Excessive production of reactive oxygen species (ROS) contributes to progression of atherosclerosis, at least in part by causing endothelial dysfunction and inflammatory activation. The class III histone deacetylase SIRT1 has been implicated in extension of lifespan. In the vasculature,SIRT1 gain-of-function using SIRT1 overexpression or activation has been shown to improve endothelial function in mice and rats via stimulation of endothelial nitric oxide (NO) synthase (eNOS). However, the effects of SIRT1 loss-of-function on the endothelium in atherosclerosis remain to be characterized.
The American Journal of Geriatric Psychiatry: Official Journal of the American Association for Geriatric Psychiatry
OBJECTIVE: A systematic genome survey was initiated to identify loci that affect the likelihood of reaching age 90 with preserved cognition. This communication describes the clinical characterization and comparison of the experimental groups, validation of the experimental method, and results for the Y chromosome. METHODS: The genome survey was conducted at 10 cM resolution for simple sequence tandem repeat polymorphisms (SSTRPs) that identify genes for successful aging by virtue of linkage disequilibrium.
The exceptional longevity of centenarians is due in part to inherited genetic factors, as deduced from data that show that first degree relatives of centenarians live longer and have reduced overall mortality. In recent years, a number of groups have performed genetic association studies on long-living individuals (LLI) and young controls to identify alleles that are either positively or negatively selected in the centenarian population as consequence of a demographic pressure. Many of the reported studies have shown genetic loci associated with longevity.
The search for longevity-determining genes in human has largely neglected the operation of genetic interactions. We have identified a novel combination of common variants of three genes that has a marked association with human lifespan and healthy aging. Subjects were recruited and stratified according to their genetically inferred ethnic affiliation to account for population structure. Haplotype analysis was performed in three candidate genes, and the haplotype combinations were tested for association with exceptional longevity.
Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project.
Nihon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics
The apolipoprotein E4 (apoE4) epsilon 4 allele is a major riks factor for Alzheimer's disease. However, epsilon 4 is neither a necessary nor a sufficient condition for the development of this disease, and many cognitively healthy elderly people carry the epsilon 4 allele. To look for age-dependent changes in epsilon 4 allele frequencies in the general population, we measured the frequencies in 141 normal healthy residents of a mountainous rural area in north-west Gunma prefecture. Levels of cholesterols in plasma were measured and their relation to apoE genotypes was studied.
Arteriosclerosis, Thrombosis, and Vascular Biology
Apolipoprotein E polymorphisms are important determinants of blood lipid levels and have been associated with longevity and atherosclerosis. However, information is limited on the effects of apo E variation on the lipids of nonwhite and elderly individuals. We tested the hypothesis that apo E polymorphisms are associated with plasma lipid levels in an elderly, multiethnic population. Cross-sectional data from 1068 noninstitutionalized individuals from northern Manhattan over the age of 64 who were not on a lipid-lowering diet or drug were analyzed.
Clinical chemistry and laboratory medicine: CCLM / FESCC
Apolipoprotein (apo) E is an important circulating and tissue protein involved in cholesterol homeostasis and many other functions. The common polymorphism in the coding region of the gene, four polymorphisms in the promoter region, other additional single nucleotide polymorphisms, as well as several apo E variants have been identified. The common coding polymorphism strongly influences the lipid metabolism and the circulating concentration of apo E itself.
Fundamental questions on the pathogenesis of Alzheimer's disease (AD) are how nontoxic, soluble amyloid beta-protein (A beta) is converted to its toxic, aggregated form and how functional tau is hyperphosphorylated to form neurofibrillary tangles. Growing evidence from recent biochemical and cell biological studies suggests that altered cholesterol metabolism in neurons may underlie such pathological processes. The possibility that cholesterol is a risk factor in the development of AD has also been supported by recent epidemiological studies.
BACKGROUND: Human atherosclerotic lesions contain elevated levels of urokinase plasminogen activator (uPA), expressed predominantly by macrophages. METHODS AND RESULTS: To test the hypothesis that macrophage-expressed uPA contributes to the progression and complications of atherosclerosis, we generated transgenic mice with macrophage-targeted overexpression of uPA. The uPA transgene was bred into the apolipoprotein E-null background, and transgenic mice and nontransgenic littermate controls were fed an atherogenic diet.