Marsh, 1980). The
degree of hearing loss may affect the two ears differentially, thus
causing defects in sound localization. Presbycusis has a great
impact upon speech perception, since consonants, which make speech
intelligible, are generated by high frequency sounds, whereas
vowels, responsible for audibility, are produced by low frequency
sounds.
Hearing defects may also result from changes in the neural
components (Allison et al., 1984) of hearing, and in particular in
the nerves connecting the cochlea with the auditory centres in the
brain, specifically in the superior temporal gyrus.
2.2.2.3 Olfaction
The age-related alteration in the sense of smell is generally
underestimated. The reduction in olfactory sensitivity is mainly due
to the progressive loss of olfactory neurons, which protrude through
cilia from the superior nasal cavity and represent the receptor
sites for odour and the chemo-electrical transducing mechanism
(Naessen, 1971). Loss of neurons have also been demonstrated in the
olfactory bulbs of the brain (Bhatnagar et al., 1987).
2.2.2.4 Taste
Taste thresholds are known to increase with age. The taste of
salt is preferentially altered in the elderly. The loss appears due
both to a decline in the number of taste buds and papillae (Bradley,
1979) in the tongue, as well as to the loss of neurons in the
cerebral centers of the gustatory system.
2.2.2.5 Somatic sensations
The somatic sensory system (touch, pressure, vibration,
proprioception, heat, cold and pain) is variably affected by age.
Tactoperceptual ability and vibrotactile sensations are decreased in
the elderly due to the loss of Meissner end-organs and Pacinian
corpuscles present in the skin (Bruce, 1980). For more complex
somatesthetic abilities (stereognosis, body part recognition) as
well as for pain and thermal sensitivity, the biological causes of
their alterations with age involve not only the sensory end-organs,
but also affective and cognitive factors (Marsh, 1980).
2.2.3 Endocrine system
Hormones play an important, often critical, role in the
regulation of a large number of physiological and behavioural
processes, and their influence can be demonstrated throughout the
lifespan. Some hormones have a role in differentiation in that their
presence or absence during certain developmental periods will affect
the way in which physiological and behavioural processes proceed or
are expressed in adulthood. Throughout each period of the life span,
the maintenance of an appropriate endocrine milieu is essential to
the numerous homeostatic processes required for survival. With
advancing age, there are several, well-documented changes in the
ability of the organism to synthesize and secrete a number of
hormones. It is, therefore, likely that the typical age-related
change in an organism's endocrine balance would result in, or at
least contribute to, the impairment of homeostasis frequently
observed in the elderly. Such impairments can be noted in the
decreased rate of recovery of the elderly from the insults of injury
or disease.
Hormones may also play a significant role in the aging process.
For example, age-related changes in several physiological functions
appear to be closely linked to the level and pattern of hormonal
stimulation present during adulthood. As such, different patterns of
exposure to a hormonal environment may alter the "rate of aging"
within a specific neuroendocrine system and, in turn, affect the
susceptibility of the organism to environmental insults at different
segments of the life span. There are a number of different ways in
which endocrine systems and the hormonal signalling operations that
they use may undergo alterations with age and toxicant exposure.
These can be categorized as changes in: (a) the availability of
hormones for binding to the target tissues, (b) the reception of the
pertinent transmitter or hormonal signal by the target cells, and
(c) the nature of the hormonal message.
At any point in time, the concentration of a hormone in the
blood is a consequence of both its metabolism and secretion. Such
changes in the size of the available signal pool may have
corresponding effects on the magnitude of the response by the target
tissue. Other changes may reflect declines with age in the
homeostatic controls, which rely heavily on endocrine feedback
relationships within organ systems.
Serum hormonal levels, as a rule, are not maintained at
constant levels. They tend to fluctuate, sometimes markedly,
throughout a 24-h period. In the young adult man, peak morning
testosterone values can fall by one-third to an early evening nadir,
before rising again through the late evening and early morning hours
(Bremner et al., 1983). A similar circadian rhythm in circulating
levels of testosterone is prevalent in the rat (e.g., Kinon & Liu,
1973; Ellis & Desjardins, 1982). Human cortisol (Bilchert-Toft,
1978) and rat corticosterone (Moberg et al., 1975; Kato et al.,
1980) concentrations also exhibit well-known rhythmic fluctuations,
as do those of thyrotropin (Vanhaelst et al., 1972; Leppaluoto
et al., 1974) and growth hormone (Millard et al., 1985). Reported
attenuations with age in the rhythms of human and rat serum
testosterone (Bremner et al., 1983; Steiner et al., 1984),
luteinizing hormone (LH) (Vermeulen et al., 1989), and growth
hormone (Sonntag et al., 1980; Prinz et al., 1983), among other
hormones, can present differences in young-versus-old comparisons,
depending on when such sampling is performed.
While observable changes in hormonal rhythms or significant
differences in circulating hormone concentrations may reflect
disturbances in the overall functional integrity of the associated
organ system, the absence of such changes should not be necessarily
assumed to indicate a corresponding absence of a functional
alteration. The notion of a "system at risk" presupposes an increase
in the susceptibility to disruption of the homeostatic controls. An
aging system that may be undergoing a subtle erosion in its
endocrine balance could be more likely to exhibit alterations in its
response to a stressor or toxic insult. In this respect the
stimulation of growth hormone release by clonidine, L-dopa and
insulin is substantially depressed (Riegel & Miller, 1981), while
arginine-stimulated growth hormone (GH) secretion after arginine
infusion is preserved (Aschoff, 1979). Secretion stimulated by GHRH
(GH releasing hormone) is only partially reduced (Coiro et al.,
1991).
Regardless of these alterations, it remains established that
the 24 h production of GH is significantly reduced in elderly humans
(Prinz et al., 1983), whereas that of prolactin is increased
(McGinty et al., 1988; Blackman, 1987). These data have been
confirmed in animals (Ceda et al., 1986; Sonntag & Gough, 1988),
although measurements of hormonal profiles may have involved
different procedures in animals and man, thus giving rise to
slightly different interpretations.
Similar difficulties are encountered in studies of age-related
alterations in pineal hormone secretion, including melatonin, whose
circadian rhythmicity is certainly changed with age (Reiter, 1986;
Anisimov & Reiter, 1990).
In order to illustrate age-related alterations in hormone
control, it is useful to focus on the integrated systems which
involve more than one gland or hormone. Although three such systems
are reviewed below, this discussion is by no means intended to be
comprehensive. One theme common to studies of age-related changes in
endocrine function is that such alterations are often hormone and
species specific. Finally, the extent to which any of these changes
relate to potential adverse health outcomes in the older organism
remains to be demonstrated.
2.2.3.1 The pituitary-thyroid axis and the basal metabolism
Thyroid hormones are required during development for growth and
in adult life for regulating oxygen consumption. Maintenance of
thyroid function is generally assured even in old age, although
following repeated stress and demands the reserve function may
become exhausted and a dysthyroid state may follow (Ingbar, 1978).
Changes with aging in the levels of both thyroid stimulating
hormone (TSH) and thyroid hormones (thyroxine (T4) and
triiodothyronine (T3)) are controversial, because concomitant health
disturbances may cause significant fluctuations in the levels of
these hormones (Gregerman & Solomon, 1967; Utiger, 1980). Both hypo-
and hyperthyroidism are not uncommon in the elderly. In general, the
size of the thyroid decreases with age (Gambert & Tsitouras, 1985).
Older people show a normal response to decreased thyroid
function by increased secretion of TSH (Eden, 1987). TSH levels
undergo few changes (Miller, 1989), suggesting that the hypothalamic
control of TSH release has not been altered. However, structural
modifications of TSH have been reported (Klug & Adelman, 1977). T4
levels remain unchanged with age, even though the rate of synthesis
is reduced. However, the blood levels of T3 are reduced with
advanced age (Chopra et al., 1978), while levels of reverse T3 are
unchanged. It should be noted that severe and chronic illnesses, not
directly involving the thyroid, can lower the levels of T3 and
T4.
The alterations observed in thyroid hormone levels are
inadequate to explain the age-associated decline in various
functions that are dependent on thyroid hormone. One possible
explanation is that peripheral sensitivity to thyroid hormone action
is modified by aging. However, with advancing age, the basal
metabolic rate remains unchanged if based on lean body mass, but
decreases if expressed based on body surface area (Masoro, 1985).
2.2.3.2 The pituitary-adrenal axis
The major function of this axis, which is largely based on
pituitary hormones (ACTH) and adrenal hormones (corticosteroids), is
to provide an adaptive response to environmental stress (Selye,
1950; Sapolsky et al., 1986). Any harmful agent, in addition to
inducing a specific reaction in the body (anaesthesia, emotion,
fever, etc.), activates a specific and common response, the
so-called "General Adaptation Syndrome" (Selye, 1950), characterized
by increased adrenocortical secretion, thymic involution,
lymphopenia and eosinopenia. With advancing age this axis may
undergo desynchronization, thus resulting in a failure of
homeostasis and adaptation (Anisimov & Reiter, 1990).
ACTH secretion, which shows a circadian rhythm based on
melatonin fluctuations, is generally preserved in advanced age
(Halberg, 1982), although minor modifications of blood levels may
occur due to variations in renal clearance or alterations in sleep
patterns. However, there is evidence of diminished sensitivity of
the hypothalamic/pituitary axis feedback inhibition by
glucocorticoids (Greden et al., 1986; Blackman, 1987; Dilman, 1987;
Sapolsky et al., 1987). The elderly suffering from Alzheimer's
disease are extremely resistant to glucocorticoid negative feedback
(Sapolsky et al., 1986).
Finally, certain cell populations (e.g., CA3 neurons in the
hippocampus) are particularly susceptible to glucocorticoids.
Long-term stress may result in their dysfunction and death (Sapolsky
et al., 1987).
2.2.3.3 The endocrine pancreas and carbohydrate metabolism
It is well documented that with advancing age the ability to
maintain glucose homeostasis is impaired, but the underlying
mechanisms are still not well defined. Several hormones contribute
to the regulation of glucose homeostasis: above all, insulin and
glucagon, secreted by the endocrine pancreas, and somatostatins and
the pancreatic polypeptide, which modulate the secretion of insulin
and glucagon, respectively. In addition, glucose metabolism may be
affected by other hormones, including T3 and T4, growth hormone,
glucocorticoids and epinephrine (Minaker et al., 1985).
Only modest morphological alterations are observed in the
endocrine pancreas with advancing age. In spite of this fact, blood
sugar levels after fasting are elevated and glucose tolerance is
lowered in the elderly (Magal et al., 1986; Eden, 1987; Ammon
et al., 1987; Wang et al., 1988; Groop, 1989). Plasma insulin
concentration increases and insulin sensitivity decreases.
Alterations in insulin turnover are detectable in the elderly after
glucose load, such as reduced insulin secretion and increased
secretion of the inactive prohormone, proinsulin (Marx, 1987), but
these changes are too modest to account for the observed glucose
intolerance. One alternative explanation is an increase in
peripheral resistance to insulin. In fact, peripheral uptake of
glucose is indeed reduced in the elderly, due to a reduction in
insulin receptors (Pagano et al., 1981) as well as alterations in
the post-receptor signalling process (Rowe et al., 1983). No
evidence exists regarding the possible involvement of age-related
changes in glucagon affecting glucose intolerance in the elderly.
Other factors, however, may contribute to glucose intolerance.
These include: (a) reduced liver sensitivity to insulin, resulting
in reduced glycogenesis; (b) changes in diet and physical exercise;
and c) increased body fat with reduced muscle mass. This last point
seems to merit particular consideration in view of the observation
that insulin resistance is certainly increased in obese humans
(Runcie, 1985). In fact, intracellular fat accumulation leads to a
reduced concentration of insulin receptors (Bolinder et al., 1983).
2.2.4 Reproductive system
The age-related modifications of the reproductive system are
primarily based on alterations in the central nervous system,
pituitary gland and gonads. While menopause is a time-fixed event
involving cessation of ovarian function, the decline of testicular
function is a slow and gradual process, involving limited hormonal
alterations. Older persons show the normal response to deficient
gonadal function by increased synthesis of gonadotropins (Piva
et al., 1987). This occurs in both sexes. In fact, alterations in
serum levels of both luteinizing hormone (LH) and follicle
stimulating hormone (FSH) have been reported (Blackman, 1987). The
reduced presence of sex steroids in women may have an influence on
the function of other endocrine glands. Estrogens have
well-documented effects on salt and water balance and on plasma
proteins, which in turn have effects on the level of thyroid
hormones through a suppression of TSH secretion. Estrogen also
stimulates the production of growth hormone and prolactin. Thus, the
decline in gonadal function during age could have far-reaching
consequences on the individual's physiological function.
2.2.4.1 Female aging
In females, cessation of ovarian function consists of the
transfer from regular menstrual cycles to amenorrhoea, usually
preceded by a period of cycle irregularity. The initial changes have
been reported to occur in hypothalamic-pituitary control of the
ovaries. For example, the age-related decline in reproductive
function is associated with a decreased sensitivity of the
hypothalamic-pituitary complex to feed-back regulation by estrogens
(Dilman, 1971, 1987). This leads to an age-related enhancement of
pituitary gonadotropins (FSH, LH) (Chakravarty et al., 1976),
leading in turn to hyperstimulation of the ovaries. However, despite
the compensatory increase in ovarian hormone production, the level
of estrogens is insufficient to induce ovulation because of
hypothalamic insensitivity, possibly due to an age-related decrease
in the level of biogenic amines and/or peptide hormone receptors
(Dilman & Anisimov, 1979). In addition, the progressive loss of
oocytes plays an important role in the decline in reproductive
function since the reduction of maturating oocytes may induce
desynchronization of pituitary-ovary hormonal interactions
(Aschheim, 1976).
The most common consequences of menopause include imbalances of
the autonomic nervous system, psychological modifications, and
physiological alterations of target organs due to metabolic changes.
Alterations of estrogen target organs are among the most evident
effects of menopause. Vulvar skin and vaginal epithelium may undergo
atrophy. Glycogen content is generally reduced, with a consequent
decrease of lactobacilli, rise of vaginal pH, and increased growth
of pathogenic microbes. The uterus and oviducts atrophy due to the
decreases in estrogen levels. In ovaries, follicular cysts and
atresia result in response to the altered hormonal status.
Hyperplasia of the theca cells occurs. Fibrosis also occurs in these
tissues but, in addition, can affect the bladder and urethra,
resulting in an increased incidence of cystitis, dysuria and
non-infectious urethritis. The reduced thickness of the skin is also
a result of the decrease in estrogen (Schiff & Wilson, 1979).
Menopause has major health consequences for the cardiovascular
and skeletal systems. The reduction in estrogen secretion removes
the protection offered by these hormones against coronary heart
disease, development of atherosclerosis, and accompanying
alterations of lipid metabolism. Osteoporosis, resulting from
increased bone reabsorption relative to bone formation, is a common
problem in postmenopausal women (Riggs, 1987). Two types of
osteoporosis may be identified. Type I is associated with estrogen
withdrawal and may begin in middle age (Riggs & Melton, 1983). The
biological effects are linked to disruption of the complex
relationship between calcium intake and loss, and the secretion of
calcitonin, parathyroid hormone and 1,25-dihydroxy-vitamin D.
Estrogens prevent the transfer of calcium from bone to blood and its
loss through urine. This induces parathyroid hormone secretion,
which stimulates the formation of 1,25-dihydroxycholecalciferol, the
active metabolite of vitamin D. The function of the parathyroid is
affected by increasing age (Eden, 1987). The relevance of estrogen
for bone loss is further supported by the effectiveness of estrogen
therapy in delaying the osteoporotic process in post-menopausal
women (Edman, 1983). With advancing age type II osteoporosis (senile
osteoporosis) may occur, which is probably due to the poor
intestinal absorption of calcium (Riggs, 1987).
2.2.4.2 Male aging
The reproductive system is less affected by aging in males than
in females. It is generally accepted that testosterone levels are
maintained within the physiological range throughout life, although
a decrease in testosterone production in response to gonadotropin
action may occur in old age due to a reduction in Leydig cell number
and function (Harman et al., 1982). Testis and accessory sex organs
do not show substantial modifications with age, and sperm is found
in the ejaculate of very elderly men. The volume of seminal fluid is
generally decreased.
While the prostate undergoes involution in the majority of old
men, in about one-third of males it undergoes hypertrophy with
consequent obstruction of the urethra and urinary flow from the
bladder. The cause of the hypertrophy is still unclear (Mawhinney,
1985). The prostatic enlargement results in compensatory hypertrophy
of the bladder. When such compensation is no longer sufficient,
retrograde filling of the renal pelvis and ureters may occur,
resulting in hydronephrosis and eventually renal failure.
2.2.5 Immune system
With advancing age a progressive increase occurs in the
incidence of various infectious diseases, autoimmune processes and
tumours. These may be in part based on age-related defects in the
immune system. The association of so many age-related pathologies
with defects in the immune system has led to the suggestion that
aging of the immune system may be rate limiting for life span
(Walford, 1969). However, while there are numerous experimental and
clinical studies demonstrating an age-related deterioration in
immune efficiency, this decline is not sufficient to account for all
manifestations of aging.
There are several recent reviews on aging and the immune system
(Revskoy et al., 1985; Lipschitz, 1987; Segre et al., 1989; Miller,
1991). However, it is still difficult to draw a comprehensive
picture, because of the many cellular and humoral components
involved in immune reactions and the many modulating
extra-immunological factors which may also be compromised in the
elderly. The immune and haematopoietic systems are intimately
related, being derived from a common pluripotent stem cell. Both
play central roles in host defense, prevention of neoplasia, and
response to infectious agents (Lipschitz, 1987). However, basal
haematopoiesis in both animal models and man seems to be either
unchanged or minimally altered with age (Dybkder et al., 1981;
Lipschitz, 1987). The reserve capacity may be reduced resulting in a
decreased ability to respond to stress.
2.2.5.1 Aging of lymphoid organs
Peripheral lymphoid organs, such as the spleen and lymph nodes
do not show consistent modifications in size with aging. Bone marrow
is not consistently affected by age. Stem cell production is
generally well preserved in old age (Harrison et al., 1978),
although a slight change in the replication rate of stem cells has
been reported by some authors (Schneider et al., 1979). Thymic
involution has been considered to account for the major age-related
changes in the immune system, beginning at puberty. Such an
involution consists of a progressive loss of cellularity with
lymphoid cell depletion in the cortical areas and cystic changes in
the epithelial cells. These are the source of various peptides
involved in differentiating thymic lymphocytes (T-cells) from
lymphoid cells of earlier lineage. The export of newly
differentiated T-cells is reduced with advancing age (Globerson
et al., 1989). The synthesis and the secretion of polypeptide thymic
hormones, such as thymosin (McClure et al., 1982), thymopoietin
(Lewis et al., 1978) and thymulin (Bach et al., 1972), are
progressively diminished. In all cases, the reduction of thymic
endocrine activity seems to have a pathogenic role in age-related
immune dysfunctions, since replacement by exogenous administration
of the hormones is capable of restoring various immune functions in
old age (Zatz & Goldstein, 1985). The turnover of zinc, which is
essential for immunocompetence (Iwata et al., 1979; Chandra, 1985),
decreases in old age. Zinc supplementation can restore immune
functions (Fabris et al., 1990).
2.2.5.2 Aging of cellular constituents
Mature T-cells, bone marrow lymphocytes (B-cells) and natural
killer cells (NK-cells) can be detected in blood and in lymphoid
organs by specific monoclonal antibodies. With this type of
analysis, no major modifications in the proportion of the various
lymphoid cell subpopulations have been observed in humans. However,
the major alteration in the immune system appears to arise in the
functioning of T-cells (Thompson et al., 1987). While the total
number of T-cells in the peripheral blood does not change
appreciably with age, there are clear-cut differences in the
relative proportion of T-cell subtypes (Wagner et al., 1983;
Fernandes, 1984; Revskoy et al., 1985; Thompson et al., 1987;
Lipschitz, 1987).
The number of immature lymphocytes of the T-lineage increases
with age, as does the percentage of apparently activated
T-lymphocytes bearing immature thymic phenotypic markers. There is a
relative increase in cytotoxic/suppressor T-cells, and a decrease in
the number of helper/inducer T-cells (Lipschitz, 1987; Thompson et
al., 1987). Correlated with the decrease in the helper/inducer
population, is a functional defect in cell-mediated immunity
(Lipschitz, 1987; Thompson et al., 1987). Cells from aged humans or
experimental animals are less capable of responding to allogeneic
lymphocytes, phytohaemagglutinin, concanavalin A and soluble
antigens. Lymphocytes from older mice are less able to elicit
graft-versus-host reactions than those from younger mice of the same
inbred strains (Thompson et al., 1987). Fifty percent of healthy
people over age 50 have impaired cutaneous hypersensitivity
(Lipschitz, 1987; Dilman, 1987). Accompanying the decrease in
helper/inducer T-cells and cell-mediated immune functions is a rise
in autoantibodies and autoimmunity (Thompson et al., 1987).
Changes in humoral immunity (B-cell function) with aging are
more subtle (Lipschitz, 1987; Senda et al., 1989). Studies on the
effects of age on antibody production have yielded conflicting
results, perhaps because of the wide range of experimental values
generally observed in older individuals. It has, however, been well
established that aging is significantly associated with the presence
of various autoantibodies, in particular, antibodies against nuclear
antigens. There is also evidence that aging effects the rate of
antibody production by activated B-cells (Lipschitz, 1987).
From a functional point of view, defects have been observed at
various levels. Firstly, the proliferative capacity of T-cells from
old individuals is generally reduced, regardless of the stimuli used
(antigens, mitogens), and the defect consists both in a reduced
number of cells responding to stimulus and in a precocious
exhaustion of the cloning capacity (Fabris et al., 1983) of
responding cells. Secondly, the response to interleukins, which
physiologically mediate the modulation of the proliferative
reaction, is depressed and this phenomenon has been documented not
only for T-cells but also for NK cells, which are less sensitive in
old age to the boosting action of IL-2 or interferons (Provinciali &
Fabris, 1990).
With respect to accessory cells (phagocytic cells,
macrophages), their number and function are not altered by age, and,
in certain circumstances, their activity seems to be enhanced.
2.2.5.3 Neuroendocrine-immune interactions
The immune system, although regulated to a large extent by
intrinsic cellular and humoral events, is also sensitive to signals
generated from the nervous and endocrine systems. Communication
between nervous and immune networks is mediated by hormones and
neurotransmitters which reach lymphoid organs and cells via blood or
direct autonomic nervous system connections (Bullock, 1985; Felten
et al., 1985). The neuroendocrine immune interactions are mediated
by circulating humoral factors from the
pineal-hypothalamic-pituitary axis, either directly via
neuropeptides and hormones, or indirectly by the effects of this
axis on the hormonal secretion of peripheral endocrine glands, which
also exert immunomodulating actions (for review, see Fabris, 1991).
The nervous and neuroendocrine systems not only act as
modulators of the immune network, but also as targets for signals
generated within the immune system, such as those exerted by thymic
factors (Hall et al., 1989) and interleukins, (Besedovsky et al.,
1985), and by pituitary-like factors (ACTH, TSH, GH, PRL,
gonadotropins, endorphins), which are produced by mature lymphocytes
upon antigenic stimulation (Weigent et al., 1990).
The sharing of humoral signals, as well as of the specific
receptors between neuroendocrine and immune cells (for reviews, see
Fabris & Provinciali, 1989; Weigent et al., 1990), implies that
biological response modifiers of neuroendocrine-immune origin might
be developed in the near future for therapeutical purposes. On the
other hand, potentially harmful agents for one of these homeostatic
systems may also cause alterations in others.
From an experimental point of view, it has been demonstrated that
treatments of old animals with thyroid hormones (Fabris et al., 1989),
GH (Kelley et al., 1986) and analogues of LH releasing hormone
(Greenstein et al., 1987) are able to induce regrowth of the thymus
and reacquisition of its endocrine activity (for review, see Fabris
1991). Analogous treatments, such as with melatonin (Pierpaoli
et al., 1991), GH (Davila et al., 1987), TSH and thyroid hormones
(Provinciali & Fabris, 1990), are also able to recover various
age-related peripheral immune deficiencies, such as T-cell
functioning and NK cytotoxicity. In humans, little work has been
done in this area, although indirect evidence, obtained primarily
from studies on endocrinopathies in the elderly (Fabris et al.,
1989; Travaglini et al., 1990), suggest that recovery of both thymic
and peripheral immune function can be achieved by a neurohumoral
approach.
Little is known on the potential effect of thymosins,
interleukins and lymphocyte-derived pituitary-like cytokines on
age-related alterations of the nervous and of the neuroendocrine
system. Experimental information from old animals showing recovery
of the hormonal and metabolic profile following immune manipulation
(for review, see Fabris et al., 1988) is undoubtedly opening a new
research approach for human investigations.
Receptor sites for many hormones are present on the membrane of
lymphoid cells (Fabris & Provinciali, 1989). The number of
glucocorticoid receptors in spleen cells decreases in old animals
(Roth, 1979a). Hormones that modify the turnover of cyclic
nucleotides result in consequent activation or inhibition of immune
functions (Hadden, 1983). Hormones influence the production of
several lymphokines and monokines (Kelso & Munck, 1984).
The neuro-endocrine system seems to act not only as a modulator
of the immune network but also as a target for signals generated
within the immune system. Examples of such interactions are the
alterations that can be induced in the neuroendocrine balance,
either by removal of relevant lymphoid organs such as the thymus or
by dysfunction of the immune system itself as a result of reactions
to immunogenic or tolerogenic doses of antigen (Besedovsky et al.,
1975). In addition, mature lymphoid cells, when stimulated by
antigens, produce humoral factors similar, if not identical, to
classical hormones and neurotransmitters (such as ACTH, TSH, GH,
PRL, gamma-endorphins) (Blalock et al., 1985). These reciprocal
influences between the neuroendocrine and the immune systems
(Fabris, 1981; Fabris et al., 1988) occur throughout life, but have
particular relevance during aging (Fabris & Piantanelli, 1982).
2.2.6 Cardiovascular system
The frequency of cardiovascular diseases, which are the major
cause of death in industrialized countries, increases with age.
Diseases such as hypertension and atherosclerosis occur most
commonly in the elderly. In addition, degenerative changes of the
cardiovascular system, involving the myocardial cells as well as
cells of the pacing-conduction system, that arise during the aging
process lead to impaired cardiac function and arrhythmia even in
people without any clinical evidence of hypertension or coronary
artery diseases. Inadequate function of the cardiovascular system
induces effects in peripheral tissues and organs. Changes in
peripheral organs resulting in hyperlipidaemia,
hypercholesterolaemia, and hypo- and hyperglycaemia can also effect
the cardiovascular system in the elderly.
2.2.6.1 Heart
The heart itself can be considered to be made up of two parts:
a) the conduction system responsible for electrically controlling
the heart rhythm; and b) the myocardium performing the contractile
function of the heart and composed of a system of trabeculae.
The biophysical and biochemical mechanisms that govern cardiac
muscle change with age, resulting in characteristic alterations in
muscle function (Lakatta, 1987a,b). Many of the steps in the
excitation-contraction system in cardiac muscle are altered by
aging. In an isometric contraction, the transmembrane action
potential (TAP) excites the cell and the contractions that ensue are
longer in duration. The magnitude of the prolongation of
depolarization of the TAP in senescent muscle is striking (i.e.
about twofold). The action potential amplitude is also greater in
senescent than in adult muscle in both high and low calcium-loading
conditions. These deficits of the senescent muscle may be related in
part to the diminished Ca2+ pumping rate by sarcoplasmic
reticulum. The duration of the elevated myoplasmic Ca2+ level is
prolonged in senescent muscle.
Sagiv et al. (1988) found that left ventricular contractility
increases less on stimulation in elderly subjects than in younger
people. Although the aging process is associated with normal resting
contractile function, diastolic properties are altered, resulting in
reduced and delayed early left ventricular filling and enhanced
atrial contribution to diastolic volume. Exercise cardiac output is
maintained in healthy elderly individuals, but there is a shift from
reliance on an increase in heart rate and a decrease in end systolic
volume to use of the Frank-Starling mechanism to increase stroke
volume. This age difference in the cardiovascular response to
exercise is probably mediated by an age-associated decreased
responsiveness to beta-adrenergic stimulation.
In muscle tissue of the aging heart, some morphological changes
are observed both in animal and human studies (Koobs et al., 1978;
Speijers, 1983). The most common change in the aging heart is
hypertrophy (Lakatta, 1985). Other alterations consist of the
appearance of slight focal necrosis and fibrosis in the myocardium,
amyloidosis (Finch & Hayflick, 1977) and the appearance of
lipofuscin (Hendley et al., 1963; Koobs et al., 1978). Peroxidative
damage to the myocardium is cumulative and irreversible (Koobs
et al., 1978).
2.2.6.2 Blood vessels
Both physiological and morphological changes are observed in
the vascular system, especially in the small and large arteries. The
morphological changes in the arteries seen in the elderly vary
considerably both in appearance and in localization (Goyal, 1982;
Hazzard, 1985). The thickness of the aorta increases significantly
with age, while the number of nuclei in the cells of the arterial
media decreases in humans as well as in mice. The majority of these
changes in humans are categorized as atherosclerotic. These changes
can progress and result in complicated coronary atherosclerosis and
ischemic heart disease, but other factors may also cause clinical
effects such as angina pectoris, arterial spasms, and myocardial
infarcts (Speijers, 1989a).
Morphological changes in the veins are less pronounced than in
the arteries.
The physiological changes observed with aging are often a
result of changes both in heart function and in the arteries. These
changes are reflected in haemodynamic parameters such as an increase
in diastolic and systolic blood pressure, mean arterial blood
pressure and vascular resistance, and a decrease in responsiveness,
and in contraction and relaxation responses (Lakatta, 1986, 1987b;
Duckles, 1987; Mazzeo & Horvath, 1987; Zemel & Sowers, 1988;
O'Malley et al., 1988; Cleroux et al., 1988).
Aging is often accompanied by increases in the incidence and
prevalence of hypertension. Geriatric hypertension is generally of a
salt-sensitive nature with a disproportionate frequency of isolated
systolic hypertension. The age-related increase in salt sensitivity
is due to a decline in renal function (Zemel & Sowers, 1988) and
deregulation of vascular tonus. Age-associated declines in the
activity of membrane sodium/potassium-ATPase may also contribute to
geriatric hypertension because this results in increased
intracellular sodium loading, causing reduced sodium/calcium
exchange and thus increased intracellular calcium and vascular
resistance.
It is commonly accepted that atherosclerotic changes take place
to a certain extent in every individual. Multiple factors determine
the extent and velocity of the atherosclerotic process (Hazzard,
1985). The incidence of clinically observed atherosclerotic effects
is higher in elderly subjects than in younger individuals.
Atherosclerotic damages result in impaired cardiovascular function.
Atherosclerosis is defined as a multifactorial disease with
variable effects in the intima followed by changes in the media of
arteries. These changes consist of focal accumulation of lipids,
proliferation of smooth muscle cells, and accumulation of complex
carbohydrates (i.e. glycosaminoglycans, proteoglycans), blood and
blood products, collagen and calcium compounds (Campbell &
Chamley-Campbell, 1981; Velican, 1981; Speijers, 1989a). The
resultant modifications of arterial wall integrity can lead to the
following: erosion of the wall with consequent reduced resistance to
blood pressure, rupture, and haemorrhage; progressive thickening of
the wall due to reactive proliferation of tissues with consequent
reduction of blood flow; and clotting of the blood at the level of
the injured wall with consequent sudden obstruction. The basic
lesion seems to develop in the first decade of life (Lee, 1985).
In the etiology of the lesion two localized cofactors should be
taken into account: the blood supply of the arterial wall; and blood
turbulence, since lesions are more frequently found around the
orifices of arteries branching off major arteries or at bifurcations
(Patel & Vaishnaw, 1980). Hypertension, diabetes, autoimmunity and
stress are also risk factors contributing to atherosclerosis.
2.2.6.3 Characteristics of atherosclerotic lesions
The first event in the formation of the lesion is still
debated. Both an initial thickening of intima, due to an
accumulation of blood-born amorphous material (lipids, protein and
sulfated proteoglycans) and a proliferation of muscle cells (due to
still undefined stimuli), with consequent degeneration and reactive
macrophage and connective tissue accumulation, have been proposed as
major initiating phenomena (Benditt, 1977; Ross, 1981). The
subsequent phase of the lesion involves repair mechanisms that cause
further thickening of the intima. Following this, lipid increases
both in the cells and in the intercellular spaces. Lipid
accumulation is progressive, leading to an increased number of foam
(lipid-containing) cells which disintegrate and form the gruel-like
substance that has given the name of atheroma to the lesion. The
accumulation of such material acts as an irritant, inducing a
proliferative reaction (encapsulation) which leads to the
development of a plaque. Calcification follows, making the arterial
wall more rigid. Alternatively, when the capsule breaks, an ulcer
can occur, leading to loss of tissue in the arterial wall, blood
clots, haemorrhage, and consequent thrombosis and/or rupture of the
arterial wall.
2.2.6.4 Theories of atherosclerosis
Atherosclerosis is undoubtedly a multifactorial process, which
is reflected by the many theories proposed (Baker & Rogul, 1987).
The lipid accumulation theory is based on the progressive
accumulation of oxidized lipids (mainly low density lipoproteins)
not only in smooth muscle cells but also in migrating monocytes
(Avogaro et al., 1983). The link between lipid deposition and
consequent alterations remains unclear (McCaffrey et al., 1988).
Theories on monoclonal proliferation of smooth muscles cells
are based on a mutagenic event in these cells, due to a
physico-chemical or viral insult (Benditt, 1977; McCaffrey et al.,
1988), leading to the formation of a kind of benign tumour. The
thrombogenic theory is based on the early adherence of platelets to
small alterations in the endothelium, leading to thrombus formation
and release of growth factors by platelets which induce smooth
muscle cell proliferation (Ross, 1981; Bang et al., 1982). Other
risk factors that should be taken into consideration are
hypertension, cigarette smoking, increased body weight, high serum
uric acids and consumption of saturated fats.
The immune system in the elderly is weakened. Consequently
there is increased susceptibility to chronic infections,
autoimmunity, and elevation of circulating immune complexes. New
data in the literature indicate that some viral agents may cause
cardiac and arterial cell lesions and subsequent inflammation. Thus,
viruses and altered immune cells may cooperate and play a role in
arterial wall lipid accumulation, possibly acting as initiating
factors for atherosclerosis (Butenko, 1985).
2.2.7 Respiratory function
Respiratory function is based on gas exchange (oxygen
absorption and carbon dioxide elimination), gas transport (red blood
cells), and on internal metabolic processes that utilize oxygen at
the cellular level. Aging may affect all of these processes (Masoro,
1981), but it is the first that is usually most compromised in
advanced age. The decline in the gas-exchange system may involve the
lungs, the thoracic cage, the respiratory muscles and the
respiratory centres in the CNS. The deterioration of the lungs is
largely dependent on environmental factors, in particular on the
contamination of air with toxic substances, dust and microbiological
agents. Therefore, age-related lung alterations may vary according
to life styles (smoking, physical exercise), environmental
conditions (urban/rural), and intercurrent diseases (infections,
work-related diseases) (Davies, 1985).
2.2.7.1 Gas-exchange organs
The most evident lung alterations with advancing age are
represented by enlargement of alveolar ducts with flattening of
alveoli and loss of septal tissue, reduction of elastic fibres, and
increased fibrosis of the capillary system (Liebow, 1964).
Functional consequences are a reduction in the surface area for gas
exchange with an increase in the physiological dead space, reduction
of the ventilatory flow rate, and irregular distribution of blood
flow (Mauderly, 1978). Age-related alterations also occur in the
chest as a consequence of calcification of costal cartilage,
increased stiffness of costovertebral and vertebral joints, and
general rigidity of the chest. Both lung and chest alterations
contribute to the changes in lung volume and pressure: vital
capacity decreases, residual volume increases, and flow rates
(particularly expiratory flow rate) decline (Morris et al., 1971).
The alteration in the gas-exchange capacity causes reductions in
oxygen uptake and pressure and lower arterial pO2, whereas pCO2
remains constant even in very old age (Morris et al., 1971). The
control of ventilation by brain centres is also altered in old age.
It is still unknown whether such alterations are due to intrinsic
damage of the neural component or to a reduced responsiveness of
neuromuscular activity in the chest (Peterson et al., 1981).
All these alterations, while not necessarily life-threatening
for the elderly, may favour pathologies such as chronic bronchitis,
pneumonia and emphysema (Peterson et al., 1981). The concomitant
hypoxia (low oxygen levels) may cause increased production of red
blood cells with consequent polycythaemia. This may contribute to
hypertension and cardiac failure.
2.2.7.2 Erythropoietic activity
Although specific age-related alterations in the life cycle of
erythrocytes have been reported (Danon, 1969), the overall function
of the erythropoietic system seems to be well preserved. The
regenerative potential following hypoxia seems nearly inexhaustible.
In addition, haemoglobin turnover does not seem to be affected by
age (Lipschitz, 1987).
2.2.8. Kidney and body fluid distribution
The urinary tract is affected by aging both in its renal
functions of excretion and ionic control of body fluids, and in its
control of bladder and urethral activity.
2.2.8.1 Renal function
Kidney function decreases both due to anatomical and
physiological alterations with age (Wesson, 1969; Kaysen & Myers,
1985; Brown et al., 1986; Corman & Michel, 1986; Owen & Heywood,
1986; Meyer & Bellucci, 1986; Anderson & Brenner, 1986, 1987;
Goldstein et al., 1988; Euans, 1988; Rudman, 1988). These
alterations have been observed in both experimental animals and in
humans.
The weight and volume of the kidney decrease by 20 to 30%
between the ages of 30 and 90 years. The atrophy is primarily
cortical and seems to be related to intrarenal vascular changes. The
number of surviving nephrons is reduced and these remaining nephrons
tend to be enlarged (Kaysen & Myers, 1985; Brown et al., 1986;
Lindeman, 1986; Rudman, 1988). The number of glomeruli decreases by
30 to 50%, and there is an increasing percentage of sclerotic and/or
abnormal glomeruli. The glomerular filtration rate (GFR) decreases
with age resulting in an adaptive increase in glomerular perfusion
pressure (Kaysen & Myers, 1985; Lindeman, 1986; Meyer & Bellucci,
1986; Anderson & Brenner, 1986, 1987; Blum et al., 1989). This
decline in GFR is due in large part to the progressive reduction in
blood flow to the kidneys (Brown et al. 1986; Lindeman, 1986).
Glomerular mesangial volume increases by 50% and 1 out of 10
glomeruli is sclerotic at the age of 80 years compared with 1 out of
100 in the young adult (Brown et al., 1986). The renal tubules
decrease in number, proximal tubule volume and length decrease, and
distal tubules develop increased diverticula. The renal arterioles
develop intimal thickening, reduplication of the lamina elastica
interna, and mild hyalinization (Brown et al., 1986; Lindeman, 1986;
Rudman, 1988).
An age-related reduction in secretory and resorptive capacity
is seen in the tubules, which is explained by a progressive loss of
functioning nephrons (Lindeman, 1986). Tubular function, which
regulates water and salt balance, is also affected. A decrease in
the ability to concentrate urine with age has been well documented
in humans. This appears to result from a decreased medullary
tonicity caused mainly by an inability to respond normally to
antidiuretic hormones (ADH) (Kaysen & Myers, 1985; Brown et al.,
1986; Meyer & Bellucci, 1986; Lindeman, 1986; Euans, 1988). Despite
age-related decreased renal function, the blood pH, partial pressure
of carbon dioxide, and serum hydrogen carbonate concentration of the
geriatric population without renal disease do not differ
significantly from those of the young under basal conditions
(Lindeman, 1986). Both the ability to maximally dilute the urine and
to maximally concentrate it, are controlled by serum ADH and by the
action of that hormone on the collecting ducts (Kaysen & Myers,
1985; Os et al., 1987). Increased arginine-vasopressin (AVP)
secretion per unit of plasma reflects a de