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AGING
MECHANISMS: from genetics to daily functioning
Jean-Pierre MICHEL*, François HERRMANN* and Jean-Marie ROBINE**
*Department of Geriatrics, University Hospitals of Geneva, Switzerland
**INSERM – Montpellier, France
jean-pierre.michel@hcuge.ch
“Although little is known about the aging process,
increasing lifespan and delaying aging
are the research challenges of the new century,
and have caused intense debate and
research activities among gerontologists
AHMED A et al J Am Geriatr Soc 1 2001; 49: 1105-6
While demographers calculate the steady increase in life expectancy and debate with biologists on the maximal human life span, gerontologists try to improve their understanding of the complex mechanisms involved in the aging process, a phenomenon that began with the origin of life about 3.5 billion years ago. Aging corresponds to the accumulation of diverse deleterious changes over the time throughout the cells and tissues which progressively impair function and can eventually cause death(1). But, as Robert BUTTLER said “we still don’t know how to define aging per se”(2).
Key
words: aging, genetics, reactive oxygen species, risk factors,
activity of daily living
Abstract:
Growth and ageing constitute a continuing process which involves genetics,
oxidative metabolic damage, risk factors, pathology and which impact greatly
on functioning and disability in the daily life in the elderly. The interactions
between these determinants have also to be considered within specific
economic and cultural environments which tailor each individual life cycle,
from early death to disabled survival, healthy or successful aging.
- More than 70 % of human genes contribute to determine longevity. The telomers’ lengths differ considerably between gender. Good and bad genes at early or late expression modify the ageing process from healthy to pathology.
- The free radical theory of the aging process is based on the hypothesis that with increasing age, mutations of the mitochondrial DNA will accumulate and lead at last to a loss of function with subsequent acceleration of cell death.
- Positive (good gene, physical activity…) and negative risk factors (overweight, smoke, alcohol…) interfere with the ageing process itself and related diseases.
- Progressive or acute onset of disease can disrupt the life cycle. Acute diseases are lesser involved in death. Chronic diseases are more and more frequent, difficult to treat and badly tolerated. Chronic diseases are the main causes of the disablement process. Locomotor and mental disabilities are the more frequent far before cardiovascular, diabetes or sensory ones.
- The analysis of this ageing process will not be complete without stressing the major impact of the individual well-being. The quality of life is one of the most complicated parts of human sciences. Despite scientist's efforts its evaluation stays very approximate.
The tufted complexity of the life process can easily explain how it is difficult to promote primary health prevention. The will, the drive, and anticipated ability, change considerably the perception of life…
Healthy ageing is perhaps a good thing for the individual and for the society but the best process is undoubtedly a successful aging with a good appreciation of what the individual did during his life, the absence of remorse and desire for himself and for his affective surroundings to continue in society involvements and projects of life.
Several reasons explain the lack of a single definition of aging:
- Aging
changes can be attributed to many events, namely: genetic defects,
developments, diseases, environmental factors, and an even inborn process, the aging process(1). Aging can be considered from different levels, according to molecular, cellular, morphological, physiological, behavioural and social changes(3).
- Moreover,
there are important variability and inequalities in the experience of
aging and being old. People enter in the last decades of their life
span with the health disadvantage of past experiences accumulated throughout
their life course. There are clear gradients of ill health in older
persons according to the socio-economic position measured at different
time (in mid-life, in early retirement, or in late life, when entering
in institution)(4).
- In
the study of aging and mortality, a number of issues are related
to inter-individual variability and the search for their solution can
lead to a highly complex approaches(5).
Why aging occurs, and why it develops in one way and not in another one, is a longstanding enigma on the role of senescence in nature. Even after half a century of progress, the elucidation remains unfolded. Evolution theory argues strongly against programmed aging, suggesting instead that organisms are programmed for survival, not death(6). Recent evidences from disciplines as diverse as molecular genetics, biology, clinical epidemiology and demography, provide a direct support to the validity of many of this assumption. So, time is ripe to re-examine the proposed and sometimes conflicting theories about aging and to rethink the scientific foundations of the field(7). Aging appears today more like a general output due to almost all the biological, social and stochastic factors involved in the life course.
The
aim of this paper is to illustrate this complexity through examples retrieved
from the literature at different levels from genes to individuals in the
daily life and dealing with four families of factors associated with aging:
Firstly genetics, Secondly oxidative metabolic damage, Thirdly pathology
and risk factors, and eventually functioning and disability in the daily
life(8). In addition we provide some examples of links and interactions
between metabolism, pathology and functioning in aging(8). Doing that
we keep in mind that the ultimate goal of gerontologists would be to slow
down aging indefinitely and in parallel to enhance the human well being,
as stressed by the 2010 health report(9).
1.
Genetics
Among gerontologists concerned with genetic approaches
to aging and longevity, there is somewhat of a dichotomization(10).
“On the one hand, there are those, who tend to be the 'complificationists',
very impressed by the enormous diversity of genetic modulations of human
senescence and who believe that senescent phenotypes per se are non-adaptive,
non-determinative, subject to stochastic events as well as highly polygenic
modulations, with a resulting wide variability in mechanisms of senescence
among and within species. On the other hand, there are those who seem to be convinced that
there are likely to be a rather small number of major gene effects for
a few major mechanisms. They include Saccharomyces
cerevisiae and Caenorhabditis
elegans geneticists, some Drosophila
melanogaster geneticists. They also include caloric restriction enthusiasts”(10). Where does the truth lie ?
A good way to try to investigate the genetic basis of longevity is to
study the centenarians, because all of them share something in common:
having survived the vicissitudes of life through a combination of robust
physiological, psychological, and social strengths; having escaped from
disease processes that shorten life and benefited from simple good fortune(11). They probably have the optimal set of genetic factors necessary
to get to 100 years and beyond(12). Numerous are the data coming from
the “search of the genetic secret of the centenarians”. New hypotheses
appear interesting because they link longevity and disease-free life expectancy:
- Inheritance of at least one Apolipoprotein E2 allele appears to promote longevity even among centenarians. The resulting lower level of cholesterol linked to low-density lipoprotein could be protective from both time- and age-related atherogenesis and cardio-vascular diseases(11).
- Mitochondrial
DNA (mtDNA) haplogroup J is significantly over-represented in healthy
centenarians with respect to younger controls, thus suggesting that
this haplogroup predisposes to successful aging and longevity. But,
the same haplogroup is reported to have elevated frequency in some complex
diseases (for example: Leber hereditary optic neuropathy). This finding
implies that the same mutations could predispose to disease or longevity,
probably according to individual-specific genetic backgrounds and stochastic
events(13).
Genetic
modulations of lifespan may involve four different kinds of somatic genes(14):
- Good
genes with early and late good effects (longevity
assurance genes)
- Good
genes down-regulated for good reasons
(developmental program genes)
- Good
genes with only bad effects late in life span (agonist/antagonist
pleitropy genes)
- Bad genes or slightly bad genes that do not show their true colours until late in life (accumulation of constitutional mutations)
Among these categories of genes, two interfere mostly with the quality of aging: Firstly, good genes with only bad effects in late life span (agonist/antagonist pleitropy). Cancer of the prostate provides a good example. A high androgen receptor sensitivity is linked with a high risk of prostate cancer. But the reverse is also true: a low androgen receptor sensitivity is linked with a low risk of prostate cancer. The main genetic difference between these two possibilities is the length of the CAG sequence (11 in the first case and 33 in the second). Secondly, bad genes or slightly bad genes that do not show their true colours until late in life (accumulation of constitutional mutations) are probably the genetic key to many neuro-degenerative diseases such as Hutington disease, amyloidosis process and probably Alzheimer disease(14).
In
parallel it appears that a long life depends on the timing of maturation
but also on the quality of the somatic maintenance. One broad-based hypothesis
is that an imperfect genome maintenance of deoxyribonucleic acid (DNA)
damage is a possible causal factor in aging. Errors during repair, replication
or recombination of a damaged DNA template may lead to the accumulation
of mutations(15). These mutations in genomic DNA result in the gradual
alteration of cellular function, exhibited in a variety of tissues and
provoke a progressive but generalized homeostatic failure leading to the
age-related decline(15).
Damage to DNA is one centrepiece of most theories of aging(16).
Evidence is also accumulating that telomere
shortening is associated with cellular senescence in vivo. Located at
the ends of eukaryotic chromosomes and synthesized by telomerase, telomeres
maintain the length of chromosomes (16).
In fact, the telomeric structure prevents
the degradation or fusion of chromosome ends and thus is essential to
maintain the integrity and stability of eukaryotic genomes. Telomeres
also allow cells to distinguish the chromosome ends from double strand
DNA breaks. In addition, and perhaps less widely appreciated, telomeres
may also indirectly influence gene expression(17). In both genders, telomere
length was inversely correlated with age. The longer telomere in women
suggests that for a given chronological age, biological aging of men is
more advanced than that of women(18). At each mitosis it seems that the
cut part of telomere is greater in men than in women. This finding is
so important to explain the difference in gender longevity that it needs
to be confirmed by larger studies in various aged populations. As it will
be stressed below, there is also increasing evidence that oxidative damage
is an important factor leading to the shortening of telomeres, induction
of mutations in genes, and damage to mitochondrial DNA. The association
between cellular senescence and telomere shortening in vitro is well established.
In the laboratory, telomerase-negative differentiated
somatic cells maintain a youthful state, instead of aging, when transfected
with vectors encoding telomerase. At this stage it is logic to think that
the key to "youthfulness" perhaps lies in our ability to control
the expression of telomerase(16). But, telomerase activity is a mechanism
that most normal cells do not possess, whereas almost all cancer cells
acquire, to overcome their mortality and extend their lifespan(19).
The existing links between genetics, oxidative metabolic damage and diseases
appear as one of the most challenging difficulty to explain longevity
and understand the aging process and its related alterations.
2.
Oxidative metabolic damage
Longevity of homozygote twins is statistically different, but this difference
is less important than between dizygote twins, proving that life expectancy
is only partially genetically determined(6, 20). These data explain why
some of the most interesting current problems are to understand how the
genetic factors influencing aging and longevity respond to a fluctuating
environment(6). The rate of random chemical damage to the genome is considered
as the major factor determining lifespan in species. The free radical
theory of the aging process is based on the hypothesis that with increasing
age, mutations of the mitochondrial DNA will accumulate and will at last
lead to a loss of function with subsequent acceleration of cell death(21).
The
free radical theory may also be used to explain many of the structural
features that develop with aging, including the lipid per-oxidation of
membranes, formation of age pigments, cross-linkage of proteins, DNA damage
and decline of mitochondrial function(22).
The mitochondrial respiratory chain is a powerful source of ROS(23) sensitive
to the oxidative stress in mitochondria which provokes:
1) a decrease in mitochondria respiratory function,
2) an increase in the rate of production of ROS,
3) an accumulation of mitochondrial DNA (mtDNA) mutations,
4) an increase in the levels of oxidative damage to DNA, protein, and
lipids and
5) a decrease in the capacities of degradation of damaged proteins and
other macromolecules(24).
Indeed, the role of mitochondria is essential in cellular aging. The rate
of oxidant production by mitochondria correlates inversely with maximal
life span of species. In many species, females live longer than males,
because mitochondrial oxidant production by females is significantly lower
than that of males. However, mitochondria from ovariectomized females
have a similar oxidant production as those of males(25).
To confirm this discovery, longevity of
ovariectomized women has now to be investigated.
Moreover,
responses to oxidative stress and their subsequent interactions in tissues
result in the deleterious effect of ROS on the cellular function, principally
accumulation of oxidatively altered proteins, lipids, and nucleic acids.
Oxidatively modified proteins have been shown to increase as a function
of age. Furthermore, a number of age-related diseases (cataract for example) have
been shown to be associated with elevated levels of oxidatively modified
proteins(26). Mutations of the mitochondrial DNA and its consequences
(production of oxidatively damaged proteins, lipids, and nucleic acids)
will accumulate and will ultimately lead to a loss of function with subsequent
acceleration of cell death(21).
The chronic exposure to oxidants and an increased activation
of mitochondrial permeability transition pores accelerate apoptotic mechanisms
which can be documented by a significant loss of cardiac and skeletal
myocytes during aging(27).
At this stage of knowledge, it appears impossible to delimitate the respective roles of genetics and oxidative metabolic damage in human longevity. To make progress in the understanding of these complex interactions, more detailed studies are needed on how population specific variables, such as life styles, risk factors and diseases, influence the selection forces that shape the life history(6).
3. Risk factors and pathology
First of all, it appears we must involve growth and development at younger ages when discussing longevity because of the major links existing between the different periods of life concerned. To illustrate this assertion, calcium, protein intake and physical exercises in youth are now recognized as important determinants of the adult peak bone mass, reached before the age of 20(28). The level of this peak is well correlated with the risk of osteoporotic fracture in old age(29). Moreover, during youth and early adulthood, the functional abilities and the physiological reserves raise to their maximum, which will prime the organism for an adaptive response, making it ready and able to react to sudden physiologic stresses(30). Alterations in the dynamics of physiologic systems, in advanced age, will lead to functional decline and frailty(31). Therefore, physical exercises are important all along our life. Recent studies demonstrated that moderate physical activity in post-menopausal women (aged between 55 and 69 y.) is associated with a reduced risk of death from cardiovascular and/or respiratory diseases(32) and from breast cancer(33). The positive role of physical activities at all ages to protect against loss of life, physical deterioration and perhaps mental decline has to be emphasized.
Other important factors acting on life expectancy and age-related disease are dietry habits and nutrition (differential consequences of famine, stravation and caloric restriction will not be discussed here). Survivors of two successive Scottish studies of " the childhood intelligence quotient" were included several decades later in a new study including MMSE and measure of blood folate, vitamin B-12, and homocysteine concentrations. Results showed that low levels of vitamins B and high levels of homocysteine are associated with cognitive variation in old age. Homocysteine accounted for approximately 7-8% of the variance in cognitive performance(34). Another recent Italian, population based cross-sectional study showed - after adjustment for age, sex, education, total energy intake, cigarette smoking, alcohol consumption and physical activity - that a better score assessing "healthy" diet (as defined in the WHO guidelines for the prevention of chronic diseases) is associated with a lower prevalence of cognitive deficit (odds ratio 0.85 [95% CI 0.77-0.93])(35). As previously stressed, dietry habits and nutrition are essential all along life. They not only allow to avoiding cognitive decline in old age but they also favourably interact with risk factors of cardiovascular pathologies. A 10 year follow-up study conducted in Argentina proved that great dietry modifications occured during the study-period (decrease in fatty foods - meat, butter, milk and other diary products - and increase in fibre rich products, oil and low fat products) producing significant positive changes in biological data (decrease in cholesterol levels and improvement of total-cholesterol/ HDL - cholesterol ratio), particularly in the younger and women(36). To testify the important contribution of diet on cardiovascular risk factors a recent meta analysis of 11 randomised controlled studies showed that the level of sodiom intake was significantly and positively linked with the systolic blood pressure, which appeared as one of the strongest risk factor of cardiovascular pathologies (stroke, myocardial infraction, heart failure) in old age(37).
Risk
factors of cardiovascular diseases are less numerous in the very old and
multiple epidemiological data now emphasize that the cardiovascular relative
risks associated with arterial hypertension, namely dyslipidemia, impaired
glucose tolerance and obesity diminish with advancing age(38). However,
if hypercholesterolemia and high blood pressure per se are no more predictors
of cardiovascular pathology, pulse pressure (the difference between systolic
and diastolic blood pressure) and murmurs in the neck are now considered
as highly predictive of heart failure in women over 80. Surprisingly in
this study, proteinuria and tachycardia were risk factors of cardiovascular
pathology in 80+ men(39). All this could simply indicate that elderly
persons are the survivors of a population where significant mortality
has already made its marks(39). But, what is important to underscore,
is the accumulation of cardiovascular risk factors with advancing age.
Among elderly hypertensive persons, about 39% of coronary events in men
and 68% in women are attributable to the presence of two or more additional
risk factors: glucose intolerance, obesity, and dyslipidemia; the latter
might be attributed to insulin resistance promoted by abdominal obesity.
These facts reinforce the need for multivariate risk assessment profiles(40).
Links
between genetic factors, ROS and behavioural risk factor
Now let us try to establish a link between genetics, ROS, risk factors and cardiovascular pathology or more exactly with the neuro-psychiatric consequences of the cardiovascular diseases. All along life the vascular vessels alter their structure, simultaneously responding to both physical and chemical stresses(41): 1) to cope with mechanical stressors, the endothelium and smooth muscle cells respond with adaptive cellular modifications in relation to signalling pathways of mechano-transduction 2) on the other hand, chemical stress (particularly oxidative stress) provokes also genetic (see above the role of stress in telomere shortening), molecular and smooth cells alterations. Moreover, a new inflammatory hypothesis of vascular aging emphasizes that stress-induced vascular aging may be the primary event that underlies the general aging phenomenon of systemic dysfunction(41). Risk factors of the adulthood (sedentary, overweight, smoking, arterial “pulse” hypertension, dyslipidemia…) and pathology of aged persons (atrial fibrillation, myocardial infarction, stroke) contribute to increase the vascular damage and the blood flow changes. The relationships between heart, vessels and brain are too often forgotten. For the geriatricians, the fundamental consequences of the vascular damage and blood flow changes are not only purely cardio-vascular alterations, but also cerebral white matter lesions. Numerous brain damages are closely linked to cardio-vascular dysfunctions:
Stenosis or occlusion of small brain vessels can provoke sudden or more chronic ischemia resulting in small areas of necrosis, known as lacunar infarction)
- Arteriolosclerotic changes involve loss of auto regulation in the deep white matter and generate consequent cerebral blood flow fluctuations
Small vessel alterations are the causes of damage to the blood-brain barrier and chronic leakage of fluid and macromolecules in the white matter (42).
As mentioned previously, the white matter lesions have important consequences on vascular vessels and blood flow changes. The cerebral white matter lesions can be found in few healthy aged persons but they essentially characterize depressed and demented elders. In depression, the white matter lesions are mainly located in the sub-cortical cortex, while in dementia (mainly vascular dementia but also Alzheimer disease) the lesions are located in the periventricular areas(43).
All these interacting factors (from genetics to biological damages - and risk profile) explain the complexity of aging and age-related disorders. For example, a 20-year follow-up of 2611 intact participants in the Framingham study with a mean age of 66 years at baseline, showed that the incidence of vascular or mixed dementia, between 65 and 100 years of age, accounted for 7.3 % in men and 16.9 % in women, while the Alzheimer disease (AD) incidence was around 25.5 % in men and 28.1 % in women(44). These data are significant because they stress the importance of an adequate cardiovascular prevention (not only in men but also in women) to avoid or postpone the emergence of vascular dementia and perhaps also certain AD. This example of cardio and cerebral vascular links could have been replaced by a lot of other age-related pathologies. The present choice was driven by the invaluable disability consequences of such pathologies.
4.
Functioning and disability in daily life
One essential question in the field of functioning in daily life is how to better distinguish the origin of the disablement process, whether it is always linked to life styles, aging or to specific pathological process. The subsidiary issue is to determine what are the ”disability-risk factors”, which differ probably from the “disease-risk factors”. Another important aspect is to evaluate the impact of disability on longevity.
A 32-year prospective study on disability incidence followed two groups of alumni, according to their life habits. The cumulative disability was postponed by 10 years in the low risk group (those who practiced regular physical exercises, had a normal body mass index and did not smoke) in comparison with the high risk group (those who did not exercise, were over weighted and smoked)(45). These data were severely discussed when published(46) and confirmed by another prospective study concerning older participants and taking into account the same associations of risk factors. The risk factor free group showed an average disability score near zero, 10-12 years before death, rising slowly over time, without evidence of accelerated functional decline. In contrast, those with two or more risk factors sustained a greater level of disability throughout the 10-12 years of follow-up and furthermore experienced an increase in their rate of decline 1.5 years prior to death(47).
A prospective Canadian study tried to identify the exact causes of disability in older community dwelling persons. It showed that:
1)
functional disabilities were twice more frequent above 85 years of age
than in the younger studied population.
2) Increasing age was the only significant explanatory variable for moderate,
severe of total disability in the 85+ group - involving difficulties in
walking, showering, shopping, getting to places out of walking distance
and preparing meals.
3) On the other hand, diseases were the most significant explanatory variable
associated with functional disabilities in the 65-84 age group(48).
These results need to be confirmed because they are not in agreement with the majority of the other publised survey findings. A systematic literature review of longitudinal studies published between 1985 and 1997 and dealing with the identification of the " disability - risk factors " did not mention afe itself but in alphabetical order: cognitive impairment (dementia), disease burden (co-morbidity such as diabetes, heart failure), increased and decreased body mass index (malnutrition and overweight), lower extremity functional limitation (osteo-arthrosis, hip fracture), low frequency of social contacts (loneliness), low level of physical activity (no regular physical exercise), alcohol abuse compared to moderate use, poor self-perceived health, smoking and vision impairment(49). Whatever the role of extreme age or malnutrition(50, 51) or disuse(52), the whole debate proves once again that one of the main characteristic of geriatrics is not only to consider the disease but also the functional impact of the disease on the person.
Moreover, abilities of performing basic and instrumental activities of daily living (ADL and IADL) are linked to the mortality risk. The 5-year follow-up of the 1986 National Health Interview Survey (5’320 community-dwelling individuals, aged 65 and over, self respondents to the ADL-IADL questionnaire) showed that the relative hazard of dying (results adjusted for age, BMI, self rated health status) reached 1.4 in men and 2.5 in women with poor ADL and IADL scores(53). A 4-year study of survival of very old patients hospitalised (n = 446, m.a. # 85 y.o.) in the geriatric department in Geneva confirmed the important relationship existing between functioning and survival. The rate of death 4-year after hospital discharge reached 58.5 %. A multivariate Cox regression model including number of diagnoses, age, gender, living arrangements before hospital admission and number of Functional Instrument Measures (FIM) - items for which help is needed - showed that for each medical diagnosis the risk of dying increased by 8 % but also that for each additional FIM-item, the risk of dying increased by 25 % and when the FIM-cognitive function (problem solving) was involved, the risk increased by 69 % (54).
Conclusion
All
the above concurrent evidences show how it is still difficult to identify
the causes of the time-related-changes in human being that we call aging.
Today we think more in term of longevity and functioning that in term
of aging. For example we consider that longevity and efficient functions
were shaped through evolution and selection not aging. But most of the
concepts that we are still using today were built around the concept of
aging. This is the case for intrinsic and extrinsic aging, as well as
“normal” (define as the non-diseased aging - (56), “aging in apparent good
health”(57) and pathological aging. The definitions of these concepts
are still unsatisfactory. Moreover, these definitions have to better integrate
the heterogeneity of aging at the individual level as well as at the population
level. The most recent and comprehensive concepts are
-
The “usual” or “average” aging that includes substantial physiological
losses and psychological or stressful events increasing the risk for disease
and disability with advancing age(56).
- The “successful” aging that corresponds classically to the combination of low probability of disease, high functioning level and active engagement with life(58). Successful aging is a worldwide concept, but it remains difficult to identify among such a heterogeneous variety of human beings, the indicators which could universally characterize elderly persons as successfully aged. In a public health perspective, successful aging is defined as “a state of well being”, but most elderly persons themselves view “success in aging” rather as “a process of adaptation” to new life situations(59). Personally, as geriatricians, we consider that the concept of “successful” aging intrinsically includes, whatever the physical and functional states, a high feeling of “good self esteem” and “life satisfaction”.
Acknowledgements:
The authors would like to thank Mr. Bernard GRAB and Pr. Ezio GIACOBINI for their valuable contributions to the editing of this paper.
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July
2004
Volume
1,
Issue 1
Table
of Contents
Home
From the Editor: Geriatrics
in the Middle East
Meet the team
Determinants of prescribing
for the elderly in primary health care
Aging mechanisms: from genetics to daily
functioning
The use of ambulatory blood pressure
monitoring in a hypertension clinic
A
study on physical, social and mental problems of the elderly in District
13 of Tehran
Epidemiology
of Self-Dependence among Kuwaiti Elderly
Population of Abdullah Al-Salem Area
Active
Aging: the whole society benefits
Clinical
quiz - Palliative Care