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Search Results: 1 - 10 of 38676 matches for " Diana van Heemst "
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Familial Longevity Is Marked by Better Cognitive Performance at Middle Age: The Leiden Longevity Study
Marjon Stijntjes, Anton J. M. de Craen, Diana van Heemst, Carel G. M. Meskers, Mark A. van Buchem, Rudi G. J. Westendorp, P. Eline Slagboom, Andrea B. Maier
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057962
Abstract: Background Decline in cognitive performance is a highly prevalent health condition in elderly. We studied whether offspring of nonagenarian siblings with a familial history of longevity, perform better on cognitive tests compared to their partners as controls. This is relevant since it could provide insights into determinants underlying decline in cognitive performance. Methods Cross-sectional analysis within the longitudinal cohort of the Leiden Longevity Study consisting of middle-aged offspring of nonagenarian siblings together with their partners (n = 500, mean age (SD) 66.3 (6.1) and 65.7 (7.2) years, respectively) as controls. Memory function, attention and processing speed were tested using the 15-Picture Learning Test, Stroop test and Digit Symbol Substitution Test. Data were analyzed with regression adjusted for age, gender, years of education and additionally for diabetes mellitus, cardiovascular diseases, alcohol use, smoking, inflammatory markers and apolipoprotein E genotype. Robust standard errors were used to account for familial relationships among the offspring. Results Cognitive performance was worse at higher calendar age (p<0.001, all except Stroop test part 1). The offspring performed better compared to their partners on trial 3 (p = 0.005), the immediate (p = 0.016) and delayed (p = 0.004) recall of the 15-Picture Learning Test as well as on the interference and combined interference score of the Stroop test (p = 0.014 and p = 0.036, respectively) in the fully adjusted model. The difference between offspring and partners was estimated to be more than three years according to the observed difference in calendar age. Conclusions Offspring of nonagenarian siblings with a familial history of longevity have better cognitive performance compared to the group of their partners of comparable age. This effect is independent of age-related diseases and known possible confounders. Possible explanations might be differences in subclinical vascular pathology between both groups.
Association of Liver Enzymes and Computed Tomography Markers of Liver Steatosis with Familial Longevity
Michiel Sala, Lucia J. M. Kroft, Boudewijn R?ell, Jeroen van der Grond, P. Eline Slagboom, Simon P. Mooijaart, Albert de Roos, Diana van Heemst
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091085
Abstract: Objective Familial longevity is marked by enhanced peripheral but not hepatic insulin sensitivity. The liver has a critical role in the pathogenesis of hepatic insulin resistance. Therefore we hypothesized that the extent of liver steatosis would be similar between offspring of long-lived siblings and control subjects. To test our hypothesis, we investigated the extent of liver steatosis in non-diabetic offspring of long-lived siblings and age-matched controls by measuring liver enzymes in plasma and liver fat by computed tomography (CT). Research Design and Methods: We measured nonfasting alanine transaminase (ALT), aspartate aminotransferase (AST), and Υ-glutamyl transferase (GGT) in 1625 subjects (736 men, mean age 59.1 years) from the Leiden Longevity Study, comprising offspring of long-lived siblings and partners thereof. In a random subgroup, fasting serum samples (n = 230) were evaluated and CT was performed (n = 268) for assessment of liver-spleen (L/S) ratio and the prevalence of moderate-to-severe non-alcoholic fatty liver disease (NAFLD). Linear mixed model analysis was performed adjusting for age, gender, body mass index, smoking, use of alcohol and hepatotoxic medication, and correlation of sibling relationship. Results Offspring of long-lived siblings had higher nonfasting ALT levels as compared to control subjects (24.3 mmol/L versus 23.2 mmol/L, p = 0.03), while AST and GGT levels were similar between the two groups. All fasting liver enzyme levels were similar between the two groups. CT L/S ratio and prevalence of moderate-to-severe NAFLD was similar between groups (1.12 vs 1.14, p = 0.25 and 8% versus 8%, p = 0.91, respectively). Conclusions Except for nonfasting levels of ALT, which were slightly higher in the offspring of long-lived siblings compared to controls, no differences were found between groups in the extent of liver steatosis, as assessed with liver biochemical tests and CT. Thus, our data indicate that the extent of liver steatosis is similar between offspring of long-lived siblings and control subjects.
ApoE Plasma Levels and Risk of Cardiovascular Mortality in Old Age
Simon P Mooijaart ,Jimmy F. P Berbée,Diana van Heemst,Louis M Havekes,Anton J. M de Craen,P. Eline Slagboom,Patrick C. N Rensen,Rudi G. J Westendorp
PLOS Medicine , 2006, DOI: 10.1371/journal.pmed.0030176
Abstract: Background The ε2, ε3, and ε4 alleles of the apolipoprotein E gene (APOE) encode three isoforms, apoE2, E3, and E4, respectively. The apoE isoforms circulate in different plasma concentrations, but plasma concentrations of the same isoform also differ between individuals. Whereas the isoforms have been associated with cardiovascular disease, the relation between plasma apoE levels and cardiovascular disease is unknown. Methods and Findings We assessed APOE genotypes, plasma levels of apoE, cardiovascular risk factors, and mortality in a population-based sample of 546 individuals aged 85 y who participated in the Leiden 85-plus Study and were prospectively followed for specific causes of death for 5 y. Participants in the highest tertile of apoE levels suffered a twofold-increased risk of cardiovascular mortality (hazard ratio compared to lowest tertile, 2.08; 95% confidence interval [CI], 1.30 to 3.33). Among the 324 participants with the ε3ε3 genotype, the hazard from cardiovascular disease was threefold increased (highest versus lowest tertile 3.01; 95% CI 1.60 to 5.66), with similar estimates for men and women. Other causes of death were not increased significantly. Plasma levels of apoE in ε3ε3 participants were positively correlated with total cholesterol ( p < 0.001), low-density lipoprotein cholesterol ( p < 0.001) and triglycerides ( p < 0.001) and negatively with high-density lipoprotein cholesterol levels ( p = 0.010). Adjustment for plasma lipids did not change the hazard ratios, whereas interaction was absent. The risk associated with high levels of apoE, however, was strongest in participants from the lowest tertile of C-reactive protein (CRP) levels and absent in those from the highest tertile ( pinteraction < 0.001). Among participants from the lowest tertile of CRP levels, those with a high apoE levels had a significantly steeper increase in CRP than those with low apoE levels ( p = 0.020). Similar cardiovascular mortality risks as in ε3ε3 participants were found in ε2 and ε4 carriers. Conclusions In old age, high plasma apoE levels precede an increase of circulating CRP and strongly associates with cardiovascular mortality, independent of APOE genotype and plasma lipids.
Homocysteine and Familial Longevity: The Leiden Longevity Study
Carolien A. Wijsman,Diana van Heemst,Maarten P. Rozing,P. Eline Slagboom,Marian Beekman,Anton J. M. de Craen,Andrea B. Maier,Rudi G. J. Westendorp,Henk J. Blom,Simon P. Mooijaart
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017543
Abstract: Homocysteine concentrations are a read-out of methionine metabolism and have been related to changes in lifespan in animal models. In humans, high homocysteine concentrations are an important predictor of age related disease. We aimed to explore the association of homocysteine with familial longevity by testing whether homocysteine is lower in individuals that are genetically enriched for longevity. We measured concentrations of total homocysteine in 1907 subjects from the Leiden Longevity Study consisting of 1309 offspring of nonagenarian siblings, who are enriched with familial factors promoting longevity, and 598 partners thereof as population controls. We found that homocysteine was related to age, creatinine, folate, vitamin B levels and medical history of hypertension and stroke in both groups (all p<0.001). However, levels of homocysteine did not differ between offspring enriched for longevity and their partners, and no differences in the age-related rise in homocysteine levels were found between groups (p for interaction 0.63). The results suggest that homocysteine metabolism is not likely to predict familial longevity.
Targeted Biomarker Discovery by High Throughput Glycosylation Profiling of Human Plasma Alpha1-Antitrypsin and Immunoglobulin A
L. Renee Ruhaak, Carolien A. M. Koeleman, Hae-Won Uh, Jord C. Stam, Diana van Heemst, Andrea B. Maier, Jeanine J. Houwing-Duistermaat, Paul J. Hensbergen, P. Eline Slagboom, André M. Deelder, Manfred Wuhrer
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073082
Abstract: Protein N-glycosylation patterns are known to show vast genetic as well as physiological and pathological variation and represent a large pool of potential biomarkers. Large-scale studies are needed for the identification and validation of biomarkers, and the analytical techniques required have recently been developed. Such methods have up to now mainly been applied to complex mixtures of glycoproteins in biofluids (e.g. plasma). Here, we analyzed N-glycosylation profiles of alpha1-antitrypsin (AAT) and immunoglobulin A (IgA) enriched fractions by 96-well microtitration plate based high-throughput immuno-affinity capturing and N-glycan analysis using multiplexed capillary gel electrophoresis with laser-induced fluorescence detection (CGE-LIF). Human plasma samples were from the Leiden Longevity Study comprising 2415 participants of different chronological and biological ages. Glycosylation patterns of AAT enriched fractions were found to be associated with chronological (calendar) age and they differed between females and males. Moreover, several glycans in the AAT enriched fraction were associated with physiological parameters marking cardiovascular and metabolic diseases. Pronounced differences were found between males and females in the glycosylation profiles of IgA enriched fractions. Our results demonstrate that large-scale immuno-affinity capturing of proteins from human plasma using a bead-based method combined with high-throughput N-glycan analysis is a powerful tool for the discovery of glycosylation-based biomarker candidates.
Transcriptional Profiling of Human Familial Longevity Indicates a Role for ASF1A and IL7R
Willemijn M. Passtoors, Judith M. Boer, Jelle J. Goeman, Erik B. van den Akker, Joris Deelen, Bas J. Zwaan, Ann Scarborough, Ruud van der Breggen, Rolf H. A. M. Vossen, Jeanine J. Houwing-Duistermaat, Gert Jan B. van Ommen, Rudi G. J. Westendorp, Diana van Heemst, Anton J. M. de Craen, Andrew J. White, David A. Gunn, Marian Beekman, P. Eline Slagboom
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0027759
Abstract: The Leiden Longevity Study consists of families that express extended survival across generations, decreased morbidity in middle-age, and beneficial metabolic profiles. To identify which pathways drive this complex phenotype of familial longevity and healthy aging, we performed a genome-wide gene expression study within this cohort to screen for mRNAs whose expression changes with age and associates with longevity. We first compared gene expression profiles from whole blood samples between 50 nonagenarians and 50 middle-aged controls, resulting in identification of 2,953 probes that associated with age. Next, we determined which of these probes associated with longevity by comparing the offspring of the nonagenarians (50 subjects) and the middle-aged controls. The expression of 360 probes was found to change differentially with age in members of the long-lived families. In a RT-qPCR replication experiment utilizing 312 controls, 332 offspring and 79 nonagenarians, we confirmed a nonagenarian specific expression profile for 21 genes out of 25 tested. Since only some of the offspring will have inherited the beneficial longevity profile from their long-lived parents, the contrast between offspring and controls is expected to be weak. Despite this dilution of the longevity effects, reduced expression levels of two genes, ASF1A and IL7R, involved in maintenance of chromatin structure and the immune system, associated with familial longevity already in middle-age. The size of this association increased when controls were compared to a subfraction of the offspring that had the highest probability to age healthily and become long-lived according to beneficial metabolic parameters. In conclusion, an “aging-signature” formed of 21 genes was identified, of which reduced expression of ASF1A and IL7R marked familial longevity already in middle-age. This indicates that expression changes of genes involved in metabolism, epigenetic control and immune function occur as a function of age, and some of these, like ASF1A and IL7R, represent early features of familial longevity and healthy ageing.
Familial Longevity Is Marked by Lower Diurnal Salivary Cortisol Levels: The Leiden Longevity Study
Raymond Noordam, Steffy W. M. Jansen, Abimbola A. Akintola, Nicole Y. L. Oei, Andrea B. Maier, Hanno Pijl, P. Eline Slagboom, Rudi G. J. Westendorp, Jeroen van der Grond, Anton J. M. de Craen, Diana van Heemst, On behalf of the Leiden Longevity Study group
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031166
Abstract: Background Reported findings are inconsistent whether hypothalamic-pituitary-adrenal (HPA) signaling becomes hyperactive with increasing age, resulting in increasing levels of cortisol. Our previous research strongly suggests that offspring from long-lived families are biologically younger. In this study we assessed whether these offspring have a lower HPA axis activity, as measured by lower levels of cortisol and higher cortisol feedback sensitivity. Methods Salivary cortisol levels were measured at four time points within the first hour upon awakening and at two time points in the evening in a cohort comprising 149 offspring and 154 partners from the Leiden Longevity Study. A dexamethasone suppression test was performed as a measure of cortisol feedback sensitivity. Age, gender and body mass index, smoking and disease history (type 2 diabetes and hypertension) were considered as possible confounding factors. Results Salivary cortisol secretion was lower in offspring compared to partners in the morning (Area Under the Curve = 15.6 versus 17.1 nmol/L, respectively; p = 0.048) and in the evening (Area Under the Curve = 3.32 versus 3.82 nmol/L, respectively; p = 0.024). Salivary cortisol levels were not different after dexamethasone (0.5 mg) suppression between offspring and partners (4.82 versus 5.26 nmol/L, respectively; p = 0.28). Conclusion Offspring of nonagenarian siblings are marked by a lower HPA axis activity (reflected by lower diurnal salivary cortisol levels), but not by a difference in cortisol feedback sensitivity. Further in-depth studies aimed at characterizing the HPA axis in offspring and partners are needed.
A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function
Eleonora Porcu equal contributor,Marco Medici equal contributor,Giorgio Pistis equal contributor,Claudia B. Volpato,Scott G. Wilson,Anne R. Cappola,Steffan D. Bos,Joris Deelen,Martin den Heijer,Rachel M. Freathy,Jari Lahti,Chunyu Liu,Lorna M. Lopez,Ilja M. Nolte,Jeffrey R. O'Connell,Toshiko Tanaka,Stella Trompet,Alice Arnold,Stefania Bandinelli,Marian Beekman,Stefan B?hringer,Suzanne J. Brown,Brendan M. Buckley,Clara Camaschella,Anton J. M. de Craen,Gail Davies,Marieke C. H. de Visser,Ian Ford,Tom Forsen,Timothy M. Frayling,Laura Fugazzola,Martin G?gele,Andrew T. Hattersley,Ad R. Hermus,Albert Hofman,Jeanine J. Houwing-Duistermaat,Richard A. Jensen,Eero Kajantie,Margreet Kloppenburg,Ee M. Lim,Corrado Masciullo,Stefano Mariotti,Cosetta Minelli,Braxton D. Mitchell,Ramaiah Nagaraja,Romana T. Netea-Maier,Aarno Palotie,Luca Persani,Maria G. Piras,Bruce M. Psaty,Katri R?ikk?nen,J. Brent Richards,Fernando Rivadeneira,Cinzia Sala,Mona M. Sabra,Naveed Sattar,Beverley M. Shields,Nicole Soranzo,John M. Starr,David J. Stott,Fred C. G. J. Sweep,Gianluca Usala,Melanie M. van der Klauw,Diana van Heemst,Alies van Mullem,Sita H.Vermeulen,W. Edward Visser,John P. Walsh,Rudi G. J. Westendorp,Elisabeth Widen,Guangju Zhai,Francesco Cucca,Ian J. Deary,Johan G. Eriksson,Luigi Ferrucci,Caroline S. Fox,J. Wouter Jukema,Lambertus A. Kiemeney,Peter P. Pramstaller,David Schlessinger,Alan R. Shuldiner,Eline P. Slagboom,André G. Uitterlinden,Bijay Vaidya,Theo J. Visser,Bruce H. R. Wolffenbuttel
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003266
Abstract: Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals
Zari Dastani equal contributor,Marie-France Hivert equal contributor,Nicholas Timpson equal contributor,John R. B. Perry equal contributor,Xin Yuan equal contributor,Robert A. Scott equal contributor,Peter Henneman equal contributor,Iris M. Heid equal contributor,Jorge R. Kizer equal contributor,Leo-Pekka Lyytik?inen equal contributor,Christian Fuchsberger equal contributor,Toshiko Tanaka,Andrew P. Morris,Kerrin Small,Aaron Isaacs,Marian Beekman,Stefan Coassin,Kurt Lohman,Lu Qi,Stavroula Kanoni,James S. Pankow,Hae-Won Uh,Ying Wu,Aurelian Bidulescu,Laura J. Rasmussen-Torvik,Celia M. T. Greenwood,Martin Ladouceur,Jonna Grimsby,Alisa K. Manning,Ching-Ti Liu,Jaspal Kooner,Vincent E. Mooser,Peter Vollenweider,Karen A. Kapur,John Chambers,Nicholas J. Wareham,Claudia Langenberg,Rune Frants,Ko Willems-vanDijk,Ben A. Oostra,Sara M. Willems,Claudia Lamina,Thomas W. Winkler,Bruce M. Psaty,Russell P. Tracy,Jennifer Brody,Ida Chen,Jorma Viikari,Mika K?h?nen,Peter P. Pramstaller,David M. Evans,Beate St. Pourcain,Naveed Sattar,Andrew R. Wood,Stefania Bandinelli,Olga D. Carlson,Josephine M. Egan,Stefan B?hringer,Diana van Heemst,Lyudmyla Kedenko,Kati Kristiansson,Marja-Liisa Nuotio,Britt-Marie Loo,Tamara Harris,Melissa Garcia,Alka Kanaya,Margot Haun,Norman Klopp,H.-Erich Wichmann,Panos Deloukas,Efi Katsareli,David J. Couper,Bruce B. Duncan,Margreet Kloppenburg,Linda S. Adair,Judith B. Borja,DIAGRAM+ Consortium ?,MAGIC Consortium ?,GLGC Investigators ?,MuTHER Consortium ?,James G. Wilson
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002607
Abstract: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10?8–1.2×10?43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10?4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10?3, n = 22,044), increased triglycerides (p = 2.6×10?14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10?5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10?3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10?13, n = 96,748) and decreased BMI (p = 1.4×10?4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
Consistent nonlinear KK reduction of 11d supergravity on $AdS_7\times S_4$ and self-duality in odd dimensions
Horatiu Nastase,Diana Vaman,Peter van Nieuwenhuizen
Physics , 1999, DOI: 10.1016/S0370-2693(99)01266-6
Abstract: We show that there exists a consistent truncation of 11 dimensional supergravity to the 'massless' fields of maximal (N=4) 7 dimensional gauged supergravity. We find the complete expressions for the nonlinear embedding of the 7 dimensional fields into the 11 dimensional fields, and check them by reproducing the d=7 susy transformation laws from the d=11 laws in various sectors. In particular we determine explicitly the matrix U which connects the Killing spinors to the gravitinos in the KK ansatz, and the dependence of the 4-index field strength on the scalars. This is the first time a complete nonlinear KK reduction of the original d=11 supergravity on a nontrivial compact space has been explicitly given. We need a first order formulation for the 3 index tensor field $A_{\Lambda\Pi\Sigma}$ in d=11 to reproduce the 7 dimensional result. The concept of 'self-duality in odd dimensions' is thus shown to originate from first order formalism in higher dimensions. For the AdS-CFT correspondence, our results imply that one can use 7d gauged supergravity (without further massive modes) to compute certain correlators in the d=6 (0,2) CFT at leading order in N. This eliminates an ambiguity in the formulation of the correspondence.
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