The quest for the fountain of youth is no longer a myth. Results in research laboratories – although still experimental – now suggest that there are real prospects of slowing the aging process and even rejuvenating certain types of tissue. The potential impact of these results is considerable, given current demographic trends: the proportion of over-60s in the world’s population is set to double between now and 2050. In France, 18% of the population was 65 or over in 2013, and this percentage will rise to 26% in 2040; the number of over-85s could increase fourfold by 2070.
The "geroscience" era
The demographic trend means that the health of older people is a major and growing concern. We have entered the era of "geroscience", which offers hopes of challenging the inexorability of the aging process and increasing "Healthy Life Years".
The effects of aging strike unevenly, and there is no "typical" older person. "Some 80 year-olds have physical and mental capacities similar to many 20 year-olds. Other people experience declines in physical and mental capacities at much younger ages," states the World Health Organization.
A group devoted to the study of aging at the Institut Pasteur
In January 2016, a multidisciplinary working group bringing together scientists studying the mechanisms of aging was formed on the initiative of the Center for Translational Science. "Regular dialog to exchange ideas about approaches and techniques with other scientists working on different aspects of aging is extremely beneficial," confirmed Elisa Gomez-Perdiguero, who heads up a five-year group (research team led by young scientists with high potential, created for a duration of five years) "This gives us a comprehensive overview of aging." The overall aim is to achieve a better understanding of the mechanisms involved, which is a crucial stage for reaching the ultimate goal of allowing people to enjoy better health during the aging process.
Mysterious, tissue-resident cells
In 2012, Elisa Gomez-Perdiguero, who heads up the five-year group Macrophages and Endothelial Cells at the Institut Pasteur, made an important discovery about certain cells, known as macrophages, that are resident in our tissue. Macrophages in blood are well known: they are immune system cells, the job of which is to "eat" debris or pathogens. These "garbage collectors" within the organism are regularly renewed and produced in bone marrow. Elisa’s team has shown that the macrophages present in tissue do not originate in bone marrow. "They are inherited from the embryo," she explained. "They are resident in tissue from the very beginning of our body's development, and would appear to be important to tissue maintenance. If they are destroyed tissue cannot regenerate. Our theory is that we lose these "resident macrophages" during the aging process, which partly explains why tissue repair is less effective and why there is an increase in fibrosis. This is where we got our idea to assist tissue repair by stimulating macrophages."
An increased risk of disease
The fact remains, however, that the risk of certain deficiencies or diseases increases statistically with age. Common health problems in the elderly include hearing loss, cataracts, back pain, osteoarthritis, chronic obstructive pulmonary disease, diabetes, depression and dementia, and older people are also more likely to suffer from cardiac disease, strokes or cancer.
Sadly, the list is a long one. This has been the impetus for some of the research to focus on diseases linked to aging, from late-onset deafness (see inset below) to neurodegenerative diseases. Increasingly, however, studies are looking more fundamentally at "how" we age, with the primary goal of slowing the aging process.
Preventing age-related deafness
In France, age-related neurosensory hearing loss, or presbycusis, affects 50% of people over 75 and one-third of people over 55. It starts with a loss of perception of high frequencies and difficulty hearing and locating sound sources in noisy environments. Over time, other frequencies become inaudible, and conversations are difficult to follow even without peripheral noise. Social interaction becomes problematical for affected people; they feel isolated, which may lead to distress or even depression and contributes to cognitive impairment. Hearing aids or cochlear implants are helpful, but their effectiveness is limited in noisy environments.
At the Institut Pasteur, Prof. Christine Petit, who heads up the Genetics and Physiology of Hearing Unit – a pioneer laboratory in the field of identifying and uncovering the mechanisms of the genes responsible for hearing loss – is focusing her efforts on presbycusis: "Our aim is to understand the defective processes in late-onset deafness, in order to slow its progress or prevent it from occurring at all. We know that the impairment of certain genes leads to a predisposition to presbycusis and to hearing loss linked to noise exposure. Most of these genes have yet to be identified. This is an essential step, so that we can characterize the pathogenic causes responsible. We are identifying an increasing number of hearing problems linked to alterations in antioxidant metabolism, which we could probably prevent using existing drugs."
Our aim is to understand the defective processes in late-onset deafness, in order to slow its progress or prevent it from occurring at all.
Pr Christine PetitResponsable de l’unité de Génétique et Physiologie de l'Audition
Christine Petit has created a network comprising a number of ENT departments in order to bring together and carry out analyses on families affected by presbycusis and research the genes responsible. At the heart of this strategy is the hope of finding new therapies for preventing presbycusis – which could affect half a billion people globally by 2050.
Cell and molecular damage
It is not a simple matter, because there is no single process responsible for aging. From a biological point of view, it is the combined effect of an extensive accumulation of molecular and cell damage over time. In order to understand it, we need to get up close and personal with our cells.
At the core of each cell, the nucleus is the site of our DNA molecule, which contains our genetic information (the genome). A common denominator in aging is the instability of the genome, which is linked to an accumulation of DNA lesions (mutations and other damage) over the years caused by environmental factors (UV radiation, chemical molecules, etc.) or intrinsic factors (replication errors, free radicals, etc.). Our cells have a network of complex mechanisms on permanent standby to repair these lesions. One possible "anti-aging" strategy aims at strengthening this natural system of DNA maintenance and repair.
Other damage is caused by the shortening with age of sections of DNA known as telomeres, which are located at the end of each of our chromosomes (chromosomes are formed by DNA when cells divide), and serve to protect them. A strong link has been established in humans between short telomeres and risk of mortality, as well as the early onset of certain diseases. A large number of research programs aim to stimulate an enzyme called telomerase, which is involved in maintaining telomeres.
Cell powerhouses lose their strength
The powerhouses of our cells – little organelles known as mitochondria – also suffer from the effects of aging. If there is not enough energy, or if energy is produced only intermittently, muscle cells are unable to contract, and neurons are unable to generate nervous influxes. Mitochondrial malfunction is linked to acceleration of the aging process. Restoring mitochondrial efficiency is another option currently being studied.
Another phenomenon under scrutiny is cellular senescence: senescent cells are cells that have ceased to divide, and amongst others, secrete pro-inflammatory factors. Their numbers increase with age, and this would appear to play a part in aging: in experimental models, the suppression of senescent cells delays the appearance of age-related diseases and may increase average life expectancy by 30%, according to an American study published in February 2016. Paradoxically, however, the primary objective of cellular senescence is to prevent the propagation of damaged cells and stimulate the immune system to eliminate them. Senescent cells would therefore appear to have beneficial as well as harmful effects, and these must be understood more closely before we attempt to control them in humans (see inset below).
Senescent cells: from osteoporosis to cancer
At the Institut Pasteur, Oliver Bischof’s group in the Nuclear Organization and Oncogenesis Unit specializes in the study of cellular senescence (as does Han Li’s team – see inset "Hopes for muscle regeneration"), which is an as yet poorly understood phenomenon involving the cessation of cell division, and which the team is trying to decode at molecular level. "We have already uncovered several mechanisms but we would now like to know exactly what happens in sick people," stressed Oliver Bischof. "In particular we are working with bone biopsies of osteoporosis sufferers. We take samples of stem cells – which are involved in bone formation – to see if there is a process of senescence in these cells and if it is linked to the disease. If we find a malfunction, we can intervene to inhibit cell aging in the case of osteoporosis." This prospect is all the more important given that there is currently no treatment for this disease, which reduces bone density, affects 40% of women over 65 (and also some men) and causes 370,000 fractures each year in France.
In addition to studying the aging process, Oliver Bischof is exploring therapeutic avenues against cancer, aiming to control senescent cells to prevent tumorigenesis. He is organizing an international symposium to take place at the Institut Pasteur in May, entitled "The Ins and Outs of Cellular Senescence: Understanding the Biology to Foster Healthy Aging and Suppression of Disease". This title sums up everything that stands to be gained by a study of senescent cells.
Aging: what do we know today? What are the prospects for combating age-related diseases?
You are cordially invited to a public conference organized on May 19, 2017. Entry is free, but prior registration is required. The theme is: Aging: what do we know today? What are the prospects for combatting age-related diseases? From 5:30-7:30pm at the Institut Pasteur, 28 rue du Dr Roux 75015 Paris.
Organized by Oliver Bischof (Institut Pasteur, Paris) and modertated by Eric Gilson (Institut de Recherche sur le Cancer et le Vieillissement, Nice).
Entry is free but registration is required (before May 16, 2017) and places are subject to availability.
Stem cell depletion
The other effect of aging worthy of note is the depletion of stem cells, which are responsible for tissue regeneration. It is well known that older people heal much more slowly than children when they cut themselves. The main cause of this is a reduction in the number of stem cells in skin, and in their ability to multiply and differentiate into "specialized" skin cells. This reduction in stem cell quantity and efficiency – which is a consequence of several types of damage, as outlined above – has been shown in various types of tissue, such as bone or muscle. Current research on these cells is providing hope of new therapies for repairing tissue or organs, in the form of "regenerative" medicine (see inset below).
Hopes for muscle regeneration
"Muscle mass reduces from the age of 35. This process is exacerbated by increasing age and leads to sarcopenia – a deterioration in muscle strength and physical performance, which is often the cause of serious falls," explained Prof. , who heads up the Stem Cells and Development Unit and is a specialist in skeletal muscle. "Muscle regeneration is compromised with age due to a number of factors affecting stem cells: they reduce in number, their ability to differentiate decreases, as does their microenvironment, or "niche" in the muscle. Our strategies for slowing or even reversing muscle aging aim to find the means to restore the number and quality of muscle stem cells." The team is working in particular, in experimental models, on comparing gene expression and DNA modification in muscle stem cells in old and young organisms. Other experiments examine the sometimes beneficial and sometimes detrimental role of senescent cells in muscle repair. This is a phenomenon that is also being closely studied, but from a different angle, by Han Li, who heads up the five-year group Cellular Plasticity and Disease Modeling, in the hope, she told us, of "finding key components for muscle regeneration that could boost tissue repair". In the meantime, "the best way at the moment to prevent sarcopenia is to stay fit," stressed Shahragim Tajbakhsh.
These examples demonstrate that in-depth study of the cellular or molecular damage that accumulates over time brings a number of avenues of hope for preventing, countering or repairing this damage and so act against aging.
In parallel, more general studies have shown the benefit of certain "anti-aging" candidates, for example restricting calorie intake, or the administration of certain molecules such as aspirin, rapamycin (an immunosuppressant used in transplants), resveratrol (found in grapes) or substances that occur naturally in blood, such as GDF11 (see inset below), and experimental models have shown that these can slow down the aging process – and even reverse it in some cases. However, nothing has as yet been demonstrated in humans.
The serum of youth under the microscope
A clinical trial to slow down aging
At this stage, only one clinical trial is being conducted on the potential effects against aging of a drug. The drug, metformin, has for some years been used to treat type 2 diabetes. It would appear to slow down the aging process and in particular reduce the risk of cardiovascular disease, and is being assessed in 3,000 elderly people. The trial was launched in the USA in 2016, and is to last six years.
Pending elixirs of youth and the advent of regenerative medicine, we should perhaps remember that some recipes for longevity and good health are already known to us all: refrain from smoking, take regular physical exercise and eat a smaller, balanced diet, with less fat and sugar, and so on. Although future drugs will probably be able to slow the aging process and prevent age-related diseases, we can all do something in the immediate term towards achieving this goal ourselves.
Early aging: repairing diseased cells
A number of rare genetic diseases cause accelerated premature aging, and there has been no treatment available to date. One of these is Cockayne syndrome, which is associated with a life expectancy of less than seven years in its most severe form. Children with Cockayne syndrome show marked signs of premature aging, such as loss of weight, hair, hearing and sight, as well as facial deformation and neurodegeneration.
The team led by Miria Ricchetti*, in the Institut Pasteur’s Stem Cells and Development Unit, has shown that defects in the cells of patients with Cockayne syndrome are largely produced by overexpression of the HTRA3 molecule. This molecule is induced by cellular oxidative stress (in particular due to "free radicals"), and disrupts the activities of the cells’ powerhouses, or mitochondria. The scientists succeeded in restoring mitochondrial function in the cells of patients by using an HTRA3 inhibitor or an antioxidant that captures free radicals. "It’s the first time that we have been given a glimpse of possible treatments for patients suffering from Cockayne syndrome, and we have made an application to conduct preclinical and clinical trials," said Miria Ricchetti. "We would also like to find out whether these defective mechanisms occur in normal physiological aging. They may also take place more slowly in healthy cells. We have therefore started a study of the cells of people of different ages and we are soon to start working on the cells of centenarians."
*In collaboration with Alain Sarasin (CNRS, Institut Gustave Roussy) and Denis Biard (CEA).
A world report on ageing from the World Health Organization
Comprehensive public health action on population ageing is urgently needed. This will require fundamental shifts, not just in the things we do, but in how we think about ageing itself.