Lee Butcher

Educational attainment but not measures of current socioeconomic circumstances are associated with leukocyte telomere length in healthy older men and women

Low socioeconomic status (SES) may be associated with accelerated biological aging, but findings relating SES with telomere length have been inconsistent. We tested the hypotheses that shorter telomere length and telomerase activity would be related more robustly to education, an early life indicator of socioeconomic position, than to current indicators of socioeconomic circumstances. Healthy men and women aged 53-76 years from the Whitehall II epidemiological cohort provided blood samples from which telomere length was assessed in 448 and telomerase activity in 416. Educational attainment was classified into four levels, while household income and grade of employment were measured as indicators of current socioeconomic circumstances. Age, gender, blood pressure, glycated hemoglobin, high density lipoprotein cholesterol, smoking, body mass index and physical activity were included as covariates. We found that lower educational attainment was associated with shorter telomere length after controlling statistically for biological and behavioral covariates. Neither household income nor employment grade was related to telomere length. The association between telomere length and education remained significant after adjusting for current socioeconomic circumstances. In men, highest levels of telomerase activity were found in the lowest education group. We conclude that low SES defined in terms of education but not current socioeconomic circumstances is associated with shortened telomeres. Low educational attainment may be an indicator of long-term SES trajectories, and be associated with accumulated allostatic load resulting in telomere shortening. Education may also promote problem-solving skills leading to reduced biological stress responsivity, with favorable consequences for biological aging.

Short sleep duration is associated with shorter telomere length in healthy men: findings from the Whitehall II cohort study.

Background Shorter telomere length and poor sleep are more prevalent at older ages, but their relationship is uncertain. This study explored associations between sleep duration and telomere length in a sample of healthy middle and early old age people. Methods Participants were 434 men and women aged 63.3 years on average drawn from the Whitehall II cohort study. Sleep duration was measured by self-report. Results There was a linear association between sleep duration and leukocyte telomere length in men but not in women (P = 0.035). Men reporting shorter sleep duration had shorter telomeres, independently of age, body mass index, smoking, educational attainment, current employment, cynical hostility scores and depressive symptoms. Telomeres were on average 6% shorter in men sleeping 5 hours or fewer compared with those sleeping more than 7 hours per night. Conclusion This study adds to the growing literature relating sleep duration with biomarkers of aging, and suggests that shortening of telomeres might reflect mechanisms through which short sleep contributes to pathological conditions in older men.

Hostility and cellular aging in men from the Whitehall II cohort.

Background Hostility is associated with a significantly increased risk of age-related disease and mortality, yet the pathophysiological mechanisms involved remain unclear. Here we investigated the hypothesis that hostility might impact health by promoting cellular aging. Methods We tested the relationship between cynical hostility and two known markers of cellular aging, leukocyte telomere length (TL) and leukocyte telomerase activity (TA), in 434 men and women from the Whitehall II cohort. Results High-hostile men had significantly shorter leukocyte TL than their low-hostile counterparts. They also had elevated leukocyte TA, with a significantly increased likelihood of having both short TL and high TA, compared with low-hostile individuals. Conclusions Because telomerase is known to counteract telomere shortening by synthesizing telomeric DNA repeats, particularly in the context of shortened telomeres, heightened TA might represent a compensatory response in high-hostile individuals. The relationship between hostility and disease is stronger in men than in women, and men generally have a shorter life expectancy than women. Our findings suggest that telomere attrition might represent a novel mechanism mediating the detrimental effects of hostility on mens health.

Exercise-associated generation of PPARγ ligands activates PPARγ signaling events and upregulates genes related to lipid metabolism

The aim of the present study was to test the hypotheses that exercise is associated with generation of peroxisome proliferator-activated receptor-γ (PPARγ) ligands in the plasma and that this may activate PPARγ signaling within circulating monocytes, thus providing a mechanism to underpin the exercise-induced antiatherogenic benefits observed in previous studies. A cohort of healthy individuals undertook an 8-wk exercise-training program; samples were obtained before (Pre) and after (Post) standardized submaximal exercise bouts (45 min of cycling at 70% of maximal O(2) uptake, determined at baseline) at weeks 0, 4, and 8. Addition of plasma samples to PPARγ response element (PPRE)-luciferase reporter gene assays showed increased PPARγ activity following standardized exercise bouts (Post/Pre = 1.23 ± 0.10 at week 0, P < 0.05), suggesting that PPARγ ligands were generated during exercise. However, increases in PPARγ/PPRE-luciferase activity in response to the same standardized exercise bout were blunted during the training program (Post/Pre = 1.18 ± 0.14 and 1.10 ± 0.10 at weeks 4 and 8, respectively, P > 0.05 for both), suggesting that the relative intensity of the exercise may affect PPARγ ligand generation. In untrained individuals, specific transient increases in monocyte expression of PPARγ-regulated genes were observed within 1.5-3 h of exercise (1.7 ± 0.4, 2.6 ± 0.4, and 1.4 ± 0.1 fold for CD36, liver X receptor-α, and ATP-binding cassette subfamily A member 1, respectively, P < 0.05), with expression returning to basal levels within 24 h. In contrast, by the end of the exercise program, expression at the protein level of PPARγ target genes had undergone sustained increases that were not associated with an individual exercise bout (e.g., week 8 Pre/week 0 Pre = 2.79 ± 0.61 for CD36, P < 0.05). Exercise is known to upregulate PPARγ-controlled genes to induce beneficial effects in skeletal muscle (e.g., mitochondrial biogenesis and aerobic respiration). We suggest that parallel exercise-induced benefits may occur in monocytes, as monocyte PPARγ activation has been linked to beneficial antidiabetic effects (e.g., exercise-induced upregulation of monocytic PPARγ-controlled genes is associated with reverse cholesterol transport and anti-inflammatory effects). Thus, exercise-triggered monocyte PPARγ activation may constitute an additional rationale for prescribing exercise to type 2 diabetes patients.

Anagrelide represses GATA-1 and FOG-1 expression without interfering with thrombopoietin receptor signal transduction.

Summary.  Background: Anagrelide is a selective inhibitor of megakaryocytopoiesis used to treat thrombocytosis in patients with chronic myeloproliferative disorders. The effectiveness of anagrelide in lowering platelet counts is firmly established, but its primary mechanism of action remains elusive. Objectives and Methods: Here, we have evaluated whether anagrelide interferes with the major signal transduction cascades stimulated by thrombopoietin in the hematopoietic cell line UT‐7/mpl and in cultured CD34+‐derived human hematopoietic cells. In addition, we have used quantitative mRNA expression analysis to assess whether the drug affects the levels of known transcription factors that control megakaryocytopoiesis. Results: In UT‐7/mpl cells, anagrelide (1 μm) did not interfere with MPL‐mediated signaling as monitored by its lack of effect on JAK2 phosphorylation. Similarly, the drug did not affect the phosphorylation of STAT3, ERK1/2 or AKT in either UT‐7/mpl cells or primary hematopoietic cells. In contrast, during thrombopoietin‐induced megakaryocytic differentiation of normal hematopoietic cultures, anagrelide (0.3 μm) reduced the rise in the mRNA levels of the transcription factors GATA‐1 and FOG‐1 as well as those of the downstream genes encoding FLI‐1, NF‐E2, glycoprotein IIb and MPL. However, the drug showed no effect on GATA‐2 or RUNX‐1 mRNA expression. Furthermore, anagrelide did not diminish the rise in GATA‐1 and FOG‐1 expression during erythropoietin‐stimulated erythroid differentiation. Cilostamide, an exclusive and equipotent phosphodiesterase III (PDEIII) inhibitor, did not alter the expression of these genes. Conclusions: Anagrelide suppresses megakaryocytopoiesis by reducing the expression levels of GATA‐1 and FOG‐1 via a PDEIII‐independent mechanism that is differentiation context‐specific and does not involve inhibition of MPL‐mediated early signal transduction events.

The contributions of oxidative stress, oxidised lipoproteins and AMPK towards exercise-associated PPARγ signalling within human monocytic cells

Abstract Peroxisome proliferator-activated receptor gamma (PPARγ) is known to be activated via exercise-associated transient increases in oxidative stress. However, the precise mechanism(s) triggering PPARγ activation in monocytes during/following exercise remain to be confirmed. Here, two cohorts of five healthy male individuals undertook exercise bouts (cycling; 70% O2max; 45 min) in the presence/absence of dietary antioxidant supplementation (vitamins C (1000 mg/day) and E (400IU/day) for four weeks before exercise); monocytic 5’ adenosine monophosphate-activated protein kinase (AMPK)/PPARγ co-activator-1alpha (PGC-1α)/PPARγ signalling was investigated in samples obtained before exercise and up to 24 h after exercise, while THP-1 cells were cultured as an in vitro monocyte model. In THP-1 cells, AMPKα1 was phosphorylated within 1h of menadione (15 μM)-triggered increases in [reactive oxygen species (ROS)]cyto, an effect which was followed by upregulation of PPARγ and several of its target genes (PGC-1α, liver X receptor alpha [LXRα] and ATP-binding cassette subfamily A, member 1 [ABCA1]; 24–72 h), with these effects being blunted by co-administration of vitamin C (62.5 μM). Conversely, treatment with oxidised low-density lipoprotein (oxLDL) (1 μg/mL; 24–72 h), but not non-oxidised LDL, upregulated the above PPARγ-regulated genes without affecting AMPKα1 phosphorylation. In vivo, dietary antioxidant supplementation (which is known to prevent exercise-triggered increases in oxLDL levels) blunted exercise-associated upregulation of the above PPARγ-regulated genes, but had no effect on exercise-associated transient [ROS]cyto increases, or on AMPK phosphorylation. These data suggest that exercise-associated PPARγ signalling effects appear, at least in monocytes, to be mediated by increased generation of PPARγ ligands via oxidation of lipoproteins (following exercise-associated transient increases in oxidative stress), rather than via [ROS]cyto-mediated AMPK activation. These findings may be of clinical relevance, as PPARγ activation in monocytes is associated with beneficial effects related to type-2 diabetes and its cardiovascular complications.

The age‐dependent association between aortic pulse wave velocity and telomere length

Age significantly modifies the relationship between aortic pulse wave velocity and telomere length. The differential relationships observed between aortic pulse wave velocity and telomere length in younger and older individuals suggest that the links between cellular and vascular ageing reflect a complex interaction between genetic and environmental factors acting over the life‐course.

The gene expression signature of anagrelide provides an insight into its mechanism of action and uncovers new regulators of megakaryopoiesis.

Anagrelide is a cytoreductive agent used to lower platelet counts in essential thrombocythemia. Although the drug has been known to selectively inhibit megakaryopoiesis for many years, the molecular mechanism accounting for this activity is still unclear.

Association between plasma CCL11 (eotaxin-1) and cognitive status in older adults: Differences between rural and urban dwellers

&NA; The chemokine CCL11 has been implicated in age‐related cognitive deterioration in mice, yet evidence on the relationship between CCL11 and cognitive function in humans is limited. This study explored associations between CCL11 and cognition in rural and urban community‐dwelling older adults. Participants were 515 urban dwellers from the 3C‐Bordeaux cohort and 318 rural dwellers from the AMI cohort. Plasma CCL11 was measured using an enzyme‐linked immunoassay. Mini Mental State Examination (MMSE) test scores were used as the main measure of cognitive performance. Multivariate regression analysis was used to evaluate the cross‐sectional association between CCL11 and cognitive performance. CCL11 was significantly higher in rural dwellers compared to city dwellers (median [IQR]: 145 [115–201] pg/mL vs. 103 [85–129] pg/mL; p < 0.001). After adjustment for confounders, CCL11 was found to be negatively associated with cognitive performance in rural dwellers but not in city dwellers. These results suggest that CCL11 may be an independent determinant of cognitive function in older rural dwellers and that the residential environment modifies this association.

Evidence for a role of TRIB3 in the regulation of megakaryocytopoiesis

Megakaryocytopoiesis is a complex differentiation process driven by the hormone thrombopoietin by which haematopoietic progenitor cells give rise to megakaryocytes, the giant bone marrow cells that in turn break down to form blood platelets. The Tribbles Pseudokinase 3 gene (TRIB3) encodes a pleiotropic protein increasingly implicated in the regulation of cellular differentiation programmes. Previous studies have hinted that TRIB3 could be also involved in megakaryocytopoiesis but its role in this process has so far not been investigated. Using cellular model systems of haematopoietic lineage differentiation here we demonstrate that TRIB3 is a negative modulator of megakaryocytopoiesis. We found that in primary cultures derived from human haematopoietic progenitor cells, thrombopoietin-induced megakaryocytic differentiation led to a time and dose-dependent decrease in TRIB3 mRNA levels. In the haematopoietic cell line UT7/mpl, silencing of TRIB3 increased basal and thrombopoietin-stimulated megakaryocyte antigen expression, as well as basal levels of ERK1/2 phosphorylation. In primary haematopoietic cell cultures, silencing of TRIB3 facilitated megakaryocyte differentiation. In contrast, over-expression of TRIB3 in these cells inhibited the differentiation process. The in-vitro identification of TRIB3 as a negative regulator of megakaryocytopoiesis suggests that in-vivo this gene could be important for the regulation of platelet production.