Selection for genetic variation inducing pro-inflammatory responses under adverse environmental conditions in a Ghanaian population.

Background: Chronic inflammation is involved in the pathogenesis of chronic age-associated, degenerative diseases. Pro-inflammatory host responses that are deleterious later in life may originate from evolutionary selection for genetic variation mediating resistance to infectious diseases under adverse environmental conditions.

Methodology/principal Findings: In the Upper-East region of Ghana where infection has remained the leading cause of death, we studied the effect on survival of genetic variations at the IL10 gene locus that have been associated with chronic diseases.

Unraveling the directional link between adiposity and inflammation: a bidirectional Mendelian randomization approach.

Context: Associations between adiposity and circulating inflammation markers are assumed to be causal, although the direction of the relationship has not been proven.

Objective: The aim of the study was to explore the causal direction of the relationship between adiposity and inflammation using a bidirectional Mendelian randomization approach.

Methods: In the PROSPER study of 5804 elderly patients, we related C-reactive protein (CRP) single nucleotide polymorphisms (SNPs) (rs1800947 and rs1205) and adiposity SNPs (FTO and MC4R) to body mass index (BMI) as well as circulating levels of CRP and leptin.

Common CFTR gene variants influence body composition and survival in rural Ghana.

Various studies in mice have found support for the hypothesis that heterozygous carriers of cystic fibrosis transmembrane conductance regulator (CFTR) mutations have an increased resistance to fatal infection compared to both homozygous mutation carriers and non-carriers, while in humans such evidence is scarce. In this study, we assessed the CFTR heterozygotes survival advantage hypothesis in a contemporary rural population that lives under adverse environmental conditions in the Upper-East region of Ghana. We genotyped 30 SNPs throughout the CFTR gene in 4,230 participants and tested their influence on survival and on body composition in the population at large.

Apolipoprotein e genotype, plasma cholesterol, and cancer: a Mendelian randomization study.

Observational studies have shown an association between low plasma cholesterol levels and increased risk of cancer, whereas most randomized clinical trials involving cholesterol-lowering medications have not shown this association. Between 1997 and 2002, the authors assessed the association between plasma cholesterol levels and cancer risk, free from confounding and reverse causality, in a Mendelian randomization study using apolipoprotein E (ApoE) genotype. ApoE genotype, plasma cholesterol levels, and cancer incidence and mortality were measured during a 3-year follow-up period among 2,913 participants in the Prospective Study of Pravastatin in the Elderly at Risk.

Vascular factors and markers of inflammation in offspring with a parental history of late-onset Alzheimer disease.

Context: Alzheimer disease (AD) is a complex disorder with a strong heritable component. Amyloid pathology, vascular factors, and inflammation are postulated to be involved in its pathogenesis, but causality has not been established unequivocally.

Objective: To identify heritable traits in middle age that contribute to AD.

Genetic variation in pentraxin (PTX) 3 gene associates with PTX3 production and fertility in women.

Pentraxin 3 (PTX3) plays an important role in innate immune responses and in female fertility, as discovered with studies in mice. However, the role of PTX3 in human fertility is unknown. Here, we report on a population-based study from a rural area of Upper East Ghana (n = 4346).

Polymorphisms in TLR4 and TLR2 genes, cytokine production and survival in rural Ghana.

Toll-like receptors (TLRs) are involved in the induction of an adequate immune response on infection. We hypothesized that genetic variation in TLR4 and TLR2 genes could influence this response and lead to variability in cytokine production and survival. We tested this hypothesis in 4292 participants who were followed up for all-cause mortality for 6 years and live under adverse environmental conditions in the Upper-East region of Ghana, where malaria is endemic.

Rapid flow cytometric method for measuring senescence associated beta-galactosidase activity in human fibroblasts.

Senescence associated-beta-galactosidase (SA-beta-gal) activity is a widely used marker for cellular senenescence. SA-beta-gal activity is routinely detected cytochemically, manually discriminating negative from positive cells. This method is time-consuming, subjective and therefore prone to operator-error.

Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly.

Niemann-Pick C1-like 1 protein (NPC1L1) plays a critical role in intestinal cholesterol absorption. Our objective was to examine whether five variants (-133A>G, -18A>C, L272L, V1296V, and U3_28650A>G) at the NPC1L1 gene have effects on lipid levels, prevalence, and incidence of coronary heart disease (CHD) and lipid-lowering response to pravastatin. We studied 5,804 elderly participants from the PROSPER study, who were randomized to prava-statin 40 mg/day or placebo and were followed on average for 3.

Nonagenarian siblings and their offspring display lower risk of mortality and morbidity than sporadic nonagenarians: The Leiden Longevity Study.

Objectives: To compare the risk of mortality of nonagenarian siblings with that of sporadic nonagenarians (not selected on having a nonagenarian sibling) and to compare the prevalence of morbidity in their offspring with that of the offsprings' partners.

Design: Longitudinal (mortality risk) and cross-sectional (disease prevalence).

Setting: Nationwide sample.

Stress-induced responses of human skin fibroblasts in vitro reflect human longevity.

Unlike various model organisms, cellular responses to stress have not been related to human longevity. We investigated cellular responses to stress in skin fibroblasts that were isolated from young and very old subjects, and from offspring of nonagenarian siblings and their partners, representatives of the general population. Fibroblasts were exposed to rotenone and hyperglycemia and assessed for senescence-associated beta-galactosidase (SA-beta-gal) activity by flow cytometry.

Pravastatin and cognitive function in the elderly. Results of the PROSPER study.

Observational studies have given conflicting results about the effect of statins in preventing dementia and cognitive decline. Moreover, observational studies are subject to prescription bias, making it hard to draw definite conclusions from them. Randomized controlled trials are therefore the preferred study design to investigate the association between statins and cognition.

Effect of anemia and comorbidity on functional status and mortality in old age: results from the Leiden 85-plus Study.

Background: There is limited insight into the attributable effect of anemia and comorbidity on functional status and mortality in old age.

Methods: The Leiden 85-plus Study is a population-based prospective follow-up study of 562 people aged 85 years. Anemia was defined according to World Health Organization criteria.

Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?

Background: Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke.

Methods And Findings: In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), baseline inflammatory markers in up to 5,680 men and women aged 70-82 y were related to risk for endpoints; nonfatal CVD (i.

Relation between replicative senescence of human fibroblasts and life history characteristics.

Replicative ageing of fibroblasts in vitro has often been used as a model for organismal ageing. The general assumption that the ageing process is mirrored by cellular senescence in vitro is based on lower replicative capacity of human fibroblasts from patients with accelerated ageing syndromes, patients with age related diseases such as diabetes mellitus, and donors of higher chronological age, but these inverse relations have not been reported unequivocally. Therefore, we have performed a formal review on the replicative capacity of fibroblasts from patients suffering from accelerated ageing syndromes, age related diseases and donor age.

Adverse environmental conditions influence age-related innate immune responsiveness.

Background: The innate immune system plays an important role in the recognition and induction of protective responses against infectious pathogens, whilst there is increasing evidence for a role in mediating chronic inflammatory diseases at older age. Despite indications that environmental conditions can influence the senescence process of the adaptive immune system, it is not known whether the same holds true for the innate immune system. Therefore we studied whether age-related innate immune responses are similar or differ between populations living under very diverse environmental conditions.

Clinical relevance of a raised plasma N-terminal pro-brain natriuretic peptide level in a population-based cohort of nonagenarians.

Objectives: To investigate whether plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) remains a specific marker of cardiac illness in very old age and can be used to identify very elderly people at high risk for death independent of the presence of known cardiac diagnoses.

Design: Prospective, observational, population-based follow-up study within the Leiden 85-Plus Study of a 2-year birth cohort (1912-1914).

Setting: General population, municipality of Leiden, the Netherlands.

The effect of age on the association between blood pressure and cognitive function later in life.

Objectives: To determine the prospective relationship between blood pressure (BP) and cognitive function across a wide age range.

Design: Prospective population-based cohort study.

Setting: The Rotterdam Study and the Leiden 85-plus Study.

Genome-wide association study of smoking initiation and current smoking.

For the identification of genes associated with smoking initiation and current smoking, genome-wide association analyses were carried out in 3497 subjects. Significant genes that replicated in three independent samples (n = 405, 5810, and 1648) were visualized into a biologically meaningful network showing cellular location and direct interaction of their proteins. Several interesting groups of proteins stood out, including glutamate receptors (e.

Socio-economic status by rapid appraisal is highly correlated with mortality risks in rural Africa.

Socio-economic status is an important determinant of health and survival in rural Africa and necessitates a practical and valid instrument to implement in health studies. Our objective was to investigate the validity of the rapid appraisal method to assess socio-economic status and its ability to identify individuals at risk. Among 1573 households in rural northern Ghana, we calculated the Demographic Health Survey (DHS) wealth index and conducted two rapid appraisal methods: self-reported wealth and interviewer-reported wealth.

Reduced glomerular filtration rate and its association with clinical outcome in older patients at risk of vascular events: secondary analysis.

Background: Reduced glomerular filtration rate (GFR) is associated with increased cardiovascular risk in young and middle aged individuals. Associations with cardiovascular disease and mortality in older people are less clearly established. We aimed to determine the predictive value of the GFR for mortality and morbidity using data from the 5,804 participants randomized in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).

Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study.

Objectives: To investigate the performance of classic risk factors, and of some new biomarkers, in predicting cardiovascular mortality in very old people from the general population with no history of cardiovascular disease.

Design: The Leiden 85-plus Study (1997-2004) is an observational prospective cohort study with 5 years of follow-up.

Setting: General population of the city of Leiden, the Netherlands.

Complement factor H Y402H decreases cardiovascular disease risk in patients with familial hypercholesterolaemia.

Aims: Activation of the complement system seems an important link between inflammation and atherogenesis. The Y402H polymorphism of complement factor H (CFH) has been associated with cardiovascular events, but results are conflicting and possibly modified by age of onset of cardiovascular disease (CVD).

Methods And Results: We determined whether or not the Y402H polymorphism influenced CVD risk in a multicentre cohort study involving 2,016 unrelated patients with familial hypercholesterolaemia (FH), who have an extremely increased susceptibility to premature CVD.

Does low to moderate alcohol intake protect against cognitive decline in older people?

Objectives: To determine whether low to moderate alcohol intake is protective against cognitive decline in older people.

Design: Prospective cohort study.

Setting: Community-based study in Ireland, the Netherlands, and Scotland.