Jeanne Calment and her daily glass of port. The image made the rounds of television news until his death in August 1997, at the age of 122. Will this Arlesian who had known Van Gogh one day lose her crown as dean of humanity? The scenario is probable. Today, centenarians are no longer an exception and, if the mechanisms of aging have not yet revealed all their secrets, research is advancing. As a result, life expectancy continues to increase. If it first grew, since the beginning of the 20th century, thanks to the gradual collapse of infant mortality, it is now at the other end of life, in old age, that the gains are made. The tracks followed by the researchers suggest that the lengthening of life is still far from having reached a ceiling. What give ideas of eternal life in Silicon Valley. In 2013, Google created its own laboratory, called Calico, with the objective of “killing death”. A few months ago, the start-up Altos Labs, financed in particular by Jeff Bezos, the former CEO of Amazon, raised 3 billion dollars to work on the subject. Delirium of science-fiction-fed billionaires or credible scientific ambition? “The interference of Gafam [Google, Apple, Facebook, Amazon and Microsoft, Editor’s note] in this sector, with their fantasies of immortality, contributes to polluting research by getting lost in scientifically unproven tracks”, considers the geneticist Hugo Aguilaniu. In reality, the challenge is not to chase after eternal life, but to improve aging. Die later, okay, provided you enjoy the extra years while staying healthy.
As strange as it may seem, we don’t know exactly how the human body ages. “There are many avenues of research on aging. It’s a very complex mechanism,” says Bertrand Friguet, professor at the Sorbonne University and director of the SU-CNRS joint research unit on biological adaptation and aging, and of Inserm unit 1164 at the Institute of biology of Paris Seine.
Cellular senescence
Let’s start from the observation: beyond wrinkles and brown spots on the skin, age is above all associated with a significant prevalence of diseases, such as cancer, cardiovascular or neurodegenerative pathologies. One of the explanations for this decline in physiological functions is due to cellular senescence, in other words “our limited ability to repair, regenerate and replace damaged cells”, specifies the biologist. One of the markers of this cellular alteration is the shortening of telomeres, stretches of DNA located at the ends of chromosomes. Throughout the life of an organism, healthy cells divide to replicate. This replicative faculty is exhausted over time. Two choices are then offered to the cells: enter into apoptosis, which amounts to dying, or into senescence. In the latter case, the cells retain metabolic activity, but in another form. “We find these senescent cells in a number of aged organs and they most often show a shortening of telomeres which lose a little of their length with each replication”, reports Bertrand Friguet, who sees in this cellular senescence a kind of escape. “It prevents cells that have reached the end of their race from proliferating uncontrollably to turn into cancerous cells,” he explains.
If the anarchic multiplication of malignant tumors is spared us, the senescence of the cells nevertheless leads to a low noise inflammation, combined with the secretion of pro-inflammatory cytokines. However, when they are too abundant, these molecules create lesions. In the end, the combination of the deficiency of cellular protection tools and the occurrence of morbid phenomena contributes to weakening the organs. Bertrand Friguet observes, however, that “the repair capacities of cells vary not only from one organism to another, but also from one organ to another”. In fact, if advancing age is accompanied by a form of both physical and psychological vulnerability, the organs do not deteriorate all at once. “Some people age and others less”, confirms Professor Nathalie Salles, head of the gerontology center at the Bordeaux University Hospital. Muscle is a good example.
Muscle loss
With senescence, the muscle phenotype changes. The lean mass is gradually replaced by adipose tissue which, by a succession of mechanisms, will slow down the synthesis of the proteins which the muscle needs to maintain itself. Fast-twitch muscle fibers (type 2) gradually give way to slow-twitch fibers (type 1). As a result, muscle strength also decreases, leading to a loss of functional mobility, especially in sedentary people. Cartilage and bone mineral density also tend to thin quite early, due to the decline in cartilage cells and hormones, especially in women over 50, following menopause. On the artery side, elastin, a protein that gives elasticity to tissues, like the skin, becomes scarce. As a result, the “ducts” stiffen, “hence the risk of high blood pressure, past a certain age, to circulate the blood”, adds Professor Salles, also president of the French Society of Geriatrics and Gerontology (SFGG ).
Among the most valiant organs, the prize goes to the digestive tract. “The stomach does not change, its acidity remains the same whether you are 20 or 90 years old. Only the muscles of the digestive tract slow down, including that of the colon,” continues the specialist. The respiratory system is also maintained quite well, enough in any case to perform everyday actions without discomfort. Same observation for the brain: “Even if brain performance is a little slower, aging does not affect the brain, and in particular its memory capacities”, notes the geriatrician. In addition, if aging results in a decrease in reserve capacities, both of cells and organs, it varies greatly from one person to another, at the same age. “The organism is not just a bag of organs and the organs are bags of cells. The interconnections are multiple, adds Bertrand Friguet. In the end, aging is one of the best examples of the interactions between the genome and the environment.” While it is inevitable, its trajectory remains, for the most part, unpredictable.
If the hope of living forever or, at the very least, of significantly postponing the hour of death, has always fueled the imagination of novelists, science has only recently taken hold of the subject seriously. “The first genes that have an impact on aging were discovered in the early 1990s and it was during the following decade that the first clues emerged suggesting that we could lengthen human life”, observes Hugo Aguilaniu, geneticist specializing in aging and director of the Brazilian Serrapilheira Institute. Over the past fifteen years, research work has multiplied in various directions, both in public structures and in private laboratories, to unravel the mysteries of aging and limit its stigma. Since 2013, there has thus been a scientific consensus on the existence of markers allowing the evolution of aging to be monitored.
Reprogram cells
“Among these markers, we find genome damage, telomere shortening, the level of proteostasis – the quality control of our proteins – or mitochondria dysfunction, lists Jean-Marc Lemaitre, research director of the Plasticity team genomics and aging at Inserm and co-director of the Institute of Regenerative Medicine and Biotherapies in Montpellier. But two major pathways seem to stand out in particular: senescence and cell deprogramming.” It is therefore in these directions that the biologist has focused his research since the creation of his laboratory, in 2006: “The initial idea was based on the observation that the cells are deprogrammed over time, functioning de facto a little less well , as a kind of drift. It was a question of showing that this deprogramming was reducible.”
The same year, thunderclap in Kyoto where Professor Shinya Yamanaka, who is also exploring this path, manages to bring an adult cell back to an undifferentiated state, that is to say to the state of a pluripotent stem cell equivalent to an embryonic stem cell, capable of specializing into any cell in the body. To achieve these reprogrammed stem cells called iPSC (induced Pluripotent Stem Cells), the Japanese researcher’s team is developing a cocktail of 4 genes. For his part, Jean-Marc Lemaitre intends to go even further, showing that this manipulation also works on senescent cells: “We worked on skin cells taken from elderly subjects, some being more than a hundred years old”, says -he. At first, the attempts met only with failures. But, by adding two genes to Professor Yamanaka’s cocktail, everything changes. “We succeeded in erasing the marks of aging and converting old cells into pluripotent cells. In other words, we demonstrated the concept of reversibility of cellular aging.”
Viewing old age as a disease
The work that follows makes it possible to discover that it is not necessary to completely reprogram a cell and go to a pluripotent state to take advantage of the rejuvenation mechanism. “It suffices, for example, to activate growth factors for 2 and a half weeks in mice before their adulthood to achieve convincing results, continues Jean-Marc Lemaitre. All functions are improved (less osteoporosis, osteoarthritis, skin aging, etc.) and life expectancy increases by 15%, and up to 30%, if this reprogramming is prolonged.” The challenge now is to apply these discoveries to humans, but for this it is necessary to gather proof of concept on small cohorts. Easier said than done, because it is not easy to set up clinical studies to treat old age, considered an inevitable development. “We would have to imagine a longevity medicine with strategies to keep cells functional and prevent them from aging. A medicine that would consider old age as a disease that can be treated,” says Jean-Marc Lemaitre. This is what he presents in his book recently published by humenSciences Guérir la vieillesse, prefaced by the philosopher Luc Ferry, where he takes stock of all the strategies being developed in laboratories around the world.
Eliminate senescent cells
Another way to slow down aging is to find molecules capable of suppressing senescent cells that accumulate in the body and induce deleterious effects. These molecules – senolytics – are beginning to be identified, particularly among drugs already prescribed in other settings. “They offer great therapeutic promise,” enthuses Hugo Aguilaniu. A few years ago, we were able to eliminate senescent cells from mice, which allowed them to live longer and in good health. More than twenty senolytics have already been identified, such as datasinib, an anti-cancer drug, and quercetin, a flavonoid with antioxidant properties. Other teams are interested in senotherapies: molecules that do not destroy senescent cells, but reduce their secretions of deleterious factors. “This is a field of study that is still very young, but extremely promising,” remarks Jean-Marc Lemaitre.
lengthen telomeres
The hope of warding off aging also rests on telomerase. With each cycle of cell division, the end of the chromosomes – the telomeres – get shorter. When telomeres reach a limit size, they trigger the entry into senescence of the cell. The enzyme telomerase would reverse this phenomenon by lengthening the telomeres. Rodent trials seem to show a gain in healthy life expectancy. However, believes Hugo Aguilaniu, do not expect miracles: “Telomerase is relevant in cells that have many divisions throughout life, such as liver cells. But extending the length of telomeres has little impact on cells that divide little, such as neuronal cells.
Calorie restriction
In parallel with this work, other researchers are interested in complex systems, no longer at the level of the cell but of the living being. Among the main lines of research, there is the route of caloric restriction. “Schematically, explains Hugo Aguilaniu, when cells detect a source of stress such as a decrease in nutritional intake, they set up defense systems including detoxification and alternative metabolism tools, in short, cellular protection allowing them to last longer. long time. But this has a cost: the energy developed to protect itself against stress will burden the reproductive capacities of the animal. It will therefore live longer but will have a less efficient reproductive function.” The challenge facing researchers thus consists in inducing false caloric restrictions to encourage cells to protect themselves without inducing reproductive problems. “All the science aimed at understanding caloric restriction consists in identifying the molecular pathways to uncouple these two aspects, summarizes Hugo Aguilaniu. This is a very complicated task, for which there is still much progress to be made. For the time being, we manage to uncouple the two functions in primitive animals such as the Drosophila fly or the nematode worm which have an almost normal reproduction and gains in longevity and quality of aging.
200,000 centenarians in 2050
Is there an age beyond which no human can ever live despite all the advances in science? Or, on the contrary, is it possible to constantly postpone the hour of death, or even to live forever? “In the scientific field, researchers who want to achieve immortality are extremely rare, observes Hugo Aguilaniu in any case. They pursue a quest that is more mystical than scientific. The more realistic goal pursued by the majority of scientists is to improve the conditions of aging. Without pursuing chimerical objectives of eternal life, Jean-Marc Lemaitre believes, for his part, that the accumulation of discoveries “will allow us, within a reasonable horizon, to all live centenarians. France has some 27,000 today, there is no doubt that there will be more than 200,000 in 2050”.
We are always living longer
In 20 years, in France, life expectancy at birth for men has increased by 4.7 years and for women by 2.9 years.
85.7 years for women
79.9 years for men
We live healthier
In 20 years, in France, life expectancy at age 60 for men has increased by 3.2 years and that of women by 2.3 years.
27.6 years for women
23.2 years for men
Source: Insee, 2018
