HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging

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. An HRAS1 haplotype enhanced the effect of an APOE haplotype on exceptional survival, and a LASS1 haplotype further augmented its magnitude. These results were replicated in a second population. A profile of healthy aging was developed using a deficit accumulation index, which showed that this combination of gene variants is associated with healthy aging. The variation in LASS1 is functional, causing enhanced expression of the gene, and it contributes to healthy aging and greater survival in the tenth decade of life. Thus, rare gene variants need not be invoked to explain complex traits such as aging; instead rare congruence of common gene variants readily fulfills this role. The interaction between the three genes described here suggests new models for cellular and molecular mechanisms underlying exceptional survival and healthy aging that involve lipotoxicity. © 2010 The Authors Aging Cell © 2010 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland

Longitudinal assessment of cognitive and psychosocial functioning after Hurricanes Katrina and Rita: Exploring disaster impact on middle-aged, older, and oldest-old adults

The authors examined the effects of Hurricanes Katrina and Rita on cognitive and psychosocial functioning in a lifespan sample of adults 6-14 months after the storms. Participants were recruited from the Louisiana Healthy Aging Study. Most were assessed during the immediate impact period and retested for this study. Analyses of pre- and post-disaster cognitive data confirmed that storm-related decrements in working memory for middle-aged and older adults observed in the immediate impact period had returned to pre-hurricane levels in the post-disaster recovery period. Middle-aged adults reported more storm-related stressors and greater levels of stress than the two older groups at both waves of testing. These results are consistent with a burden perspective on post-disaster psychological reactions. © 2012 Wiley Periodicals, Inc

A new method for obtaining explicit estimators in unbalanced mixed linear models

The general unbalanced mixed linear model with two variance components is considered. Through resampling it is demonstrated how the fixed effects can be estimated explicitly. It is shown that the obtained nonlinear estimator is unbiased and its variance is also derived. A condition is given when the proposed estimator is recommended instead of the ordinary least squares estimator

Brain Transcriptional Responses to High-Fat Diet in <em>Acads</em>-Deficient Mice Reveal Energy Sensing Pathways

<div><h3>Background</h3><p>How signals from fatty acid metabolism are translated into changes in food intake remains unclear. Previously we reported that mice with a genetic inactivation of <em>Acads</em> (acyl-coenzyme A dehydrogenase, short-chain), the enzyme responsible for mitochondrial beta-oxidation of C4–C6 short-chain fatty acids (SCFAs), shift consumption away from fat and toward carbohydrate when offered a choice between diets. In the current study, we sought to indentify candidate genes and pathways underlying the effects of SCFA oxidation deficiency on food intake in <em>Acads−/−</em> mice.</p> <h3>Methodology/Principal Findings</h3><p>We performed a transcriptional analysis of gene expression in brain tissue of <em>Acads−/−</em> and <em>Acads+/+</em> mice fed either a high-fat (HF) or low-fat (LF) diet for 2 d. Ingenuity Pathway Analysis revealed three top-scoring pathways significantly modified by genotype or diet: oxidative phosphorylation, mitochondrial dysfunction, and CREB signaling in neurons. A comparison of statistically significant responses in HF <em>Acads−/−</em> vs. HF <em>Acads+/+</em> (3917) and <em>Acads+/+</em> HF vs. LF <em>Acads+/+</em> (3879) revealed 2551 genes or approximately 65% in common between the two experimental comparisons. All but one of these genes were expressed in opposite direction with similar magnitude, demonstrating that HF-fed <em>Acads</em>-deficient mice display transcriptional responses that strongly resemble those of <em>Acads+/+</em> mice fed LF diet. Intriguingly, genes involved in both AMP-kinase regulation and the neural control of food intake followed this pattern. Quantitative RT-PCR in hypothalamus confirmed the dysregulation of genes in these pathways. Western blotting showed an increase in hypothalamic AMP-kinase in <em>Acads−/−</em> mice and HF diet increased, a key protein in an energy-sensing cascade that responds to depletion of ATP.</p> <h3>Conclusions</h3><p>Our results suggest that the decreased beta-oxidation of short-chain fatty acids in <em>Acads</em>-deficient mice fed HF diet produces a state of energy deficiency in the brain and that AMP-kinase may be the cellular energy-sensing mechanism linking fatty acid oxidation to feeding behavior in this model.</p> </div