Does aging affect the immune status? A comparative analysis in 300 healthy volunteers from France, Austria and Spain

Background: As the European population is getting older, there is growing need in scientific data on how to achieve healthy and successful aging. A decline in immune function with age is unanimously supported by many epidemiological and clinical observations, with a decrease in T-cell mediated function encompassing a large part of this alteration. In the EU-funded VITAGE project, the effects of aging on biomarkers of immune status are being studied in three European countries. According to strict inclusion/exclusion criteria, a cohort of 300 healthy male non-smoking 20-75 years old volunteers were enrolled in France (n = 99), Spain (n = 100) and Austria (n = 101). In each country, the volunteers were classified as a function of age (one age group per decade). Biomarkers of immune status were determined including delayed-type hypersensitivity tests, measurement of lymphocyte surface markers, and serum determinations of interleukin-2, complement fractions and immunoglobulins. [br/] Results: There were moderate differences in the biomarkers of immune status of the VITAGE study volunteers among the three European centres. The percentage of Natural Killer (NK) cells was 156% and 142% higher in Spain as compared to France and Austria, respectively (p < 0.0001), and this increase was observed at any age group above 30 years. Comparison between age-groups showed that in Spain, but not in France or Austria, older individuals had significantly a lower B lymphocyte distribution and conversely, a higher NK cell distribution. Moreover, the CD4/CD8 ratio was positively correlated with age in Austrian subjects (p < 0.0001). [br/] Conclusion: Our results provide evidence of an increased NK cell distribution in the elderly, especially in the Spanish population. NK cell status may predict morbidity and mortality in the elderly, emphasizing the importance of innate as well as adaptive immunity in ensuring healthy longevity and cancer resistance, possibly in link with the Mediterranean diet

Search for standard model production of four top quarks in the lepton + jets channel in pp collisions at √s = 8 TeV

Open Access, Copyright CERN, for the benefit of the CMS Collaboration. Article funded by SCOAP3.Abstract: A search is presented for standard model (SM) production of four top quarks (Formula presented.) in pp collisions in the lepton + jets channel. The data correspond to an integrated luminosity of 19.6 fb−1 recorded at a centre-of-mass energy of 8 TeV with the CMS detector at the CERN LHC. The expected cross section for SM (Formula presented.) production is (Formula presented.). A combination of kinematic reconstruction and multivariate techniques is used to distinguish between the small signal and large background. The data are consistent with expectations of the SM, and an upper limit of 32 fb is set at a 95% confidence level on the cross section for producing four top quarks in the SM, where a limit of 32 ± 17 fb is expected

Muscle Immune Cells, Obesity, and High-Fat Feeding

Muscle Immune Cells, Obesity, and High-Fat Feedin

Immunomodulatory effects of Vitamin D: Focus In the gut

SESSION 1 - EPIDEMIOLOGY - NUTRITIONAL PREVENTION AND CANCER RISKIntroduction:Vitamin D deficiency is observed in more than 80% of the elderly in France and is correlated with the appearance of pathophysiological processes related to aging (cancers and inflammatory diseases). Owing to the expression of its receptor (VDR) in immuno-competent cells (immune cells and barrier cells), vitamin D has the capacity to modulate innate and adaptive immune responses. The richness of intestinal tissue in immuno-competent cells (GALT: Gut Associated Lymphoid Tissue) makes this organ as a preferred target of the anti-inflammatory effects of vitamin D. Several epidemiological studies have yet established a correlation between vitamin D deficiency and the risk of developing a Chronic Inflammatory Bowel Disease and colorectal cancer.Objectives:This study aims to assess immunomodulatory effects of vitamin D in in the ileum of depleted and supplemented young and old rats.Methods:After 2 weeks acclimatization, 6 male Wistar rats aged 2 months and 8 rats aged 18 months were divided into 3 groups: Young control group (n = 6): 1 IU vitD / g diet; Elderly control group (n = 4): 1 IU vitD / g diet;- Elderly supplemented group (n = 4): 10 IU vitD / g diet.The rats were sacrificed after 3 months of diet and ileum was removed. These tissues were disrupted and subjected to a transcriptomic analysis targeted on genes of the metabolism of vitamin D and immunity in order to characterize the immune and inflammatory profile of intestine.Results:Our data demonstrated an overexpression of CYP24A1 with aging. This hydroxylases is known to inactivate vitamin D. Supplementation of vitamin D reduced its expression. Nevertheless, there was not significant difference of VDR expression between young and elderly rats, which remained at the same level after supplementation. mRNA expression levels of cathelicidin, IL6 and NFkB (p65) significantly increased in the elderly group. Supplementation of vitamin D significantly decreased expression of these pro-inflammatory molecules.Conclusion:Aging is accompanied by a majored degradation of active form of vitamin D and an inflammation status at the intestinal level. This inflammation could contribute to a major risk of carcinogenesis. Supplementation of vitamin D is able to limit the pathophysiological effects associated with aging, such as the appearance of low grade inflammatory status. A better understanding of the regulatory mechanisms induced by vitamin D in gut will enable us to acquire new knowledge useful in the prospects of a re-evaluation of the vitamin D requirements of the elderly population or even the systematic administration of a complementatio

Skeletal muscle regeneration and impact of aging and nutrition

In pressAfter skeletal muscle injury a regeneration process takes place to repair muscle. Skeletal muscle recovery is a highly coordinated process involving cross-talk between immune and muscle cells. It is well known that the physiological activities of both immune cells and muscle stem cells decline with advancing age, thereby blunting the capacity of skeletal muscle to regenerate. The age-related reduction in muscle repair efficiency contributes to the development of sarcopenia, one of the most important factors of disability in elderly people. Preserving muscle regeneration capacity may slow the development of this syndrome. In this context, nutrition has drawn much attention: studies have demonstrated that nutrients such as amino acids, n-3 polyunsaturated fatty acids, polyphenols and vitamin D can improve skeletal muscle regeneration by targeting key functions of immune cells, muscle cells or both. Here we review the process of skeletal muscle regeneration with a special focus on the cross-talk between immune and muscle cells. We address the effect of aging on immune and skeletal muscle cells involved in muscle regeneration. Finally, the mechanisms of nutrient action on muscle regeneration are described, showing that quality of nutrition may help to preserve the capacity for skeletal muscle regeneration with age

La vitamine D induit ex vivo une production dose -dépendante de cathélicidine par les cellules mononucléées du sang périphérique

National audienc

Can vitamin D boost production and circulating cathelicidin levels?

Introduction : The vitamin D deficiency (vitD) is widespread in France, especially in the elderly, causing in addition to osteoskeletal disorders, an increase of the infectious risk. VitD exerts immunomulatory effects after binding to its receptor (VDR) expressed by certain immune cells including peripheral blood mononuclear cells (PBMC). These effects could be explained in part by the ability of vitD to stimulate the production of antimicrobial peptides, such as human cathelicidin, which has vitD response elements in its promoter (VDRE). The aim of this work was to determine whether vitD can induce the expression and production of cathelicidin in circulating immune cells both by i) ex vivo and ii) in vivo approaches. Methods: i) PBMCs collected from healthy donors were incubated ex vivo for 24 h and 48 h in the presence of different doses of vitD (0 ng/ml: control; 25 ng/ml: deficiency; 75 ng/ml: physiological; 125 ng/ml : supraphysiological) and then stimulated or not by a bacterial agent (extract of Escherichia coli Lipopolysaccharides (LPS): 100 ng / ml); or a viral mimetic agent(synthetic double-stranded RNA Poly (I: C) (PIC): 10 μg / ml). ii) Leukocytes and serum from healthy volunteers (> 65 years) were collected after randomization (V1), then 3 months after vitD or placebo supplementation (V2), and then 28 days later after influenza vaccination (V3). Gene expression was assessed by quantitative PCR and protein expression by western blot. Cathelicidin concentrations were determined by ELISA. Results: i) Ex vivo, vitD significantly induced cathelicidin gene expression at t24 h with a maximum effect at 125 ng / ml in either unstimulated (x9) or stimulated LPS (x37) and PIC (x23). This intracellular overexpression is found significantly at the protein level at t48h under unstimulated conditions (x 1.5, D125) and stimulated at LPS (x1.7, D125). The excretion of the peptide in the supernatant is induced significantly by LPS and PIC with a tendency to a dose effect of vitamin D. ii) In vivo, a significant overexpression of cathelicidin is observed in the supplemented vs placebo group at V3 after vaccination (x9.15, p <0.05). The circulating rate of cathelicidin remained unchanged throughout the study, while vitamin D levels were significantly increased in the supplemented group (x 2.1, V2 vs V1, x 1.8, V3 vs V1) Conclusion: Intracellular expression of human cathelicidin in circulating leukocytes is induced by vitD in a dose-dependent manner, whereas extracellular production appears to be less influenced by vitD but more by stimulation of the immune system. These results suggest that vitamin supplementation in people with deficiencies may enhance the intracellular availability of cathelicidin that will be required in case of infection

Caractérisation fonctionnelle et métabolique des cellules Natural Killer en situation de stress nutritionnel

National audienceIntroduction : Les cellules Natural Killer (NK), impliquées dans la vigilance anti-tumorale, sont modulées par des facteurs nutritionnels et métaboliques. Au niveau du micro-environnement tumoral mammaire, la biodisponibilité en certaines molécules contrôle non seulement les cellules néoplasiques mais également les cellules immunes infiltrées. Ainsi, la leptine, à forte concentration, pourrait favoriser la croissance tumorale et altérer les cellules NK. Dans un premier temps, a été exploré, in vivo, l’impact d’un régime hypercalorique sur l’activité des cellules NK et sur le développement tumoral mammaire. Ensuite, ont été identifiées in vitro les altérations fonctionnelles des cellules NK induites par la leptine. Méthodes : Des souris Balb-c « nude » soumises à un régime hypercalorique (HC) versus une diète normo-calorique (NC) pendant 6 mois ont été implantées, à 5 mois de régime, avec des cellules tumorales mammaires (groupes NCT et HCT). Sous régime HC, le développement tumoral s’accompagne d’une perte de poids corporel avec un volume et un poids de tumeur augmentés. Bien que la présence de tumeur stimule l’activité cytolytique des cellules NK, la cytotoxicité de ces cellules reste inférieure dans le groupe HCT comparativement à celle du groupe NCT. Résultats: La leptine stimule, in vitro, de façon dose-dépendante l’activité métabolique des cellules NK. En forte concentration, elle active leur cytotoxicité vis-à-vis des cellules cibles MDA-MB-231. Cet effet passe par une stimulation de l’expression, par les cellules NK, de TRAIL et de l’IFN-γ. En revanche, face aux cellules cibles MCF7, les cellules NK présentent une activité cytotoxique réduite en présence de forte concentration en leptine probablement en lien avec une réduction de l’expression de la perforine. Conclusion : Ainsi, un apport énergétique élevé favorise le développement tumoral mammaire notamment en inhibant la cytotoxicité des cellules NK. De plus, la leptine en concentration élevée stimule ou réduit, in vitro, la cytotoxicité des cellules NK selon la nature des cellules cancéreuses cibles

Impact d’une supplémentation en vitamine D sur les fonctions immunitaires et la réponse vaccinale chez des sujets âgés carencés

National audienceIntroduction et but de l’étude : Il est bien établi que l’immunosénescence contribue à l’augmentation de l’incidence des maladies infectieuses et à la diminution de la réponse vaccinale. Le système immunitaire est une cible privilégiée de la vitamine D qui potentialise la réponse innée, et inversement, inhibe la réponse adaptative. Au cours du vieillissement, la déficience en vitamine D est fréquemment observée et contribue probablement au risque accru de dysimmunité. Dans ce contexte, l’objectif de notre étude est d’évaluer l’impact d’une supplémentation en vitamine D chez des sujets de plus de 65 ans carencés en vitamine D sur la capacité des cellules immunocompétentes et la réponse vaccinale. Matériel et méthodes : Après randomisation (V1), les volontaires carencés en vitamine D (25(OH)D<30ng/mL) ont reçu durant 3 mois soit une supplémentation en 25-hydroxyvitamine D (groupe D, n=20 ; 100 000 UI / 15j) soit un placebo (groupe P, n=20). A l’issue de cette période, une vaccination antigrippale (Vaxigrip®, Sanofi-Aventis) a été réalisée chez tous les sujets (V2) puis la réponse vaccinale été évaluée 28 jours plus tard (V3). A ces 3 temps ont été explorés : les taux plasmatiques de 25(OH)D et de cathélicidine (peptide antimicrobien et antiviral), la réponse vaccinale (taux de séroprotection et de séroconversion), le phénotypage lymphocytaire et les taux plasmatiques de cytokines pro et antiinflammatoires. Une analyse de variance à 2 voies a été réalisée suivie d’un test post-hoc de Newman-Keuls. Résultats et Analyse statistique : Pour le groupe D, le taux plasmatique de 25(OH)D augmente significativement (V1 20,7 ± 5,7 vs V2 44,3 ± 8,6 ng/mL) puis diminue significativement à 36,5 ng/mL à V3. Le taux de cathélicidine reste inchangé quel que soit le groupe et le temps considérés (V2 : D- 67,5 ± 7,3 vs P- 56,6 ± 4,4 ; V3 : D- 69,4 ± 6,0 vs P- 64,5 ± 4,7 ng/mL, ns). Les taux de séroprotection (H3N2 : D- 79,0 vs P- 84,2%, ns) et de séroconversion ne varient pas à V3 (H1N1 : D- 21,1 vs P- 26,3% ; H3N2 : D- 36,8 vs P- 42,1%, ns). Le phénotypage lymphocytaire indique dans le groupe D à V2 une baisse des Th1 (D- 5,1 ± 0,8 vs P- 7,1 ± 1,1%, ns) et une augmentation des Th2 (D- 42,0 ± 2,7 vs P- 39,4 ± 5,0%, ns) avec une diminution significative du rapport Th1/Th2 (D- 0,12 vs P- 0,18). L’exploration cytokinique montre pour le groupe D une diminution significative du taux d’IFNγ à V2 (D- 7,3 ± 1,3 vs P- 15,8 ± 7,5 pg/mL, p<0,05) et à V3 (D- 16,3 ± 3,8 vs P- 42,1 ± 20,7 pg/mL, p<0,05) et une augmentation du taux de TGFβ à V3 (D- 20,8 ± 2,4 vs P- 11,5 ± 2,6 pg/mL, p<0,05). Conclusion : Dans nos conditions, la supplémentation en vitamine D du sujet âgé carencé permet de normaliser le taux de 25(OH)D, de modifier le rapport Th1/Th2 en faveur d’un profil tolérogène, de favoriser la production de cytokines antiinflammatoires et de limiter celle de cytokines pro-inflammatoires. Ces effets pourraient contribuer à limiter l’inflammation à bas bruit et l’immunosénescenc

Étude in vitro de l'effet de la vitamine D sur la différenciation des cellules musculaires L6 en situation d'agression

This abstract has also been published in Cahiers de Nutrition et de Diététique, Volume 48, Supplement 1 (Hors-série 1), December 2013"absen