Recent work has linked psychological stress with premature cellular aging as indexed by reduced leukocyte telomere length. The combination of shorter telomeres with high telomerase activity (TA) may be indicative of active cell stress. We hypothesized that older individuals characterized by shorter telomeres with high TA in unstimulated leukocytes would show signs of high allostatic load and low levels of protective psychosocial resources. We studied 333 healthy men and women aged 54-76 y who underwent laboratory testing in which we measured cardiovascular, neuroendocrine, and inflammatory responses to standardized mental stress tasks. The tasks elicited prompt increases in blood pressure (BP), heart rate, cortisol, and mediators of inflammation and reductions in heart rate variability, returning toward baseline levels following stress. However, men having shorter telomeres with high TA showed blunted poststress recovery in systolic BP, heart rate variability, and monocyte chemoattractant protein-1, together with reduced responsivity in diastolic BP, heart rate, and cortisol, in comparison to men with longer telomeres or men with shorter telomeres and low TA. Shorter telomeres with high TA were also associated with reduced social support, lower optimism, higher hostility, and greater early life adversity. These effects were independent of age, socioeconomic status, and body mass index. We did not observe differences among older women. Our findings suggest that active cell stress is associated with impaired physiological stress responses and impoverished psychosocial resources, reflecting an integration of cellular, systemic, and psychological stress processes potentially relevant to health in older men. cellular senescence | allostasis | psychological distress T elomeres are nucleoprotein structures composed of tandem hexanucleotide repeats of the sequence TTAGGG that cap the ends of eukaryotic chromosomes, protecting them from end-to-end fusion and degradation during cell division. Human telomeric DNA naturally shortens with age during somatic cell divisions and as a result of oxidative attack (1, 2). At critical shortness, telomeres exhibit impaired function, leading to genomic instability, apoptosis, and cell senescence, often with altered transcriptional programming and mitochondrial dysfunction (1). Telomere attrition represents one of the hallmarks of aging (3). In humans, Mendelian singlegene mutations that directly compromise telomere maintenance cause premature mortality and onset of a spectrum of diseases overlapping with the age-related diseases common in the population (4). In addition, genome-wide association studies show that certain combinations of SNPs at genetic loci encoding known telomere-maintenance factors are associated with increased relative risks for pulmonary and coronary diseases (5). Shorter telomere length (TL) in white blood cells is linked and, in some cases, anticipates aging-related morbidity and mortality from conditions with immune system involvement, such as infectious disease...

Rationale Evidence suggests that depression is crosssectionally and longitudinally associated with activation of inflammatory response system. A few studies, however, have investigated the longitudinal relationship between raised inflammatory biomarkers and persistence of depressive symptoms. We examined the temporal relationship between serum levels of inflammatory biomarkers and persistence of depressive symptoms among older participants. Methods Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressive symptoms at baseline and at 5-year follow-up in 656 participants (233 men, 423 women) aged >60 years of the Rotterdam Study. Markers of inflammation interleukin (IL)-6, alpha-1-antichymotrypsin (ACT) and C-reactive protein (CRP) were assessed at baseline, and all participants taking antidepressant medications were excluded from the analysis. Results No cross-sectional association was found between IL-6, ACT and CRP with depressive symptoms at baseline. However, higher levels of IL-6 and CRP predicted depressive symptoms at 5-year follow-up. Adjustment for confounding variables had no impact on the observed associations. Similarly, a positive association was found between baseline levels of IL-6 (OR=2.44, p=0.030) and CRP (OR=1.81, p=0.052) and persistence of depressive symptoms over 5 years. Conclusion Our data suggest that dysregulation of the inflammatory response system is associated with a more severe form of depression more likely to re-occur.

Rationale The percentage of regulatory T cells (T Regs )-a subtype of T lymphocyte that suppresses the immune response-appears to be reduced in a number of stress-related diseases. The role of the T Reg in stress-disease pathways has not yet been investigated. Objectives The aim of the study was to investigate the association between biological responsivity to acute psychosocial stress and the percentage of T Regs in healthy older adults. The secondary purpose was to measure the associations between T Reg percentage and psychological and physical well-being in the participants. Methods Salivary cortisol and plasma interleukin (IL)-6 samples were obtained from 121 healthy older men and women from the Whitehall II cohort following acute psychophysiological stress testing. Three years later at a follow-up visit, we measured T Reg percentages and psychological and physical well-being were recorded using the Short Form 36 Health Survey and the Center for Epidemiologic Studies Depression Scale.Results Blunted cortisol responses (p=0.004) and elevated IL-6 responses (p=0.027) to acute psychophysiological stress were associated with greater T Reg percentage independently of age, sex, BMI, smoking status, employment grade, time of testing, and baseline measures of cortisol and IL-6, respectively. Percentage of T Regs was associated cross-sectionally with lower physical (p=0.043) and mental health status (p=0.008), and higher levels of depressive symptoms (p=0.002), independently of covariates. Conclusions Increased levels of T Regs may act as a defence against increased inflammation and may be a pre-indication for chronically stressed individuals on the cusp of clinical illness.

BackgroundBone morphogenetic and activin membrane‐bound inhibitor (BAMBI) is a transmembrane protein related to the type I transforming growth factor‐ β (TGF‐β) receptor family that is present on both platelets and endothelial cells (ECs). Bambi‐deficient mice exhibit reduced hemostatic function and thrombus stability characterized by an increased embolization.ObjectiveWe aimed to delineate how BAMBI influences endothelial function and thrombus stability.Methods Bambi‐deficient mice were subjected to the laser‐induced thrombosis model where platelet and fibrin accumulation was evaluated. Expression of thrombomodulin and tissue factor pathway inhibitor (TFPI) was also assessed in these mice.ResultsThrombus instability in Bambi −/− mice was associated with a profound defect in fibrin deposition. Injection of hirudin into Bambi +/+ mice prior to thrombus formation recapitulated the Bambi −/− thrombus instability phenotype. In contrast, hirudin had no additional effect upon thrombus formation in Bambi −/− mice. Deletion of Bambi in ECs resulted in mice with defective thrombus stability caused by decreased fibrin accumulation. Increased levels of the anticoagulant proteins TFPI and thrombomodulin were detected in Bambi −/− mouse lung homogenates. Endothelial cells isolated from Bambi −/− mouse lungs exhibited enhanced ability to activate protein C due to elevated thrombomodulin levels. Blocking thrombomodulin and TFPI in vivo fully restored fibrin accumulation and thrombus stability in Bambi −/−mice.ConclusionsWe demonstrate that endothelial BAMBI influences fibrin generation and thrombus stability by modulating thrombomodulin and TFPI anticoagulant function of the endothelium; we also highlight the importance of these anticoagulant proteins in the laser‐induced thrombosis model.