Mechanisms of protein homeostasis in health, aging and disease.

When emerging from the ribosomes, new polypeptides need to fold properly, eventually translocate, and then assemble into stable, yet functionally flexible complexes. During their lifetime, native proteins are often exposed to stresses that can partially unfold and convert them into stably misfolded and aggregated species, which can in turn cause cellular damage and propagate to other cells. In animal cells, especially in aged neurons, toxic aggregates may accumulate, induce cell death and lead to tissue degeneration via different mechanisms, such as apoptosis as in Parkinson's and Alzheimer's diseases and aging in general. The main cellular mechanisms effectively controlling protein homeostasis in youth and healthy adulthood are: (1) the molecular chaperones, acting as aggregate unfolding and refolding enzymes, (2) the chaperone-gated proteases, acting as aggregate unfolding and degrading enzymes, (3) the aggresomes, acting as aggregate compacting machineries, and (4) the autophagosomes, acting as aggregate degrading organelles. For unclear reasons, these cellular defences become gradually incapacitated with age, leading to the onset of degenerative diseases. Understanding these mechanisms and the reasons for their incapacitation in late adulthood is key to the design of new therapies against the progression of aging, degenerative diseases and cancers.

Genome-wide linkage and association analyses to identify genes influencing adiponectin levels: the GEMS Study.

Adiponectin has a variety of metabolic effects on obesity, insulin sensitivity, and atherosclerosis. To identify genes influencing variation in plasma adiponectin levels, we performed genome-wide linkage and association scans of adiponectin in two cohorts of subjects recruited in the Genetic Epidemiology of Metabolic Syndrome Study. The genome-wide linkage scan was conducted in families of Turkish and southern European (TSE, n = 789) and Northern and Western European (NWE, N = 2,280) origin. A whole genome association (WGA) analysis (500K Affymetrix platform) was carried out in a set of unrelated NWE subjects consisting of approximately 1,000 subjects with dyslipidemia and 1,000 overweight subjects with normal lipids. Peak evidence for linkage occurred at chromosome 8p23 in NWE subjects (lod = 3.10) and at chromosome 3q28 near ADIPOQ, the adiponectin structural gene, in TSE subjects (lod = 1.70). In the WGA analysis, the single-nucleotide polymorphisms (SNPs) most strongly associated with adiponectin were rs3774261 and rs6773957 (P < 10(-7)). These two SNPs were in high linkage disequilibrium (r(2) = 0.98) and located within ADIPOQ. Interestingly, our fourth strongest region of association (P < 2 x 10(-5)) was to an SNP within CDH13, whose protein product is a newly identified receptor for high-molecular-weight species of adiponectin. Through WGA analysis, we confirmed previous studies showing SNPs within ADIPOQ to be strongly associated with variation in adiponectin levels and further observed these to have the strongest effects on adiponectin levels throughout the genome. We additionally identified a second gene (CDH13) possibly influencing variation in adiponectin levels. The impact of these SNPs on health and disease has yet to be determined.

Men and women differ in their cardiovascular responses to affective pictures

Empirical evidence supports the hypothesis that emotional states might contribute to cardiovascular disease and health through multiple pathways. To the extent that the acute cardiovascular response to emotional events plays a role in cardiovascular health and disease, an essential step in order to understand this possible link is to define the hemodynamic response to affective challenges. This was the aim of the present study. We assessed blood pressure (BP), heart rate (HR), stroke volume (SV), cardiac output, and total peripheral resistance (TPR) in response to 13 picture series in 18 men and 19 women (mean age 26) in order to investigate their hemodynamic responses associated with activation of the appetitive and defensive motivational systems underlying emotional experience. The hemodynamic parameters were recorded by finger-cuff photoplethysmography with Finometer™ (FMS Finapres Medical Systems, Amsterdam) and electrocardiography with the Lifeshirt system (VivoMetrics Inc., Ventura, California). Participants rated self-perceived pleasantness and arousal for each series. In men, BP and SV, but not TPR, increased with increasing self-rated arousal both for appetitive and defensive activation, whereas in women these relationships were almost absent, especially, for defensive activation. HR decelerated more in response to negative than positive and neutral pictures, and more so in men than women. These findings indicate striking sex differences. In particular, it is suggested that the sympathetic inotropic effect to the heart increases with increasing self-rated arousal strongly in men but only weakly in women. Regardless of sex differences, the modulation of the cardiovascular response to affective pictures along the dimensions of pleasantness and arousal is primarily myocardial, and the pattern of cardiovascular response is consistent with a configuration of cardiac sympathetic-parasympathetic coactivation. One possible implication of the observed sex differences concerns the link between affective states and cardiovascular health and disease. Men have a higher incidence of cardiovascular diseases than premenopausal women, and exaggerated sympathetic reactivity to emotional events is a potential pathophysiological mechanism. These findings extend current knowledge showing that under several acute behavioral challenges men demonstrate stronger cardiovascular reactivity than women.