INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 144
PRINCIPLES OF EVALUATING CHEMICAL EFFECT ON THE AGED
This report contains the collective views of an international group of
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policy of the United Nations Environment Programme, the International
Labour Organisation, or the World Health Organization.
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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
comparable results, and the development of manpower in the field of
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
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
ISBN 92 4 157144 6 (NLM Classification: WT 104)
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PRINCIPLES FOR EVALUATING CHEMICAL EFFECTS ON THE AGED POPULATION
1. SCOPE OF THE PROBLEM
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
2.2. Changes in tissues, organs and systems in aging
2.2.1. Nervous system
188.8.131.52 Structural changes
184.108.40.206 Biochemical changes
220.127.116.11 Functional changes
2.2.2. Sensory organs
18.104.22.168 Somatic sensations
2.2.3. Endocrine system
22.214.171.124 The pituitary-thyroid axis and the
126.96.36.199 The pituitary-adrenal axis
188.8.131.52 The endocrine pancreas and
2.2.4. Reproductive system
184.108.40.206 Female aging
220.127.116.11 Male aging
2.2.5. Immune system
18.104.22.168 Aging of lymphoid organs
22.214.171.124 Aging of cellular constituents
2.2.6. Cardiovascular system
126.96.36.199 Blood vessels
188.8.131.52 Characteristics of atherosclerotic
184.108.40.206 Theories of atherosclerosis
2.2.7. Respiratory function
220.127.116.11 Gas-exchange organs
18.104.22.168 Erythropoietic activity
2.2.8. Kidney and body fluid distribution
22.214.171.124 Renal function
126.96.36.199 Lower urinary tract
2.2.9. Gastrointestinal function
188.8.131.52 Gastrointestinal tract
2.2.10. Musculo-skeletal system
184.108.40.206 Skeletal muscles
3. BASIS OF ALTERED SENSITIVITY TO ENVIRONMENTAL CHEMICALS
3.2.1. Central nervous system
3.2.2. Endocrine system
220.127.116.11 Changes in hormonal availability
18.104.22.168 Changes with age in the reception
of the signal by the target cells
22.214.171.124 Changes in the nature of the
hormonal message with age
3.2.4. Immune system
3.2.5. Other tissues and systems
3.3. Modifying factors
3.3.2. Alcohol intake
3.4. Interactions of chemicals and diseases
3.4.2. Other diseases
4. APPROACHES TO EXAMINING THE EFFECTS OF CHEMICALS ON THE AGED
4.1. Experimental approaches
4.1.1. Principles for testing chemicals in
the aged population
4.1.2. Animal models
126.96.36.199 Animal species
188.8.131.52 Animal strain
184.108.40.206 Animal sex
220.127.116.11 Selection of age groups for
18.104.22.168 Underlying pathology of animals of
22.214.171.124 Transgenic animals
126.96.36.199 Animal husbandry
4.1.3. Chemical exposure
188.8.131.52 Dose level
184.108.40.206 Route of administration
220.127.116.11 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
6. FURTHER RESEARCH
PARTICIPANTS IN THE PLANNING AND TASK GROUP MEETINGS ON PRINCIPLES
FOR EVALUATING CHEMICAL EFFECTS ON THE AGED POPULATION
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,
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,
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,
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
Dr K.T. Suzuki, National Institute for Environmental Studies,
Dr J. Vijg, Medscand Ingeny, Leiden, The Netherlandsb
Dr J.R. Zhu, Zhong Shan Hospital, Shanghai Medical University,
Dr E.I. Komarov, Central Research Institute of Roentgenology and
Radiology, Ministry of Health, St Petersburg, Russian
Dr G.C. Becking, International Programme on Chemical Safety,
Interregional Research Unit, World Health Organization,
Research Triangle Park, North Carolina, USA (Secretary for the
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,
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
* 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.
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
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.
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
HDL high density lipoprotein
hnRNA heterogeneous nuclear RNA
LDL low density lipoprotein
LH luteinizing hormone
mRNA messenger RNA
SDAT senile dementia of Alzheimer type
TSH thyroid-stimulating hormone
UDP uridine diphosphate
UDPGA UDP-glucuronic acid
1. SCOPE OF THE PROBLEM
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
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
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
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,
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,
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
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;
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
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.
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,
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.
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.
18.104.22.168 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.
22.214.171.124 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).
126.96.36.199 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
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).
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
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).
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
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.
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).
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.
188.8.131.52 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
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.,
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.
184.108.40.206 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
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).
220.127.116.11 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).
18.104.22.168 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.
22.214.171.124 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
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).
126.96.36.199 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
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.
188.8.131.52 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).
184.108.40.206 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;
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 &
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.
220.127.116.11 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
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.
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).
18.104.22.168 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 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
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.
22.214.171.124 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
126.96.36.199 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).
188.8.131.52 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.
184.108.40.206 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.
220.127.116.11 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
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;
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 decrease in collecting
tubule sensitivity to AVP. This change in sensitivity is not
completely offset by increased ADH release (Davis & Davis, 1987).
The suppression of ADH secretion is not maximal when serum
osmolality is reduced.
The renin-angiotensin-aldosterone system is also poorly
responsive to volume depletion in aging subjects. As a result, the
elderly cannot maximally retain sodium under conditions of plasma
volume contraction (Kaysen & Myers, 1985; Lindeman, 1986; Euans,
1988). The activity of the renin-angiotensin system is progressively
reduced with age. It has been suggested that angiotensin II does not
play an important role in the maintenance of blood pressure and
kidney hemodynamics in normal senescence (Corman & Michel, 1986).
The mean blood pressure is correlated with age and the decline in
renal function (Lindeman et al., 1987).
The kidney is also the site of vitamin D1 hydroxylation, which
is dramatically reduced during aging (Kaysen & Myers, 1985).
18.104.22.168 Lower urinary tract
The most frequent age-related alterations in the lower urinary
tract result in urine incontinence in both sexes and urine retention
in males. Incontinence occurs at high incidence although it is not
an inevitable consequence of aging. The high number of physiological
requirements for urinary continence may account for such frequent
failure (Williams & Pannill, 1982). In women, the reduction of
estrogen levels after menopause may decrease the tone of the smooth
muscle around the pelvic floor and the bladder outlet, thus
favouring urinary incontinence. In men, hypertrophy of the prostate
represents the major cause for involuntary loss of urine, because of
the associated frequent instability of the detrusor muscle. Other
causes for urinary incontinence are represented by delirium,
infections, restricted mobility and polyuria.
2.2.9 Gastrointestinal function
Changes in the gastrointestinal tract during aging consist
mainly of a reduced cell turnover, leading to mucosal hypoplasia.
Accessory organs, such as the exocrine pancreas and the liver, are
affected by aging independently.
22.214.171.124 Gastrointestinal tract
In contrast to the cardiovascular or excretory system, the
gastrointestinal (GI) tract does not exhibit marked structural or
functional changes with age (Penzes, 1984). Aging may affect all
regions of the GI tube. The first signs of aging are generally
observed in the mouth. Teeth undergo discoloration, pulp recedes
from the crown, dentine is often poorly renewed, and the gingiva
frequently recede (Walker, 1985). These alterations favour bacterial
growth which can lead to chronic periodontal inflammation and tooth
In the stomach, reduced secretion of hydrochloric acid and
pepsin is often found in the elderly. These changes result from
alterations in enzyme-secreting cells or from altered hormonal and
neural regulation. However, in some cases, increased acid secretion
may occur with advancing age, leading to gastritis, erosions and,
ultimately, ulcers (Kumpuris, 1983).
No major morphological alterations are observed in the
intestine. The relatively mild modification of villi, the increased
collagen content and the reduced mucosal cell proliferation
(Webster, 1985) cannot account for the impaired absorption of
nutrients, including minerals (calcium, iron and zinc) and vitamins
often found in the elderly. Other factors such as reduced motility
and inadequate intestinal blood supply may play a more important
role than the slightly altered anatomical integrity.
In the lower GI tract the rectal tone is generally decreased in
the elderly and the sphincter is weakened, leading to incontinence.
Neurological alterations (dementia), muscle atrophy, diarrhoea and
constipation can all contribute to anal incontinence.
Pancreatic function is not seriously compromised during normal
aging. Structural changes mainly involve a reduction in the number
of secreting cells, with a consequent decrease in size of the
pancreas and a moderate increase in collagen content. Reduction in
the levels of trypsin, hydrogen carbonate, amylase and lipase in the
pancreatic juice occurs commonly in the elderly (Vellas et al.,
1988). Overall, however, the functional efficiency of the pancreas
is not lost during aging.
Structural changes in the liver with age are relatively minor.
However, the most significant change in human liver is a decrease in
volume (Wynne et al., 1989). The life-span of the hepatocyte is
long, with cells only dividing once or twice during the lifetime in
the absence of a growth stimulus (Popper, 1986). Whether the
function of the aging hepatocyte is impaired is unclear. Kupffer
cell function may be impaired as demonstrated by a reduction in
phagocytic activity. Endocytosis is reduced in Kupffer, but not
endothelial, cells. An increase in collagen also characterizes aging
The function of aging liver also undergoes a number of
alterations. In humans, cholesterol synthesis is reduced in the
elderly, while biliary secretion is increased (Popper, 1986).
Hepatic blood flow is reduced by as much as 50% (Sherlock et al.,
1955). Age-related changes in liver enzyme expression have been
studied in more detail in rodents (Fishbein, 1991). The efficiency
of carbohydrate and intermediary metabolism is decreased in
senescent rats or mice of both sexes, due in part to decreased
insulin-binding and the impaired regulation of enzymes such as
pyruvate kinase. Hepatic protein synthesis also decreases with age,
and the sex-specific expression of drug and steroid-metabolizing
enzymes in male rats appears to be feminized in senescence (Kitani,
2.2.10 Musculo-skeletal system
Aging dramatically affects bone, joints and skeletal muscles.
The basic phenomena responsible for the aging of the
musculo-skeletal system are not completely understood because of the
involvement of many factors, e.g., hormones, nutrition and physical
exercise, in addition to specific age-related alterations at the
tissue level, resulting in general deterioration of the system.
Bone should not be considered as metabolically quiescent since
it is constantly remodelled according to mechanical demand and
continuous turnover due to new bone formation (by osteoblasts) and
bone resorption (by osteoclasts) (Exton-Smith, 1985).
With aging, the balance between bone formation and bone
resorption is altered in favour of resorption, resulting in a
reduction of bone mass. This starts from the medullary region with
enlargement of the cavity and moves towards the epiphysis of the
bone and then to the outer surface with a final reduction of cortex
thickness. As a consequence, the bone strength is reduced (Smith
et al., 1981). The prolonged period where bone resorption exceeds
bone formation may result in osteoporosis (Dawson-Hughes et al.,
1987; Eastell & Riggs, 1987; Riggs, 1987; Croucher et al., 1989).
The factors responsible for bone resorption and remodelling are
not well known. More knowledge is available concerning two other
factors which profoundly affect bone metabolism: calcium turnover
and hormonal profile. Calcium is absorbed through the intestinal
mucosa and is excreted from the kidney, the blood level remaining
remarkably constant throughout life. Calcium is required for many
essential functions in the body, such as cell division, cell
intermediary metabolism, and cell functions (excitability, secretion
and movement). In the case of a negative balance, calcium is
mobilized from the bone with a consequent reduction in bone mass.
Calcium metabolism is under hormonal control. Parathyroid
hormone increases the plasma calcium level by promoting bone
resorption and mobilization, whereas calcitonin lowers blood calcium
by inhibiting bone resorption. Calcitriol (the active derivative of
vitamin D) increases intestinal absorption and decreases excretion
of calcium, thus acting to increase the body burden of calcium. The
age-associated decrease in intestinal calcium absorption lowers the
plasma calcium level, leading to an increase in parathyroid hormone.
Calcitriol levels may also be deficient in the elderly, as a result,
perhaps in part, of the decrease in vitamin D synthesis in old skin
and alterations in renal metabolism.
Bone metabolism also depends on other hormonal factors.
Estrogens have a strong positive effect on bone density. After
menopause, bone resorption exceeds bone formation resulting in bone
mass loss. However, the occurrence of osteoporosis greatly depends
on the adult bone peak mass, physical activity, and calcium intake
(Eastell & Riggs, 1987; Riggs, 1987; Bornor et al., 1988; Stevenson
et al., 1988; Lindsay, 1989).
Glucocorticoids lower plasma calcium levels, which can increase
bone resorption by stimulating parathormone secretion. Thyroid
hormones may also cause bone loss, although the mechanism is still
unclear. Growth hormone, somatomedins and insulin all promote bone
formation, and therefore defective secretion (as in diabetes) may
Articular disorders are practically universal in elderly
people, and are associated with pain and disability. The major
alteration consists of the loss of the smooth surface of cartilage,
which becomes thicker and less elastic. The cartilage develops rough
surfaces and mechanical irregularities, which represent the early
steps in osteoarthritis (Evens & Hawkins, 1984).
126.96.36.199 Skeletal muscles
With advancing age muscles become smaller in size, due to
reduction in the number of fibres, and less elastic, due to an
increase in collagen content. The fat content of muscle tissue also
increases with age. The causes for such defects are still
controversial: alteration of sarcoplasmic reticulum, decrease of
contractile protein synthesis and a reduction in the number of
mitochondria are all found in aged muscle cells.
In addition to muscle cell alterations, the neuromuscular
junction is modified in aged muscle. The acetylcholine content of
nerve terminals is consistently reduced and acetylcholine receptors
are irregularly distributed. Motor nerve conduction velocity is also
impaired. All these defects contribute to the progressive failure of
muscular efficiency, although some muscles, such as the diaphragm,
do not seem to suffer age-related effects (Finch & Hayflick, 1977).
Thus, the additive results of the loss of bone mass, disorder of
joints, decline in skeletal muscle power and nervous system
discoordination may lead to loss of body stability, falls and bone
fracture in old people.
The age-related modification of the skin is the most dramatic,
common and constant event in life, so that it may constitute one of
the best external markers of aging. Only recently has it been
possible to distinguish between intrinsic aging of the skin and
photo-aging (Gilchrest, 1984). Cutaneous neoplasia is one of the
best documented interactions between aging of the organism and
environmental effects. A variety of environmental factors, the most
notable being ultraviolet radiation, has been shown to cause cancer
of the skin in humans and animal models (Rogers & Gilchrest, 1990).
The structure of skin changes throughout life (Behl et al.,
1987), although many of the alterations are due to exposure to
sunlight rather than intrinsic aging (Gilchrest, 1984). Skin
thickness increases during maturation and then gradually declines
(Vogel, 1983). However, recent studies in mice and rats by
Monteiro-Riviere et al. (1991) have not reported any significant
changes in skin thickness or blood flow from maturity throughout the
life span. Hydration, which can affect chemical solubility,
decreases while keratinization increases.
Skin aging is linked to alterations affecting both the
epidermal and the dermal components. The epidermis suffers from a
reduction in the turnover of epidermal cells, due both to a
reduction of basal cell renewal and to a slower maturation toward
the stratum corneum. The dermo-epidermal interface is flattened so
that the total external body surface area is reduced (Selmanovitz
et al., 1977). The reduction in epidermal cell turnover is
responsible for the slowing of wound healing and possibly for the
dryness and/or roughness of aged skin. The dermis is reduced in
thickness in the elderly and is characterized by a reduced collagen
content with a biochemical modification of the collagen itself,
which makes it more strong and less elastic. Vascularization in
humans is also reduced.
Aging also results in modifications in the skin appendages.
Sweat gland function is decreased resulting in impaired
thermoregulation. Sebaceous glands produce less oil and wax (dryness
of skin), and hair usually loses pigment. The numbers of skin
sensory organs (Pacinian and Meissner's corpuscles) decrease with
age and sensation is consequently modified.
Collagen aging occurs in the skin, as in other tissues, leading
to increased rigidity. Collagen is composed of several related
proteins, which are produced by fibroblasts and extruded into the
extracellular space. Here they can be chemically deposited in a
nearly pure form, as in the tendons, or immersed in an extracellular
matrix, also produced by fibroblasts, as in the skin. The collagen
fibres undergo maturation in the extracellular ground substance by
parallel arrangements of tropocollagen fibres which became assembled
together through cross-linking. This phenomenon is an index of
maturational change. With age, however, the cross-linking increases
(Houck et al., 1967), leading to a reduction of tensile strength and
plasticity (Verzar, 1968). The extracellular matrix also shows
age-related changes, since alterations in its physicochemical
composition lead to increased density, reduced permeability and
impaired transport of nutrients (Imayama & Braverman, 1989).
3. BASIS OF ALTERED SENSITIVITY TO ENVIRONMENTAL CHEMICALS
The perception of altered sensitivity of the elderly to
environmental insults is based in large part on the enhanced
incidence of adverse or idiosyncratic drug reactions in this segment
of the population (Vestal et al., 1985). The clinical pharmacology
of the aged has been extensively reviewed in the last two decades
(Triggs & Nation, 1975; Crooks et al., 1976; Reidenberg, 1980;
Vestal et al., 1985), and evidence indicates that the response to
drugs changes with age, as does the frequency of adverse drug
reactions (Krupka & Vener, 1979). This may be in part related to
issues of polypharmacy and compliance (Weber & Griffin, 1986).
Morbidity and malnutrition, which are often associated with aging,
could also contribute to altered pharmacokinetics in the elderly
(Kitani, 1988). However, it is clear that age-related differences in
drug/chemical disposition (pharmacokinetics/toxicokinetics) or
sensitivity (pharmacodynamics/toxicodynamics) also play a role in
altered responses to chemicals in the elderly. For sake of
simplicity, the terms "pharmacokinetics" and "pharmacodynamics" will
be used for both drugs and environmental chemicals.
Pharmacokinetics describes the processes of the absorption,
distribution, metabolism and excretion of drugs or other chemicals
in the body. The numerous physiological and biochemical changes that
occur during aging can modulate any of these processes of
disposition. Changes in chemical disposition (pharmacokinetics being
the mathematical description of these processes) can lead to an
altered dose or dose-rate to the target tissue resulting in changes
in response. This topic has been the subject of several recent
reviews (Sellers et al., 1983; Van Bezooijen, 1984; Stevenson &
Hosie, 1985; Blumberg, 1985; Birnbaum, 1987, 1989, 1991; Ritschel,
1988; Loi & Vestal, 1988; McMahon & Birnbaum, 1990a).
The highlights in this field will be covered as well as the
more recent data, especially that focusing on age-related
alterations in the pharmacokinetic behaviour of xenobiotics, as
opposed to drugs.
The absorption of drugs and environmental chemicals, defined as
uptake into the blood, occurs primarily via the skin, lungs and
gastrointestinal (GI) tract. Alterations in the structure and
function of these three organs clearly occur with age. In contrast
to the skin and GI tract, little is known about the effects of aging
on pulmonary absorption of xenobiotics. Few age-related differences
have been reported in lung structure (Stiles & Tyler, 1988),
although the lung volume is greater in old rats. An age-related
decrease in respiratory function has been reported in several
species (Mauderly, 1979a,b, 1982). In addition, there appears to be
a decrease in the rate of alveolar-capillary gas exchange in older
organisms (Mauderly, 1979b).
Dermal exposure represents a major portal of entry for
environmental chemicals. Several studies have indicated a decline in
human skin permeability with aging (Christophers & Kligman, 1965).
In experimental animals, the scarce data suggest that percutaneous
absorption is decreased in senescent rodents as compared to young
adults. The chemical absorption of
2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) and related chemicals
is greatest at weaning (Jackson et al, 1990), decreases at maturity
and then undergoes a further decline during aging (Banks et al.,
Age-related alterations in GI absorption have been studied in
more depth. A decrease in gastric acid secretion is commonly seen in
the elderly (Bender, 1968). The resulting increase in pH can alter
the ionization of compounds, enhancing or retarding their ability to
diffuse passively across cellular membranes. Decreases in gastric
motility (Lin & Hayton, 1983) can prolong the transit time of
chemicals in the gut, thus enhancing their potential for absorption.
In rats, splanchnic blood flow declines in the first year of life
but stays unchanged in the second year (Yates & Hiley, 1979; Kitani,
1988). In contrast, splanchnic blood flow declines progressively
with age in humans (Sherlock et al., 1955). An increase with age in
mucosal weight (Holt et al., 1984; Hebert & Birnbaum, 1987), as well
as intestinal epithelial cell proliferation (Holt et al., 1988), has
been reported in rats.
GI absorption can be active, passive or involve phagocytosis.
Xenobiotics are primarily absorbed by passive diffusion. Age-related
changes in the oral absorption of a variety of drugs in people have
not been observed (Castleden et al., 1977b; Stevenson et al., 1979;
Greenblatt et al., 1988). The passive absorption of TCDD in the
small intestine does not change with age in rodents (Hebert &
Birnbaum, 1987), nor does that of many small endogenous molecules,
such as glucose (Eastin & Birnbaum, 1987), vitamin A (Hollander
et al., 1986), vitamin D, vitamin B12 and niacin (Fleming &
Barrows, 1982a,b) and many amino acids (Penzes, 1974).
Active transport appears to decrease with age (Eastin &
Birnbaum, 1987). Doubek & Armbrecht (1987) have demonstrated that
the decrease in the carrier-mediated component of glucose transport
in rats occurs in the brush-border membrane of the small intestine.
Their suggestion that the decrease is due to a reduction in the
number of sodium-linked glucose carriers has been supported by
recent studies in human intestinal tissue (Vincenzini et al., 1989).
The active transport of other small molecules such as calcium and
phosphorus (Armbrecht, 1986), and galactose and iron (Reidenberg,
1980) has also been reported to decrease with age. As with the
active transport of glucose, the marked decrease in calcium active
transport of calcium occurs between young adulthood and middle age
(Mooradian & Song, 1989) and results from changes in the number of
calcium transporters in the intestinal basal lateral membranes
(Armbrecht et al., 1988).
The distribution of chemicals throughout the body is governed
by the fact that the physicochemical properties of the compound
affect its transport within the body and localization to various
tissues. Lipophilic molecules readily pass across cellular membranes
and accumulate in lipid-rich tissues. Binding to proteins also
modulates distribution, since few compounds are transported free in
the blood. While there is no evidence of alterations in relative
blood volume with age, changes in body composition, blood flow and
macromolecular binding have all been documented.
The decrease in lean body mass in both animals (Lesser et al.,
1973) and humans (Novak, 1972) has been well documented. Loss of
body water with age (Edelman & Leibman, 1959) results in a decrease
in the volume of distribution for water-soluble compounds, leading
to enhanced toxicity of ethanol (York, 1982) and ethylenediamine
(Yang et al., 1984). Body fat can account for approximately 15-40%
of the total body weight in humans (Ritschel, 1983) and rats
(Bertrand et al., 1980; Birnbaum, 1983). The increased size of the
fat compartment in older, sedentary animals would be expected to
increase the body burden of lipid-soluble substances and reduce the
overall rate of elimination from older animals. Following an
inhalation exposure of old rats to methylchloroform (Schumann
et al., 1982a,b), a better fit to a physiologically based
pharmacokinetic (PbPk) model was obtained by increasing the volume
of the fat compartment from 7 to 18% of the body weight for rats and
from 4 to 18% for mice (Reitz et al., 1988). Similar improvements
were noted by Lutz et al. (1977) in their PbPk model of
polybrominated biphenyl compounds in rats.
Not only does cardiac output decrease with age (Bender, 1965),
but regional blood flow can change differentially (Yates & Hiley,
1979). Since adipose tissue volume increases but blood flow
decreases with age, lipophilic compounds tend to show greater
retention in the elderly. This has been shown for polychlorinated
biphenyls (Birnbaum, 1983) and halogenated solvents (Schumann
et al., 1982a,b). A clinical pharmacokinetic study (Klotz et al.,
1975) which demonstrated a 5-fold increase in the distribution
volume of diazepam in the elderly is in agreement with the data on
Binding to blood components can also change with age. Although
the total plasma protein content does not change dramatically with
age, there is a small but significant reduction in albumin in both
animals (Rodgers & Gass, 1983) and humans (Bender et al., 1975). For
drugs or xenobiotics that can be bound, such a decrease in albumin
enables a higher concentration of free drug to reach the target
site. A decrease in binding of drugs to red blood cells has also
been reported to occur during aging (Chan et al., 1975), again
leading to a higher level of free drug.
As with absorption and distribution, there are physiological
changes that occur during aging which can influence
biotransformation reactions, both in the liver and in extrahepatic
tissues. Although the liver is the main site for the metabolism of
drugs and environmental chemicals, significant metabolic reactions
occur in all the portals of entry tissues (skin, respiratory tract,
GI tract) as well as the kidneys, gonads, adrenals, etc. Metabolism
is often considered to be divided into two types of reactions: phase
I (functionalization reactions) and phase II (conjugation
reactions). Phase I reactions tend to increase the polarity of
chemicals, and the corresponding enzymes include the
cytochrome-P450- and FAD-containing monooxygenases as well as the
alcohol and aldehyde dehydrogenases, monoamine oxidases, nitro- and
azo-reductases, esterases and amidases. Phase II reactions involve
the conjugation of functional group (either already present on the
chemical or as a result of phase I activity) with an endogenous
cofactor such as an amino acid (glycine, glutamate), peptide
(glutathione), sugar (glucuronic acid) or a small molecule such as a
sulfate, acetate or methyl group. These reactions may occur on
cellular membranes or in the cytosol, and are regulated in a
The only generalization that can be made concerning age-related
changes in biotransformation is that few patterns exist. Metabolic
changes with aging appear to be substrate, sex, strain and species
dependent (Schmucker & Wang, 1989; Kitani, 1988; Birnbaum, 1989;
McMahon & Birnbaum, 1990b). In addition to intrinsic changes related
to altered physiology, the study of the influence of age on
metabolism is further complicated by the effects of diet, alcohol,
drugs and pollutants, which can induce or inhibit enzyme activities
Most of the research on the effects of aging on metabolism has
focused on the microsomal mixed-function oxidases. The protein
components of this system have been reported to decline or remain
unchanged with age. In general, the decline in total cytochrome P450
levels reported in rats appears to be due to the age-related
decrease in the amount of the male-specific forms (Kamataki et al.,
1985a,b; Sun et al., 1986). This results from the age-related
decrease in circulating testosterone levels (Kitani, 1985) or to
alterations in the secretory profiles of growth hormone (Fishbein,
1991). This pattern is most pronounced in rats, few changes being
observed in other rodents or sub-human primates (Birnbaum, 1987).
However, recent human studies have suggested that some degree of
sexual dimorphism does exist in hepatic drug metabolism. Plasma
antipyrine half-lives were prolonged in elderly males, but not
elderly females, as compared to young adults (Greenblatt et al.,
1988). This was caused by an age-related reduction in clearance,
which has been interpreted as being the result of an impairment of
antipyrine metabolism in elderly men. Similar gender-specific
results were observed for the kinetics of chlordiazepoxide, another
low-clearance oxidatively metabolized drug (Loi & Vestal, 1988).
A study by Chengelis (1988a) has supported the earlier report
of Rikans (1984) that measuring components of the monooxygenase
system cannot lead to predictions of toxicity. Sex differences in
rats were only significant up to one year of age. However, Rikans
(1989a) has recently reported that metabolism of specific substrates
(aniline, benzphetamine and nitroanisole) does decline with age in
the female as well as in the male rat, but the magnitude of change
in the female is smaller. This agrees with a study by Bitar &
Shapiro (1987), who suggested that an age-related increase in haem
degradation plays a role in the decreased metabolism of hexobarbital
and aniline. This observation, that microsomal drug metabolism
activities do not have to be sexually dimorphic to be altered in old
age, implies that factors other than loss of the male-specific
cytochromes P450 contribute to the age-associated alterations in
some rat strains. Decreases in NADPH cytochrome P450 reductase in
rat liver with age have been reported by Blanco et al. (1987),
Chengelis (1988a) and Rikans (1989a).
Despite a large body of data obtained from experimental animal
studies, there is no clear evidence that monooxygenase activities
decline in the livers of healthy elderly humans. All the data
derived so far from human liver biopsy specimens have shown no
correlation between enzyme activities expressed per mg protein and
age of subjects (Boobis & Davies, 1984; Schmucker et al., 1990). The
often reported decreases in clearance values of drugs metabolized
primarily by the liver in the elderly may in large part be accounted
for by the decrease in liver volume with age (Kitani, 1988). Further
evidence is needed to determine whether hepatic drug-metabolizing
enzyme activities in humans decline with age, as is observed in some
rodents, but the extent is unlikely to be as drastic as that
observed in male rat liver.
A change in the composition of cytochrome P450 enzymes,
suggested by differential changes in enzyme activity, has been
demonstrated in male rats (Kamataki et al., 1985a; Sun & Strobel,
1986). Leakey et al. (1989a) showed that dietary restriction could
also alter the profile of cytochrome P450 isoforms, possibly by
delaying the age-related demasculinization of the liver. Friedman
et al. (1989) showed that aging affected the composition of
testosterone-binding cytochromes P450 in the liver of male rats.
Changes in P450 isoforms in old rats were also reported by
Paramonova & Dovgi (1987). Studies with humans have demonstrated
that the effect of age on metabolism even varies for different
metabolites of the same parent compound (Posner et al., 1987). This
supports the observation of changes in cytochrome P450 isoform
composition with age, as has been reported for male rat liver.
Hepatic xenobiotic metabolism can be modulated by many factors.
In humans, smoking often confounds studies of age-related changes in
pharmacokinetics. However, the age-related decrease in the
metabolism of antipyrine (Loft et al., 1988), theophylline and
cortisol (Crowley et al., 1988) may be independent of smoking
status. In fact, the inductive properties of smoking on hepatic
metabolism do not appear to diminish with age. Phenytoin also
increased theophylline metabolism to an equal extent in both young
and old healthy men (Crowley et al., 1988). In contrast, Rath &
Kanungo (1989) demonstrated that the rate of transcription of the
phenobarbital-specific isozymes was nearly two-fold higher in young
rat liver than in old. However, these differential effects may
reflect the specific isoforms involved, since smoking and
phenobarbital preferentially induce different forms. The recent
studies of Rikans (1989b), which demonstrate that induction of
hepatic microsomal drug metabolism by ethanol or acetone is
unaffected by the aging process, lend support to this concept.
Age-related changes in phase I hepatic drug-metabolizing
enzymes other than the mixed-function oxidases have been subjected
to much less examination. Rikans & Moore (1987) demonstrated an
age-related increase in liver alcohol dehydrogenase in male rats.
However, no age differences have been observed in the activity of
this enzyme in female rats. Hydrolytic reactions may decrease with
age. For example, liver esterase activity, using diethylhexyl
phthalate as a substrate, declines in old rats (Gollamudi et al.,
1983). Using aspirin as a substrate, no correlation was found
between age and esterase activity in human liver (Yelland et al.,
1991). These results provide further evidence that age is not a
major determinant of hepatic drug metabolism in the elderly
(Schmucker et al., 1990).
Alterations with age in extrahepatic phase I metabolism also
appear to be substrate, sex, strain and species specific. Pulmonary
metabolism of benzo[a]pyrene was found to increase in old rats (Sun
& Strobel, 1986) in agreement with earlier studies of Rabovsky
et al. (1984). In contrast, oxidation of 2-aminofluorene, which is
catalysed by a different isoform of cytochrome P450, decreased
(Robertson & Birnbaum, 1982). Renal metabolism of acetaminophen has
been reported to decrease with age (Beierschmitt & Weiner, 1986),
while salicylate oxidation by kidney extracts did not change in rats
(Kyle & Kocsis, 1985). Age-related alterations in intestinal Phase I
metabolism appear to be site specific. Sun & Strobel (1986) reported
that oxidation of benzo [a]pyrene in the colon increased throughout
the life of rats, while McMahon et al. (1987) observed no
age-related change in the metabolism of this substrate in the small
intestine. Newaz et al. (1983) observed higher metabolic rates of
dimethylhydrazine in colonic tissue from aging humans as compared to
younger individuals. McMahon et al. (1989) suggested that plasma
esterase hydrolysis of benzyl acetate may decline with age in both
rats and mice. Alcohol dehydrogenase activity was found to remain
unchanged in the aging colon (McMahon et al., 1987).
Changes in phase II enzymes also appear greatly variable in
rodent liver, although Loi & Vestal (1988) conclude that age has
little effect on phase II reactions in humans. The major conjugation
reactions involve sulfation, glucuronidation or reaction with
glutathione leading to mercapturic acid formation. All these
reactions are catalysed by multiple isoforms showing varying degrees
of substrate and sex specificity, as is the case for the phase I
enzymes. Iwasaki et al. (1986) demonstrated differential age effects
on two distinct sulfotransferases using male and female rats and
various alcohols and amines. Sulfation of phenolic substrates
appears to decline with age (Galinsky et al., 1986; Sweeny & Weiner,
1986) while conjugation of bile salts increases in old male rats
(Galinsky et al., 1986). In contrast, changes in female rats were
not seen (Galinsky et al., 1990). Chengelis (1988b) observed no
significant changes in sulfotransferase activity with age in either
male or female rats using beta-naphthol as the substrate. Similar
results were seen by Leakey et al. (1989b) for the conjugation of
both estrone and naphthol, whereas the sulfation of androsterone and
corticosterone increased with age in male rats.
Hepatic glucuronidation also shows substrate specificity for
alterations with age. Depending on the substrate, increases with
estrone and acetaminophen (Galinsky et al., 1986), decreases with
the rubber antioxidant 4,4'-thiobis-(6- t-butyl- m-cresol)
(Borghoff et al., 1988), or no effect with naphthol,
p-nitrophenol, morphine and testosterone have been observed
(Galinsky et al., 1986; Sweeny & Weiner, 1986) in male rats. In
contrast, Chengelis (1988b) observed a marked decrease in senescent
male and female rats using both p-nitrophenol and chloramphenicol.
To complicate matters further, Leakey et al. (1989b) also saw a
decrease in naphthol, testosterone, androsterone and
tetrahydrocortisone conjugation with glucuronic acid, but observed
no effects of aging on conjugation with 2-aminophenol,
5-hydroxytryptamine, bilirubin or estrone. Tarloff et al. (1989b)
saw no change in acetaminophen glucuronidation with advancing age.
Although the activities of the UDP-glucuronosyltransferases appear
highly variable, an age-related decrease in hepatic levels of the
cofactor, UDP-glucuronic acid (UDPGA) (Borghoff et al., 1988),
suggests that glucuronidation could be limited in older animals.
The concentration of hepatic glutathione, the cofactor involved
in the third major class of conjugation reactions, has been reported
to increase (Borghoff & Birnbaum, 1986), decrease (Stohs et al.,
1982) or remain unchanged (Chengelis, 1988b; Rikans & Moore, 1988)
in old rodents. Variability in age effects has also been reported in
the activity of the glutathione- S-transferases, which exist as a
family of dimeric proteins having broad and overlapping substrate
specificity. The isozymes are composed of two subunits from at least
six different peptides, including both homo- and heterodimers. Thus
reports of an increase (Leakey et al., 1989b), decrease (Fujita
et al., 1985; Blanco et al., 1987; Leakey et al., 1989b), or no
change (Birnbaum & Baird, 1979; Sweeny & Weiner, 1985; Borghoff &
Birnbaum, 1986; Chengelis, 1988b; Leakey et al., 1989b; Carrillo
et al., 1991) in hepatic glutathione-S-transferase activity may, as
in the cases of cytochrome P450 mixed-function oxidases,
sulfotransferases and UDP-glucuronosyltransferases, reflect
age-dependant changes in isozyme ratios (Spearman & Leibman, 1984;
Carrillo et al., 1991). Restriction in dietary protein decreases the
activity of the glutathione-S-transferases more in old than young
rodents (Carrillo et al., 1989, 1990).
Much less has been reported on the effects of aging on other
phase II metabolic reactions in the liver. Hydrolysis of expoxides
to form diols or dihydrodiols is catalysed by the epoxide
hydrolases. Epoxide hydrolase activity has been reported both to
increase (Birnbaum & Baird, 1979) and decrease (Ali et al., 1985;
Kaur & Gill, 1985; Leakey et al., 1989b) with age. Again, this may
reflect differential age effects on multiple enzymatic species.
However, some of the difference may be due to the ages of animals
used for comparison, since Chengelis (1988b) reported a gradual
increase in epoxide hydrolase activity throughout much of the life
span, followed by an abrupt decrease in senescence.
Human studies have suggested that the alterations observed in
salicylate pharmacokinetics (Cuny et al., 1979) with age might be
due to a decrease in glycine conjugation (Kyle & Kocsis, 1985).
However, elevated levels of salicyluric acid, the glycine conjugate
of salicylate, have been observed in elderly humans undergoing
chronic salicylate treatment (Montgomery & Sitar, 1981). Recent
studies in rodents have not demonstrated any age-related decline in
glycine conjugation with non-nephrotoxic doses of salicylate
(McMahon et al., l990a) or in the formation of hippuric acid from
benzoate (McMahon et al., 1989). Acetylation, however, has been
reported to decline both in man (Bauer et al., 1989) and rats
(Leakey et al., 1989b).
Changes in extrahepatic phase II reactions have been
investigated in even less depth than extrahepatic phase I reactions.
In the lung and small intestine, glucuronidation of p-nitrophenol
appeared not to change with age (Borghoff & Birnbaum, 1985), whereas
in the colon an age-related decrease was reported by McMahon et al.
(1987). In contrast, colonic glucuronidation of
4-methylumbelliferone rose significantly in older rats (McMahon
et al., l990b). A decrease in UDP-glucuronosyl transferase activity
in the kidney (Borghoff & Birnbaum, 1985; Tarloff et al., 1989a) was
accompanied by a decrease in the renal concentration of UDPGA
(Borghoff et al., 1988).
Glutathione content has been examined in a variety of tissues
(lung, kidney, brain, testes and blood) and, except for an
age-related decrease in the lens, has been found to remain constant
(Rikans & Moore, 1988). Unchanged glutathione levels in the colon
occurred although the activity of glutathione- S-transferase
decreased in this tissue (McMahon et al., 1987). Spearman & Leibman
(1983, 1984) observed differential age- and sex-related changes in
this activity in the lung depending on the substrate examined. The
renal activity of glutathione- S-transferase declines significantly
in old rats (Beierschmitt & Weiner, 1986). In contrast, elevated
gluthathione- S-transferase levels were observed in the brain of
old rats (Blanco et al., 1987), while no changes were observed in
Epoxide hydrolase activity has been examined in the lungs,
small intestine and kidneys by Kaur & Gill (1985). They observed a
decrease in lung and small intestine activity in old rats which was
substrate dependent. In the rat kidney, epoxide hydrolase activity
decreased using trans-stilbene oxide as the substrate but did not
change with cis-stilbene oxide, supporting again the differential
effects of aging on different isozymic forms of drug-metabolizing
enzymes. In addition, deacetylation of acetaminophen in the kidney
appears to be either unchanged with age (Beierschmitt & Weiner,
1986) or slightly decreased (Tarloff et al., 1989b). Acetylation in
the kidney also decreases with age (Wabner & Chen, 1984).
One additional enzyme which can be considered to fall into the
phase II class is beta-glucuronidase. This enzyme hydrolyses
glucuronic acid from conjugated xenobiotics. The activity of this
enzyme has been reported to increase with age in rat liver
(Schmucker & Wang, 1979; Van Manen et al., 1983) and kidney
(Borghoff & Birnbaum, 1985), but remain unchanged in the colon
(McMahon et al., 1987). However, beta-glucuronidase was found to
decrease with age in fecal contents (McMahon, 1988). The balance
between glucuronidation and deglucuronidation reactions may play a
role in determining the level of reactive compounds in the organism.
Depending on the chemical, aging can result in either an
increase or a decrease in the metabolizing capacity of different
organs and tissues (liver, kidney, gastrointestinal tract, lungs and
skin). The elevation or reduction in metabolism can both lead to
higher and lower toxicity, depending on the relative reactivity of
the metabolic intermediates and end-products. Thus studies on the
effect of aging on metabolism should be considered case by case.
Excretion leads to the elimination of a chemical and/or its
metabolites from the body. The kidney is the major excretory organ,
with the liver and lung also playing important roles in the
elimination process. In addition, sweat, saliva and sex-linked
processes such as lactation can serve as routes of excretion.
The effects of age on renal function appear to play a major
role in altered pharmacokinetics in the elderly (Vestal, 1978;
Koch-Weser et al., 1982). The fact that changes in the physiology of
the kidney occur has been known for many years (Schmucker, 1979).
Renal blood flow decreases with age leading to a decrease in
glomerular filtration rate. Tubular secretion and resorption are
also reduced in the elderly. The number of functional nephrons
declines to a similar extent as the decline in glomerular filtration
rate and active secretion, suggesting that the nephron loses its
function as a unit (Friedman et al., 1972). Decreases in renal
function can result in a decreased rate of renal clearance, leading
to a greater potential for elevated and/or persistent levels of
chemicals in the body which could lead to toxicity (Sellers et al.,
1983). In humans, decreased renal clearance in the elderly has been
demonstrated for many drugs, including the aminoglycosides,
tetracyclines, lithium, digoxin, procainamide, methotrexate, and
phenobarbital (Kampmann & Hansen, 1979).
Aging rodents are extremely susceptible to chronic
glomerulonephropathy (Goldstein et al., 1988), much of which may be
attributable to diet (Masoro & Yu, 1989). Altered glomerular
morphology, characterized by thickening of the basement membrane and
sclerosis, is progressive and increases in severity with advancing
age, eventually resulting in scarring and loss. Renal tubules are
also subject to degenerative changes, which are accompanied by
proteinuria, especially albuminuria (Neuhaus & Flory, 1978). This
appears to result from increases in glomerular permeability and a
loss of fixed glomerular polyanion (Baylis et al., 1988). The high
percentage of urinary protein represented by albumin in the aging
rat may be due to non-selective protein leakage into the urine
resulting from increases in glomerular permeability to large
proteins, since the protein percentage in urine approaches that in
the plasma of senescent rats (Horbach et al., 1988a). Similar
albuminuria has been observed in aging mice (Yumura et al., 1989),
and was correlated with glomerular sclerosis. Such changes, however,
should not be simply extrapolated to humans, since there is no
evidence for an increase in protein loss in the urine of the healthy
Additional tubular changes occur in the aging kidney, resulting
in hyperplastic and degenerative changes. Some of these changes
resemble responses to specific environmental chemicals (Konishi &
Ward, 1989). A decrease in renal transport of organic acids has been
observed (Wabner & Chen, 1984). Aging appears to diminish the
turnover of sodium/potassium ATPase in the proximal tubules (Marin
et al., 1985), which could play a role in the observed age-related
decrease in tubular secretion.
Hepatic elimination may also be compromised by aging. Kitani
(1985) has suggested that the excretory capacity of the liver
decreases with age due to some functional alteration in the
hepatocytes. In contrast to rats, where blood flow does not change
after maturity (Kitani, 1988), blood flow to the liver declines in
humans (Sherlock et al., 1955). Bile flow rate has been reported to
be reduced (Borghoff et al., 1988) or remain unchanged (Kitani
et al., 1985a) in rats. Biliary transport declines, especially in
the case of polar compounds (Kitani et al., 1985a). The elimination
of sulfobromophthalein, a model compound for the study of biliary
excretion of organic anions, is also decreased in old rats (Kanai
et al., 1985). Sato et al. (1987) demonstrated that the biliary
excretion of the neutral glycoside ouabain decreases with age in
both males and females. This may be due to an age-related decrease
in hepatic uptake, resulting in less biliary elimination (Ohta
et al., 1988). In addition, the biliary canalicular transport system
declines steadily during aging (Kanai et al., 1988). The decreases
in both hepatic uptake and biliary excretion may reflect changes in
the hepatocyte plasma membrane (Zs-Nagy et al., 1986).
Age-related changes in chemical sensitivity cannot all be
explained on the basis of altered pharmacokinetics in the elderly.
Pharmacodynamic changes occur at the target site and may involve
changes in cell populations, cellular receptors, cellular
responsiveness or in the regulation of the amount or activity of
drugs, including the cardiac glycosides, benzodiazepines, tricyclic
anti-depressants, and the non-steroidal anti-inflammatory agents
(Bender, 1979), which have demonstrated altered receptor sensitivity
in the aged (Wilson & Hanson, 1980).
3.2.1 Central nervous system
Numerous studies have shown that, with advancing age, there is
a decrease in the ability of the nervous system to synthesize and/or
release neurotransmitters and neuropeptides (for review, see Rogers
& Bloom, 1985). This decline may reflect the fact that there are
fewer neurons present to synthesize the chemical messenger or that
the enzymes involved in their synthesis are altered. This would
imply that xenobiotics which lead to neuronal death or interfere
with neurotransmitter or neuropeptide synthesis and release could
have a greater adverse effect on the elderly than on the young
organism. An example of such an interaction has been noted within
the dopaminergic extrapyramidal circuits controlling motor movements
(nigrostriatal pathway). This pathway has been the subject of many
experimental and clinical studies and provides one of the best
functional units in which to study neurotoxicity in the aged.
Nigrostriatal neurons are lost as a normal correlate of aging, and
while these losses may not be expressed in the majority of
individuals as movement disorders, there is a clear reduction in the
functional reserve of this dopaminergic system, making it more
vulnerable to neurotoxicants. This has been demonstrated by the
observed acceleration or simulation of "age-associated" movement
disorders by neurotoxicants such as
The reduced capacity to synthesize neurotransmitters that
occurs in the aged organism may also potentiate the effect of toxic
substances. Carbon disulfide is an organic solvent with a variety of
industrial applications that produces neurobehavioural dysfunctions
(Wood, 1981). The mechanism of CS2 toxicity seems to be inhibition
of dopamine-beta-hydroxylase, the enzyme that converts dopamine to
norepinephrine (McKenna & DiStefano, 1977). Since norepinephrine
metabolism declines with age, the spectrum of physiological effects
regulated by this catecholamine would be expected to suffer greater
disturbance, following exposure to CS2 or to pesticides that
reduce brain catecholamines such as methyl bromide (Honma et al.,
1987), in old rats compared to young ones.
Toxic compounds that serve as neurotransmitter receptor
blockers could have their effects on behaviour accentuated, making
neuroendocrine control of homeostasis more difficult in the elderly.
For example, the formamidine pesticides, amitraz and chlordimeform,
have been shown to block alpha-noradrenergic receptors (Costa &
Murphy, 1987; Costa et al., 1988) and induce a variety of
behavioural disorders (Boyes & Dyer, 1984; Hsu & Kakuk, 1984;
Landauer et al., 1984) in rats. Since there is an age-related
decline in noradrenergic receptors in several species (Rogers &
Bloom, 1985), exposure to these compounds may have a more pronounced
effect on the older organism.
Certain movement disorders associated with senescence may be
related to age-related impairments in the brain dopaminergic systems
(Marshall & Berrios, 1979). Waddington et al. (1985) observed a
decrease in the density of brain dopamine receptors in old rats,
with no changes in affinity. In contrast to young animals, the
receptors of old animals were not able to respond effectively to
long-term treatment. The decrease in dopamine receptor density was
selective for the D-2 receptor subtype, although the coupling
between D-1 receptors and adenylate cyclase appears to be affected
by aging. A similar loss of D-2 receptors in the elderly has also
been measured using positron tomography in the living human brain
(Wong et al., 1984). An age-related decrease in binding to the
serotonin receptor may relate to cerebral dysfunction in the elderly
(Shih & Young, 1978).
Studies with rats have indicated that the increased sensitivity
of older rats to diazepam is due to pharmacodynamic differences
(Guthrie et al., 1987). Pedigo et al. (1981) suggested this could
relate to changes in the benzodiazepine/GABA/chloride ionophore
complex. Human studies have also indicated that the site of
increased sensitivity to the benzodiazepines lies distal to the
receptor (Swift, 1985), possibly involving changes in the chloride
Alterations in endogenous opioid systems may play a role in
some of the behavioural changes observed in the elderly. Binding of
dihydromorphine to the opiate receptor decreases in specific areas
of the brain in aged rats as compared to young ones (Messing et al.,
1980). This reduction is due to a decrease in receptor number, with
no change in affinity. Despite a relatively large body of evidence
that some receptors and neurotransmitters are at least qualitatively
altered with aging, it is still not clear whether and how these
changes are causally related to increased sensitivity of the CNS to
certain drugs with aging, as described below.
The brain appears to exhibit increased sensitivity to
phenobarbital (Kitani et al., 1985b; Van Bezooijen et al., 1989) in
both mice and rats. Such enhanced sensitivity with age to an
anticonvulsant supports earlier studies with phenytoin (Kitani
et al., 1984). It is possible that the aging brain of both
experimental animals and humans has increased sensitivity to all CNS
depressants. Enhanced brain sensitivity has also been reported for
hexobarbital in rats (Van Bezooijen et al., 1989) and oxazepam in
mice (Kitani et al., 1986). The aging human brain appears to be more
sensitive to nitrazepam (Castleden et al., 1977a) and other
benzodiazepines (Reidenberg, 1980). Recently, zonisamide, a new drug
whose anticonvulsant properties are distinct from the other drugs,
was demonstrated to have an increased anticonvulsant effect in aging
mice (Kitani et al., 1987). Taken together, these results suggest
that these pharmacodynamic changes with age may reflect a decreased
response capability for seizures in the elderly, rather than a
specific age effect on all the distinct receptors (Kitani et al.,
1986). In fact, the lethal threshold for pentylenetetrazole in mice
has been shown to decrease with age (Nokubo & Kitani, 1988), coupled
to an increase in the threshold for maximal seizure.
The action of other environmental compounds on CNS function may
be more diffuse. Recent studies have demonstrated enhanced
sensitivity of old mice to cyanide intoxication (McMahon & Birnbaum,
1990b). Exposure to various metals has been shown to alter a variety
of CNS functions. There has been a particular interest in a
potential link between Alzheimer's disease and aluminium toxicity.
It was initially reported that the autopsied brains of Alzheimer's
patients showed elevated aluminium levels (e.g., Perl & Brody,
1980). However, others have found no such correlation. Marksberry
et al. (1981) compared the brains of Alzheimer's patients with older
adult controls and found no correlation between the density of
aluminium content and the density of neurofibrillary tangles and
neuritic plaques. However, a more recent study showed that the brain
aluminum levels were significantly increased as a function of age in
both control and Alzheimer patient populations (Bjorksten et al.,
Manganese is a metal that causes age-type neuropathy. However,
unlike aluminium, it is associated with extrapyramidal disorders,
characterized by intention tremor (Donaldson, 1987). In monkeys,
the neurological symptoms of choreo-athetoid movement, rigidity and
tremor occurred after 18 months of manganese exposure. These
clinical signs, in association with severe lesions of the globus
pallidus and subthalamic nucleus, resembled Parkinson's disease and
suggested a possible link between environmental exposure and
occurrence of the disease in aging individuals.
The neurotoxic effects of other metals have been widely
studied, particularly those of lead, which has been implicated in
reduced intellectual abilities in children (Needleman et al., 1979),
slowed reaction time (Hunter et al., 1985), and impairment of other
cognitive abilities (Winneke et al., 1982; Hansen et al., 1985).
While psychophysiological parameters appear to be relatively
insensitive to low levels of lead exposure, several studies have
demonstrated both cognitive and emotional effects due to long-term
exposure to lead (Hogstedt et al., 1983; Mantere et al., 1984).
Long-term exposure to mercury vapour has been reported to interfere
with verbal intelligence and memory performance (Piikivi et al.,
1984). Hanninen (1982) suggested that abnormalities due to mercury
exposure affect the motor system and result in intellectual
impairment, a gradual and progressive deterioration of memory
function, and emotional disability. Other metals including copper,
iron and manganese have also been reported to cause CNS dysfunction
(Grandjean, 1983). However, there are no available data on the role
of exposure to these metals in dysfunction of the CNS in the aged.
Examples of naturally occurring neurotoxic agents that
stimulate nervous system senescence have been reported in certain
island populations. For example, the Chamorro peoples of the
Marianna Island, specifically Guam and Rota, exhibited a high
incidence of amyotrophic lateral sclerosis, Parkinsonism and
Alzheimer's-like dementia that was recently linked to their diet.
The Chamorro's diet consists in part of a flour made from the seeds
of Cycas circinalis. When one of the components of these seeds,
beta- N-methylamino-l-alanine (BMAA), a compound similar in
structure to excitotoxic amino acids, was fed to macaques, they
exhibited signs of motor neuron, extrapyramidal and behavioural
dysfunction (Spencer et al., 1987).
It seems that several motor neuron disorders are associated
with the appearance of endogenous excitotoxic glutamate agonist-type
molecules. One such molecule is 2,3-pyridine dicarboxylic acid
(quinolinic acid), which has been isolated from the brains of
humans, rabbits and laboratory rodents (Moroni et al., 1984) and has
been shown to excite CNS neurons when applied iontophoretically
(Perkins & Stone, 1983). An interesting correlate is the fact that
brain concentrations of quinolinic acid increase with age (Moroni
et al., 1984), suggesting that its presence may result in the
spontaneous onset of neurode-generative conditions that are mimicked
by environmental neurotoxicants such as BMAA and
beta- N-oxalylamino-L-alanine (BOAA).
3.2.2 Endocrine system
There are several different ways in which the endocrine system
and the hormonal signalling operations involved 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
188.8.131.52 Changes in hormonal availability with age
Age-related or toxicant-induced shifts in synthesis, rate of
clearance and rate of secretion will all function to alter hormonal
concentrations. Such changes in the size of the available signal
pool may have corresponding effects on the magnitude of the response
by the target tissue. These changes may reflect a decline with age
in the homeostatic controls, which rely heavily on endocrine
Several toxicants have also been observed to cause changes in
circulating hormonal levels (Cooper et al., 1986). Significant
reductions in serum testosterone, for example, have been seen
following short-term exposure of rats to the plasticizer
dinitrobenzene (Rehnberg et al., 1988b) and the pesticide
chlordimeform, the latter also causing marked reductions in serum
LH, thyroid-stimulating hormone (TSH), T4 and T3 levels. The
effects, moreover, may be remarkably specific. Following three days
of exposure in male rats, the pesticide linuron, for instance, was
reported to decrease the serum T4 level in a dose-related manner,
while leaving T3 and the pituitary and gonadal hormones unaffected
(Rehnberg et al., 1988a).
There is also a growing body of evidence for a hormonal
influence on toxicant metabolism. A sizeable number of xenobiotics,
including both drugs and environmental toxicants, are metabolized by
the hepatic cytochrome P450 monooxygenase system (Nebert & Gonzalez,
1987). Components of this system have been found to be influenced by
glucocorticoids (Schuetz et al., 1984; Simmons et al., 1987) and
markedly affected by sex steroids (Kamataki et al., 1985b) and
growth hormone (Yamazoe et al., 1987; Zaphiropouos et al., 1989).
Consequently, persistent shifts in the circulating levels of such
hormones, as have been reported for the aging animal, could affect
the manner in which xenobiotics are metabolized following exposure.
Reported attenuations with age in the rhythms of human and rat
serum testosterone (Bremner et al., 1983; Steiner et al., 1984;
Tenover et al., 1988), LH (Vermeulen et al., 1989) and GH (Sonntag
et al., 1980), among other hormones, can present differences in
young-versus-old comparisons, depending on when such sampling is
performed. Comparable effects on hormonal rhythms have been reported
to occur in response to toxicant exposure. For example, single
injections of 2,3,7,8-tetrachlorinated dibenzo-p-dioxin (TCDD)
resulted in some evidence of alterations in prolactin and
corticosterone rhythms in rats (Jones et al., 1987). It may be that
an aging system, while still exhibiting rhythmic hormonal changes,
may be increasingly sensitive to their disruption by low toxicant
184.108.40.206 Changes with age in the reception of the signal by the
A general decline in the transmitter regulation of hormonal
function may also place an aging animal at increased risk for
toxicant exposure (Govoni et al., 1988), given that various
environmental toxicants (including, for example, the solvents
vinyltoluene, ethylbenzene and styrene, the halogenated hydrocarbon
TCDD, and certain heavy metal cations) have been reported to
interact with catecholaminergic systems (Govoni et al., 1979; Lucchi
et al., 1981; Arfini et al., 1987; Mutti et al., 1988; Russell
et al., 1988).
These changes have been observed for both neurotransmitter and
hormone receptors. There is some evidence of a decreased
responsiveness of target tissues to steroid hormones during
senescence. For example, age-related declines in the concentration
of the estrogen receptor may reflect a decline in the circulating
estrogen levels (Thakur, 1988). Impaired responsiveness could also
be due to reduced receptor translocation (Belisle & Lehoux, 1983) or
other steps in steroid action which occur after hormone binding. In
fact, age-related alterations in glucocorticoid responsiveness are
due to both receptor and post-receptor events (Kalimi, 1982).
Testicular luteinizing hormone receptor concentration and total
content also decrease with age (Amador et al., 1985). In general,
receptors for steroids, insulin, glucagon, catecholamines and
prolactin appear to decrease in concentration with increasing age in
rodents, dogs and humans (Roth, 1979b).
An additional consideration of alterations with age or toxicant
exposure in the reception of a hormonal (or transmitter) signal by
target cells concerns not only effects on the receptor itself, but
changes in the cell's membranes. In the aging rat brain, there is
evidence for a progressive decrease in membrane fluidity
(Hershkowitz, 1983; Nagy et al., 1983). This is at least partially
attributable to alterations in the lipid composition. For example,
it has been reported that aging is associated with elevations in
cholesterol, sphingolipids and saturated fatty acid chains, all
leading to increases in rigidification (Rouser et al., 1972). Since
protein activity in the membrane is influenced by the fluidity of
the lipid micro-environment, any alterations with age in membrane
viscosity may affect not only receptor functions but also enzymatic
220.127.116.11 Changes in the nature of the hormonal message with age
The antigenic site(s) on a hormone recognized by antibodies can
be quite distinct from those regions that bind to the receptors and
trigger a physiological response in the target tissue. This
distinction may have an added importance for studies in aging, since
alterations with age in peptide hormone structure have been reported
(Conn et al., 1980) that reflect changes in post-translational
processes. These effects, moreover, may be influenced by shifts in
the steroid hormonal milieu in the older animal (Ulloa-Aguirre
et al., 1988). A number of hormones are glycosylated to varying
degrees and such differences in their carbohydrate residues may
alter biological activity (Ulloa-Aguirre & Chappel, 1982; Warner
et al., 1985) and/or plasma half-life (Morell et al., 1971).
Consequently, hormonal measures based solely on immunoreactivity
per se potentially offer a somewhat inaccurate picture of
endocrine alterations with age.
The aging kidney appears to be more susceptible than the young
one to drug-induced nephrotoxicity as well as to renal ischaemia. In
fact, cortical tubules of senescent rats seem more sensitive to
oxygen deprivation than do those of young rats (Miura et al., 1987).
Thus, increased susceptibility of the aging kidney can be
independent of pharmacokinetic effects.
Age-related susceptibility to nephrotoxicity has been
demonstrated for numerous drugs including salicylate, acetaminophen,
cephaloridine and doxorubicin. Kyle & Kocsis (1985) showed that
kidneys from older rats develop nephrotoxicity to a greater extent
than do those of young rats following an equal dose of salicylate on
a body weight basis. However, the dose to the kidney could be
greater in the older rats due to a decrease in the volume of
distribution. In addition, McMahon et al. (l990a) has recently
demonstrated that at toxic doses old rats produce more reactive
metabolites of salicylate than do young ones. The age-related
enhancement in cephaloridine nephrotoxicity may also be due to
pharmacokinetic changes (Goldstein et al., 1986), although renal
cortical slices from old rats demonstrated alterations in active
uptake of organic anions and cations following exposure to the
antibiotic, which were not observed in young rats. Doxorubicin
treatment resulted in greater toxicity in old rats (Colombo et al.,
1989). The onset of the delayed nephrotoxicity was noticeably faster
in the old rats; this may have been related to higher drug retention
in the kidneys of old rats.
Age-related increased susceptibility to acetaminophen
nephrotoxicity has been investigated more than that of any other
chemical in rats. Tarloff et al. (1989b) stressed that while
enhanced sensitivity to acetaminophen nephrotoxicity clearly occurs
with advancing age, great care must be taken in choosing the ages
for comparison. Beierschmitt et al. (1986a) demonstrated by both
functional and histological criteria that susceptibility to
acetaminophen-induced acute tubular nephrotoxicity increases with
age in rats. This may reflect altered susceptibility rather than an
alteration in pharmacokinetic parameters, since the generation of
reactive metabolites from acetaminophen decreases with age
(Beierschmitt & Weiner, 1986). Increasing delivery of acetaminophen
to functioning nephrons, whose numbers are decreased in the aged
kidney, does not appear to be responsible for the age-related
increase in susceptibility (Beierschmitt et al., 1986b).
Alterations with advancing age do not have to result in
increasing sensitivity. Studies by Murty et al. (1988b) indicated a
decrease in hydrocarbon-induced hyaline droplet nephropathy in male
rats during senescence. This male-specific nephropathy is associated
with the presence of alpha2u-globulin, whose synthesis is strongly
age dependent (Roy et al., 1983). Although gasoline causes extensive
nephrotoxicity in young rats, old rats are resistant. In fact,
gasoline failed to alter hyaline droplet numbers in aged male rats,
which also demonstrated an altered lysosomal response as compared to
young rats. This lack of response of aged rats to
hydrocarbon-induced hyaline droplet nephropathy suggests that these
rats would also be resistant to hydrocarbon-induced renal neoplasia.
3.2.4 Immune system
With advancing age a progressive decline in the concentration
of glucocorticoid receptors occurs in the spleen (Roth, 1979a). This
alteration may depend either on an age-related modification of the
ratio among various subsets of lymphoid cells carrying different
receptor densities or on an intrinsic failure of aged cells to
maintain an adequate turnover of receptor molecules. With advancing
age, membrane receptors for hormones of low relative molecular mass
on lymphoid cells also show alterations, although these are more
related to impaired coupling to signal transduction systems (Feldman
et al., 1984; Roth, 1988). It has been shown that the number of
receptor molecules decreases with advancing age whereas the affinity
does not seem to change. In the aged population with altered
function of the immune system, it is possible that immunomodulatory
agents present in the food potentiate immune dysfunction, making the
elderly more vulnerable to age-related diseases.
The effects of immunosuppressive compounds can be identified
from toxicological experiments with young adult rodents. These
chemicals include organotin compounds, some pesticides, halogenated
aromatic hydrocarbons (e.g., hexachlorobenzene and dioxins) and
cyclosporin (Poland & Knutson, 1982; Vos & Penninks, 1987; Vos &
Luster, 1989; Schuurman et al., 1990; Vos et al., 1990), and they
can also potentiate autoimmunity, which is found more frequently in
3.2.5 Other tissues and systems
There are few data on pharmacodynamic changes in other tissues
and systems during aging. An increase in the sensitivity of the
aging human myocardium to digoxin (Chavaz et al., 1974), as well as
to intravenous anaesthetics (Dundee, 1979), has been suggested. The
stomach, kidney and bone marrow are more susceptible to the adverse
effects of non-steroidal anti-inflammatory agents in the elderly
than in the young, and cerebral side effects are more common
(Huskisson, 1983). The anticoagulation properties of warfarin are
also changed in the elderly, with the aged demonstrating increased
sensitivity (Shepherd et al., 1979).
Although in most toxicological studies the cardiovascular
system is not well examined, there are several chemicals known which
can cause cardiovascular toxic or atherosclerotic effects. Such
compounds in food include erucic acid in combination with
omega-3-linolenic acid, cetolenic acid, brominated vegetable oils,
cobalt salts in combination with ethanol, lead, nitrates and high
amounts of caffeine (Speijers, 1983). On the other hand, compounds
such as saturated fatty acids, odd-numbered cyclopropenoid fatty
acids (sterculia acid), ergot alkaloids, halogenated aromatic
hydrocarbons and cadmium induce toxic effects on the vascular system
and possible potentiate atherosclerotic effect (Speijers, 1989a,b).
Conrad & Bressler (1982) investigated the cardiovascular effects of
caffeine in elderly men. Caffeine, in doses equal to those contained
in 2 to 3 cups of coffee, produces an increase in blood pressure,
but has no positive inotropic effect in healthy elderly men.
Kim & Kaminsky (1988) suggested that age plays an important
role in modifying susceptibility to the toxic metabolite of
fluroxene, 2,2,2-trifluoroethanol. They noted greater effects on the
stomach, liver, testicles, brain and kidneys of aged rats as
compared to younger animals. Enhanced sensitivity to ethanol
intoxication has also been noted in old rats (Guthrie et al., 1987),
suggesting altered tissue sensitivity. Acute ethanol hepatotoxicity
may be due to enhanced liver susceptibility to the toxin (Rikans &
3.3 Modifying factors
Nutrition has been shown to influence the aging processes in
rodents and the occurrence and progression of age-associated
diseases in rodents and humans. Moreover the age-associated changes
in physiological processes affect the nutrition of the mammalian
organism. However, there is little information on how aging
influences the nutritional requirements of humans, a subject that
urgently requires scientific study.
Nitrates in foods can be reduced to nitrites in the oral
cavity, GI tract and urinary bladder (Tannenbaum et al., 1978).
Nitrites react with amines in the stomach forming N-nitroso
compounds, many of which have been shown to be carcinogenic in
animal studies, and it is difficult to deny their hazard to man
(Searle, 1976; Bartsch, 1991).
During commercial processing and domestic preparation, foods
may become contaminated with toxic chemicals. For example, smoked
and grilled foods contain small amounts of polycyclic aromatic
hydrocarbons and a wide variety of phenols and other organic
compounds derived from smoke (IARC, 1990). Canned foods can become
contaminated with tin or lead.
In a study by Spagnoli et al. (1991), both 4-month-old and
4-year-old New Zealand white rabbits were fed an atherogenic diet.
Increased incidence and degree of atherosclerotic lesions were seen
in the 4-year-old rabbits. These results showed an increased
susceptibility of the older arterial wall to hypercholesterolaemia.
Although 4-year-old rabbits are still relatively young, considering
the life span of this species (10-12 years), this study suggests
that aging arteries might be vulnerable to atherogenic compounds.
Malnutrition associated with inadequate intake or uptake of
nutrients in the elderly is caused by several factors. These include
socio-economic conditions (Munro, 1984) such as a) ignorance of the
need for a balanced diet, b) poverty, c) social isolation, d)
physical dependence (disability) and physical inactivity, e) mental
disorders, and f) changes in habits, e.g., retirement (Munro, 1984;
American Dietetic Association, 1984; Ferro-Luzzi et al., 1988).
Other conditions resulting in malnutrition include malabsorption due
to a variety of intestinal conditions, alcoholism, and the use of
therapeutic drugs that interfere with nutrient utilization and
therefore with the toxicity of chemicals (Krupka & Vener, 1979;
Kohrs, 1981; Munro, 1984; Chen et al., 1985; Robertson et al, 1988).
Malnutrition in much of the aged population can enhance the
vulnerability of the elderly to the effects of the toxic chemicals
in food. It has also been reported that malnutrition alters
pharmacokinetics in different ways depending on the drugs examined
(Roe, 1983; Cusack & Denham, 1984). This can be another factor in
the altered sensitivity of the malnourished elderly to toxicants.
Major deficits or marginal nutrient status occur for proteins,
calcium, vitamins A, C and B (thiamin, riboflavin, niacin, B6 and
B12) and zinc (American Dietetic Association, 1984; Ferro-Luzzi
et al., 1988).
In aged women, a deficiency in calcium is especially associated
with osteoporosis (American Dietetic Association, 1984; Munro, 1984;
Caraceni et al., 1988; Cauley et al., 1988). The deficiency in iron
and zinc might play a role in haematological status and immune
function, while a higher intake of aluminium might have neurological
sequelae (American Dietetic Association (ADA), 1984). An iron
deficiency might make individuals more vulnerable to compounds toxic
for the haematopoietic system, e.g., hexachlorobenzene and lead.
Data showing that older individuals have a reduced need for
energy, due to slower metabolism and decreased activity, has an
important impact on the intake of both macro and micronutrients,
because the composition of the diet is based on the average caloric
or energy intake (American Dietetic Association (ADA), 1984;
Ferro-Luzzi et al., 1988). Considering this reduced need for energy,
the elderly often reduce their intake of nutrients.
Dietary manipulation can alter life span in laboratory animals
(Barrows & Kokkonen, 1978; Young 1979). Restricting food intake in
laboratory rats produces a significant extension of life span (McCay
et al., 1935; Ross, 1961). Similar effects have been observed in
mice (Weindruch & Walford, 1988; Kubos et al., 1984), as well as in
more primitive organisms including fruit flies (Harman, 1981), and
nematodes and Neurospora (Harman, 1982). Other studies have
indicated that the reduction in caloric intake that accompanies
protein restriction, and not the protein restriction per se, is
responsible for the increased longevity (Leto et al., 1976; Davis
et al., 1983; Schneider & Reed, 1985). Dietary restriction has been
shown to be effective when started as late as middle age (Cheney
et al., 1983; Kubos et al., 1984; Masoro, 1988). Food restriction
appears to act either by influencing primary aging processes or by a
general protective mechanism, rather than directly modulating
multiple specific pathogenic processes underlying specific diseases
(Masoro et al., 1991).
Chronic nephropathy in rats has been reported to be retarded by
food restriction (Saxton & Kimball, 1941). Rats fed ad libitum a
semisynthetic diet of 21% casein as the protein source exhibited a
marked age-associated progression of chronic nephropathy, whereas
rats fed 60% of the ad libitum intake developed almost no
age-related progression of this disease process (Maeda et al.,
1985). Caloric restriction appears to be more important than protein
restriction in retarding nephropathy (Maeda et al., 1985). Fat or
mineral restriction was found to have no influence on longevity
(Iwasaki et al., 1988).
Dietary restriction delays the age-dependent loss of adipocyte
responsiveness to hormones, prevents the decline in serum free fatty
acid levels, delays the increase in serum cholesterol, and reduces
the increasing triglyceride level observed in aging rats (Cooper
et al., 1977; Liepa et al., 1980; Masoro et al., 1980; Yu et al.,
Dietary restriction from weaning has been shown to delay the
onset and reduced the severity of chronic nephrosis, periarteritis,
myocardial degeneration and muscular dystrophy in very old animals
(Berg, 1976). Chronic restriction has also been shown to inhibit
certain types of tumours, decrease the incidence of neoplasms, and
increase tumour latency (Ross, 1976; Weindruch et al., 1982;
Weindruch & Walford 1988). Early work using a chemically induced
mammary carcinoma model suggested that the primary effect of caloric
restriction was on tumour promotion (Weindruch & Walford, 1988).
More recent data (Fishbein, 1991) have demonstrated that the
initiation of chemical carcinogenesis can also be decreased by
caloric restriction. For example, exposure to aflatoxin B1
resulted in less DNA-adduct formation in liver from young
calorically restricted male rats than from controls fed ad libitum.
Such changes are most probably due to changes in hepatic cytochrome
P-450 expression (Fishbein, 1991).
There is ample evidence of better maintenance of
T-cell-dependent immunological responses in aging mice chronically
restricted from weaning (Weindruch & Walford, 1988). However, it has
been reported that restriction initiated at an adult age can also
delay the age-specific decrease in immune function (Fernandes
et al., 1977; Friend et al., 1978; Weindruch & Walford, 1988).
Although caloric restriction extends life span in invertebrate
and lower vertebrate species as well as rodents (Weindruch &
Walford, 1988), as yet there is no definitive evidence whether or
not caloric restriction will increase longevity, or decrease
neoplastic and degenerative diseases, in higher mammals or in man.
There is some evidence that reduced caloric intake in man reduces
urinary output of thymidine glycol and 8-hydroxy-guanosine, which
implies reduced free-radical-mediated DNA damage (Fishbein, 1991).
However, until the mechanisms by which caloric restriction evokes
its effect are fully understood, the only way that it can be
conclusively proved whether or not caloric restriction does prolong
life in higher mammals, is to perform longevity studies in these
species. Such experiments, using non-human primates, are underway in
the USA (Fishbein, 1991), but it will be some time before definitive
data are available.
Chronic disease in the elderly is accompanied by caloric
deficit, which in turn causes breakdown of body proteins and
negative nitrogen balance as well as the utilization of fat stored
in adipose tissues. Dietary protein appears to promote
age-associated renal disease in both humans and rats (Brenner
et al., 1982).
When illness occurs, nutritional deficiencies frequently become
clinically manifest (Rudman, 1987). For example, trauma or a fall
causing fractures leads to immobilization resulting in rapid loss of
body stores of nitrogen and calcium. This slows down mending of the
fracture. Similarly, surgical procedures in the elderly often result
in delayed recovery and risks far exceeding those of younger
persons. Heart failure and malignancies can lead to cachexia with
loss of weight, muscle mass and nutrient reserves. Infection may
produce similar changes and intervene to become the terminal event.
3.3.2 Alcohol intake
Ethanol is one of the chemicals most commonly ingested by
humans. Its effects on the body are numerous and varied. Loneliness
and isolation would seem to foster consumption of alcohol beverages
among older persons. The decrease in lean body mass and body water
that occurs with aging is responsible for higher blood levels of
alcohol in elderly people than in younger adults consuming the same
quantities (Vestal et al., 1977).
Elderly individuals have a decreased tolerance for alcohol, due
to an increased sensitivity of the CNS to the depressant effect of
ethanol. The metabolic effects of ethanol are the result of either
the increase in the NADH/NAD+ ratio occurring due to ethanol
metabolism or to direct toxic effects of ethanol or its metabolite,
acetaldehyde. An increase in serum uric acid level (hyperuricaemia)
is common during heavy alcohol ingestion, thus inducing acute gouty
arthritis in patients with known gout. Hypoglycaemia and
hyperlipidaemia occur in patients who are not eating adequately or
who are ingesting a high-fat diet with ethanol, respectively.
Thrombocytopenia is caused by alcoholism in patients with advanced
alcoholic liver disease (IARC, 1988).
The use of drugs increases with aging. Acceleration or
inhibition of drug metabolism by ethanol depends on the duration of
ethanol ingestion and the presence or absence of ethanol in the body
at the time the drug is ingested (Mezey, 1981). The presence of
alcohol in the body causes a decrease in the metabolism of certain
drugs, such as antipyrine, meprobamate, pentobarbital and
benzodiazepines, resulting in increased bioavailability of the drugs
to the CNS and thereby contributing to unwanted side-effects. In
contrast, ethanol can increase the metabolism and metabolic
activation of certain xenobiotics, such as the known human
leukaemogen benzene, thus potentially leading to enhanced toxicity
Chronic ethanol ingestion increases tolerance to CNS
depressants in young individuals, but its effect in the elderly is
unknown. The concomitant administration of ethanol and barbiturates
results in an enhanced depressant effect of these drugs on the CNS
and can result in coma or even death. All other sedative-hypnotic
drugs tested have either synergistic or additive effects with
ethanol. Intellectual deterioration and dementia are common
complications of chronic alcoholism. Alcoholic patients show more
signs of mental aging at every chronological age (Gaitz & Baer,
Chronic excessive alcohol ingestion is associated with
increased mortality from cancer, cirrhosis, non-malignant
respiratory diseases such as emphysema, and accidents (Klatsky
et al, 1981; IARC, 1988). However, a decrease in coronary artery
disease and mortality is associated with moderate alcohol ingestion.
This may be due to increases in plasma HDL-cholesterol and decreases
in LDL-cholesterol that occur during ingestion of alcohol (Mezey,
1981). Ethanol consumption is also associated with hypertension and
an increased mortality from cerebrovascular accidents (Kozararevic
et al., 1980; Blackwelder et al., 1980).
Smoking clearly plays an etiological role and produces an
acceleration of a wide spectrum of age-associated disease. Smoking
contributes to an increased mortality rate (Gupta et al., 1980). It
also provides an excellent example of problems faced in the
consideration of the environmental impact on aging.
Scientists recognize that smoking presents a complex toxic
insult through inhalation. Increased pathology in aged mice has been
reported after exposure to cigarette smoke (Matulionis, 1984). The
immune response in aged mice exposed to cigarette smoke has been
shown to be decreased at some ages but not at others (Keast & Ayre,
1981). The role of smoking in coronary heart disease has been
reviewed by Kannel (1981), who observed that the relative effect of
cigarette smoking decreases in old age and proposed that this could
be due to the selection of a more resistant population.
Estrogen-related diseases have also been associated with smoking
(Baron, 1984). Reif (1981) has examined susceptibility to lung
cancer and concluded that the shape of the susceptibility
distribution is determined by the effects of all environmental
carcinogens (both known and unknown) to which the population has
been exposed, as well as by differences in genetic susceptibility
among members of the population. Smokers and non-smokers both get
lung cancer during the same age range. Some of these studies suggest
that aged individuals are more susceptible to the effects of
smoking, whereas others suggest that duration of smoking appears to
be the critical factor (IARC, 1990). The smoker is exposed to
multiple toxic agents simultaneously, the effects of which are more
pronounced in aged individuals. Major aspects of metabolism and
pharmacokinetics are altered in aged individuals. Therefore, the
effective dose of any chemical reaching the systemic target tissues
in aged humans would be dependent on these perturbations.
3.4 Interactions of chemicals and diseases
Cancer morbidity is expected to rise with age and with an
increasing percentage of elderly people living in industrialized
countries (Magnus, 1982). There is no consensus on the causes of the
age-related increase in tumour incidence. Various arguments support
the concept that an age-related accumulation of total dose of all
carcinogens accounts for tumour induction as a function of age in
sensitive individuals (Peto et al., 1975, 1985). One viewpoint is
that the sensitivity to carcinogens is stable and independent of
age, whereas another is that changes in the internal milieu of the
organism, such as the metabolic and immunological shifts of natural
aging, provide favourable conditions for tumour development with
increasing age (Burnet, 1970; Dilman, 1971).
Comparison of human epidemiological data with in vivo and
in vitro animal experimental results is difficult but does allow
some limited conclusions. It seems that environmental carcinogenic
factors as well as endogenous carcinogens are important causes of
increased tumour incidence in old people (IARC, 1990). This
conclusion is supported by the increasing incidence of occupational
cancer with increased exposure time to carcinogenic agents and by
the correlation of lung cancer incidence with the number of
cigarettes smoked (Doll & Peto, 1981; Peto, 1986). Humans, in
general, have an age-related increase in the incidence of epithelial
neoplasms (Doll, 1978), but the relationship of age to incidence of
other cancers in different organs varies (Doll, 1973; Moolgavkar &
Venzon, 1979; Anisimov, 1987; Dix, 1989). Some tumours appear most
frequently in childhood, some increase exponentially with age, and
others reach a peak at a certain age and then decline.
The data on cancer incidence among the atomic bomb survivors in
Hiroshima and Nagasaki, Japan, have been very informative concerning
radiation-related solid tumours as well as leukaemia. Age at time of
exposure appears to be a strong determinant of leukaemia risk; the
greatest absolute risk was experienced by those who were exposed at
ages 0-9 or 50 years and over (Beebe, 1979). Most of the excess
cancer deaths from solid tumours among the atomic bomb survivors
have occurred among those who were over 35 at the time of the blast.
Analysis of data on the positive correlation between the aging
rates of different species with their cancer rates and the
observation that these two processes, aging and carcinogenesis, may
be initiated and promoted by impairments of gene regulation led
Cutler & Semsei (1989) to conclude that both cancer and aging may
arise from a common set of genetic alterations. The analysis of the
interrelationship between aging and carcinogenesis should be based
on epidemiologically and experimentally confirmed data.
Epidemiological data, analysed in terms of a multi-stage model
(Kaldor & Day, 1987), can estimate the importance of age at onset,
duration of carcinogen exposure, and latency in a population. On the
level of the organism, carcinogenic agents influence not only the
cell, causing genomic damage that leads to neoplastic
transformation, but also create in the cell a microenvironment that
facilitates proliferation and clonal selection (Anisimov, 1987,
1989). Multi-stage carcinogenesis is accompanied by various
disturbances in tissue homeostasis and systems of anti-tumour
resistance that, in turn, are under the influence of systemic
(nervous, hormonal and metabolic) factors. How long it takes for
frank neoplasia to develop depends on the state of those systems at
the moment of exposure to a carcinogen or tumour promoter and the
According to the multi-stage model of carcinogenesis, the
carcinogen whose effect increases in proportion to age at exposure
affects the partially transformed cell. In this case the tumour
incidence would increase and latency would decrease, as compared to
a population exposed to the same effective dose of carcinogen at a
young age. For example, application of 7,12-
dimethylbenz [a]anthracene in small doses or
12-0-tetradecanoylphorbol-13-acetate to the skin of mice of
different ages caused neoplasms more frequently in older animals
(Stenbäck et al., 1981; Ebbesen, 1985). Exposure of mice and rats of
various ages to phenobarbital resulted in hepatocarcinogenesis only
in old animals (Ward, 1983; Ward et al., 1988). The number of events
necessary for complete malignant transformation in 15-month-old rats
under the influence of N-nitrosomethylurea is lower than in
3-month-old rats (Anisimov, 1988). In every tissue, the number of
events occurring in the stem cell before its complete transformation
is variable and depends on many factors, in particular the rate of
aging of the target tissue and of the regulatory system(s) of the
tissue (Anisimov, 1987, 1989). This model is consistent with the
analysis of age-related distribution of tumour incidence in
different sites in humans and experimental animals (Doll, 1978; Dix,
1989; Anisimov, 1987).
Epidemiological observations have shown that exposure to some
carcinogenic agents leads to a rise in cancer incidence independent
of age at the start of exposure (e.g., smoking), while other agents
induce more tumours when the exposure begins in the elderly (e.g.,
lung cancer following asbestos exposure) (Kaldor & Day, 1987; IARC,
3.4.2 Other diseases
Aging affects the functional capacity and structural integrity
of many organ systems. Environmental chemicals can also affect
several target organs. The combination of the influence of aging and
the toxic effects of chemicals in the environment might potentiate
the risk for elderly persons. An inherent problem common to all
research in chronic disease is the dissection of the respective
roles of time per se from those of primary aging. Hazzard (1985)
stated that an essential feature of human aging is the change in
physiological competence across the life span, as reflected in
homeostatic reserve. Homeostatic reserve declines at an accelerating
rate with age, normally producing death in old age from
The relationship between aging and atherosclerosis is a prime
example of this conundrum. It seems most likely that the changing
picture of atherogenesis in western society has led to a large
number of people who survive into old age with not only a degree of
clinical atherosclerosis, but also with other chronic progressive
diseases, such as chronic obstructive pulmonary disease, immobility
from osteoarthritis and/or osteoporosis, and mental incompetence
from Alzheimer's disease, multi-infarct dementia or other
age-related dementing processes.
These diseases could significantly modify the response of the
organism to various environmental chemicals by decreasing or
increasing their susceptibility, followed by an acceleration of
these diseases or induction of new ones.
4. APPROACHES TO EXAMINING THE EFFECTS OF CHEMICALS ON THE AGED
4.1 Experimental approaches
4.1.1 Principles for testing chemicals in the aged
There are two principal approaches to the study of age-related
changes of any functional, morphological and/or biochemical
parameter, i.e. "longitudinal" and "cross-sectional". Longitudinal
studies consist of repeated estimations of any parameter in the same
animal in different periods of life. Cross-sectional studies involve
separate groups of animals of different ages who are examined at a
given point in time. Results obtained using the longitudinal
approach may significantly differ from the results from experiments
carried out using cross-sectional approaches. In studies on the
toxicity of chemicals, it is obligatory that identical conditions be
provided and maintained for all the animals. Problems related to the
choice of animal species, strain, sex, age, life stage and chemical
treatment (both route and dose selection) will be considered below.
4.1.2 Animal models
An extensive discussion of the choice and use of animal models
in research has been recently published (Rogers et al., 1991).
18.104.22.168 Animal species
The selection of suitable species obviously involves both
practical and economic factors. Animals with a short life span are
preferred. However, good life-table information is not available for
all species. A knowledge of species-related differences in metabolic
pathways and inherent sensitivities is also important in choosing
animal species for study. The choice of species should depend on the
experimental question as well as homology of response. For example,
while closely related isoforms of drug-metabolizing enzymes may
exist in different species, their tissue distribution and substrate
specificity may vary greatly (Nebert et al., 1991). Such differences
in isoform expression, together with reported differences in DNA
repair efficiency, could be responsible for species-related
differences in an organism's susceptibility to chemical carcinogens
(Daniel et al., 1983; Mehta et al., 1984; Anisimov, 1987; 1989).
Regardless of such metabolic differences, mice and rats are
most often used in aging research because of a short life span,
relative ease of maintenance under defined conditions, wide use in
biological research, and suitability for a variety of molecular and
genetic analyses. There are extensive life-table information for
some strains of mice and rats as well as a data base on their
spontaneous pathology. If old animals are purchased from a supplier
rather than being maintained in an investigator's own laboratory, it
is necessary to obtain information on the lifetime environment of
the animals, including housing conditions and dietary history. It
may be preferable to keep animals from weaning until the desired age
for investigation under the same controlled conditions.
Mammalian species other than rodents have only been used
sporadically in aging research, owing to their long life span, lack
of life-table information, genetic heterogeneity, restricted
availability and high cost. However, it is critical that such larger
species be used to answer certain questions. For example, studies
are currently underway to determine if dietary restriction can
prolong the lifespan of two different monkey species (Ingram et al.,
22.214.171.124 Animal strain
The choice of adequate rodent strain for experiments on aged
animals is critical. The male Fischer-344 rats is a popular model in
aging studies because of its size and growth characteristics.
However, testicular interstitial cell tumours begin to appear at the
age of 18 months in rats fed ad libitum, and by the age of 2 years
the tumour incidence approaches 100% (Fishbein, 1991). Recently, a
highly significant positive trend with time has been observed for
the increasing prevalence of leukaemia, anterior pituitary tumours
and thyroid c-cell tumours in both sexes, adrenal pheochromocytomas
in males, and mammary tumours and endometrial stromal polyps in
female F-344 rats (Rao et al., 1990). Some mouse strains suffer
from a single major disease process (e.g., tumours of the mammary
gland or liver, or chronic nephropathy), and the presence of this
disease in most animals could modify the response to chemical
exposure and complicate the interpretation of the results.
In the USA and Japan, Fischer-344 and Sprague-Dawley rats and
B6C3F1, Swiss, and CD-1 mice are most frequently used, whereas
in European countries Wistar-derived and Brown Norway rats and NMRI
and Swiss mice are the most popular strains. Inbred animals have the
advantages of greater stability and predictability of response.
However, heterogeneity of outbred animals more closely resembles the
heterogeneity of human populations. The choice of a certain animal
strain also depends on previous experience with these animals, the
final choice of an appropriate species and/or strain being dependant
on the scientific hypothesis under investigation. Each strain has
its own pattern of background pathology, which can be greatly
influenced by animal husbandry.
126.96.36.199 Animal sex
Sex-differences in response to chemicals are well known. Thus,
the use of both sexes is often necessary in toxicity testing.
However, the large gender differences in chemical toxicity and
pharmacokinetics that occur in rats become less apparent in old age
due to the decreased expression of sex-specific isoforms of the
hepatic drug-metabolizing enzymes (Kitani, 1991).
Ovarian status may significantly influence the sensitivity to
some chemical agents, modifying the biological response, as been
demonstrated for chemical carcinogens (Anisimov, 1971, 1987). It is
noteworthy that, when using females of the post-reproductive period,
the investigator must be aware that a) the ovaries in females of
some species (i.e. rats and mice) are not atrophied and may continue
to secrete steroid hormones, and b) some animals may be in
persistent estrus, while others may be in anestrus or
pseudopregnancy status (Aschheim, 1976). Furthermore, an animal's
reproductive history could influence its response to a chemical in
188.8.131.52 Selection of age groups for comparison
The problem of appropriately characterizing the animal's age
within the context of its life span is of particular importance in
experimental gerontology. Since the aging process causes significant
changes in various systems of the organism, there is a need for the
definition of some reference points for adequate comparison of the
results of different experiments. The importance of these points is
particularly significant in cross-sectional studies. One of the
confounding factors in such comparisons between experiments is the
need for frequent comparisons of results from different animal
species with different life spans (long-lived and short-lived
species and/or strains). Many authors have used two kinds of age
groups: "mature" or "adult" animals; and "old" animals. However, the
true age of "mature" rats in the reports from different
investigators fluctuates from 2 to 14 months and the age of "old"
animals from 12 to 37 months. The life cycle of experimental animals
can be divided into four periods: a) prior to weaning
(developmental); b) sexual maturation (maturational);
c) reproductive; d) pronounced age-related changes (senescent
period) (Zapadnyuk, 1971). All studies should compare animals from
multiple age periods.
184.108.40.206 Underlying pathology of animals of different ages
As mentioned previously, the background pattern of pathology
must be taken into account in the selection of animal species and
strains. A species-, strain- and sex-specific incidence of
pathology, whether neoplastic or not, is observed to increase
rapidly in the second half of the life span, even for those animals
maintained under specific pathogen-free conditions (Burek, 1978;
Anisimov, 1987; Frith & Ward, 1988; Fishbein, 1991). Among
non-neoplastic diseases in rats, the most frequent are chronic
glomerulonephropathy, cardiomyopathy, amyloidosis, and peripheral
nerve degeneration. For example, the incidence of spontaneous
leukaemia in F-344 rats frequently used in long-term studies may
exceed 30%, and the frequency of intertitial cell tumours of the
testis may reach 100% in old males. This pathology may significantly
modulate the host response to xenobiotics.
220.127.116.11 Transgenic animals
During the last decade it has become possible to add new
genetic information to the germ line of experimental animals
(Jaenisch, 1988). More recently successful attempts have even been
made to specifically alter gene sequences in the mouse germ line,
thereby ablating or correcting specific gene functions (Capecchi,
1989). In the study of the effects of chemicals on the aged
population, transgenic animal models have at least two contributions
to make. Firstly, the influence of specific genes on the age-related
susceptibility to environmental chemicals can be assessed in the
in vivo situation (Vijg & Papaconstantinou, 1990). Secondly, by
using transgenic animals harbouring a shuttle vector with one or
more mutational target genes, mutagenic effects can be studied in
different organs and tissues of animals as a function of age (Gossen
et al., 1989).
18.104.22.168 Animal husbandry
In experimental research on the sensitivity of aged animals and
the aging process, the husbandry aspects should be defined. The
quantitative and qualitative results might depend greatly on the
dietary conditions. The dietary composition should meet the minimal
requirements for nutrients, minerals, vitamins and (raw) fibre for
adult animals according to established and published standards for
laboratory animal diets. Another important dietary factor is the
quantity to which the test animals have access. They may either
receive a restricted diet containing adequate level of nutrients or
be fed ad libitum. The choice of diet depends on the questions to
In addition to the dietary status of the animals, their
microbiological status should be defined. In some cases interaction
of the chemical with the gut microflora might modify the outcome of
the study. Specific-pathogen-free (SPF) animals are preferred. The
direct environment of the test animal, including relative humidity,
temperature, light and dark cycles, seasonal influence and stress
can all influence the final outcome of a study and therefore should
be defined carefully (Masoro, 1991).
Differences in animal husbandry may cause large variations in
biochemical and pathological effects. This is clearly illustrated by
alterations in the background data among different laboratories.
4.1.3 Chemical exposure
22.214.171.124 Dose level
The selection of dose is a difficult issue. The usual
requirement is to have a minimum number of test groups (3) plus one
control (vehicle) group. This permits the development of a
"dose-response" curve and allows for appropriate statistical
evaluation of the results. The highest dosage should induce minimal
signs of toxicity, bearing in mind that the maximum tolerated dose
for young animals could in some cases be toxic for old ones, and
that high doses may alter the toxicokinetics of the chemical.
Considering that the body weight of young and old animals could
be significantly different, a correct dosage calculation of test
substances in comparison groups is an important problem, i.e.
whether it is better to normalize per unit of body weight or body
surface, or to some other parameter such as lean body mass (Travis
et al., 1990). The available data indicate similarity of the results
when calculation of dose is performed per unit of body weight or
body surface. It should be taken into consideration that the growth
and development of various organs may have different rates, and that
relative organ weight (and consequently, the effective target dose
of the substance) may not be the same in animals of different ages.
When the substance is administered in food or water, the consumed
quantities should be taken into account, because they may differ in
animals of various ages. When the oral or dermal route of
administration is used, age-related changes in the extent and rate
of absorption may be important. Age-related changes in lung
ventilation capacity may also alter the internal dose of a chemical
when the inhalation route of administration is used. When looking
for portal-of-entry effects, a constant concentration of the agent
may be used in all age groups.
126.96.36.199 Route of administration
There is general agreement that the test substance should be
administered by the route that corresponds most closely to human
exposure. For humans, the main exposure routes are oral, dermal and
inhalation, while in animal experiments the oral route is most
frequently used. However, when pharmacokinetic studies show that
other routes of administration result in equivalent target tissue
levels, such alternative routes can be used. The use of injections
(subcutaneous, intraperitoneal, intramuscular or intravenous) may be
expedient under certain circumstances.
188.8.131.52 Duration of exposure
The question being addressed should guide the design of the
study. If the potential risk involves acute exposure of the elderly,
then an acute experimental scenario is required. If human exposure
is ongoing, long-term studies may be necessary. Exposure to the test
substance in chronic studies should start shortly after weaning and
continue for the major portion of the animal's life (at least
through the mean life span). IARC (1986) recommended 24 months of
exposure for rats and mice, and 18 to 20 months for hamsters when
studying the carcinogenic potential of chemicals. Choice of exposure
duration based on life-table characteristics would be optimal.
However, these guidelines do not apply to experiments when animals
of different ages are used at the start of the study. In this case
the dose and duration of exposure could differ in groups of young
and old animals. However, it is preferable to use identical exposure
durations whenever possible.
4.1.4 Non-mammalian models
Many species can be used as models in the study of age-related
sensitivity to environmental toxicants. These include fungi
(Neurospora crassa and Podospora anserina), protozoa
(Paramecium tetraurelia and Tetrahymena pyriformis), rotifers,
nematodes (Caenorhabditis elegans, C. briggsae and Turbatrix
aceti), and insects (Drosphila melanogaster, Musca domestica and
Tribolium confusum) (Committee on Chemical Toxicity and Aging,
1987). Non-mammalian species such as fish and salamanders have been
used in aging research (Weindruch & Walford, 1988) and are
potentially available for toxicology studies. Several of these
models have already been used to examine the effects of chemicals on
aging. Because of their short life span, ease of use and relatively
low cost, non-mammalian organisms could be important in the initial
phases of a test system to identify environmental chemicals that
might affect aging.
4.1.5 In vitro studies
For the purposes of screening xenobiotics, the use of in vitro
models can result in substantial economy and efficiency. Stock cells
and, in some cases, tissue explants can be cryopreserved in large
amounts. This permits repeated assays with comparable materials and
the sharing of common stocks by numerous laboratories. Moreover,
such stocks can be used to investigate cell-to-cell interactions,
such as metabolic cooperation and metabolic transformation. Finally,
tissue culture approaches can substantially reduce the numbers of
animals required for experimentation. Such methods cannot, however,
be expected to substitute for the intact animal experiment.
There are three general categories of in vitro methods: organ
culture, tissue explants and cell culture. Organ culture involves
the short-term maintenance of variable intact segments of tissue,
for example, the full thickness of a segment of aorta. In tissue
explants, the early migration and proliferation of epithelial and
fibroblast cell types can be observed. Cell cultures are of four
(a) primary cell cultures and mass cultures of cells taken directly
from the animal, usually after enzymatic dispersion of biopsied
(b) established, serially passaged cultures with relatively
reproducible cycles of growth in early phases, but with limited
replicative life span, and with a genetic make-up reflecting
that of the donor age;
(c) "transformed" cell cultures with indefinite replicative
potential and generally with altered genetic makeup;
(d) established or transformed cell lines into which specific DNA
sequences ("transgenes") have been transfected.
Each of these types of models could prove useful for studies of
the effects of environmental agents on the elderly. One general
approach would be to explore the toxic effect of an agent as a
function of donor age, so as to detect unusual susceptibilities of
the cells and tissues of aged subjects. Another general approach
would be to culture the cells in vitro after in vivo treatments.
If a set of behaviours or phenotypes was observed with tissue from
young, treated subjects that proved to be comparable to that
observed with tissue from old untreated animals, an effect of the
in vivo treatments on the aging process could be inferred.
An entirely different experimental paradigm could be based on
the hypothesis that established cultures with finite replicative
life spans recapitulate the natural history of comparable cell types
in vivo - the well-known " in vitro model of cellular aging"
first developed by Hayflick & Moorhead (1961). The appropriateness
of such models for the study of aging is controversial, since it has
been proposed that the attenuation of growth observed in vitro
corresponds to terminal differentiation in vivo (Norwood & Smith,
1985; Bayreuther et al., 1988).
Of special interest would be the evaluation of agents that
exhibit unusual toxicity to putative stem cells. An excessive
depletion of stem cells could seriously compromise the regenerative
potential of tissues in aging subjects. In such studies, it would be
important to investigate a variety of cell types. Most research to
date has concentrated on in vitro aging of cultures of
fibroblastoid cells established from the fetal lung or from the
dermis of individual subjects of various ages. The precise origin of
such cells is not clear. Thus, with such cells it would be difficult
to compare age-related changes in vivo with those observed
A final experimental paradigm would be to use postreplicative
terminally differentiated cells in culture in order to investigate
agents for their potential to accelerate age-related alterations
observed in vivo. Such cell types might be derived through
in vitro terminal differentiation, or from normal or transformed
embryonic neuroblasts or myoblasts. A major concern, however, would
be the extent to which the experimental milieu reflected in vivo
4.1.6 Statistical considerations
For statistical treatment of the results of short-term testing,
the statistical methods that are generally available may be used.
However, for statistical analysis of the results of long-term
testing, in particular carcinogenicity testing, the comparison of
results from treatment groups with different survival rates is a
major issue. In these cases the recommendation of IARC (Peto et al.,
1980; Gart et al., 1986) could be applied. All the tumours found at
necropsy must be evaluated as "fatal" or "incidental". This approach
permits one to conduct a comparison between young and old animals
despite the very different patterns of survival from those expected.
A crude analysis, ignoring the fact that young animals survive
longer than old ones, will overestimate the ratio of tumour
incidence in young and old animals. Conversely, a "death-rate"
analysis, treating all tumours as if they were fatal, will
over-correct for the effects of differences in survival on the
incidence of tumours discovered at the autopsy of animals that died
of unrelated causes. Bias can be eliminated only if tumours that
were discovered in an incidental context are analysed by the
prevalence method, while tumours discovered in a fatal context are
analysed by the death-rate method (Peto et al., 1980; Gart et al.,
4.1.7 Extrapolation of animal data to humans
Extrapolation of animal data to humans may be either
qualitative or quantitative. On the basis of experimental results,
the weight-of-evidence approach can help predict whether a given
substance may be considered dangerous for humans. Such information
includes data on the pharmacokinetics of a chemical, its
cytotoxicity and other toxic properties, as well as the data
obtained in in vitro and short-term tests. Of primary importance
for quantitative extrapolation, a dose-response relationship must be
detected in experimental animals. An important stage of quantitative
evaluation is extrapolation of the data obtained from exposure to
rather high doses to lower doses to which humans may be exposed in
the environment. It is necessary to take into account biological
differences, both in pharmacokinetics and pharmacodynamics, between
the test species and humans. For example, a dose taken per unit of
the body surface area, or its concentration in the daily ration,
includes a correction factor for species sensitivity and allows
extrapolation of experimental doses to man (Mantel & Schneiderman,
1975; Turusov & Parfenov, 1986; Travis et al., 1990). Of course,
species sensitivity to the action of some chemicals may also vary
Various physiological and mathematical models have been
proposed for extrapolation of toxicological effects. Most of these
models refer to carcinogenesis (Turusov & Parfenov, 1986; Swenberg
et al., 1987; Clayson, 1988). The predictive nature of these models
for non-carcinogenic end-points remains to be determined.
4.2 Epidemiological and clinical approaches
4.2.1 Disease pattern of aged population
In order to study the pattern of disease occurring in the
elderly, the first question is "What illnesses are most common and
important among the elderly?" The answer can be most easily provided
in terms of diseases that cause death, hospitalization or visits to
a doctor's surgery.
The assessment of health status among the elderly on an
international basis is essentially limited to the use of mortality
data, since these are the only comprehensive data available. In the
developed countries, roughly 50% of all deaths occurring between the
ages of 65 and 74 years are attributable to cardiovascular diseases.
Among males in this age group, ischaemic heart disease accounts for
25% of deaths, while 11% are due to cerebrovascular diseases. For
women, 20% of deaths are attributed to ischaemic heart disease and
about 15% to stroke. Cancer accounts for another 25% of deaths among
men and women aged 65-74, lung cancer being the cause of 10% of all
deaths among elderly males. Roughly 7% of deaths are due to
respiratory diseases and 3% to external causes (WHO, 1989).
The trends in the four leading causes of death, i.e. malignant
neoplasms, heart diseases, cerebrovascular diseases and respiratory
diseases, within the age range 65-74 showed that, in selected
developed countries between 1950-1954 and 1980-1984, death rates
from all malignant neoplasms rose slightly for men but remained
essentially unchanged for women except in France. A more marked
decline in mortality is apparent for heart disease in the USA and
Australia where death rates have fallen by 25-30% since the late
1960s. Male mortality has fallen in France and Japan, but has risen
in Hungary. A similar pattern of change is also apparent for
females. Mortality from stroke has also declined in most countries,
although the timing and extent of the duration has varied from
country to country. For example, the decline in Japan occurred ten
years earlier than that in Australia. In the United Kingdom, France
and USA, rates have been falling since the 1950s. The trend in
mortality from respiratory diseases is less clear, there being
little evidence of sustained and comprehensive decline. However, it
is apparent that there has been some progress in reducing mortality
from these diseases in Australia and the United Kingdom over the
last decade (WHO, 1989).
It must be recognized from the outset that mortality data do
not always accurately reflect the underlying morbidity and are
particularly inappropriate in the case of many conditions for which
the fatality rate is low, yet which are important causes of
morbidity among the elderly. Data on causes of death are also less
reliable for the elderly than for other age groups owing to the
multiple pathological conditions often present at the time of death.
Nevertheless, with few exceptions, comprehensive morbidity data are
not available for the elderly.
Data from the USA shows that cardiovascular diseases cause the
largest proportion of hospitalization in the elderly. As a group,
diseases of the digestive system account for the second most common
diagnostic category while neoplastic diseases (90% malignant) are
the third most common cause of hospitalization. The remaining causes
are diseases of the respiratory system, injury or poisoning, and
diseases of the genitourinary or musculoskeletal systems (White,
1989). In a study from Shanghai, China, the common diseases of
hospitalized patients over 65 years of age in the 1950s, when
arranged in order of frequency, were hypertension, coronary artery
disease, chronic bronchitis, prostate hypertrophy, femur fracture,
pulmonary tuberculosis, diabetes mellitus, cholelithiasis and
tumours of various organs. Coronary artery disease, pneumonia,
hypertension and chronic bronchitis became the leading causes of
hospitalization in the 1970s (Zhu et al., 1982). In the 1980s, data
from other parts of China (Jiangxi, Liaoning, Xinjiang) showed that
chronic bronchitis or pneumonia was the most frequent cause of
hospitalization for elderly patients, followed by hypertension and
coronary artery disease (Xu et al., 1986; Shen et al., 1987; Xiong,
Data from the USA shows that diagnoses arising from visits to
the doctors surgery by people aged 75 or older, when arranged in
order of frequency, are hypertension (17.6%), chronic ischaemic
heart disease (9.5%), diabetes mellitus (6.7%), osteoarthritis (6%),
cataracts (5.1%), heart failure (4.4%), cardiac arrhythmia (3.6%),
arthropathies (3.6%), glaucoma (2.8%), hypertensive heart disease
(2.6%), angina pectoris (2.3%), chronic airway obstruction (2%) and
neoplasms (1.4%) (White, 1989).
4.2.2 Assessment of effects of environmental chemicals in the
There are more limitations in clinical studies than in animal
toxicology studies. Firstly, the conditions in the study are not
easily controlled. Secondly, presumably harmful effects to the
subjects under study need to be avoided in designing the protocol.
The following approach is suggested.
Comprehensive, multidimensional functional assessment of the
elderly should be carried out. This involves analysis of the
physical, psychological, social, environmental and other aspects of
functioning (Zarit et al., 1985; Kane, 1987). Measurements of the
ability to perform the activities of daily life should be obtained.
Physical functioning can be measured by a combination of diagnosis,
symptom description, health reporting, days in bed or hospital
during a specific period, and reported pain or discomfort. The
subject's orientation with respect to time, place and person, as
well as short-term and long-term memory, should be assessed.
Psychological measures are used to evaluate depression, anxiety,
loneliness and sense of mental well-being, and a psychiatric history
should be recorded.
Clinical assessment involves a complete physical examination
and selective laboratory or instrumental examinations. As most
environmental chemicals affect certain parts or organ systems of the
body, laboratory or instrumental examination of these particular
parts or organ systems should be performed. The purpose of clinical
assessment is to find any structural or functional abnormalities
that may occur during the course of exposure to the environmental
Measures of environmental chemicals in the human body, such as
the determination of their concentration or that of their
metabolites in blood, body fluids or tissues (including nails,
hairs, etc.), faeces, urine and expired air, should be conducted.
Biomarkers of exposure, such as haemoglobin adducts, may be used
The results of the above-mentioned assessments may be
correlated and analysed to arrive at a conclusion as to whether the
environmental chemicals have harmful effects on the subjects
4.2.3 Acute episodes
There are few epidemiological reports on the effects of
exposure to environmental toxicants on the aged population. Several
acute air pollution incidents resulted in marked increases in
illness and death, mostly among the elderly. One such incident
occurred in the Meuse River Valley in Belgium in 1930 when
accumulating air contaminants trapped by an inversion caused the
death of 63 people and illness in 6000 residents. An incident in
1948 in Donora, Pennsylvania, USA, resulted from a similar inversion
that covered a wide area. Of the population of 14 000, 20 died
(compared with the expected two deaths for the same period) and 43%
fell ill. Again, the elderly were the most seriously affected. In
London, 4000 excess deaths were attributed to smoke and sulfur
dioxide in the fog of 1952, and an incident in 1962 caused 400
deaths above the normal value for the period. Similar episodes of
fog-induced mortality in various places have been described (Amdur,
1986). In all these episodes, the most vulnerable people were the
elderly, and the victims were usually suffering from acute
bronchitis and pneumonia, resulting in acute respiratory failure.
However, detailed and systematic study of the effects of
environmental chemicals on the elderly is still lacking (Amdur,
4.2.4 Concerns for the aged population
The health conditions of the elderly are quite different from
those in the early or middle age of human life. Many chronic
diseases that begin at an early age extend into advanced age. Some
pathological conditions occurring in middle age may become
symptomatic in the elderly. Certain medical problems are clearly
more prominent among the elderly, e.g., cancer of the prostate,
temporal arteritis and osteoarthritis. Illness in older people often
involves multiple organ systems that are interrelated by symptoms,
physical findings, functional capacity and treatment. The emotional
and social consequences of the physical conditions are also related.
Furthermore, the manifestations of aging processes that usually
comprise degeneration, both structural and functional, may sometimes
be difficult to differentiate from those of diseases. Aging
processes and existing diseases, as well as social and environmental
factors, act together to make the assessment and care of the elderly
complex and difficult.
As far as the effects of chemicals upon human health are
concerned, the elderly are subjected to long-term exposure to
environmental chemicals. Some exposures occur daily. The source may
be polluted air, water, food or products made of inorganic or
organic chemicals with which people frequently come into contact.
Some exposures occur during occupational activities in which people
are engaged for many years. The cumulative effect of continuous or
repeated exposure to chemicals may result in pathological changes
and clinical manifestations found in later stages of life. In
addition, the structural and functional changes of aging, usually
degenerative in nature, make the elderly more vulnerable to adverse
effects of environmental chemicals.
As mentioned above, the multiple disease status in the elderly
is usually accompanied by polypharmacy. In developed countries, the
consumption of drugs by people over 65 years of age accounts for
25-50% of total drug consumption (Vestal, 1978). The most commonly
used are neuropsychiatric and cardiovascular drugs,
anti-inflammatory analgesics and diuretics. Since these drugs are
used for the relief of symptoms rather then the cure of diseases,
repeated or sustained prescribing is the rule. Under such
conditions, interactions between environmental chemicals and drugs
should be carefully considered.
4.3 Biomarkers of aging
The term "biomarker of aging" arose in conferences sponsored by
the Fund for Integrative Biomedical Research (Regelson, 1983) and
the National Institute on Aging (Reff & Schneider, 1982). The
Committee on Chemical Toxicity and Aging (1987) defined a biomarker
of aging as "a biological event or measurement of a biological
sample that is considered to be an estimate or prediction of one or
more of the aging processes". Baker & Sprott (1988) offered the
following specific features for a biomarker of aging: (a) nonlethal;
(b) highly reproducible within and across species; (c) reflects
physiological age or some basic biological process of aging or
metabolism; (d) displays significant alterations during relatively
short time periods; (e) is crucial to the effective maintenance of
health and prevention of disease; and (f) reflects a measurable
parameter that can be predicted at a later age. Development of a
panel of biomarkers would assist in assessing the effects of
environmental chemicals that modulate aging processes in laboratory
animals and man.
There is currently a significant research effort, especially
with rodent species, to establish batteries of biological markers of
aging (Allaben et al., 1990). But how can one differentiate
alterations that are simple functions of chronological time from
those that are the results of intrinsic aging or of intrinsic aging
coupled with the effects of chronological time? One approach has
been that of comparative gerontology. Starting with a group of
taxonomically related species that vary substantially in their
maximum life-span potentials, one simply asks if the rate of change
of the putative biomarker reflects the maximum life-span potential
of the species.
From a practical point of view, various biomarkers may be used
for the measurement of aging. For different levels of integration of
an organism, different parameters may be used. At the subcellular
and cellular levels, measurements of macromolecular lesions, the
degree of collagen cross-linking, the level of lipofuscin
accumulation, specific enzyme activities, the number of particular
hormone receptors, numbers of cell divisions, etc. may be
investigated as biomarkers. Tissue and organ weights, cellularity,
growth or some functional activity (muscle strength, visual acuity,
secretion rate) may be considered. The functional activity of
motor, cardiovascular, nervous, endocrine, immune, haematopoietic
and other systems and subsystems may be considered at the systemic
level as potential biomarkers of aging. In addition, at the level of
the whole organism, the functions of the main integrative systems
should be addressed.
Test batteries that attempt to measure functional age (Webster
& Logie, 1976), physiological age (Hollingsworth et al., 1965) and
biological age (Furukawa et al., 1975; Nakamura et al., 1982;
Voitenko & Tokar, 1983; Reis & Poethig, 1984; Dubina et al., 1984;
Hochschild, 1989) have similar conceptual underpinnings in that they
utilize the great variability in performance that emerges among
adults of the same chronological age in standardized, age-sensitive
tests. Studies using this approach have been conducted on human
populations, and similar measures have been employed in a few rodent
studies (Hofecker et al., 1980; Dubina et al., 1983). This approach
can be viewed as the performance variability model of biological
age. It has considerable intuitive appeal and, in many cases,
statistical elegance. An individual may be judged biologically
younger if he is performing better than expected for his
chronological age. However, in their extensive and critical reviews,
Costa & McCrae (1980, 1985) revealed many conceptual and
methodological flaws in this approach.
Biomarkers of aging, which are markers of susceptibility, may
have their greatest utility in the study of the effects of
environmental chemicals on the processes of aging. The effects of
environmental chemicals on the elderly would be assessed most
efficiently by using biomarkers of effect (NAS, 1989).
a) With increasing age, humans become more vulnerable to
environmental challenges due to the deterioration of
physiological and psychological processes. Therefore, it is
likely that the elderly will be more susceptible to the harmful
effects of environmental chemicals.
b) The elderly are heterogeneous with respect to the extent of
deterioration of physiological and psychological processes.
c) Few, if any, of the hundreds of thousands of environmental
chemicals have been tested for increased toxicity in the
d) Some of the many age-associated diseases may cause an increased
susceptibility to the harmful action of specific environmental
e) The use of animal models for aging research requires special
considerations, such as housing conditions, diets, monitoring
for infectious agents, and specifically defined pathologies. It
is also necessary to assess several age ranges based on
life-table information in order to distinguish the senescent
from the mature and developing animal.
f) The selection of the animal model should be based on the
likelihood of providing information of relevance to specific
problems in humans.
g) The characteristics of the elderly result from intrinsic aging
processes, environmental factors, and other life-span events.
Therefore, the study of the elderly may not provide
information on basic aging processes.
h) Both the size of the aged population and the number of
chemicals in the environment will undoubtedly increase over
the next few decades. It is therefore expected that the adverse
effects of chemical exposure on the elderly will increase in
importance as a health care issue.
6. FURTHER RESEARCH
a) Experimental, epidemiological and clinical data should be
* the toxicity, mutagenicity and carcinogenicity of
environmental chemicals in old individuals as compared to
* the effect of age on the pharmacokinetics and
pharmaco-dynamics of environmental chemicals;
* the long-term effect of environmental chemicals on
molecular, cellular and physiological parameters as
potential biomarkers in the elderly.
b) New models should be developed for assessing the susceptibility
of the elderly to environmental chemicals as compared to young
adults. Such models should be suitable for assessment of
particular consequences and relevant to humans, and could
* non-mammalian and mammalian models (e.g., Drosophila,
fish, rabbits, mini-pigs);
* transgenic animal models;
* cell lines with specific genetic characteristics.
c) For each study the appropriate applicability and use of
experimental models and techniques must be validated:
* animal models should be well-defined in terms of survival,
pathology and husbandry;
* human subjects should be examined carefully for subtle
disease status, medical history, life-style and
* standard procedures for measuring molecular, cellular and
physiological parameters should be defined (and developed
if necessary) in order to prevent misinterpretation.
d) The effects of environmental chemicals on the processes of
aging remain to be evaluated. A special scientific workshop
should be devoted to this topic.
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APPENDIX 1. Background Papers
Anisimov, V.N., Approaches to examine the effects of chemicals on
the aged population: experimental approaches.
Birnbaum, L.S., Basis of altered sensitivity of the elderly to
chemicals - pharmacokinetics and pharmacodynamics.
Cooper, R.L., & Goldman, J.M., Alterations in susceptibility to
toxic compounds in the aged central nervous system and endocrine
Dilman, V.M., Theories and mechanics of aging.
Fabris, N., Systemic biology of aging.
Ingram, D.K., Evaluating effects of chemical exposure on aging:
development of conceptual models.
Li, S., Aged population: demographic, life expectancy, and
Likhachev, A.J., Age related peculiarities of repair of DNA damage
Martin, G.M., Definitions on aging.
Ray, P.K., Jaffery, F.N., & Viswathan, P.N.,
1. Chemical exposure of the elderly
2. Modifying factors: nutrition, state of health, life style,
alcohol intake, smoking and ionizing radiation.
Richardson, A., The molecular biology of aging: translation,
transcription and chromatin structure.
Speijers, G.J.A., Groups at risk and their chemical exposure as well
as nutrition as a source of chemicals and as a confounding factor.
Zhu, J.R., Approaches to examine the effects of chemicals on the
aged population: epidemiological and clinical approaches.