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Month: April 2022

Infertility: New Avenues to Understand the Harmful Effects of Chemotherapy

Posted on by Léa Surugue

Immunostaining of a mouse testicle section

Immunostaining of a mouse testicle section, with (in red) the undifferentiated germ cells and (in green) the GFP protein reflecting TGR5 receptor expression in this study model. ©David Volle/Inserm

Infertility is a public health problem affecting millions of couples in France. Among the possible causes, chemotherapy has been singled out as having particularly harmful effects on the fertility of both women and men. In order to better prevent and restore fertility in cancer survivors, understanding the mechanisms behind these negative effects is a priority. In a new study, researchers from Inserm, CNRS and Université Clermont Auvergne investigated a receptor found on male germ cells that produce gametes, their aim being to find out more about its role in chemotherapy-related infertility. Their findings, published in Advanced Science, pave the way for a better understanding of male infertility and the development of treatments to reduce the risk of sterility from chemotherapy.

Around 3.3 million people in France are directly affected by infertility. Concerning both men and women, it has continued to increase in recent years, making it a major public health problem [1].

While there are many causes of infertility, it is currently well established that cancer treatments, including chemotherapy, can have particularly harmful effects on male and female fertility. Although cancer therapies have improved in recent years, tackling this issue is becoming a matter of urgency, as an increasing number of cancer survivors will be affected by infertility problems.

For almost 15 years, Inserm researcher David Volle and his team at the Genetics, Reproduction and Development Laboratory (Inserm/CNRS/Université Clermont Auvergne) have sought to improve their understanding of the biological mechanisms underlying infertility. Part of their research focuses on the impact of chemotherapy on male fertility, with the longer-term objective of identifying avenues to counter the adverse effects of this treatment.

In their new study, the researchers looked at TGR5 receptors, which are present on cell membranes, in order to understand their role in the harmful effects of chemotherapy.

TGR5 receptors are widely studied in the context of metabolic diseases, such as diabetes and obesity. They are activated by bile acids – molecules produced in the liver that regulate certain physiological functions, including blood glucose and energy expenditure.

 However, previous research by the team had shown that these receptors are also present in germ cells, the cells that produce gametes. In mouse models mimicking liver disease, with elevated bile acid levels, the scientists had found that the TGR5 receptors on germ cells were activated – which was associated with increased sterility in animals.

Germ cell death

To further understand the impact of TGR5 on fertility in the context of chemotherapy, the scientists in their latest study exposed mice to a chemotherapy agent called busulfan. They then showed that the chemotherapy induces the death of some of the germ cells in healthy mice, thereby affecting their fertility. “The fact that it is the germ cells, at that point undifferentiated, which are affected is particularly problematic because we are talking about the reserve of cells that produce gametes. This can reduce their renewal and contribute to post-chemotherapy infertility,” says Volle.

However, in mice that have been genetically modified to have an absence of TGR5 receptors, the effects of chemotherapy on germ cells are attenuated. This results in an accelerated return of fertility in these busulfan-treated mice compared with the control mice.

“Our study has therefore improved our understanding of the molecular mechanisms involved in the harmful effects of chemotherapies on germ cells and fertility. These findings show that TGR5 receptors play an important role in the harmful effects of chemotherapy on infertility,” adds Volle.

In the longer term, the objective is to develop methods to modulate TGR5 receptor activation in a targeted manner within germ cells, in order to protect them and restore fertility after chemotherapy.

The idea is also to assess whether these data can be extrapolated to other disease contexts in which TGR5 receptor activity could be modulated, such as obesity and diabetes, conditions known to impair fertility.

In addition, in parallel to this research, the team observed that even when fertility was maintained in mice exposed to chemotherapy, the quality of the gametes was affected. The scientists will therefore now endeavor to understand both the quantitative and qualitative impacts on germ cells in order to limit not just fertility disorders but also the longer-term consequences on the offspring of animals.

 

[1] A report requested by the French Minister of Health and the Secretary of State for Childhood and Family in February 2022 outlines a national strategy to combat infertility: https://solidarites- sante.gouv.fr/IMG/pdf/rapport_sur_les_causes_d_infertilite.pdf

Decoding a direct dialog between the gut microbiota and the brain

Posted on by Lea Roy

Diagram showing the direct dialog between the gut microbiota and the brain

© Institut Pasteur / Pascal Marseaud

 

Gut microbiota by-products circulate in the bloodstream, regulating host physiological processes including immunity, metabolism and brain functions. Scientists from the Institut Pasteur (a partner research organization of Université Paris Cité), Inserm and the CNRS have discovered that hypothalamic neurons in an animal model directly detect variations in bacterial activity and adapt appetite and body temperature accordingly. These findings demonstrate that a direct dialog occurs between the gut microbiota and the brain, a discovery that could lead to new therapeutic approaches for tackling metabolic disorders such as diabetes and obesity. The findings are due to be published in Science on 2022 04 15.

The gut is the body’s largest reservoir of bacteria. A growing body of evidence reveals the degree of interdependence between hosts and their gut microbiota, and emphasizes the importance of the gut-brain axis.

At the Institut Pasteur, neurobiologists from the Perception and Memory Unit (Institut Pasteur/CNRS)[1], immunobiologists from the Microenvironment and Immunity Unit (Institut Pasteur/Inserm), and microbiologists from the Biology and Genetics of the Bacterial Cell Wall Unit (Institut Pasteur/CNRS/Inserm)[2] have shared their expertise to investigate how bacteria in the gut directly control the activity of particular neurons in the brain.

The scientists focused on the NOD2 (nucleotide oligomerization domain) receptor which is found inside of mostly immune cells. This receptor detects the presence of muropeptides, which are the building blocks of the bacterial cell wall. Moreover, it has previously been established that variants of the gene coding for the NOD2 receptor are associated with digestive disorders, including Crohn’s disease, as well as neurological diseases and mood disorders. However, these data were insufficient to demonstrate a direct relationship between neuronal activity in the brain and bacterial activity in the gut. This was revealed by the consortium of scientists in the new study.

Using brain imaging techniques, the scientists initially observed that the NOD2 receptor in mice is expressed by neurons in different regions of the brain, and in particular, in a region known as the hypothalamus. They subsequently discovered that these neurons’ electrical activity is suppressed when they come into contact with bacterial muropeptides from the gut. “Muropeptides in the gut, blood and brain are considered to be markers of bacterial proliferation,” explains Ivo G. Boneca, Head of the Biology and Genetics of the Bacterial Cell Wall Unit at the Institut Pasteur (CNRS/Inserm). Conversely, if the NOD2 receptor is absent, these neurons are no longer suppressed by muropeptides. Consequently, the brain loses control of food intake and body temperature. The mice gain weight and are more susceptible to developing type 2 diabetes, particularly in older females.

In this study, the scientists have demonstrated the astonishing fact that neurons perceive bacterial muropeptides directly, while this task was thought to be primarily assigned to immune cells. “It is extraordinary to discover that bacterial fragments act directly on a brain center as strategic as the hypothalamus, which is known to manage vital functions such as body temperature, reproduction, hunger and thirst,” comments Pierre-Marie Lledo, CNRS scientist and Head of the Institut Pasteur’s Perception and Memory Unit.

The neurons thus appear to detect bacterial activity (proliferation and death) as a direct gauge of the impact of food intake on the intestinal ecosystem. “Excessive intake of a specific food may stimulate the disproportionate growth of certain bacteria or pathogens, thus jeopardizing intestinal balance,” says Gérard Eberl, Head of the Microenvironment and Immunity Unit at the Institut Pasteur (Inserm).

The impact of muropeptides on hypothalamic neurons and metabolism raises questions on their potential role in other brain functions, and may help us understand the link between certain brain diseases and genetic variants of NOD2. This discovery paves the way for new interdisciplinary projects at the frontier between neurosciences, immunology and microbiology, and ultimately, for new therapeutic approaches to brain diseases and metabolic disorders such as diabetes and obesity.

 

[1] This research unit is also known as the “Genes, Synapses and Cognition Laboratory” (Institut Pasteur/CNRS).
Paris Brain Institute (CNRS/Inserm/Sorbonne Université/AP-HP) also contributed to these findings.

[2] The CNRS unit’s name is the “Integrative and Molecular Microbiology Unit” and the Inserm unit’s name is the “Host-Microbe Interactions and Pathophysiology Unit” (Institut Pasteur/CNRS/Inserm).

Colon cancer: how mutation of the APC gene disrupts lymphocyte migration

Posted on by Léa Surugue

Migrating human T lymphocytes

Migrating human T lymphocytes revealing a broad protrusion at the leading edge and long adhesive protrusions at the rear. Image obtained by confocal fluorescence microscopy: filamentous actin, pink; VLA4 adhesion protein, blue. © Institut Pasteur/Lymphocyte Cell Biology. Image by Marta Mastrogiovanni

In patients with familial adenomatous polyposis, a genetic disease predisposing to colon cancer, mutations of the APC gene induce the formation of intestinal polyps, but also reduce immune system activity. In a new study, researchers from the Institut Pasteur, INSERM(1) and Université Paris Cité describe the mechanisms that modify the structure of T lymphocytes and hinder their migration towards the tumors to be destroyed. This discovery, published in the journal Science Advances on April 13, 2022, provides new perspectives on the migration of immune cells, a key process in antitumor immune defense.

As its name suggests, familial adenomatous polyposis is transmitted from generation to generation. The cause: mutations of the tumor suppressor gene APC (adenomatous polyposis coli). People who inherit these mutations develop hundreds, possibly thousands, of polyps in their colon from adolescence, then colorectal cancer(2) in adulthood if the polyps are not surgically removed. “As it’s a hereditary disease, all of the body’s cells carry the mutation and can be affected in different ways”, explains Andrés Alcover, Head of the Lymphocyte Cell Biology Unit at the Institut Pasteur and joint senior author of the study. “Today we know that these mutations disrupt the functioning of colon cells but also cells of the immune system”.

In previous studies, the team of researchers from the Institut Pasteur, CNRS and Inserm – funded by the French Cancer League since 2018(3) – demonstrated the dual impact of APC mutations.

Not only do these mutations prevent intestinal epithelial cells from differentiating correctly and cause them to form tissue growths (polyps), they also adversely affect the functioning of immune cells, thereby preventing them from effectively combating polyps and tumors. Two mechanisms that together promote the growth of tumors.

In order to better understand what prevents immune cells from fulfilling their role, the researchers this time decided to take a closer look at the T lymphocytes whose mission is to detect and destroy tumors by infiltrating them. To this end, biologists and clinical research physicians of the Institut Pasteur’s ICAReB platform, Dr. Hélène Laude and Dr. Marie-Noëlle Ungeheuer, approached the patient association POLYPOSES FAMILIALES France. A new clinical research project involving the association recruited patient volunteers for the collection of blood samples. “Thanks to the association, we met patients and also clinicians specialized in polyposis. We learned a lot about this complex pathological condition, the experience of patients and families, and the different levels of disease severity. We recognize the valuable role of the patients, who were highly motivated to take part in the study, and the input of specialists”, pointed out Andrés Alcover.

The naturally mutated T lymphocytes present in the blood of these patients were cultured then subjected to several in vitro experiments. Using several microdevices – filters, channels, protein substrates and layers of vascular endothelial cells – the researchers could compare the behavior of diseased lymphocytes with that of lymphocytes from healthy volunteers.

They studied how lymphocytes moved along biological surfaces similar to blood vessel walls, but also how easily they could separate cells and cross tightly packed cell layers.

“In order to move along blood vessel walls, cross them and reach the tumor to be infiltrated, healthy lymphocytes change their morphology. Something akin to a large adhesive foot, supported by the lymphocyte’s cytoskeleton, grows longer in the direction of migration. This polarization is essential for movement in the right direction,” explains Marta Mastrogiovanni, researcher in the Institut Pasteur’s Lymphocyte Cell Biology Unit and lead author of the study. In mutated lymphocytes, the microtubules making up the cytoskeleton are disorganized and there are fewer adhesion proteins. The cells lose their polarity and their ‘muscles'”.

Although the mutated T lymphocytes are not necessarily moving more slowly than healthy lymphocytes, they adhere less well to the walls and have more difficulty moving in a given direction and passing through the walls. In short, this research showed their migration to be less effective. “This discovery is important because the motility of immune cells is a key process in antitumor immune defense. “We know that the immune system is very important in combating pathogens but we sometimes forget that it also contributes to combating cancer cells”, concludes Vincenzo Di Bartolo, researcher in the Institut Pasteur’s Lymphocyte Cell Biology Unit and joint senior author of the study.

 

(1) Collaborative project: Institut Pasteur, Department of Immunology and  and Center for Translational Science (CRT, ICAReB), and Institut Pasteur, Institut Cochin, Institut Curie, and Institut Pierre-Gilles de Gennes.

(2) Familial adenomatous polyposis accounts for 1% of all colorectal cancers. 

(3) Funding via the French Cancer League (La Ligue Contre Le Cancer), 2018-2022 “Équipe Labellisée” program, the Institut Pasteur and Inserm. Marta Mastrogiovanni was funded by the Pasteur-Paris University International Doctoral Program and the European Union Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement 665807 and La Ligue Contre Le Cancer, doctoral grant 4th year of PhD.

Long COVID: When Symptoms Persist Months after the First Wave

Posted on by Léa Surugue

During the first wave of COVID-19, participants from the Constances cohort completed two questionnaires to determine the presence of symptoms during the previous 15 days. Credits: Adobe Stock

Several months after infection with SARS-CoV-2, some patients are still having symptoms – a phenomenon known as “long COVID” or “post-COVID-19 condition”. Still poorly understood, scientists are now attentively studying long COVID in order to improve knowledge and offer patients the best possible treatment. Researchers from Inserm, Université Paris-Saclay and Sorbonne Université at the Pierre-Louis Institute of Epidemiology and Public Health, in collaboration with ANRS | Emerging Infectious Diseases, have used data from around 26,000 Constances cohort volunteers to identify the persistent symptoms most commonly reported by SARS-CoV-2 patients compared with the rest of the population. These are mainly loss of taste or smell, difficulty breathing and fatigue and are particularly seen in patients who experienced typical COVID symptoms at the time of infection. Their findings have been published in The Lancet Regional Health – Europe.

Many people report symptoms that persist for several months after infection with SARS-CoV-2. Still poorly understood, “long COVID” is currently the subject of rigorous research in order to better define its prevalence in the general population and decipher its underlying pathophysiological mechanisms.

The persistent symptoms most commonly described in the scientific literature include dyspnea (difficulty breathing), asthenia (fatigue), joint and muscle pain, cognitive complaints, digestive complaints, and anosmia/dysgeusia (loss of smell and taste).

Apart from anosmia/dysgeusia, these clinical manifestations are not specific to COVID-19 and may, for example, be related to other infections occurring during the same period or to more restricted access to health care during the pandemic.

In order to better understand and treat long COVID, it is therefore essential for scientists to determine which persistent symptoms are more specifically associated with SARS-CoV-2 infection than with other conditions.

A general population study

A new study published in The Lancet Regional Health has examined this issue. One of the aspects that makes this research original is that it was carried out in a general population cohort.

General population cohorts differ from cohorts constructed from samples of COVID patients (who, by definition, are all “symptomatic”, often with severe clinical forms or hospitalized), which are not representative of everyone with the infection.

General population cohorts therefore make it possible to understand public health problems through the creation of comparison groups, for example focusing on the severity of symptoms at the time of infection.

Another novel aspect is that the participants all underwent a serological test to screen for a history of SARS-CoV-2 infection. This differentiates this study from the majority of its counterparts, which focus on those having performed a PCR test and who have presented symptoms.

For example, this study compared the persistence of symptoms seven to eight months after the first wave of the pandemic in four groups of participants[1] distributed according to the symptoms they had during that first wave and their serological status (whether or not they had been infected with SARS-CoV-2). 

Long-term symptoms according to serological status

A total of 25,910 participants from the Constances cohort (see box) completed two questionnaires during the first wave of COVID-19 to determine the presence of symptoms during the fifteen days prior. They then underwent a serological test, between May and November 2020, to identify those who had been exposed to the virus.

Finally, between December 2020 and February 2021, they completed a third questionnaire, which looked at symptoms having persisted or persisting for at least two months. This questionnaire included the list of symptoms focused on during the first waves of questionnaires, as well as new symptoms presented by people with long COVID (problems with concentration and attention, chest pains, etc.).

The researchers compared the individuals having presented symptoms suggestive of acute respiratory infection based on the results of their serological test. They observed that symptomatic individuals seropositive for SARS-CoV-2 had more persistent anosmia/dysgeusia, dyspnea and fatigue than those who were seronegative. The frequency of the other symptoms was equivalent.

Links between symptoms at the time of infection and persistent symptoms

The researchers then explored the link between infection, acute symptoms, and persistent symptoms. The results of their statistical analyses show that SARS-CoV-2 mainly affects the persistence of symptoms if it induces certain symptoms during the acute phase of the infection.

“Our findings confirm the importance of the clinical expression of the initial infectious episode in the risk of developing persistent symptoms. They can help guide public policies by providing more accurate data on the type of persistent COVID-19 symptoms and encourage the development of strategies for more effective treatment. Promoting preventive therapies and approaches, such as vaccination, that reduce symptoms in the acute phase of the disease could also have a beneficial effect on long COVID,” the study authors noted.

These findings reflect the complexity of the mechanisms that can explain the persistent symptoms, emphasizing that these symptoms may be related to the virus, to the initial clinical presentation of the infection, and to other non-specific causes.

They also suggest the importance of conducting studies on post-infectious conditions, regardless of the micro-organism in question.

Further research is under way to understand the mechanisms behind long COVID and to quantify the extent to which these persistent symptoms can be attributed to SARS-CoV-2 infection

The Constances cohort

Constances is a large-scale French epidemiological cohort, composed of a representative sample of 220,000 adults aged 18 to 69 years at the time of their inclusion. Participants are asked to have a health check every four years and to complete an annual questionnaire. Each year, their data are matched with the French national health insurance databases. This large-scale cohort is supported by the National Health Insurance Fund and financed by the Investments for the Future Program.

The data collected, which concern health, socio-professional characteristics, use of health care services, and biological, physiological, physical and cognitive parameters, enable us to learn more about the determinants of many diseases.

Constances is one of three cohorts on which is based the SAPRIS-SERO project led by Inserm and ANRS | Emerging Infectious Diseases – a project which aims to quantify the incidence of SARS-CoV-2 in the French population on the basis of serological tests.

For more information: constances.fr

[1] The members of the first group of participants all had a positive COVID-19 serological test and had reported symptoms during the first wave. Those of the second group had a positive test but no symptoms. Those of the third group had a negative test and symptoms, while those of the fourth group were asymptomatic during the first wave and with a negative test.

New joint Declaration of Intent between the Quebec Health Research Fund and Inserm

Posted on by Lea Roy

© Scott Graham / Unsplash

 

Rémi Quirion, Quebec’s Chief Scientist, and Dr. Gilles Bloch, Chairman and Chief Executive Officer of the French National Institute of Health and Medical Research (Inserm), are pleased to announce the signing of a new joint Declaration of Intent between the Quebec Health Research Fund and Inserm.

Covering the next four years, this declaration renews an institutional partnership spanning over half a century.

It affirms the partners’ shared determination to pursue joint collaborative activities – including support for research projects, the development of consortia and networks, and support for the mobility of students and researchers. The emphasis will be on three scientific areas of mutual interest, representing major challenges for society:

  • Mental health
  • Public health
  • Aging

“The agreement strengthens a position that we have supported for a long time: the importance of international collaborations for the advancement of knowledge and the training of researchers. In that sense, Inserm has been a long-standing partner of the Quebec Research Fund in the development of health research. As we intensify the pooling of our scientific expertise, we will increase the impact of our research for the wellbeing of our populations. “

Rémi Quirion, Quebec’s Chief Scientist

 

“The renewal of our historic partnership is a testament to the strength and vitality of the relationship between our researchers and the Quebec community. This agreement will further strengthen our links in major fields, in line with Inserm’s national priorities, with a strong impact expected on both the scientific and societal levels.”

Dr. Gilles Bloch, Chairman and Chief Executive Officer, Inserm

HIV: The Antibodies of “Post-treatment Controllers”

Posted on by Léa Surugue

VIH

© Adobe Stock

A very small percentage of people with HIV-1, known as “post-treatment controllers” (PTCs), are able to control their infection after interrupting all antiretroviral therapy. Understanding the fundamental mechanisms that govern their immune response is essential in order to develop HIV-1 vaccines, novel therapeutic strategies to achieve remission, or both. A recent study investigated the humoral immune response – also known as antibody-mediated immunity – in some PTCs in whom transient episodes of viral activity were observed. The researchers have shown their humoral immune response to be both effective and robust, which could help to control the infection in the absence of treatment. The findings of this study, carried out in collaboration with teams from Institut Pasteur, Inserm and Paris Public Hospitals Group (AP-HP) and supported by ANRS | Emerging Infectious Diseases and the National Institutes of Health (NIH), were published in Nature Communications on April 11, 2022.

A very small percentage of people with HIV-1 and who received early treatment maintained over several years have the capacity to control the virus over the long-term when their treatment is interrupted. However, the mechanisms of this control have not been fully elucidated.  

The team of researchers, led by Dr. Hugo Mouquet, director of the Laboratory of Humoral Immunology at Institut Pasteur (partner research organization of Université Paris Cité), conducted an exhaustive study in PTCs in order to characterize their humoral response (i.e. their production of B cells and specific antibodies), compared with non-controllers.

The scientists have shown that the humoral immune response profiles vary according to the activity of the virus observed in the subjects.

In PTCs who experience short episodes in which the virus resumes low-level activity after interruption of treatment, transient exposure to the viral antigens induces:

  • a strong anti-HIV-1 humoral response, involving more frequent intervention of HIV-1 envelope-specific memory B cells;
  • the production of antibodies with a cross-neutralizing action and which possess “effector” antiviral activities in which the innate immune cells recognize the infected cells bound to the antibodies, thereby inducing their elimination;
  • the increase in the blood of atypical memory B cells and subpopulations of activated helper T cells.

This specific, multifunctional, and robust humoral response could help to control their infection in the absence of treatment.

However, other PTCs in whom the virus continuously remains undetectable after treatment interruption do not develop a strong humoral response. The control mechanisms in these patients continue to be investigated in the VISCONTI study.

The discovery of these two types of humoral immune response, which depend on the profile of the PTCs, sheds new light on the phenomenon of HIV control. For Dr. Mouquet, researcher at Institut Pasteur and principal investigator of the study, “these findings show that early antiretroviral treatment can facilitate the optimal development of humoral immune responses, in some cases countering viral rebound after treatment interruption.” The example of the immune response of the PTCs having short episodes of “awakening” of the virus could even inspire novel therapeutic or vaccine strategies.

ANRS VISCONTI: to improve understanding of the HIV control mechanisms in “post-treatment controllers”

The “post-treatment controllers” whose samples were used for this research are part of the VISCONTI (Viro-Immunological Sustained COntrol after Treatment Interruption) study, coordinated by Dr. Asier Sáez-Cirión (Institut Pasteur) and Dr. Laurent Hocqueloux (Orleans Regional Hospital) and supported by ANRS for several years. This is the largest cohort of long-term “post-treatment controllers”.

It includes 30 patients who had received early treatment that was maintained for several years. Upon interruption of their antiretroviral therapy, they are able to control their viremia for a period exceeding 20 years in some cases. VISCONTI therefore provides the proof of concept of a possible and sustained state of remission for HIV-1-infected patients. It has paved the way for the development of novel therapies that target remission from the infection – if not its eradication. The objective is to enable people living with HIV-1 to stop their antiretroviral treatment on a lasting basis, while maintaining viremia at the lowest level and avoiding the risk of transmission of the virus.

Older Adults: Understanding and Preventing Barriers to an Active Lifestyle

Posted on by Graziella Cara

© Fotolia

To prevent older adults from settling into an unhealthy sedentary lifestyle, public health policies have been implemented to promote physical activity, which is essential for maintaining good health. Researchers from Inserm and Université Paris Cité within the Center for Research in Epidemiology and Statistics have studied the impact of individual sociodemographic, behavioral and health factors on the practice of daily physical activity in later life, using data from 3,896 participants of the Whitehall II cohort. This research, published in JAMA Network Open, highlights the complexity of individual barriers to an active lifestyle among older adults and suggests that this complexity should be better taken into account when redefining public health policies.

By maintaining many essential functions that prevent chronic disease and mortality, physical activity is one of the keys to healthy aging. Although it is currently recommended to do 21 minutes of moderate to intense physical activity per day and reduce the amount of time spent sitting (being sedentary), few people actually follow this advice – especially older adults. In addition, public health messages aimed at older adults take little account of individual factors, whether environmental or personal, that may limit the adoption of an active lifestyle.

A team led by Séverine Sabia, Inserm researcher at the Center for Research in Epidemiology and Statistics (Inserm/Université Paris Cité), studied the factors that influence physical activity and sedentary behavior in later life.

The scientists looked at data from Whitehall II1, a British cohort of which 3,896 of its participants, between 60 and 83 years of age, had worn a measuring device for a nine-day period in 2012-2013. This device, called an accelerometer, continuously recorded data on the intensity and duration of their daily physical activity. In addition, data relating to their sociodemographic characteristics (age, sex, ethnicity, occupation, marital status), behaviors (consumption of tobacco, alcohol, fruits and vegetables), health (body mass index, quality of life, chronic diseases) and physical activity were collected between 1991-1993 and 2012-2013, representing a 20-year period prior to the accelerometer measurements.

In terms of physical activity, the researchers considered three levels of intensity: sedentary (low-energy activity while sitting or lying down), light (e.g. slow walking), and moderate to vigorous (e.g. swimming, cycling).

Their first finding was that men spend more time being sedentary or engaging in moderate to vigorous activity than women, who spend more time than men doing light physical activity.

Depending on the factors studied, a longer duration of time spent being sedentary by older adults had differing effects on the duration of the other levels of intensity. For example, in comparison with those living with partners, people living alone spend on average an additional 11 minutes being sedentary, mostly at the expense of time devoted to light physical activity. In contrast, although a five-year age difference results in a similar increase in time spent being sedentary, this comes at the expense of time devoted to moderate to vigorous activity – which is more than half the recommended daily time (21 minutes).

The behavioral factors all appear to impact the time devoted to the different levels of intensity. The largest difference is seen with male smokers, who spend 37.4 more minutes per day being sedentary, at the expense of 23.3 minutes of light activity and 14.1 minutes of moderate to vigorous activity (i.e. two-thirds of the time recommended for the latter). However, in women who smoke, the increase in sedentary time comes at the expense of moderate to vigorous activity.

Among the factors relating to health status, poor general health, the presence of chronic diseases, and obesity are associated with a significant increase in the time spent being sedentary.

The largest discrepancies are seen with obesity: at the same age, people with obesity spend 50.7 minutes longer per day being sedentary than those with a normal body mass index, at the expense of 28.6 minutes of light activity and 22.1 minutes of moderate to vigorous activity – i.e. all of the time recommended for the latter.

In general, for women, nearly all of the factors impact the time spent on the different intensities of physical activity – an impact that is similar but globally attenuated in comparison with men.

“We wanted to know if barriers to physical activity among older adults were already present earlier in life and we found that they were. Living alone, being overweight or obese, the presence of chronic diseases, poor physical functioning or poor lifestyle at the average ages of 50 and 60 were associated with low activity levels in later life,” explains Mathilde Chen, lead author of the study. We were also able to see a clustering of behavioral risk factors: people who are more sedentary tend to smoke and eat fewer fruits and vegetables. This research reflects the complexity of the determinants of an active lifestyle among older adults. “

Séverine Sabia, study investigator, concludes: “In the fight against the health impacts of high levels of inactivity among older adults, this research provides arguments in favor of targeted prevention strategies, integrating all components of physical activity and healthy lifestyle behaviors, and addressing as early as possible those who are most likely to be sedentary in later life. “

1 The Whitehall II cohort was set up between 1985 and 1988; a total of 10,308 British participants (67% male) aged 35-55 years were recruited and have been followed up ever since.

Alzheimer’s Disease: The Identification of 75 Genetic Risk Factors Brings New Insights

Posted on by Graziella Cara

Alzheimer

In Alzheimer’s disease, two brain pathological phenomena have already been well documented: the accumulation of beta-amyloid peptides and the modification of Tau, a protein, which is found as aggregates in neurons.© NIH/domaine public

Identifying genetic risk factors for Alzheimer’s disease is essential if we are to improve our understanding and treatment of it. Progress in human genome analysis along with genome-wide association studies[1] are now leading to major advances in the field. Researchers in Europe, the US and Australia have identified 75 regions of the genome that are associated with Alzheimer’s disease. Forty-two of these regions are novel, meaning that they have never before been implicated in the disease. The findings, published in Nature Genetics, bring new knowledge of the biological mechanisms at play and open up new avenues for treatment and diagnosis.

Alzheimer’s disease is the most common form of dementia, affecting around 1,200,000 people in France. This complex, multifactorial disease, which usually develops after the age of 65, has a strong genetic component. The majority of cases are thought to be caused by the interaction of different genetic predisposition factors with environmental factors.

Although our understanding of the disease continues to improve, there is no cure at this time. The medications available are mainly aimed at slowing cognitive decline and reducing certain behavioral disorders.

In order to better understand the origins of the disease, one of the major challenges of research is to better characterize its genetic risk factors by identifying the pathophysiological processes at play[2], and thereby propose novel therapeutic targets.

As part of an international collaboration, researchers from Inserm, Institut Pasteur de Lille, Lille University Hospital and Université de Lille conducted a genome-wide association study (GWAS) on the largest Alzheimer’s patient group set up until now[3], under the coordination of Inserm Research Director Jean-Charles Lambert.

Encouraged by advances in genome analysis, these studies consist of analyzing the entire genome of tens of thousands or hundreds of thousands of individuals, whether healthy or sick, with the aim of identifying genetic risk factors associated with specific aspects of the disease.

Using this method, the scientists were able to identify 75 regions (loci) of the genome associated with Alzheimer’s, 42 of which had never previously been implicated in the disease. “Following this major discovery, we characterized these regions in order to give them meaning in relation to our clinical and biological knowledge, and thereby gain a better understanding of the cellular mechanisms and pathological processes at play,” explains Lambert.

Highlighting pathological phenomena

In Alzheimer’s disease, two pathological brain phenomena are already well documented: namely, the accumulation of amyloid-beta peptides and the modification of the protein Tau, aggregates of which are found in the neurons.

Here, the scientists confirmed the importance of these pathological processes. Their analyses of the various genome regions confirm that some are implicated in amyloid peptide production and Tau protein function.

Furthermore, these analyses also reveal that a dysfunction of innate immunity and of the action of the microglia (immune cells present in the central nervous system that play a “trash collector” role by eliminating toxic substances) is at play in Alzheimer’s disease.

Finally, this study shows for the first time that the tumor necrosis factor alpha (TNF-alpha)-dependent signaling pathway is involved in disease[4].

These findings confirm and add to our knowledge of the pathological processes involved in the disease and open up new avenues for therapeutic research. For example, they confirm the utility of the following: the conduct of clinical trials of therapies targeting the amyloid precursor protein, the continuation of microglial cell research that was initiated a few years ago, and the targeting of the TNF-alpha signaling pathway.

Risk score

Based on their findings, the researchers also devised a genetic risk score in order to better evaluate which patients with cognitive impairment will, within three years of its clinical manifestation, go on to develop Alzheimer’s disease. “While this tool is not at all intended for use in clinical practice at present, it could be very useful when setting up therapeutic trials in order to categorize participants according to their risk and improve the evaluation of the medications being tested,” explains Lambert.

In order to validate and expand their findings, the team would now like to continue its research in an even broader group. Beyond this exhaustive characterization of the genetic factors of Alzheimer’s disease, the team is also developing numerous cellular and molecular biology approaches to determine their roles in its development.

Furthermore, with the genetic research having been conducted primarily on Caucasian populations, one of the considerations for the future will be to carry out the same type of studies in other groups in order to determine whether the risk factors are the same from one population to the next, which would reinforce their importance in the pathophysiological process.

 

[1] These studies consist of analyzing the entire genome of thousands or tens of thousands of people, whether healthy or sick, to identify genetic risk factors associated with specific aspects of the disease.

[2] All functional problems caused by a particular disease or condition.

[3] Here, the researchers were interested in the genetic data of 111,326 people who were diagnosed with Alzheimer’s disease or had close relatives with the condition, and 677,663 healthy “controls”. These data are derived from several large European cohorts grouped within the European Alzheimer & Dementia BioBank (EADB) consortium.

 [4] Tumor necrosis factor alpha is a cytokine: an immune system protein implicated in the inflammation cascade, particularly in tissue lesion mechanisms.

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