First evidence for STING SNP R293Q being protective regarding obesity-associated cardiovascular disease in age-advanced subjects - a cohort study

Obesity is a risk factor for several aging-related diseases such as type 2 diabetes, cardiovascular disease, and cancer. Especially, cardiovascular disease is triggered by obesity by inducing vascular senescence and chronic low-grade systemic inflammation, also known as inflamm-aging. Released molecules from damaged cells and their recognition by the innate immune system is one of the mechanisms driving inflamm-aging. Obesity results in mitochondrial damage, leading to endothelial inflammation triggered by cytosolic mtDNA via the cGAS/STING pathway. Recently, we have shown STING SNP R293Q to be associated with a decreased risk for aging-related diseases in current smokers. Since current smoking triggers DNA damage that, similar to obesity, may result in the release of DNA into the cytoplasm, we hypothesized that the cGAS/STING pathway can modify the phenotype of aging also in obese subjects. Therefore, the objective of our study was to investigate whether STING R293Q is associated with aging-related diseases in obese individuals. We indeed show that STING 293Q is associated with protection from combined aging-related diseases (P = 0.014) and, in particular, cardiovascular disease in these subjects (P = 0.010). Therefore, we provide the first evidence that stratification for obesity may reveal new genetic loci determining the risk for aging-related diseases

TLR-6 SNP P249S is associated with healthy aging in nonsmoking Eastern European Caucasians - A cohort study

Background To investigate mechanisms that determine healthy aging is of major interest in the modern world marked by longer life expectancies. In addition to lifestyle and environmental factors genetic factors also play an important role in aging phenotypes. The aged immune system is characterized by a chronic micro-inflammation, known as inflamm-aging, that is suspected to trigger the onset of age-related diseases such as cardiovascular disease, Alzheimer’s disease, cancer, and Diabetes Mellitus Type 2 (DMT2). We have recently shown that a Toll-like receptor 6 variant (P249S) is associated with susceptibility to cardiovascular disease and speculated that this variant may also be associated with healthy aging in general by decreasing the process of inflamm- aging. Results Analyzing the PolSenior cohort we show here that nonsmoking S allele carriers are significantly protected from age-related diseases (P = 0.008, OR: 0.654). This association depends not only on the association with cardiovascular diseases (P = 0.018, OR: 0.483) for homozygous S allele carriers, but is also driven by a protection from Diabetes Mellitus type 2 (P = 0.010, OR: 0.486) for S allele carriers. In addition we detect a trend but no significant association of this allele with inflamm-aging in terms of baseline IL-6 levels. Conclusion We confirm our previous finding of the TLR-6 249S variant to be protective regarding cardiovascular diseases. Furthermore, we present first evidence of TLR-6 249S being involved in DMT2 susceptibility and may be in general associated with healthy aging possibly by reducing the process of inflamm-aging

Cholesteryl ester transfer protein (CETP) I405V polymorphism and cardiovascular disease in eastern European Caucasians – a cross-sectional study

Methods A cross-sectional study was conducted to genotype 1028 healthy blood donors and 1517 clinically well characterized elderly for CETP I405V. Results We could not find any association of this polymorphism with age for both, males or females, in any of these cohorts (P = 0.71 and P = 0.57, respectively, for males and P = 0.55 and P = 0.88, respectively, for females). In addition, no association with cardiovascular diseases could be observed in the elderly cohort (males OR = 1.12 and females OR = 0.88). In the same cohort, the CETP V405V genotype was associated with significantly enhanced HDL levels (P = 0.03), mostly owing to the female sex (P = 0.46 for males, P = 0.02 for females), whereas LDL and triglyceride levels were unchanged (P = 0.62 and P = 0.18, respectively). Conclusion Our data support the recent hypothesis that variations enhancing HDL levels without affecting LDL levels are not associated with the risk for cardiovascular diseases

Is flood defense changing in nature? Shifts in the flood defense strategy in six European countries

In many countries, flood defense has historically formed the core of flood risk management but this strategy is now evolving with the changing approach to risk management. This paper focuses on the neglected analysis of institutional changes within the flood defense strategies formulated and implemented in six European countries (Belgium, England, France, the Netherlands, Poland, and Sweden). The evolutions within the defense strategy over the last 30 years have been analyzed with the help of three mainstream institutional theories: a policy dynamics-oriented framework, a structure-oriented institutional theory on path dependency, and a policy actors-oriented analysis called the advocacy coalitions framework. We characterize the stability and evolution of the trends that affect the defense strategy in the six countries through four dimensions of a policy arrangement approach: actors, rules, resources, and discourses. We ask whether the strategy itself is changing radically, i.e., toward a discontinuous situation, and whether the processes of change are more incremental or radical. Our findings indicate that in the European countries studied, the position of defense strategy is continuous, as the classical role of flood defense remains dominant. With changing approaches to risk, integrated risk management, climate change, urban growth, participation in governance, and socioeconomic challenges, the flood defense strategy is increasingly under pressure to change. However, these changes can be defined as part of an adaptation of the defense strategy rather than as a real change in the nature of flood risk management

Functional and structural neuroplasticity induced by short-term tactile training based on Braille reading

Neuroplastic changes induced by sensory learning have been recognized within the cortices of specific modalities as well as within higher ordered multimodal areas. The interplay between these areas is not fully understood, particularly in the case of somatosensory learning. Here we examined functional and structural changes induced by short-term tactile training based of Braille reading, a task that requires both significant tactile expertise and mapping of tactile input onto multimodal representations. Subjects with normal vision were trained for three weeks to read Braille exclusively by touch and scanned before and after training, while performing a same-different discrimination task on Braille characters and meaningless characters. Functional and diffusion-weighted magnetic resonance imaging sequences were used to assess resulting changes. The strongest training-induced effect was found in the primary somatosensory cortex (SI), where we observed bilateral augmentation in activity accompanied by an increase in fractional anisotropy (FA) within the contralateral SI. Increases of white matter fractional anisotropy were also observed in the secondary somatosensory area (SII) and the thalamus. Outside of somatosensory system, changes in both structure and function were found in i.e. the fusiform gyrus, the medial frontal gyri and the inferior parietal lobule. Our results provide evidence for functional remodeling of the somatosensory pathway and higher ordered multimodal brain areas occurring as a result of short-lasting tactile learning, and add to them a novel picture of extensive white matter plasticity

NRX-1 knock down increases longevity in <i>C. elegans</i>.

<p>A. Lifespan curves for N2 <i>C. elegans</i> worms (Bristol strain) in control conditions (filled squares) or subjected to <i>NRX-1</i> bacterial RNAi (hollow squares). B. Mean lifespan of control worms and worms subjected to <i>NRX-1</i> RNAi in three independent experiments. Statistical significance was evaluated by Student’s t-test using Excell^® software. Statistically significant differences from control are indicated by symbols * (p<0.05) and ** (p<0.01).</p

A Common Copy Number Variation (CNV) Polymorphism in the <i>CNTNAP4</i> Gene: Association with Aging in Females

<div><p>Background</p><p>Aging is a biological process strongly determined by genetics. However, only a few single nucleotide polymorphisms (SNPs) have been reported to be consistently associated with aging. While investigating whether copy number variations (CNVs) could fill this gap, we focused on CNVs that have not been studied in previous SNP-based searches <i>via</i> tagging SNPs.</p> <p>Methods</p><p>TaqMan qPCR assays were developed to quantify 20 common CNVs in 222 senior American Caucasians in order to reveal possible association with longevity. The replication study was comprised of 1283 community-dwelling senior European Caucasians. Replicated CNVs were further investigated for association with healthy aging and aging-related diseases, while association with longevity was additionally tested in <i>Caenorhabditis elegans</i>.</p> <p>Results</p><p>In the discovery study of ≥80 <i>vs</i>.<80 years old seniors, a homozygous intronic CNV deletion in the <i>CNTNAP4</i> gene was inversely associated with survival to the age of 80 (OR=0.51, 95%CI 0.29-0.87, p=0.015 before correction for multiple testing). After stratification by sex, association remained significant in females (OR=0.41, 95%CI 0.21-0.77, p=0.007), but not in males (OR=0.97, 95%CI 0.33-2.79, p=1). The finding was validated in a replication study (OR=0.66, 95%CI 0.48-0.90, p=0.011 for females). <i>CNTNAP4</i> association with longevity was supported by a marked 25% lifespan change in <i>C. elegans</i> after knocking down the ortholog gene. An inverse association of the CNV del/del variant with female healthy aging was observed (OR=0.39, 95%CI 0.19-0.76, p=0.006). A corresponding positive association with aging-related diseases was revealed for cognitive impairment (OR=2.17, 95%CI 1.11-4.22, p=0.024) and, in independent studies, for Alzheimer’s (OR=4.07, 95%CI 1.17-14.14, p=0.036) and Parkinson’s (OR=1.59, 95%CI 1.03-2.42, p=0.041) diseases.</p> <p>Conclusion</p><p>This is the first demonstration for association of the <i>CNTNAP4</i> gene and one of its intronic CNV polymorphisms with aging. Association with particular aging-related diseases awaits replication and independent validation.</p> </div