Age determines the prognostic role of the cancer stem cell marker aldehyde dehydrogenase-1 in breast cancer.

Background: The purpose of this study was to compare the expression and the prognostic effect of the breast cancer stem cell marker aldehyde dehydrogenase-1 (ALDH1) in young and elderly breast cancer patients.

Methods: The study population (N = 574) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1994. Median follow-up was 17.

Transcriptional profiling of human familial longevity indicates a role for ASF1A and IL7R.

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.

Subclinical thyroid dysfunction and the risk of heart failure in older persons at high cardiovascular risk.

Context: Subclinical thyroid dysfunction is common in older people. However, its clinical importance is uncertain.

Objective: Our objective was to determine the extent to which subclinical hyperthyroidism and hypothyroidism influence the risk of heart failure and cardiovascular diseases in older people.

Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity.

In this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case-control study of 1,089 oldest-old (ages 92-93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95-110) and 1,104 middle-aged Germans.

Cerebrovascular hemodynamics in Alzheimer's disease and vascular dementia: a meta-analysis of transcranial Doppler studies.

Background And Purpose: Alteration in cerebrovascular hemodynamics has reported in both ageing and dementia. However, it is still unclear whether this alteration follows similar pattern in ageing and in different dementia pathologies. The aim of this meta-analysis was to investigate changes in cerebral blood flow velocity and pulsatility index in two most common forms of dementia; Alzheimer's disease and vascular dementia, using transcranial Doppler studies.

Age-specific nonpersistence of endocrine therapy in postmenopausal patients diagnosed with hormone receptor-positive breast cancer: a TEAM study analysis.

Background: Early discontinuation of adjuvant endocrine therapy may affect the outcome of treatment in breast cancer patients. The aim of this study was to assess age-specific persistence and age-specific survival outcome based on persistence status.

Methods: Patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational trial were included.

KIF6, LPA, TAS2R50, and VAMP8 genetic variation, low density lipoprotein cholesterol lowering response to pravastatin, and heart disease risk reduction in the elderly.

Single nucleotide polymorphisms (SNPs) at the KIF6 (kinesin like protein 6, rs20455 or 719Arg), LPA (lipoprotein(a), rs3798220), TAS2R50 (taste receptor type 2, member 50, rs1376251) and VAMP8 (vesicle-associated membrane protein 8, rs1010) have previously been associated with low density lipoprotein cholesterol (LDL-C) lowering response to statins, coronary heart disease (CHD) at baseline, or CHD events on trial. We examined SNPs at the KIF6 (rs20455 or 719Arg), LPA (rs3798220), TAS2R50 (rs1376251) and VAMP8 (rs1010) in 5,411 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and were followed for a mean of 3.

Genetic variation at the SLCO1B1 gene locus and low density lipoprotein cholesterol lowering response to pravastatin in the elderly.

Our goal was to determine whether genetic variation at genes affecting statin metabolism or targets of statin therapy would influence low density lipoprotein (LDL) cholesterol lowering with pravastatin, baseline heart disease, or cardiac endpoints on trial. We examined associations of single nucleotide polymorphisms (SNPs) at the liver X receptor alpha (LXRA, rs12221497), and the solute carrier organic anion transporter (SLCO1B1, rs4149056 and rs2306283) gene loci with these variables. We studied 5411 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.

The inverse relationship between alanine aminotransferase in the normal range and adverse cardiovascular and non-cardiovascular outcomes.

Background: High serum alanine aminotransferase (ALT) levels have been associated with increased risk of diabetes and with increased mortality, but associations of variations of ALT in the normal range with outcomes have been less well studied.

Methods: We studied the relationship between ALT, mortality and cardiovascular events in the West of Scotland Coronary Prevention Study (WOSCOPS) and the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trials that explicitly excluded subjects with clinically significant liver damage, plus the Leiden 85-plus, a study of survivors to age 85 years. The associations between ALT and morbidity and mortality outcomes were investigated using Cox proportional hazard models adjusting for a comprehensive panel of cardiovascular risk factors.

Surgical treatment of early stage breast cancer in elderly: an international comparison.

Over 40% of breast cancer patients are diagnosed above the age of 65. Treatment of these elderly patients will probably vary over countries. The aim of this study was to make an international comparison (several European countries and the US) of surgical and radiation treatment for elderly women with early stage breast cancer.

Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways.

In genome-wide association studies (GWAS) of complex traits, single SNP analysis is still the most applied approach. However, the identified SNPs have small effects and provide limited biological insight. A more appropriate approach to interpret GWAS data of complex traits is to analyze the combined effect of a SNP set grouped per pathway or gene region.

High serum glucose levels are associated with a higher perceived age.

Estimating perceived age by facial photographs is a good estimate of health in elderly populations. Previously, we showed that familial longevity is marked by a more beneficial glucose metabolism already at middle age. As glucose is also related to skin aging, this study aimed to investigate the association between glucose metabolism and perceived age.

C-reactive protein haplotypes and dispositional optimism in obese and nonobese elderly subjects.

Background: Chronic low-grade inflammation, characterized by elevated plasma levels of C-reactive protein (CRP), has been inversely associated with dispositional optimism. Using a Mendelian randomization design, this study explores whether CRP haplotypes that determine CRP plasma levels are also associated with dispositional optimism.

Methods: In a sample of 1,084 community-dwelling subjects (aged 60-85 years) from three cohort studies (Arnhem Elderly Study, n = 426; Leiden Longevity Study, n = 355; Zutphen Elderly Study, n = 303), six CRP polymorphisms (rs2808628, rs2808630, rs1205, rs1800947, rs1417938, and rs3091244) coding for five common haplotypes were genotyped.

Replication of LDL GWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses.

Background: The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients.

Cerebral microbleeds and cognitive functioning in the PROSPER study.

Objectives: Cerebral microbleeds (MBs) are an important indicator of cerebral small-vessel disease, and their prevalence increases with increasing age. Little is known about the functional consequences of MBs in the aging population. In this study we investigated whether the presence and location of MBs are associated with cognition in the PROSPER study.

Screening for cognitive impairment in older general hospital patients: comparison of the Six-Item Cognitive Impairment Test with the Mini-Mental State Examination.

Objective: To investigate the performance and usability of the Six-Item Cognitive Impairment Test (6CIT) as a screening instrument for cognitive impairment in older, general hospital inpatients/outpatients.

Method: In 253 general hospital patients aged ≥ 70 years, diagnostic accuracy of the 6CIT and time required to administer it were assessed using the Mini-Mental State Examination (MMSE) as the criterion standard.

Results: The (negative) correlation between the 6CIT and the MMSE was very high (r = -0.

C-reactive protein and genetic variants and cognitive decline in old age: the PROSPER study.

Background: Plasma concentrations of C-reactive protein (CRP), a marker of chronic inflammation, have been associated with cognitive impairment in old age. However, it is unknown whether CRP is causally linked to cognitive decline.

Methods And Findings: Within the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial, with 5680 participants with a mean age of 75 years, we examined associations of CRP levels and its genetic determinants with cognitive performance and decline over 3.

Morphometric skin characteristics dependent on chronological and biological age: the Leiden Longevity Study.

The effect of chronological age on skin characteristics is readily visible, and its underlying histological changes have been a field of study for several years. However, the effect of biological age (i.e.

Diastolic carotid artery wall shear stress is associated with cerebral infarcts and periventricular white matter lesions.

Background And Purpose: Low wall shear stress (WSS) is an early marker in the development of vascular lesions. The present study aims to assess the relationship between diastolic and systolic WSS in the internal carotid artery and periventricular (PWML), deep white matter lesions, and cerebral infarcts (CI).

Methods: Early, mid, and late diastolic and peak systolic WSS were derived from shear rate obtained by gradient echo phase contrast magnetic resonance sequences multiplied by individually modeled viscosity.

Design, recruitment, logistics, and data management of the GEHA (Genetics of Healthy Ageing) project.

In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90 years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition.

Handgrip strength at midlife and familial longevity : The Leiden Longevity Study.

Low handgrip strength has been linked with premature mortality in diverse samples of middle-aged and elderly subjects. The value of handgrip strength as marker of "exceptional" human longevity has not been previously explored. We postulated that the genetic influence on extreme survival might also be involved in the muscular strength determination pathway.

Infection with cytomegalovirus but not herpes simplex virus induces the accumulation of late-differentiated CD4+ and CD8+ T-cells in humans.

Human cytomegalovirus (CMV) establishes persistent, usually asymptomatic, infection in healthy people. Because CMV infection is associated with the presence of lower proportions of peripheral naïve CD8+ T-cells and a higher fraction of late-differentiated CD8+ cells, commonly taken as biomarkers of age-associated compromised adaptive immunity ('immunosenescence'), we asked whether chronic exposure to any persistent virus mediates these effects. Herpes simplex virus (HSV) is also a widespread herpesvirus that establishes lifelong persistence, but, unlike CMV, its impact on the distribution of T-cell subsets has not been established.

Factor VII Activating Protease Polymorphism (G534E) Is Associated with Increased Risk for Stroke and Mortality.

Introduction. The FSAP-Marburg I polymorphism (1704G > A), which reduces FSAP activity, is associated with late complications of carotid stenosis in humans. Therefore, this study examines the influence of the Marburg I polymorphism and the closely linked Marburg II polymorphism (1280G > C) on various cardiovascular outcomes in two large independent study populations.

The survival gap between middle-aged and elderly colon cancer patients. Time trends in treatment and survival.

Aims: For several types of cancer, including colon cancer, the survival gap between middle-aged patients and elderly patients widened between 1988 and 1999 in Europe. The aim of our study was to describe treatments and compare survival rates over time (1991-2005) between middle-aged (<65 years), aged (65-74 years) and elderly (≥ 75 years) colon cancer patients in the mid-western part of the Netherlands to assess whether this survival gap further increased.

Methods: All 8926 patients with invasive colon cancer diagnosed between 1991 and 2005 were selected from the Comprehensive Cancer Centre West.

Circulating interleukin-10 and risk of cardiovascular events: a prospective study in the elderly at risk.

Objective: The goal of this study was to examine the association of the antiinflammatory interleukin-10 (IL-10) with risk of cardiovascular disease (CVD).

Methods And Results: In the PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) cohort, we related baseline concentrations of circulating IL-10 to risk of CVD events in a nested case (n=819)-control (n=1618) study of 3.2 years of follow-up.