Middle

Chief Editor

Dr Abdulrazak Abyad
Abyad Medical Center & Middle East Longevity Institute
Azmi Street, Abdo Center,
PO BOX 618
Tripoli
Lebanon

Phone:
(961) 6-443684
Fax:
(961) 6-443685
Email: aabyad@cyberia.net.lb

Editorial Board

Current issues

Past issues

Submission of articles

Advertising detail

Publishers
medi+WORLD International
572 Burwood Road
Hawthorn
Australia

Ph: +61 3 9819 1224
Fax: +61 3 9819 3269

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⁾.

As a result of aerobic metabolism, aging is primarily the cumulative sum of oxidative damages to the cells and tissues of the body. Several lines of evidence have been used to support this hypothesis including the claims that: 1) free radical damage at cellular level increase with age, 2) variation in species life span is correlated with metabolic rate and protective antioxidant activity, 3) reduced calorie intake leads to a decline in the production of reactive oxygen species (ROS) and an increase in life span and 4) enhanced expression of anti-oxidative enzymes in experimental animals can produce a significant increase in longevity⁽²²⁾.

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.

Bibliography

1) HARMAN D Aging: overview. Ann N Y Acad Sci 2001; 928:1-21.

2) HOLDEN C. The quest to reverse time's toll. Science 2002; 295:1032-3.

3) BALCOMBE NR; SINCLAIR A. Ageing: definitions, mechanisms and the magnitude of the problem. Best Pract Res Clin Gastroenterol 2001 ; 15 : 835-49

4) FETCHER A, SMEETH L, BREEZE E. The end of age: but not for the worse off. Age Ageing 2002; 31:11-2

5) ROSSOLINI G, PIANTANELLI L. Mathematical modeling of the aging processes and the mechanisms of mortality: paramount role of heterogeneity. Exp Gerontol 2001; 36:1277-88.

6) KIRKWOOD TB Evolution of ageing Mech Ageing Dev 2002; 123:737-45.

7) HELFAND SL, INOUYE SK. Rejuvenating views of the ageing process. Nat Rev Genet 2002; 3:149-53.

8) DE GREY AD, AMES BN, ANDERSEN JK et al. Time to talk SENS: critiquing the immutability of human aging. Ann N Y Acad Sci 2002 ; 959 : 452-62; discussion 463-5.

9) US DEPARTMENT OF HEALTH AND HUMAN SERVICES. Healthy people 2010 objectives: draft for public comment. Washington DC: US Government Printing Office; 1998

10) MARTIN GM. Keynote: mechanisms of senescence--complificationists versus simplificationists. Mech Ageing Dev 2002; 123: 65-73; discussion 75-9

11) HAZZARD WR. What heterogeneity among centenarians can teach us about genetics, aging, and longevity. J Am Geriatr Soc 2001; 49:1568-9

12) PERLS T. Genetic and environmental influences on exceptional longevity and the AGE nomogram. Ann N Y Acad Sci 2002; 959:1-13.

13) ROSE G, PASSARINO G, CARRIERI G, ET AL. Paradoxes in longevity: sequence analysis of mtDNA haplogroup J in centenarians. Eur J Hum Genet 2001; 9:701-7.

14) MARTIN GM. Genetic modulations of human life span: an overview. IUSSP meeting, Montpellier 2001

15) HASTY P, VIJG J.Aging. Genomic priorities in aging. Science 2002; 296: 1250-1

16) AHMED A, TOLLEFSBOL T. Telomeres and telomerase: basic science implications for aging J Am Geriatr Soc 2001; 49: 1105-9

17) CAMPISI J, KIM SH; LIM CS et al. Cellular senescence, cancer and aging: the telomere connection. Exp Gerontol 2001; 36: 1619-37

18) BENETOS A, OKUDA K, LAJEMI M et al. Telomer length as an indicator of biological aging: the gender effect and relation with pulse pressure and pulse wave velocity. Hypertension. 2001; 37(2 Part 2): 381-5

19) GRANGER MP, WRIGHT WE, SHAY JW. Telomerase in cancer and aging. Crit Rev Oncol Hematol 2002; 41: 29-40

20) SWAN GE, CARMELLI D. Evidence for genetic mediation of executive control: a study of aging male twins. J Gerontol B Psychol Sci Soc Sci 2002; 57: 133-4

21) BIESALSKI HK. Free radical theory of aging. Curr Opin Clin Nutr Metab Care 2002; 5 : 5-10

22) WICKENS AP. Ageing and the free radical theory. Respir Physiol 2001; 128: 379-91

23) LENAZ G, BOVINA C, D'AURELIO M et al. Role of mitochondria in oxidative stress and aging. Ann N Y Acad Sci 2002; 959: 199-213

24) LEE HC, WEI YH. Mitochondrial alterations, cellular response to oxidative stress and defective degradation of proteins in aging. Biogerontology 2001; 2: 231-44

25) SASTRE J, BORRAS C, GARCIA-SALA D et al. Mitochondrial damage in aging and apoptosis. Ann N Y Acad Sci 2002; 959: 448-51

26) STADTMAN ER. Protein oxidation in aging and age-related diseases. Ann N Y Acad Sci 2001; 928:22-38.

27) POLLACK M, LEEUWENBURGH C. Apoptosis and aging: role of the mitochondria. J Gerontol A Biol Sci Med Sci 2001; 56: B475-82

28) BONJOUR JP, RIZZOLI R. The property of calcium in the child and the adolescent: importance in the acquisition of bone mineral density. Arch Pediatr 1999; 6: 155s-157s

29) RIZZOLI R, BONJOUR JP. Determinants of peak bone mass and mechanisms of bone loss. Osteoporosis Int 1999; 9: S17-23

30) CARLSON JE, ZOCCHI KA, BETTENCOURT DM et al. Measuring frailty in the hospitalized elderly: concept of functional homeostasis. Am J Phys Med Rehabil 1998; 77: 252-7

31) LIPSITZ LA. Dynamics of stability: the physiologic basis of functional health and frailty. J Gerontol A Biol Sci Med Sci 2002; 57: B115-25

32) KUSHI LH, FEE RM, FOLSOM AR et al. Physical activity and mortality in postmenopausal women.JAMA 1997; 277: 1287-92

33) THUNE I, BRENN T, LUND E et al. Physical activity and the risk of breast cancer . N Engl J Med 1997; 336: 1269-75

34) DUTHIE SJ, WHALLEY LJ, COLLINS AR et al. Homocysteine, B vitamin status, and cognitive function in the elderly. Am J Clin Nutr 2002; 75 : 908-13

35) CORREA LEITE ML, NICOLOSI A, CRISTINA S et al. Nutrition and cognitive deficit in the elderly: a population study. Eur J Clin Nutr 2001 ; 55 : 1053-8

36) MARCILLA DE PARADA N, COZZA E, PARADA JL. Relationship between food habits and serum cholesterol levels in a suburban population in Argentina.Arch Latinoam Nutr 1999; 49: 333-7

37) ALAM S, PURDIE DM, JOHNSON AG. Evaluation of the potential interaction between NaCl and prostaglandin inhibition in elderly individuals with isolated systolic hypertension. J Hypertens 1999 ;17: 1195-202

38) KANNEL WB. Coronary heart disease risk factors in the elderly. Am J Geriatr Cardiol 2002; 11:01-7

39) CASIGLIA E, MAZZA A, TIKHONOFF V et al.Weak effect of hypertension and other classic risk factors in the elderly who have already paid their tsoll. J Hum Hypertens 2002 ; 16 : 21-31

40) O'DONNELL CJ, KANNEL WB. Epidemiologic appraisal of hypertension as a coronary risk factor in the elderly.Am J Geriatr Cardiol 2002; 11:86-92.

41) YU BP, CHUNG HY. Oxidative stress and vascular aging. Diabetes Res Clin Pract 2001; 54 Suppl 2:S73-80.

42) PANTONI L. Pathophysiology of age-related cerebral white matter changes. Cerebrovasc Dis 2002; 13:7-10.

43) DE LEEUW FE, DE GROOT JC and VAN GIJN J. [Cerebral white matter lesions in the elderly: vascular risk factors and cognitive consequences]. Ned Tijdschr Geneeskd 2001; 145 : 2067-71

44) SESHADRI S, WOLF PA, BEISER A et al .Lifetime risk of dementia and Alzheimer disease: The impact of mortality on risk estimates in Framinghton study . Neurology 1997; 49: 1498-504

45) VITA AJ, TERRY RB, HUBERT HB et FRIES JF. Aging, health risks and cumulative disability
New Engl J Med 1998; 338: 1035-41

46) CAMPION EW.Aging Better. New Engl J Med 1998; 338: 1064-6

47) HUBERT HB, BLOCH DA, OEHLERT JW, FRIES JF. Lifestyle habits and compression of morbidity. J Gerontol A Biol Sci Med Sci 2002; 57:M347-51

48) HOGAN DB, ELBY EM, FUNG TS. Disease, disability, and age in cognitively intact seniors: results from the Canadian Study of Health and Aging. J Gerontol A Biol Sci Med Sci 1999; 54(2): M77-82

49) STUCK AE, WALTHERT JM, NIKOLAUS T et al . Risk factors for functional status decline in community-living elderly people: a systematic literature review . Soc Sci Med 1999; 48: 445-69

50) ROMAGNONI FG, BOLLINI C et al . Disability is associated with malnutrition in institutionalized elderly people. The I.R.A. Study. Aging (Milano) 1999; 11: 194-9

51) CHEN H, BERMUDEZ OI, TUCKER KL. Waist circumference and weight change are associated with disability among elderly Hispanics. J Gerontol A Biol Sci Med Sci 2002; 57: M19-25

52) TIMIRAS PS. Disuse and aging : same problem, different outcomes. J Gravit Physiol 1994; 1: 5-7

53)SCOTT WK, MACERA CA, CORNMAN CB et al. Functional health status as a predictor of mortality in men and women over 65. J Clin Epidemiol 1997; 50: 291-6

54) MICHEL JP. unpublished data

55) WORLD HEALTH ORGANIZATION. International classification of functioning, disability and health: ICF. Publication of the World Health Organization, Geneva 2001

56) ROWE JW, KAHN RL. Human aging: Usual and successful. Science 1987; 237-1439

57) FELDMAN HA, LONGCOPE C, DERBY CA, ET AL. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal result from the Massachusetts male aging study. J Clin Endocrinol Metab 2002; 87:589-98

58) ROWE JW, KAHN RL. Future of aging. Contemp Long term care 1999; 22: 36-8, 40, 42-4

59) VON FABER M, BOOTSMA-VAN DER WIEL A, VAN EXEL E, ET AL. Successful aging in the oldest old: Who can be characterized as successfully aged? Arch Intern Med 2001; 161:2694-700.

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