Healthy aging: the Swiss experience

The quantitative importance of ageing both in developed or in developing countries raised the subtle question of the quality of life of the ageing person. Precise definitions of life expectancy, healthy life expectancy and quality of life are presented. Then, presentation of the results of two cross-sectional studies performed with the same methodology at a 15-year time interval in French-speaking Switzerland illustrates compression of morbidity theory, with increased longevity, increased good perception of health and increased quality of life. Moreover, quantitative data concerning the longevity impact of hospital geriatric care are presented from Geneva. The 4-year survival rate of over 85 year old women, discharged from the hospital for acute care, reached 48%. Explanations of these outstanding medical progresses on longevity and socio-economical challenges of extreme ageing are discussed in the world context.     

The aged: medical and social aspects

Physical health is affected by physiological aging that impacts on all tissues and organs, notably sensorial systems (hearing, sight), the locomotory and the immunological systems (lowering of resistance to infections). There is an increase with age in the incidence of many cancers (particularly breast, prostate, and colon cancers) and cardiovascular diseases. Regular check-ups are useful in order to take appropriate measures in time. It is important that people maintain regular physical activity and a balanced diet even up to an advanced age and the elderly must learn to adapt themselves to the ever-changing abilities of their organism. It is possible to slow down the aging process through good hygiene and often to maintain autonomy until the end of life. Mental health is threatened by impairment of mental functions, depressive tendencies, and the risk of senile dementia that cannot be foreseen or avoided. It appears that keeping intellectually active and having a good level of education impact favorably on mental aging. Social health depends, for a large part, on the way society accepts and treats the elderly. They must be kept integrated into society and allowed to live at home for as long as possible. Any measures of rejection, discrimination, and exclusion should be opposed. The dignity of the elderly must be respected and activities giving them a feeling of usefulness should be encouraged. It is important to help families who care for their parents at home, to develop and evaluate healthcare networks, and encourage medical professionals and social services to work together. The change in the demographic structure of France is a considerable phenomenon requiring a long-term strategy and not only superficial and cosmetic measures.     

Research strategies in the pharmaceutical industry to cope with the problems of ageing

The present research strategies for ageing are focussed around three areas. The first area is the demographic study of the present-day populations and those in the future. The analysis of the evolution of the metropolitan French population from 1950 to 2050 indicates that the proportion of subjects aged greater than 60 years will pass from 16% to 35%. In addition, the level of dependence of these subjects will vary considerably from one to another. The second area is the integration of epidemiological data of the pathologies related to the aged subject. Numerous epidemiological studies of the aged show that the elderly population is in better health, better informed about the diseases that affect them and also financially more secure, which allows them to take better care of themselves. The epidemiological studies of certain dementias show, for example, that if we reduce the delay to when the disease appears by five years, then we reduce the prevalence by a factor of 2. The third area relates to the important new progress in the understanding of the biological mechanisms involved in cellular ageing. The recent progress in the area of cellular biology has started to decode the complex mechanisms underlying cellular ageing. The important understanding of the phenomena of apoptose with the development of relevant biological models of the natural ageing process have anticipated future treatments and, eventually, the prophylactic treatment of specific pathologies of the elderly patient.     

Electrophoretic study of aged butyrylcholinesterase after inhibition by soman

The following states of purified tetrameric form (C₄) of human plasma butyrylcholinesterase were studied by electrophoretic techniques: native, inhibited by soman and by methane sulfonyl fluoride and soman-aged.In order to detect a significant conformational change of the aged cholinesterase as compared to the non-inhibited (native) species, enzymes were treated with a set of bifunctional reagents (diimidates) of different chain lengths. After denaturation, the cross-link products were subjected to sodium dodecyl-sulfate polyacrylamide gel electrophoresis. The peak areas of the cross-linked species and the parameters of cross-linkability were calculated from densitometric data, versus the maximal effective reagent length.The effect of occupancy of the esteratic site by substituted phosphonyl group and by methyl-sulfonyl residue on the binding activity of the anionic site was studied by affinity electrophoresis at varying temperatures with immobilized-procaïnamide as ligand. Apparent dissociation-constants of the enzyme-ligand complexes were estimated from measurement of mobilities versus ligand concentration. Corresponding thermodynamic quantities were calculated from Van't Hoff plots and basic thermodynamic equations.The reactivity of aged-cholinesterase with diimidates was similar to that of the native enzyme. Affinity for immobilized-procaïnamide was slightly lowered in aged and inhibited enzymes as compared to the native and sulfonylated enzymes. As for the ligand-induced isomerization of anionic site (A → B), revealed by affinity electrophoresis, the ligand concentration at the midpoint of transition ($\text{A}\text{= 0.5}$) was slightly greater for the aged enzyme than for the native one.From these results, the following conclusions can be drawn: the dealkylation of somancholinesterase conjugate (aging) does not seem to induce structural changes detectable in the cross-linkability of lysyle residues at the subunit interfaces andthe surface of the tetrameric enzyme. On the other hand, the affinity of the anionic site and ligand-induced isomerization process are altered in soman-inhibited and aged enzymes. These data suggest the occurence of a weak conformational change of the active center and/or the formation of non-covalent bonds between the methylphosphonyl residue and side chain groups as a result of the dealkylation reaction.     

The many states of aging: a meeting and some demographic aspects

With an expectation of life at birth of 27 years in the middle of the 18th century, 21% of males reached their 60th birthday with a remaining expectation of life of 12 years. Under the conditions of mortality of 1950, in France, 70 percent could celebrate their 60th birthday, and they had still 15 years (only) to live on the average. This last figure started increasing after 1950: the expectancy of life at age 60 is now over 20 years, and it will exceed 25 years around 2050 (for women, the mean will be 31 years). Longevity is an individual capacity. It is now increasing fast, and becomes more and more responsible for the ageing of the population (the rise in the proportion of older persons in the population). We now try to forecast the number of centenarians, and even of super-centenarians (aged 110 years and more), and speculate about the maximum life span. We are in fact entering an entirely new era, when three, four, even five generations can survive simultaneously. Are we prepared to it? The French Ministers for Research and for Social affairs set up a Committee of 15 members (chaired by Henri Leridon) to prepare a National Meeting of Researchers on Ageing, in order to review the situation of research in France on this issue and to make proposals for organising and orienting new studies. The life span of human species, as well as the one of individuals, is undoubtedly depending upon genetic factors. But interactions with environmental factors and with behaviour also play a major role. To be able to disentangle these complex associations, it will be necessary to combine the work of biologists, clinicians and social sciences specialists. The main conclusions of the June 2001 meeting are reported here, together with some orientations of demographic research on mortality at oldest ages and the limits of longevity.     

Genetic susceptibility to ageing-associated diseases

The constant and rapid increase of life expectancy in western countries is associated with a major ageing of our populations. In these conditions, we can expect an epidemic progression of most chronic diseases, especially cardiovascular, neurodegenerative and metabolic disorders, the main causes of death in the world. The global burden of these diseases will have a dramatic impact on the health and on the socio-economical context of our societies. From a global point of view, the occurrence and progression of these multifactorial diseases rely upon the nature and intensity of the environmental determinants we are exposed to all life long, but also to our individual genetic susceptibility. Through the determination of this higher susceptibility to an environmental risk factor and the understanding of its mechanisms of action, prevention and management efforts will be better focused. In such multifactorial affections, the development and the transmission of the disease do not follow the simple laws of monogenic Mendelian models. The complexity of this transmission is associated with the influence, at various degrees, of several genes and of a close interaction between this particular genetic susceptibility and environmental risk factors. With the recent development of automated and high throughput molecular biology techniques and their use in epidemiological studies, gene expression regulation and post genomic studies, the determination of sub-groups facing a higher individual genetic susceptibility has begun. This determination will offer new clues for a better-targeted disease management.     

Oxidative stress: a theoretical model or a biological reality?

Although oxidative stress has been extensively studied the last fifteen years, many physicians and biologists are still sceptical concerning its interest in biology and medicine. This is probably due, in part, to the fact that this subject is a matter of biophysics, and the first studies reported were written using a physical language that inspired these people used to a more concrete problematic very little. Another problem is the difficulty to detect the species mediating oxidative stress, and to determine their role in biological processes. This review is aimed at presenting oxidative stress, as well as reactive oxygen species and free radicals--the molecules that mediate it--in a clear form able to convince all researchers involved in life sciences that these short-lived intermediates are indissociable from any aerobic organism. Moreover, if reactive oxygen species and free radicals are undoubtedly involved in many pathologies, they have physiological functions too.     

Place and function of fourth age persons in the family and in society: a challenge

The life expectancy, at the age of 75 years, is nowadays 11 years for men and 13.5 for women, and is still increasing. Two aspects are here discussed; (i) the role of independent elderly people bringing to the younger generations financial support, experience, rules of social behaviour and memory, and (ii) the specific needs of solidarity that society and family have to provide to dependent elderly people. Adequate management of these problems is certainly a challenge for our culture.