Aging and senescence

Pr. Jacques Proust & Pr. Pierre-Olivier Lang

Medical Director, Nescens Preventive Medicine Centre, Genolier Clinic, Genolier

May 9, 2021

Everything ages, one way or another. Over time, everything starts to deteriorate, some things faster than others. Plants can live up to hundreds of years, whereas a human’s maximum life span is 122 years, and even that’s extremely rare. We can actually differentiate between 3 different aging modalities and they are successful aging, normal aging, and pathological aging. Senescence is a slow, complex process, and it begins at birth, in some cases even earlier. It involves physiological, psychological, and biological factors which are all intertwined. That’s exactly why aging and senescence differs greatly for every human being.

Want to learn more? Keep reading the article by Pr. Jacques Proust & Pr. Pierre-Olivier Lang.

Generally speaking, “ageing” is defined as one or more functional changes that progressively diminish the ability of an object, information or organism to perform its functions. In the case of a living organism, it is a natural process that, sometimes exacerbated by various stresses experienced throughout its life, leads the organism to no longer maintain its physiological equilibrium (or homeostasis) and eventually to die. Some plants age extremely slowly and thus live for several hundred years. In contrast, mayflies are insects that survive only a few hours. Between these two extremes, humans have a maximum lifespan of 122 years (J. Calment, born on 21 February 1875 – died on 4 August 1997). Since 17 December 2012, when the Italian-American D. Manfredini, the oldest person in the world is the Japanese J. Kimura, born on 19 April 1897, aged 115. He is also the last male person to be born before 1900.

Strictly speaking, the word “ageing” indicates only the chronological fact of the passage of time. Thus, by convention, we speak of ageing from a certain age (the “mature” age), before differentiating the 3rd age (65 -89 years) from the 4th age or old age (> 90 years). Some also differentiate between young-old (65-75 years), old (75-85 years) and old-old (over 85 years) and or super-centenarians (over 100 years).

In medical terms, chronological definitions are generally relegated to the background in favour of those that take into account the body’s physiological reserve level. When we talk about the consequences of the passage of time on the functioning of our organism, we should use the term “senescence”.

Senescence is a complex, slow and progressive process, which begins at birth or even in utero for some of our cells. It involves various biological, physiological and psychological factors which are, for a minority, influenced by genetics and, for a very large majority, linked to our life history. The close interrelationship between all these factors means that, within the human species, ageing varies greatly from one individual to another. While some people appear relatively resistant to ageing (successful ageing), even on their hundredth birthday, others will experience shorter life spans and/or of much poorer quality (pathological ageing).

Although senescence is a natural and inevitable stage in our life cycle, it should not be considered as a long process of wear and tear of our tissues, which would be of the same nature as the wear and tear of inert material by the simple effect of the passage of time. Indeed, some species show no observable ageing or are even able to reverse their ageing process and return to the larval state. As for man, his history shows that the limits initially imposed by his ageing could be greatly extended.

The ageing of the human species

OUR LIFE EXPANSION IS INCREASING…

If we consider only our recent history, in the space of a century, due to the effect of the decrease in mortality but perhaps also due to our increased resistance to ageing, our life expectancy has practically doubled. It has risen from under 40 to over 80 years. On average, we have gained 2.5 years of life every 10 years.

This gain in life expectancy is mainly due to:

  • improved care of pregnancy and infants, progress in hygiene and asepsis, anti-infectious control (antibiotics and vaccinations), progress in surgery and medicine
  • the reduction in the arduousness of work, the introduction of paid holidays, the reduction of working hours, access to health care and schooling, the rise in the standard of living and the reduction of extreme poverty and the serious food shortages associated with it, the accessibility of the majority to domestic comfort (running water, electricity, heating, access to housing);
  • the implementation of transport safety policies, safety standards in businesses and buildings, cold storage of food, etc.

Of course, individual factors have also played a major role in increasing life expectancy. Medical information and awareness of the importance of prevention has shaped behaviour: reduced alcohol consumption, hygiene, asepsis, physical activity, balanced diet, etc. Today, the prevention of risk factors by the individual is the most effective means of ensuring that life expectancy continues to increase in developed countries.

… OUR SOCIETY IS AGING

Coupled with the decline in the fertility rate, this increase in longevity is resulting in unprecedented structural changes in our society, such as the historical inversion of the proportions of young people under 5 years of age and people aged 65 or over. Over the last 50 years, the number of people aged 65 or over has tripled. By 2025-2030, population projections show that this part of the population will grow 3.5 times faster than the general population. Today, the probability of a newborn becoming a centenarian is very high, whereas this was still a rarity only 20 years ago. According to the National Institute on Aging, the number of centenarians is expected to reach 4 million by 2050, compared to just 40,000 worldwide in 1990.

The considerable increase in the number of centenarians naturally increases the probability that some of them will reach even older ages. Thus we have recently seen the emergence of so-called “super-centenarians”. These are individuals who have reached or exceeded their one hundred and tenth birthday. Although there is, in theory, a biological limit to life expectancy, for the moment the maximum longevity of the human species is still unknown.

By modifying the environmental and biological constraints of life, man has progressively, throughout his history, pushed back the limits of life without knowing yet where this will lead him. While this increase in longevity opens up considerable prospects for all societies and testifies to an overall improvement in people’s health, this demographic change, unprecedented in the history of humanity, also raises questions concerning the quality of the years of life gained. Indeed, we cannot hide the fact that ageing is intrinsically associated with an increase in the incidence of chronic diseases such as diabetes, neuro- or cardio-vascular diseases, cancers and neurodegenerative diseases. Should we not, therefore, fear that current progress in extending life expectancy and, even more so, future progress will lead to a deterioration in the overall health of the population?

… BUT NOT ALWAYS WITHOUT DISABILITY(S)

Indeed, while for a long time it was considered that increased life expectancy went hand in hand with improved health status, this is no longer so obvious because of the considerable increase in the incidence of chronic, disabling but non-fatal diseases with advancing age.

The latest estimates of the quality of our ageing, based on international longevity databases, indicate that the average life span continues to increase. On average, we are gaining an extra 3 months of life each year. While until the 1990s the years of life gained were years of a healthy life, it appears that since then the increase in life expectancy has been associated with an increase in disability due to health events during life.

DIFFERENT MODES OF AGEING

Ageing, understood at the population level, is characterised, as described above, by a progressive reduction in functional capacities and by an increase in the incidence of chronic diseases. On the other hand, at the level of the individual, three evolutionary modalities of ageing, underlying different life trajectories, are commonly accepted:

  • “successful ageing”, is ageing at a high level of performance with the maintenance of functional and cognitive capacities;
  • “normal ageing”, which is associated with impairment of functions defined as physiological;
  • and “pathological ageing”, corresponding to ageing accompanied by one or more illnesses (dementia, depression, locomotion disorders, organ failure etc.).

However, it is important to bear in mind that the concept of “ageing” at the individual level is not a uniform process fixed in time, but a multidimensional phenomenon that is demographic, biological, medical, sociological, psychological and economic. It must therefore be understood in its entirety in order to be able to develop and implement effective and well-thought-out prevention and treatment strategies.

Why do we age?

ARE WE GENETICALLY PROGRAMMED TO AGE?

The speed of ageing in living beings seems to be strongly influenced by genetic factors, as shown by the fact that genetically different animal species have their own longevity. For example, an elephant can live for more than 70 years, whereas the life expectancy of a laboratory mouse rarely exceeds 2 years. The influence of genes on the way we age has also been confirmed by the study of families whose ancestors have reached a high age and by the study of “identical” and “fraternal” twins. Experimentally, it has been clearly shown that genes that influence ageing can be passed on from one generation to the next. Thus, by crossing insects selected for their long life span within fly populations, it is possible to obtain, after several generations, a long-lived line.

The evolutionary theories of ageing suggest that the ageing process is the consequence of natural selection and is not the inevitable result of the “normal wear and tear” of the individual. Indeed, contrary to the most common view, our ageing and demise are not programmed. In an unprotected environment subject to natural selection, the representatives of the various species have only a very low probability of dying of old age because the ageing and therefore weakened individual is very quickly eliminated. Thus, our progressive deterioration and elimination are not programmed to avoid the risk of competition with our offspring in the fight for food and space. The real cause lies elsewhere in the selection of our genes during evolution.

Among the various theories on the genetic regulation of ageing that have been developed, the most successful is the “disposable soma theory”. It is based on the trade-offs in the allocation of available energy resources between the maintenance of the organism and its reproduction. In this theory, the decline in function results from unrepaired damage to molecules, cells and tissues. This damage is caused by life processes and accumulates with age. Repairing this damage is costly, in terms of energy resources, for the individual. As a result, the level of deterioration of individual results from a variable allocation of its energy resources between maintenance and repair and other competing activities such as growth and reproduction. The disposable soma theory postulates that there is no point in maintaining an organism beyond the age that it can reasonably be expected to reach in its normal environment. In other words, when the level of environmental mortality is high, it is less attractive to invest heavily in maintenance (and thus increase life expectancy) and more attractive to invest in rapid growth and reproduction.

UNDER GENETIC CONTROL: YES, BUT NOT ONLY

Over the past 20 years, researchers have identified more than 50 genes involved in the ageing process. Regardless of the species studied (bacteria, yeast, flies, worms, mammals), there is a high degree of homology of ageing regulatory genes suggesting universal mechanisms. Particularly interestingly, the majority of these genes are involved in the same mechanisms: growth, reproduction, resistance to biological stress and control of metabolism, i.e. the allocation of energy resources to various tasks. Thus, what appears to be genetically programmed is not ageing itself but the capacity of an organism to modify the speed of its degradation in order to adapt to the constraints of its environment.

Thus, in the natural environment, when environmental conditions are favourable and food is abundant, energy reserves are mainly used for growth and reproduction. This strategy is then associated with relative neglect of stress resistance and repair activities. This generally leads to a reduction in lifespan. Conversely, when food is scarce, energy reserves are mainly mobilised for the survival of the organism, at the expense of the growth and reproduction of the species. The life span is then prolonged until the environment becomes favourable again and reproduction is possible.

During evolution, the genes involved in reproduction were probably selected as favourable genes and seem to play a central role in regulating the survival of the individual. It is partly for this reason that there is a very close link between longevity and reproductive age for all animal species: late reproduction generally corresponds to a longer life span and vice versa.

How do we age?

YOUTH: A FAIR BALANCE BETWEEN DEGRADATION AND REPAIR

The human organism must be seen as a dynamic system, in an unstable balance between degradation and repair. Thus, youth is the result of a balance between, on the one hand, the intensity of biochemical processes that are harmful to certain cellular components and, on the other hand, the efficiency of the maintenance and repair systems with which these same cells are equipped. The ageing process then appears as a disruption of this balance, with the maintenance and repair mechanisms being largely overwhelmed by the extent of molecular and cellular degradation.

SENESCENCE: A CUMULATION OF DEFICITS

Biologically speaking, senescence appears first of all as molecular ageing. Indeed, we age because the molecules of which we are composed (proteins, lipids, nucleic acids) are gradually damaged. As a result of this molecular alteration, certain essential biochemical reactions are modified, thus compromising the functioning of our cells. This alteration in cellular metabolism will in turn lead to disturbances in the functioning of organs, major physiological systems and ultimately to overall decline and disease and death.

The most widely accepted definition of ageing is a decrease in physiological reserves which, while allowing for functioning at a stable state, results in an adaptive incapacity of the organism to cope with so-called stressful events. Thus, the occurrence of nutritional imbalances, the development of chronic or acute illnesses, physical and/or psychological trauma, but also various environmental and social factors can act in synergy and accelerate this process. However, some of the mechanisms intrinsic to senescence and/or contributing to its acceleration appear to a certain extent reversible and therefore by definition potentially modifiable.

The detrimental ones: free radicals and glucose

Free radicals are, for the most part, molecules derived from the oxygen we breathe. These activated forms of oxygen are inevitably produced in the many chemical reactions that are essential to the normal functioning of our bodies. Almost all (95%) of the free radicals are produced in the microgenerators of our cells called mitochondria. Free radicals are very unstable molecules that are potentially dangerous for the body. Highly reactive with other biological molecules such as proteins, lipids, carbohydrates and DNA, they can cause irreversible damage to the metabolic functions and structures of these substances. For example, it has been calculated that each DNA molecule in our cells is subject to 10,000 oxidative attacks per day.

Some sugars, such as glucose, were, until the 1970s, considered biologically harmless. In reality, these sugars are likely to react with the amino acids that make up our proteins by promoting the creation of abnormal bonds between the molecules that will not only alter the structure of the proteins but also seriously disrupt their function. These processes are the result of a relatively slow chemical reaction, called glycation, which leads to the progressive production in the body of glycation end products that are highly dangerous for the body. These products accumulate with age, particularly in diabetes, and thus contribute to the development of several diseases.

Naturally, our cells are equipped with defence mechanisms to reduce the harmfulness of free radicals and glycation products. Enzymes with complicated names (superoxide dismutase, catalase, glutathione peroxidase, etc.) and various synthesised molecules (glutathione, alpha-lipoic acid, etc.) can act in a coordinated manner to defuse oxidative reactions and help neutralise free radicals. Unfortunately, these different actors are themselves sensitive to the action of free radicals and glycation products, and their effectiveness diminishes over time, leading to the accumulation of unrepaired molecular lesions. Senescence can thus, at least in part, result from the progressive inability of the organism to control glycoxidative stress.

Cellular batteries get discharged

The mitochondria are the only energy generator in our cells. Located in the cytoplasm of each cell, mitochondria can be compared to “batteries” responsible for producing, storing and distributing the energy necessary for the functioning of the organism. The mitochondria use 80% of the oxygen we breathe to produce high-energy molecules that can be used directly by the cell.

The mitochondria have their own DNA. This DNA is modified during the onset of certain degenerative diseases associated with ageing (notably Alzheimer’s disease and Parkinson’s disease…). This observation quickly led to the idea that the mitochondria, and its DNA in particular, could play a role in the ageing process, thus opening the door to new research avenues. The permanent exposure of mitochondria to free radicals significantly alters the energy production capacity of these organelles from the age of 50. Indeed, it seems that mitochondrial DNA is 10 times more sensitive than cellular DNA to the action of free radicals. The mutations thus generated favour dysfunctions within the mitochondrial machinery. The drop in energy production will initially result in cellular dysfunction. Then, below a certain threshold of energy production, a cell suicide programme, called apoptosis, is triggered, leading to the death and elimination of the cell that has become incompetent. Thus, in the course of ageing, due to molecular alterations, there is a generalised disruption of cell function and a progressive reduction in the number of active cells.

Are we as old as our telomeres?

Telomeres are repetitive sequences of DNA located at the end of chromosomes, which they protect, helping to maintain the integrity of the genetic material. For the vast majority of cells, these telomeres shorten with each cell division. When a threshold is reached, i.e. when the ends of the chromosomes have been completely eroded, the cell is unable to divide and enters senescence. In theory, this progressive shortening of telomeres could be part of the ageing process, preventing cells from renewing themselves. It is true that cells from very old people have significantly shorter telomeres than those from young people. Nevertheless, the residual length of these telomeres still allows for a large number of cell divisions, far exceeding those required for the rest of life…

Some cells with a high renewal potential, such as stem cells, are equipped with an enzyme complex called telomerase, whose role is to reconstitute the end of chromosomes worn out by successive cell divisions. Over the course of a lifetime, there is a progressive reduction in telomerase activity, so this enzyme deficiency has been implicated in ageing. However, when the telomerase gene was deleted in genetically modified mice, these animals did not show accelerated ageing. The pathologies observed over several generations of these telomerase gene knockout animals were mainly digestive haemorrhages, as the turnover of cells in the digestive mucosa was intense and rapid.

Conclusion

Finally, ageing can be defined as the set of modifications, both structural and functional, which affect our organism as soon as it has completed its development, i.e. when the growth of the organs and the skeleton has stopped and when sexual maturity is reached. However, our organisms and their components all age in different ways and at different rates. While some people seem to have a greater resistance to ageing, others age more rapidly and have their lives cut short early. This heterogeneity can undoubtedly be explained by genetic predispositions, but also and above all by individual lifestyles and behaviours likely to squander health capital or conversely to preserve and strengthen it. Studies show that the speed of our physiological decline can be attributed for one third to our heredity and for two thirds to our lifestyle. While it seems difficult at present to influence the risk factors linked to heredity, it is possible to change those due to unhealthy behaviour. Smoking, excessive alcohol consumption, drugs, lack of regular physical exercise, bad eating habits (too many sweets, too much-saturated animal fats, etc.) aggravate and accelerate the deterioration of our bodies. Preventing the ageing, therefore, starts with correcting risky behaviour. The considerable progress made recently in understanding the fundamental biological mechanisms at the origin of our ageing opens the way to the development of therapeutic strategies designed to slow down the physiological degradation linked to advancing age and to maintain health until the end of our lives.

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