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Tamàs Fülöp

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Tamas Fulop, MD, PhD, is Professor of Medicine and Geriatrics, and Senior Researcher at the Research Center on Aging, University of Sherbrooke. He is the fellow of the Canadian Academy of Health Sciences. He was the deputy director of the Research Center on Aging and member of the Graduate Immunology Programme. He obtained his MD degree at Geneva University. He received his PhD in Biochemistry and Immunology from the Hungarian Academy of Sciences and was a post-doctoral fellow at University Paris XII in Biochemistry. Dr. Fulop’s research is focused on immune response changes and the mechanism of inflammation with aging and age-related diseases in humans. He has authored more than 350 publications. He is on the editorial boards of Pathology Biology, Immunity and Aging, European Geriatric Medicine. He is the editor-in-chief of GERONTOLOGY and the Interdisciplinary Topics in Gerontology.

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The University of Winnipeg

Eric S . Kim (UBC)

University of British Columbia

José Ferreira-Alves

Universidade do Minho

Kansas State University

Massachusetts General Hospital

Maro G Machizawa

Hiroshima University

Diego Sánchez-González

Universidad Nacional de Educación a Distancia

Washington Center for Consciousness Studies

Olga Louchakova-Schwartz

University of California, Davis

Bezmialem Vakif University

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Papers by Tamàs Fülöp

Tracking the progression of Alzheimer’s disease with peripheral blood monocytes

BackgroundAlzheimer’s disease (AD) is the most common form of dementia with the symptoms graduall... more BackgroundAlzheimer’s disease (AD) is the most common form of dementia with the symptoms gradually worsening over the years. However, the driving pathological processes occur well before the appearance of symptoms. AD patients display signs of systemic inflammation, suggesting that it could precede the well-established AD hallmarks. We recently showed that the innate immune response in the form of monocyte activation is detectable at the pre-clinical stage.ObjectivesOur goal here is to characterize changes of gene expression in peripheral blood monocytes from patients at different stages of AD progression and validate potential biomarkers for a better prognosis and diagnosis of AD clinical spectrum.ResultsWe performed a whole transcriptome analysis on monocytes purified from healthy subjects, Mild Cognitive Impairment (MCI) and AD patients, and established the list of genes differentially expressed in monocytes during the disease evolution. We observed that, in the top 500 genes dif...

Welcome to Advances in Geriatric Medicine and Research: An Advanced Platform for All Geriatric Clinicians and Researchers

Advances in Geriatric Medicine and Research, 2018

Exploring the Extracellular Matrix to Create Biomaterials

Composition and Function of the Extracellular Matrix in the Human Body, 2016

The extracellular matrix (ECM) represents the framework of tissues and organs and is involved in ... more The extracellular matrix (ECM) represents the framework of tissues and organs and is involved in cell differentiation and function. The study of ECM is challenging and required a combination of identification and imaging techniques to give a valuable scheme of its composition, organization, and finally function. The study of ECM enables to culture cells ex vivo, but cultures are restricted to two-dimensional surfaces, whereas in the meantime, material sciences were developing devices able to bring cell culture in a threedimensional (3D) environment. This chapter presents basic techniques to investigate extracellular matrices composition and organization. Basic knowledge on ECM composition and organization should inspire material scientists to propose more biologically relevant materials. In a second time, we present strategies available to create ex vivo models of ECM and a series of examples of 3D materials that were engineered to investigate cell adhesion, phenotype, and differentiation in a biologically relevant microenvironment. The production of a gold-standard material is possible for a specific biological question, and it might be developed from an intelligible dialogue between material scientists, that bring engineering strategies, and cell biologists who implement the material design to meet the biological process that has to be investigated ex vivo.

Identification and signal transduction mechanism of elastin peptide receptor in human leukocytes

FEBS Letters, 1989

The existence of a novel receptor on human polymorphonuclear leukocytes (PMNLs) and monocytes was... more The existence of a novel receptor on human polymorphonuclear leukocytes (PMNLs) and monocytes was demonstrated, named soluble elastin peptide receptor. Soluble elastin peptides, like K‐elastin, which are liberated from elastin fibres, can be found in the sera, and they possess several biological activities such as chemotaxis. Studying the effects of elastin peptides on leukocytes, it was found that: (i) the elastin peptide stimulates the oxidative burst, the intracellular free Ca2+ elevation through a specific receptor; and (ii) in the signal transduction mechanism of this elastin peptide receptor, the phosphatidylinositol breakdown is involved.

Age related impairment in phosphatidylinositol breakdown of polymorphonuclear granulocytes

FEBS Letters, 1989

It is well known that with aging the immune response decreases. Most of the effector functions oc... more It is well known that with aging the immune response decreases. Most of the effector functions occur through specific receptors. Thus, we investigated the effects of various stimulants, acting through receptors or directly through the GTP‐binding Gi protein, on phosphatidylinositol breakdown in PMNLs of young and elderly subjects and try to modulate it. A marked decrease in inositol phosphate (IP1, IP2, IP3) formation in PMNLs of elderly was found under FMLP stimulation when compared to that of young subjects. Neither GTPγS, nor AIF− 4 could induce an increase of IP3 in PMNLs of elderly comparable to that of young subjects. The results suggest that at least an alteration exists at the GTP‐binding Gi protein level, as well as in the mechanism of linkage of the receptor to the G protein.

The Immunomodulatory Effects of a 6-Month Extra Virgin Olive Oil Intervention on Monocyte Cytokine Secretion and Plasma Cytokine Levels in Dyslipidemic and Post-Infarct Patients: A Clinical Pilot Study

Nutrients

Atherosclerosis is an immuno-inflammatory process underlying cardiovascular diseases. One of the ... more Atherosclerosis is an immuno-inflammatory process underlying cardiovascular diseases. One of the main actors of this inflammation is monocytes, with the switch in their phenotypes and irregularities in their cytokine production. Objective: This study was aimed to investigate the nutraceutical potential of extra virgin olive oil (EVOO) on the inflammatory status of monocytes in participants showing different levels of cardiovascular risk. Methods: 43 participants 65–85 years old were recruited including 14 healthy, 12 dyslipidemic patients with hypercholesterolemia recently diagnosed, and 17 post-infarct patients. Participants from all groups were supplemented with EVOO (25 mL/day) for 6 months. IL-1β, IL-6, IL-10, TNF-α cytokine production, and monocyte phenotypes were investigated both at quiescent and at stimulated state by flow cytometry. Results: At the baseline (pre-intervention), dyslipidemic patients, compared to healthy and post-infarct participants, showed monocytes in an i...

The Susceptibility to Diet-Induced Atherosclerosis Is Exacerbated with Aging in C57B1/6 Mice

Biomedicines, 2021

The anti-atherogenic activity of HDL is mainly due to their capacity to mediate reverse cholester... more The anti-atherogenic activity of HDL is mainly due to their capacity to mediate reverse cholesterol transport (RCT). However, it is not clear to what extent this activity is affected by aging or pro-atherogenic conditions. Three and 24-month-old C57Bl/6 mice were fed an atherogenic diet (high fat, high cholesterol) for 12 weeks. The aged mice displayed a significant reduction in the capacity of HDL to mediate RCT (29.03%, p < 0.0006). Interestingly, the atherogenic diet significantly stimulated the RCT process in both young and aged mice (241% and 201%, respectively, p < 0.01). However, despite this, significant amounts of cholesterol accumulated in the aortas of mice fed an atherogenic diet as compared to regular chow. The accumulation of cholesterol was more marked in the aortas of aged mice (110% increase, p < 0.002). ABCA1 and ABCG1 protein expression on macrophages decreased significantly (52 to 37% reduction, p < 0.002), whereas their expression on hepatic cells in...

Calpain-Calpastatin System in Lymphoid Neoplasm of the Aged

Geriatric Oncology, 2018

Reply to GJ Wanten

The American Journal of Clinical Nutrition, 2006

Suppressive effect of a selective increase in plasma linoleic acid concentration and intravascula... more Suppressive effect of a selective increase in plasma linoleic acid concentration and intravascular lipolysis on peripheral T cell activation Dear Sir: With interest we read in the Journal the findings of a recent study by Larbi et al (1), in which the authors reported on the suppressive effects on T cell activation and function, together with changes in the membrane properties of these cells, that are brought about by the intravenous administration of a soybean oil-based lipid emulsion (Intralipid 20%; Baxter, Mississauga, Canada). The authors concluded that these results should have serious implications for nutritional therapy in patients at high risk of septic complications. We have several concerns with regard to the latter statement. First, the investigation by Larbi et al was performed in healthy subjects, and, therefore, their results cannot be extrapolated to patients with an inflammatory condition. Second, several reviews focused on immune modulation by parenteral lipids in general (2) and by soybean oil-based emulsions in particular (3) concluded that no clear picture exists, because of the very disparate outcomes of the studies reviewed. For instance, our group has consistently found that Intralipid, an emulsion that is rich in long-chain triacylglycerols, does not affect human neutrophil and mononuclear cell functions, including oxygen radical production, adhesion, chemotaxis, pathogen killing, and cytokine production (4-8). As in the study by Larbi et al, these observations were made in cells obtained from healthy volunteers and in studies with both in vitro and in vivo designs. It is important that, in our hands, Intralipid did not alter membrane fluidity, as measured by the same technique that Larbi et al used, or signal transduction of leukocytes (9, 10). In contrast, the administration of an emulsion containing medium-chain triacylglycerols in these investigations resulted in cell activation, altered cytokine responses, increased membrane fluidity, and attenuation of calcium signaling in neutrophils and mononuclear cells (4-10). In our opinion, these conflicting outcomes show that, at present, we do not fully comprehend the nature of the interaction of immune cells and parenteral lipids and the circumstances influencing that interaction. The author had no personal or financial conflict of interest with respect to the study of Larbi et al or the report on that study.

Extra Virgin Olive Oil Prevents the Age-Related Shifts of the Distribution of HDL Subclasses and Improves Their Functionality

Nutrients, 2021

High-density lipoproteins (HDL) maintain cholesterol homeostasis through the role they play in re... more High-density lipoproteins (HDL) maintain cholesterol homeostasis through the role they play in regulating reverse cholesterol transport (RCT), a process by which excess cholesterol is transported back to the liver for elimination. However, RCT can be altered in the presence of cardiovascular risk factors, such as aging, which contributes to the increase in the incidence of cardiovascular diseases (CVD). The present study was aimed at investigating the effect of extra virgin olive oil (EVOO) intake on the cholesterol efflux capacity (CEC) of HDL, and to elucidate on the mechanisms by which EVOO intake improves the anti-atherogenic activity of HDL. A total of 84 healthy women and men were enrolled and were distributed, according to age, into two groups: 27 young (31.81 ± 6.79 years) and 57 elderly (70.72 ± 5.6 years) subjects. The subjects in both groups were given 25 mL/d of extra virgin olive oil (EVOO) for 12 weeks. CEC was measured using J774 macrophages radiolabeled with tritiate...

Antioxidant Effect of Moroccan Pomegranate (Punica granatum L. Sefri Variety) Extracts Rich in Punicalagin against the Oxidative Stress Process

Foods, 2021

Natural antioxidants products are widely distributed in food and medicinal plants. These natural ... more Natural antioxidants products are widely distributed in food and medicinal plants. These natural antioxidants, especially polyphenols, exhibit a wide range of biological activities including anti-cancer, anti-inflammatory, and anti-atherosclerosis activities. Pomegranate (Punica granatum L.) is a rich source of polyphenolic components. The purpose of this study was to characterize the phenolic composition and flavonoids and anthocyanin content of different parts (peel and aril) of the Sefri variety of pomegranate. Our results showed that Peel extract was richer in these compounds than that of the Arils, especially in Punicalagin (A and B). DPPH free radical scavenging, reducing power (FRAP), β-carotene bleaching, and hydrogen peroxide scavenging assays revealed a greater dose-dependent activity of pomegranate peel phenolic extract (PPPE) compared to pomegranate aril phenolic extract (PAPE). PPPE was also more potent than PAPE concerning its ability to inhibit conjugated diene format...

The Aging of γδ T Cells

Cells, 2020

In the coming decades, many developed countries in the world are expecting the “greying” of their... more In the coming decades, many developed countries in the world are expecting the “greying” of their populations. This phenomenon poses unprecedented challenges to healthcare systems. Aging is one of the most important risk factors for infections and a myriad of diseases such as cancer, cardiovascular and neurodegenerative diseases. A common denominator that is implicated in these diseases is the immune system. The immune system consists of the innate and adaptive arms that complement each other to provide the host with a holistic defense system. While the diverse interactions between multiple arms of the immune system are necessary for its function, this complexity is amplified in the aging immune system as each immune cell type is affected differently—resulting in a conundrum that is especially difficult to target. Furthermore, certain cell types, such as γδ T cells, do not fit categorically into the arms of innate or adaptive immunity. In this review, we will first introduce the hum...

Are We Ill Because We Age?

Frontiers in Physiology, 2019

Growing elderly populations, sometimes referred to as gray (or silver) tsunami, are an increasing... more Growing elderly populations, sometimes referred to as gray (or silver) tsunami, are an increasingly serious health and socioeconomic concern for modern societies. Science has made tremendous progress in the understanding of aging itself, which has helped medicine to extend life expectancies. With the increase of the life expectancy, the incidence of chronic age-related diseases (ARDs) has also increased. A new approach trying to solve this problem is the concept of geroscience. This concept implies that the aging process itself is the common cause of all ARDs. The corollary and consequence of such thinking is that we can and should treat aging itself as a disease. How to translate this into the medical practice is a big challenge, but if we consider aging as a disease the problem is solved. However, as there is no common definition of what aging is, what its causes are, why it occurs, and what should be the target(s) for interventions, it is impossible to conclude that aging is a disease. On the contrary, aging should be strongly considered not to be a disease and as such should not be treated; nonetheless, aging is likely amenable to optimization of changes/adaptations at an individual level to achieve a better functional healthspan.

Methylglyoxal and Glyoxal as Potential Peripheral Markers for MCI Diagnosis and Their Effects on the Expression of Neurotrophic, Inflammatory and Neurodegenerative Factors in Neurons and in Neuronal Derived-Extracellular Vesicles

International Journal of Molecular Sciences, 2019

Methylglyoxal (MG) and glyoxal (GO) are suggested to be associated with the development of neurod... more Methylglyoxal (MG) and glyoxal (GO) are suggested to be associated with the development of neurodegenerative pathologies. However, their peripheral levels in relation to cognitive decline and their effects on key factors in neuronal cells are poorly investigated. The aim of this study was to determine their serum levels in MCI (mild cognitive impairment) and Alzheimer’s disease (AD) patients, to analyze their effects on the neurotrophic and inflammatory factors, on neurodegenerative markers in neuronal cells and in neuronal derived-extracellular vesicles (nEVs). Our results show that MG and GO levels in serum, determined by HPLC, were higher in MCI. ROC (receiver-operating characteristic curves) analysis showed that the levels of MG in serum have higher sensitivity to differentiate MCI from controls but not from AD. Meanwhile, serum GO levels differentiate MCI from control and AD groups. Cells and nEVs levels of BDNF, PRGN, NSE, APP, MMP-9, ANGPTL-4, LCN2, PTX2, S100B, RAGE, Aβ pept...

Mapping of γ/δ T cells reveals Vδ2+ T cells resistance to senescence

EBioMedicine, 2018

Background: Immune adaptation with aging is a major of health outcomes. Studies in humans have ma... more Background: Immune adaptation with aging is a major of health outcomes. Studies in humans have mainly focus on αβ T cells while γδ T cells have been neglected despite their role in immunosurveillance. We investigated the impact of aging on γδ T cell subsets phenotypes, functions, senescence and their molecular response to stress. Methods: Peripheral blood of young and old donors in Singapore have been used to assess the phenotype, functional capacity, proliferation capacity and gene expression of the various γδ T cell subsets. Peripheral blood mononuclear cells from apheresis cones and young donors have been used to characterize the telomere length, epigenetics profile and DNA damage response of the various γδ T cell subsets phenotype. Findings: Our data shows that peripheral Vδ2+ phenotype, functional capacity (cytokines, cytotoxicity, proliferation) and gene expression profile are specific when compared against all other αβ and γδ T cells in aging. Hallmarks of senescence including telomere length, epigenetic profile and DNA damage response of Vδ2+ also differs against all other αβ and γδ T cells. Interpretation: Our results highlight the differential impact of lifelong stress on γδ T cells subsets, and highlight possible mechanisms that enable Vδ2+ to be resistant to cellular aging. The new findings reinforce the concept that Vδ2+ have an "innate-like" behavior and are more resilient to the environment as compared to "adaptivelike" Vδ1+ T cells.

Human Plasma Thioredoxin-80 Increases with Age and in apoE(-/-) Mice Induces Inflammation, Angiogenesis and Atherosclerosis

Circulation, Jan 4, 2017

Background -Thioredoxin-1 (TRX1), a ubiquitous 12 kDa protein, exerts anti-oxidant and anti-infla... more Background -Thioredoxin-1 (TRX1), a ubiquitous 12 kDa protein, exerts anti-oxidant and anti-inflammatory effects. In contrast, the truncated form, called TRX80, produced by macrophages induces up-regulation of pro-inflammatory cytokines. TRX80 also promotes the differentiation of mouse peritoneal and human macrophages toward a pro-inflammatory M1 phenotype. Methods -TRX1 and TRX80 plasma levels were determined using specific ELISA. ADAM-17 and ADAM-10 activities were measured using respectively SensoLyte® 520 ADAM10 Activity Assay Kit *Fluorimetric* and InnoZyme™ TACE Activity Kit. Western immunoblots were performed using specific antibodies to ADAM-10 or ADAM-17. Angiogenesis study was evaluated in vitro using Human Microvascular Endothelial Cells-1 and in vivo using the matrigel plug angiogenesis assay in mice. The expression of macrophage phenotype markers were investigated using real-time polymerase chain reaction. Phosphorylation of Akt, mTOR and 70S6K was determined using spec...

A 3-Month Aerobic Training Program Improves Brain Energy Metabolism in Mild Alzheimer's Disease: Preliminary Results from a Neuroimaging Study

Journal of Alzheimer's disease : JAD, 2017

Aerobic training has some benefits for delaying the onset or progression of Alzheimer's disea... more Aerobic training has some benefits for delaying the onset or progression of Alzheimer's disease (AD). Little is known about the implication of the brain's two main fuels, glucose and ketones (acetoacetate), associated with thesebenefits. To determine whether aerobic exercise training modifies brain energy metabolism in mild AD. In this uncontrolled study, ten patients with mild AD participated in a 3-month, individualized, moderate-intensity aerobic training on a treadmill (Walking). Quantitative measurement of brain uptake of glucose (CMRglu) and acetoacetate (CMRacac) using neuroimaging and cognitive testing were done before and after the Walking program. Four men and six women with an average global cognitive score (MMSE) of 26/30 and an average age of 73 y completed the Walking program. Average total distance and treadmill speed were 8 km/week and 4 km/h, respectively. Compared to the Baseline, after Walking, CMRacac was three-fold higher (0.6±0.4 versus 0.2±0.1 μmol/100...

Innovative approach to older patients with malignant hemopathies

Haematologica, 2016

started an initiative to revise these criteria. We believe that the modifications (IWG 2016) will... more

Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer’s Disease

Frontiers in Molecular Neuroscience, 2016

We propose that brain energy deficit is an important pre-symptomatic feature of Alzheimer's disea... more We propose that brain energy deficit is an important pre-symptomatic feature of Alzheimer's disease (AD) that requires closer attention in the development of AD therapeutics. Our rationale is fourfold: (i) Glucose uptake is lower in the frontal cortex of people >65 years-old despite cognitive scores that are normal for age. (ii) The regional deficit in brain glucose uptake is present in adults <40 years-old who have genetic or lifestyle risk factors for AD but in whom cognitive decline has not yet started. Examples include young adult carriers of presenilin-1 or apolipoprotein E4, and young adults with mild insulin resistance or with a maternal family history of AD. (iii) Regional brain glucose uptake is impaired in AD and mild cognitive impairment (MCI), but brain uptake of ketones (beta-hydroxybutyrate and acetoacetate), remains the same in AD and MCI as in cognitively healthy age-matched controls. These observations point to a brain fuel deficit which appears to be specific to glucose, precedes cognitive decline associated with AD, and becomes more severe as MCI progresses toward AD. Since glucose is the brain's main fuel, we suggest that gradual brain glucose exhaustion is contributing significantly to the onset or progression of AD. (iv) Interventions that raise ketone availability to the brain improve cognitive outcomes in both MCI and AD as well as in acute experimental hypoglycemia. Ketones are the brain's main alternative fuel to glucose and brain ketone uptake is still normal in MCI and in early AD, which would help explain why ketogenic interventions improve some cognitive outcomes in MCI and AD. We suggest that the brain energy deficit needs to be overcome in order to successfully develop more effective therapeutics for AD. At present, oral ketogenic supplements are the most promising means of achieving this goal.

Microbes and Alzheimer's Disease

Journal of Alzheimer's disease : JAD, Jan 8, 2016

Tracking the progression of Alzheimer’s disease with peripheral blood monocytes

BackgroundAlzheimer’s disease (AD) is the most common form of dementia with the symptoms graduall... more BackgroundAlzheimer’s disease (AD) is the most common form of dementia with the symptoms gradually worsening over the years. However, the driving pathological processes occur well before the appearance of symptoms. AD patients display signs of systemic inflammation, suggesting that it could precede the well-established AD hallmarks. We recently showed that the innate immune response in the form of monocyte activation is detectable at the pre-clinical stage.ObjectivesOur goal here is to characterize changes of gene expression in peripheral blood monocytes from patients at different stages of AD progression and validate potential biomarkers for a better prognosis and diagnosis of AD clinical spectrum.ResultsWe performed a whole transcriptome analysis on monocytes purified from healthy subjects, Mild Cognitive Impairment (MCI) and AD patients, and established the list of genes differentially expressed in monocytes during the disease evolution. We observed that, in the top 500 genes dif...

Welcome to Advances in Geriatric Medicine and Research: An Advanced Platform for All Geriatric Clinicians and Researchers

Advances in Geriatric Medicine and Research, 2018

Exploring the Extracellular Matrix to Create Biomaterials

Composition and Function of the Extracellular Matrix in the Human Body, 2016

The extracellular matrix (ECM) represents the framework of tissues and organs and is involved in ... more The extracellular matrix (ECM) represents the framework of tissues and organs and is involved in cell differentiation and function. The study of ECM is challenging and required a combination of identification and imaging techniques to give a valuable scheme of its composition, organization, and finally function. The study of ECM enables to culture cells ex vivo, but cultures are restricted to two-dimensional surfaces, whereas in the meantime, material sciences were developing devices able to bring cell culture in a threedimensional (3D) environment. This chapter presents basic techniques to investigate extracellular matrices composition and organization. Basic knowledge on ECM composition and organization should inspire material scientists to propose more biologically relevant materials. In a second time, we present strategies available to create ex vivo models of ECM and a series of examples of 3D materials that were engineered to investigate cell adhesion, phenotype, and differentiation in a biologically relevant microenvironment. The production of a gold-standard material is possible for a specific biological question, and it might be developed from an intelligible dialogue between material scientists, that bring engineering strategies, and cell biologists who implement the material design to meet the biological process that has to be investigated ex vivo.

Identification and signal transduction mechanism of elastin peptide receptor in human leukocytes

FEBS Letters, 1989

The existence of a novel receptor on human polymorphonuclear leukocytes (PMNLs) and monocytes was... more The existence of a novel receptor on human polymorphonuclear leukocytes (PMNLs) and monocytes was demonstrated, named soluble elastin peptide receptor. Soluble elastin peptides, like K‐elastin, which are liberated from elastin fibres, can be found in the sera, and they possess several biological activities such as chemotaxis. Studying the effects of elastin peptides on leukocytes, it was found that: (i) the elastin peptide stimulates the oxidative burst, the intracellular free Ca2+ elevation through a specific receptor; and (ii) in the signal transduction mechanism of this elastin peptide receptor, the phosphatidylinositol breakdown is involved.

Age related impairment in phosphatidylinositol breakdown of polymorphonuclear granulocytes

FEBS Letters, 1989

It is well known that with aging the immune response decreases. Most of the effector functions oc... more It is well known that with aging the immune response decreases. Most of the effector functions occur through specific receptors. Thus, we investigated the effects of various stimulants, acting through receptors or directly through the GTP‐binding Gi protein, on phosphatidylinositol breakdown in PMNLs of young and elderly subjects and try to modulate it. A marked decrease in inositol phosphate (IP1, IP2, IP3) formation in PMNLs of elderly was found under FMLP stimulation when compared to that of young subjects. Neither GTPγS, nor AIF− 4 could induce an increase of IP3 in PMNLs of elderly comparable to that of young subjects. The results suggest that at least an alteration exists at the GTP‐binding Gi protein level, as well as in the mechanism of linkage of the receptor to the G protein.

The Immunomodulatory Effects of a 6-Month Extra Virgin Olive Oil Intervention on Monocyte Cytokine Secretion and Plasma Cytokine Levels in Dyslipidemic and Post-Infarct Patients: A Clinical Pilot Study

Nutrients

Atherosclerosis is an immuno-inflammatory process underlying cardiovascular diseases. One of the ... more Atherosclerosis is an immuno-inflammatory process underlying cardiovascular diseases. One of the main actors of this inflammation is monocytes, with the switch in their phenotypes and irregularities in their cytokine production. Objective: This study was aimed to investigate the nutraceutical potential of extra virgin olive oil (EVOO) on the inflammatory status of monocytes in participants showing different levels of cardiovascular risk. Methods: 43 participants 65–85 years old were recruited including 14 healthy, 12 dyslipidemic patients with hypercholesterolemia recently diagnosed, and 17 post-infarct patients. Participants from all groups were supplemented with EVOO (25 mL/day) for 6 months. IL-1β, IL-6, IL-10, TNF-α cytokine production, and monocyte phenotypes were investigated both at quiescent and at stimulated state by flow cytometry. Results: At the baseline (pre-intervention), dyslipidemic patients, compared to healthy and post-infarct participants, showed monocytes in an i...

The Susceptibility to Diet-Induced Atherosclerosis Is Exacerbated with Aging in C57B1/6 Mice

Biomedicines, 2021

The anti-atherogenic activity of HDL is mainly due to their capacity to mediate reverse cholester... more The anti-atherogenic activity of HDL is mainly due to their capacity to mediate reverse cholesterol transport (RCT). However, it is not clear to what extent this activity is affected by aging or pro-atherogenic conditions. Three and 24-month-old C57Bl/6 mice were fed an atherogenic diet (high fat, high cholesterol) for 12 weeks. The aged mice displayed a significant reduction in the capacity of HDL to mediate RCT (29.03%, p < 0.0006). Interestingly, the atherogenic diet significantly stimulated the RCT process in both young and aged mice (241% and 201%, respectively, p < 0.01). However, despite this, significant amounts of cholesterol accumulated in the aortas of mice fed an atherogenic diet as compared to regular chow. The accumulation of cholesterol was more marked in the aortas of aged mice (110% increase, p < 0.002). ABCA1 and ABCG1 protein expression on macrophages decreased significantly (52 to 37% reduction, p < 0.002), whereas their expression on hepatic cells in...

Calpain-Calpastatin System in Lymphoid Neoplasm of the Aged

Geriatric Oncology, 2018

Reply to GJ Wanten

The American Journal of Clinical Nutrition, 2006

Suppressive effect of a selective increase in plasma linoleic acid concentration and intravascula... more Suppressive effect of a selective increase in plasma linoleic acid concentration and intravascular lipolysis on peripheral T cell activation Dear Sir: With interest we read in the Journal the findings of a recent study by Larbi et al (1), in which the authors reported on the suppressive effects on T cell activation and function, together with changes in the membrane properties of these cells, that are brought about by the intravenous administration of a soybean oil-based lipid emulsion (Intralipid 20%; Baxter, Mississauga, Canada). The authors concluded that these results should have serious implications for nutritional therapy in patients at high risk of septic complications. We have several concerns with regard to the latter statement. First, the investigation by Larbi et al was performed in healthy subjects, and, therefore, their results cannot be extrapolated to patients with an inflammatory condition. Second, several reviews focused on immune modulation by parenteral lipids in general (2) and by soybean oil-based emulsions in particular (3) concluded that no clear picture exists, because of the very disparate outcomes of the studies reviewed. For instance, our group has consistently found that Intralipid, an emulsion that is rich in long-chain triacylglycerols, does not affect human neutrophil and mononuclear cell functions, including oxygen radical production, adhesion, chemotaxis, pathogen killing, and cytokine production (4-8). As in the study by Larbi et al, these observations were made in cells obtained from healthy volunteers and in studies with both in vitro and in vivo designs. It is important that, in our hands, Intralipid did not alter membrane fluidity, as measured by the same technique that Larbi et al used, or signal transduction of leukocytes (9, 10). In contrast, the administration of an emulsion containing medium-chain triacylglycerols in these investigations resulted in cell activation, altered cytokine responses, increased membrane fluidity, and attenuation of calcium signaling in neutrophils and mononuclear cells (4-10). In our opinion, these conflicting outcomes show that, at present, we do not fully comprehend the nature of the interaction of immune cells and parenteral lipids and the circumstances influencing that interaction. The author had no personal or financial conflict of interest with respect to the study of Larbi et al or the report on that study.

Extra Virgin Olive Oil Prevents the Age-Related Shifts of the Distribution of HDL Subclasses and Improves Their Functionality

Nutrients, 2021

High-density lipoproteins (HDL) maintain cholesterol homeostasis through the role they play in re... more High-density lipoproteins (HDL) maintain cholesterol homeostasis through the role they play in regulating reverse cholesterol transport (RCT), a process by which excess cholesterol is transported back to the liver for elimination. However, RCT can be altered in the presence of cardiovascular risk factors, such as aging, which contributes to the increase in the incidence of cardiovascular diseases (CVD). The present study was aimed at investigating the effect of extra virgin olive oil (EVOO) intake on the cholesterol efflux capacity (CEC) of HDL, and to elucidate on the mechanisms by which EVOO intake improves the anti-atherogenic activity of HDL. A total of 84 healthy women and men were enrolled and were distributed, according to age, into two groups: 27 young (31.81 ± 6.79 years) and 57 elderly (70.72 ± 5.6 years) subjects. The subjects in both groups were given 25 mL/d of extra virgin olive oil (EVOO) for 12 weeks. CEC was measured using J774 macrophages radiolabeled with tritiate...

Antioxidant Effect of Moroccan Pomegranate (Punica granatum L. Sefri Variety) Extracts Rich in Punicalagin against the Oxidative Stress Process

Foods, 2021

Natural antioxidants products are widely distributed in food and medicinal plants. These natural ... more Natural antioxidants products are widely distributed in food and medicinal plants. These natural antioxidants, especially polyphenols, exhibit a wide range of biological activities including anti-cancer, anti-inflammatory, and anti-atherosclerosis activities. Pomegranate (Punica granatum L.) is a rich source of polyphenolic components. The purpose of this study was to characterize the phenolic composition and flavonoids and anthocyanin content of different parts (peel and aril) of the Sefri variety of pomegranate. Our results showed that Peel extract was richer in these compounds than that of the Arils, especially in Punicalagin (A and B). DPPH free radical scavenging, reducing power (FRAP), β-carotene bleaching, and hydrogen peroxide scavenging assays revealed a greater dose-dependent activity of pomegranate peel phenolic extract (PPPE) compared to pomegranate aril phenolic extract (PAPE). PPPE was also more potent than PAPE concerning its ability to inhibit conjugated diene format...

The Aging of γδ T Cells

Cells, 2020

In the coming decades, many developed countries in the world are expecting the “greying” of their... more In the coming decades, many developed countries in the world are expecting the “greying” of their populations. This phenomenon poses unprecedented challenges to healthcare systems. Aging is one of the most important risk factors for infections and a myriad of diseases such as cancer, cardiovascular and neurodegenerative diseases. A common denominator that is implicated in these diseases is the immune system. The immune system consists of the innate and adaptive arms that complement each other to provide the host with a holistic defense system. While the diverse interactions between multiple arms of the immune system are necessary for its function, this complexity is amplified in the aging immune system as each immune cell type is affected differently—resulting in a conundrum that is especially difficult to target. Furthermore, certain cell types, such as γδ T cells, do not fit categorically into the arms of innate or adaptive immunity. In this review, we will first introduce the hum...

Are We Ill Because We Age?

Frontiers in Physiology, 2019

Growing elderly populations, sometimes referred to as gray (or silver) tsunami, are an increasing... more Growing elderly populations, sometimes referred to as gray (or silver) tsunami, are an increasingly serious health and socioeconomic concern for modern societies. Science has made tremendous progress in the understanding of aging itself, which has helped medicine to extend life expectancies. With the increase of the life expectancy, the incidence of chronic age-related diseases (ARDs) has also increased. A new approach trying to solve this problem is the concept of geroscience. This concept implies that the aging process itself is the common cause of all ARDs. The corollary and consequence of such thinking is that we can and should treat aging itself as a disease. How to translate this into the medical practice is a big challenge, but if we consider aging as a disease the problem is solved. However, as there is no common definition of what aging is, what its causes are, why it occurs, and what should be the target(s) for interventions, it is impossible to conclude that aging is a disease. On the contrary, aging should be strongly considered not to be a disease and as such should not be treated; nonetheless, aging is likely amenable to optimization of changes/adaptations at an individual level to achieve a better functional healthspan.

Methylglyoxal and Glyoxal as Potential Peripheral Markers for MCI Diagnosis and Their Effects on the Expression of Neurotrophic, Inflammatory and Neurodegenerative Factors in Neurons and in Neuronal Derived-Extracellular Vesicles

International Journal of Molecular Sciences, 2019

Methylglyoxal (MG) and glyoxal (GO) are suggested to be associated with the development of neurod... more Methylglyoxal (MG) and glyoxal (GO) are suggested to be associated with the development of neurodegenerative pathologies. However, their peripheral levels in relation to cognitive decline and their effects on key factors in neuronal cells are poorly investigated. The aim of this study was to determine their serum levels in MCI (mild cognitive impairment) and Alzheimer’s disease (AD) patients, to analyze their effects on the neurotrophic and inflammatory factors, on neurodegenerative markers in neuronal cells and in neuronal derived-extracellular vesicles (nEVs). Our results show that MG and GO levels in serum, determined by HPLC, were higher in MCI. ROC (receiver-operating characteristic curves) analysis showed that the levels of MG in serum have higher sensitivity to differentiate MCI from controls but not from AD. Meanwhile, serum GO levels differentiate MCI from control and AD groups. Cells and nEVs levels of BDNF, PRGN, NSE, APP, MMP-9, ANGPTL-4, LCN2, PTX2, S100B, RAGE, Aβ pept...

Mapping of γ/δ T cells reveals Vδ2+ T cells resistance to senescence

EBioMedicine, 2018

Background: Immune adaptation with aging is a major of health outcomes. Studies in humans have ma... more Background: Immune adaptation with aging is a major of health outcomes. Studies in humans have mainly focus on αβ T cells while γδ T cells have been neglected despite their role in immunosurveillance. We investigated the impact of aging on γδ T cell subsets phenotypes, functions, senescence and their molecular response to stress. Methods: Peripheral blood of young and old donors in Singapore have been used to assess the phenotype, functional capacity, proliferation capacity and gene expression of the various γδ T cell subsets. Peripheral blood mononuclear cells from apheresis cones and young donors have been used to characterize the telomere length, epigenetics profile and DNA damage response of the various γδ T cell subsets phenotype. Findings: Our data shows that peripheral Vδ2+ phenotype, functional capacity (cytokines, cytotoxicity, proliferation) and gene expression profile are specific when compared against all other αβ and γδ T cells in aging. Hallmarks of senescence including telomere length, epigenetic profile and DNA damage response of Vδ2+ also differs against all other αβ and γδ T cells. Interpretation: Our results highlight the differential impact of lifelong stress on γδ T cells subsets, and highlight possible mechanisms that enable Vδ2+ to be resistant to cellular aging. The new findings reinforce the concept that Vδ2+ have an "innate-like" behavior and are more resilient to the environment as compared to "adaptivelike" Vδ1+ T cells.

Human Plasma Thioredoxin-80 Increases with Age and in apoE(-/-) Mice Induces Inflammation, Angiogenesis and Atherosclerosis

Circulation, Jan 4, 2017

Background -Thioredoxin-1 (TRX1), a ubiquitous 12 kDa protein, exerts anti-oxidant and anti-infla... more Background -Thioredoxin-1 (TRX1), a ubiquitous 12 kDa protein, exerts anti-oxidant and anti-inflammatory effects. In contrast, the truncated form, called TRX80, produced by macrophages induces up-regulation of pro-inflammatory cytokines. TRX80 also promotes the differentiation of mouse peritoneal and human macrophages toward a pro-inflammatory M1 phenotype. Methods -TRX1 and TRX80 plasma levels were determined using specific ELISA. ADAM-17 and ADAM-10 activities were measured using respectively SensoLyte® 520 ADAM10 Activity Assay Kit *Fluorimetric* and InnoZyme™ TACE Activity Kit. Western immunoblots were performed using specific antibodies to ADAM-10 or ADAM-17. Angiogenesis study was evaluated in vitro using Human Microvascular Endothelial Cells-1 and in vivo using the matrigel plug angiogenesis assay in mice. The expression of macrophage phenotype markers were investigated using real-time polymerase chain reaction. Phosphorylation of Akt, mTOR and 70S6K was determined using spec...

A 3-Month Aerobic Training Program Improves Brain Energy Metabolism in Mild Alzheimer's Disease: Preliminary Results from a Neuroimaging Study

Journal of Alzheimer's disease : JAD, 2017

Aerobic training has some benefits for delaying the onset or progression of Alzheimer's disea... more Aerobic training has some benefits for delaying the onset or progression of Alzheimer's disease (AD). Little is known about the implication of the brain's two main fuels, glucose and ketones (acetoacetate), associated with thesebenefits. To determine whether aerobic exercise training modifies brain energy metabolism in mild AD. In this uncontrolled study, ten patients with mild AD participated in a 3-month, individualized, moderate-intensity aerobic training on a treadmill (Walking). Quantitative measurement of brain uptake of glucose (CMRglu) and acetoacetate (CMRacac) using neuroimaging and cognitive testing were done before and after the Walking program. Four men and six women with an average global cognitive score (MMSE) of 26/30 and an average age of 73 y completed the Walking program. Average total distance and treadmill speed were 8 km/week and 4 km/h, respectively. Compared to the Baseline, after Walking, CMRacac was three-fold higher (0.6±0.4 versus 0.2±0.1 μmol/100...

Innovative approach to older patients with malignant hemopathies

Haematologica, 2016

started an initiative to revise these criteria. We believe that the modifications (IWG 2016) will... more

Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer’s Disease

Frontiers in Molecular Neuroscience, 2016

We propose that brain energy deficit is an important pre-symptomatic feature of Alzheimer's disea... more We propose that brain energy deficit is an important pre-symptomatic feature of Alzheimer's disease (AD) that requires closer attention in the development of AD therapeutics. Our rationale is fourfold: (i) Glucose uptake is lower in the frontal cortex of people >65 years-old despite cognitive scores that are normal for age. (ii) The regional deficit in brain glucose uptake is present in adults <40 years-old who have genetic or lifestyle risk factors for AD but in whom cognitive decline has not yet started. Examples include young adult carriers of presenilin-1 or apolipoprotein E4, and young adults with mild insulin resistance or with a maternal family history of AD. (iii) Regional brain glucose uptake is impaired in AD and mild cognitive impairment (MCI), but brain uptake of ketones (beta-hydroxybutyrate and acetoacetate), remains the same in AD and MCI as in cognitively healthy age-matched controls. These observations point to a brain fuel deficit which appears to be specific to glucose, precedes cognitive decline associated with AD, and becomes more severe as MCI progresses toward AD. Since glucose is the brain's main fuel, we suggest that gradual brain glucose exhaustion is contributing significantly to the onset or progression of AD. (iv) Interventions that raise ketone availability to the brain improve cognitive outcomes in both MCI and AD as well as in acute experimental hypoglycemia. Ketones are the brain's main alternative fuel to glucose and brain ketone uptake is still normal in MCI and in early AD, which would help explain why ketogenic interventions improve some cognitive outcomes in MCI and AD. We suggest that the brain energy deficit needs to be overcome in order to successfully develop more effective therapeutics for AD. At present, oral ketogenic supplements are the most promising means of achieving this goal.

Microbes and Alzheimer's Disease

Journal of Alzheimer's disease : JAD, Jan 8, 2016