Proinflammatory genotype is associated with the frailty phenotype in the English Longitudinal Study of Ageing

Background: Frailty is a state of increased vulnerability to poor resolution of homeostasis after a stressor event, which increases the risk of adverse outcomes including falls, disability and death. The underlying pathophysiological pathways of frailty are not known but the hypothalamic–pituitary–adrenal axis and heightened chronic systemic inflammation appear to be major contributors. Methods: We used the English Longitudinal Study of Ageing dataset of 3160 individuals over the age of 50 and assessed their frailty status according to the Fried-criteria. We selected single nucleotide polymorphisms in genes involved in the steroid hormone or inflammatory pathways and performed linear association analysis using age and sex as covariates. To support the biological plausibility of any genetic associations, we selected biomarker levels for further analyses to act as potential endophenotypes of our chosen genetic loci. Results: The strongest association with frailty was observed in the Tumor Necrosis Factor (TNF) (rs1800629, P = 0.001198, β = 0.0894) and the Protein Tyrosine Phosphatase, Receptor type, J (PTPRJ) (rs1566729, P = 0.001372, β = 0.09397) genes. Rs1800629 was significantly associated with decreased levels of high-density lipoprotein (HDL) (P = 0.00949) and cholesterol levels (P = 0.00315), whereas rs1566729 was associated with increased levels of HDL (P = 0.01943). After correcting for multiple testing none of the associations remained significant. Conclusions: We provide potential evidence for the involvement of a multifunctional proinflammatory cytokine gene (TNF) in the frailty phenotype. The implication of this gene is further supported by association with the endophenotype biomarker results

Short-Term Exercise Training Inconsistently Influences Basel Testosterone in Older Men: A Systematic Review and Meta-Analysis

Background The age-associated decrease in testosterone is one mechanism suggested to accelerate the aging process in males. Therefore, approaches to increase endogenous testosterone may be of benefit. The aim of this paper was to undertake a Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-accordant meta-analysis concerning the effect of exercise on total (TT), bioavailable (bio-T), free (free-T), and salivary (sal-T) testosterone in older males. Methods Databases were searched up to and including 20th February 2018 for the terms ‘testosterone AND exercise AND aging AND males’, ‘testosterone AND exercise AND old AND males’, ‘testosterone AND training AND aging AND males’ and ‘testosterone AND training AND old AND males’. From 1259 originally identified titles, 22 studies (randomized controlled trials; RCTs; n=9, and uncontrolled trials; UCTs; n=13) were included which had a training component, participants ≥60 years of age, and salivary or serum testosterone as an outcome measure. Meta-analyses were conducted on change to testosterone following training using standardised difference in means (SDM) and random effects models. Results The overall SDM for endurance training, resistance training, and interval training was 0.398 (95% CI = 0.034 – 0.761; P = 0.010), -0.003 (95% CI = -0.330 – 0.324; P = 0.986), and 0.283 (95% CI = 0.030 – 0.535; P = 0.028) respectively. Resistance training exhibited a qualitative effect of hormone fraction whereby free-T resulted in the greatest SDM (0.253; 95% CI = -0.043 – 0.549; P = 0.094), followed by TT (0.028; 95% CI = -0.204 – 0.260; P = 0.813), and resistance training negatively influenced bio-T (-0.373; 95% CI = -0.789 – 0.042; P = 0.078). Due to the small number of studies, subgroup analysis was not possible for endurance training and interval training studies. Conclusions Data from the present investigation suggests that resistance training does not significantly influence basal testosterone in older men. Magnitude of effect was influenced by hormone fraction, even within the same investigation. Aerobic training and interval training did result in small, significant increases in basal testosterone. The magnitude of effect is small but the existing data are encouraging and may be an avenue for further research

Multiple imputation for estimating hazard ratios and predictive abilities in case-cohort surveys

<p>Abstract</p> <p>Background</p> <p>The weighted estimators generally used for analyzing case-cohort studies are not fully efficient and naive estimates of the predictive ability of a model from case-cohort data depend on the subcohort size. However, case-cohort studies represent a special type of incomplete data, and methods for analyzing incomplete data should be appropriate, in particular multiple imputation (MI).</p> <p>Methods</p> <p>We performed simulations to validate the MI approach for estimating hazard ratios and the predictive ability of a model or of an additional variable in case-cohort surveys. As an illustration, we analyzed a case-cohort survey from the Three-City study to estimate the predictive ability of D-dimer plasma concentration on coronary heart disease (CHD) and on vascular dementia (VaD) risks.</p> <p>Results</p> <p>When the imputation model of the phase-2 variable was correctly specified, MI estimates of hazard ratios and predictive abilities were similar to those obtained with full data. When the imputation model was misspecified, MI could provide biased estimates of hazard ratios and predictive abilities. In the Three-City case-cohort study, elevated D-dimer levels increased the risk of VaD (hazard ratio for two consecutive tertiles = 1.69, 95%CI: 1.63-1.74). However, D-dimer levels did not improve the predictive ability of the model.</p> <p>Conclusions</p> <p>MI is a simple approach for analyzing case-cohort data and provides an easy evaluation of the predictive ability of a model or of an additional variable.</p

Population screening, monitoring and surveillance for frailty: three systematic reviews and a grey literature review

Introduction. Little is known about programmes or interventions for the screening, monitoring and surveillance of frailty at population level. Methods. Three systematic searches and an opportunistic grey literature review from the countries participating in the ADVANTAGE Joint Action were performed. Results. Three studies reported local interventions to screen for frailty, two of them using a two-step screening and assessment method and one including monitoring activities. Another paper reviewed both providers’ and participants’ experiences of screening activities. Three on-going European projects and population-screening programmes in primary care await evaluation. An electronic Frailty Index for use with patients’ primary care records has been recently validated. No study described systematic processes for the rveillance of frailty. Conclusions. There is insufficient evidence for the effectiveness of population-level screening, monitoring and surveillance of frailty. Development and evaluation of community-based two-step programmes including those that incorporate electronic health records, particularly in primary care, are now needed

Prevalence of frailty at population level in European ADVANTAGE Joint Action Member States: a systematic review and meta-analysis

Introduction. Although frailty is common among community-dwelling older adults, its prevalence in Europe and how this varies between countries is unclear. Methods. A systematic review and meta-analysis of literature on frailty prevalence in 22 European countries involved in the Joint Action ADVANTAGE was conducted. Results. Sixty-two papers, representing 68 unique datasets were included. Meta-analysis showed an overall estimated frailty prevalence of 18% (95% confidence interval, CI, 15- 21%). The prevalence in community (n = 53) vs non-community based studies (n = 15) was 12% (95% CI 10-15%) and 45% (95% CI 27-63%), respectively. Pooled prevalence in community studies adopting a physical phenotype was 12% (95% CI 10-14%, n = 45) vs 16% (95% CI 7-29%, n = 8) for all other definitions. Sub-analysis of a subgroup of studies assessed as high-quality (n = 47) gave a pooled estimate of 17% (95% CI 13-21%). Conclusions. The considerable and significant heterogeneity found warrants the development of common methodological approaches to provide accurate and comparable frailty prevalence estimates at population-level

Statins but Not Aspirin Reduce Thrombotic Risk Assessed by Thrombin Generation in Diabetic Patients without Cardiovascular Events: The RATIONAL Trial

The systematic use of aspirin and statins in patients with diabetes and no previous cardiovascular events is controversial. We sought to assess the effects of aspirin and statins on the thrombotic risk assessed by thrombin generation (TG) among patients with type II diabetes mellitus and no previous cardiovascular events.Prospective, randomized, open, blinded to events evaluation, controlled, 2×2 factorial clinical trial including 30 patients randomly allocated to aspirin 100 mg/d, atorvastatin 40 mg/d, both or none. Outcome measurements included changes in TG levels after treatment (8 to 10 weeks), assessed by a calibrated automated thrombogram. At baseline all groups had similar clinical and biochemical profiles, including TG levels. There was no interaction between aspirin and atorvastatin. Atorvastatin significantly reduced TG measured as peak TG with saline (85.09±55.34 nmol vs 153.26±75.55 nmol for atorvastatin and control groups, respectively; p = 0.018). On the other hand, aspirin had no effect on TG (121.51±81.83 nmol vs 116.85±67.66 nmol, for aspirin and control groups, respectively; p = 0.716). The effects of treatments on measurements of TG using other agonists were consistent.While waiting for data from ongoing large clinical randomized trials to definitively outline the role of aspirin in primary prevention, our study shows that among diabetic patients without previous vascular events, statins but not aspirin reduce thrombotic risk assessed by TG.ClinicalTrials.gov NCT00793754

Sex Differences in the Association between Serum Levels of Testosterone and Frailty in an Elderly Population: The Toledo Study for Healthy Aging

BACKGROUND: Age-associated decline in testosterone levels represent one of the potential mechanisms involved in the development of frailty. Although this association has been widely reported in older men, very few data are available in women. We studied the association between testosterone and frailty in women and assessed sex differences in this relationship. METHODS: We used cross-sectional data from the Toledo Study for Healthy Aging, a population-based cohort study of Spanish elderly. Frailty was defined according to Fried's approach. Multivariate odds-ratios (OR) and 95% confidence intervals (CI) associated with total (TT) and free testosterone (FT) levels were estimated using polytomous logistic regression. RESULTS: In women, there was a U-shaped relationship between FT levels and frailty (p for FT(2) = 0.03). In addition, very low levels of FT were observed in women with ≥ 4 frailty criteria (age-adjusted geometric means = 0.13 versus 0.37 in subjects with <4 components, p = 0.010). The association of FT with frailty appeared confined to obese women (p-value for interaction = 0.05).In men, the risk of frailty levels linearly decreased with testosterone (adjusted OR for frailty = 2.9 (95%CI, 1.6-5.1) and 1.6 (95%CI, 1.0-2.5), for 1 SD decrease in TT and FT, respectively). TT and FT showed association with most of frailty criteria. No interaction was found with BMI. CONCLUSION: There is a relationship between circulating levels of FT and frailty in older women. This relation seems to be modulated by BMI. The relevance and the nature of the association of FT levels and frailty are sex-specific, suggesting that different biological mechanisms may be involved

Hormone Treatment, Estrogen Receptor Polymorphisms and Mortality: A Prospective Cohort Study

International audienceBACKGROUND: The association between hormone treatment (HT) and mortality remains controversial. This study aimed to determine whether the risk of mortality associated with HT use varies depending on the specific characteristics of treatment and genetic variability in terms of the estrogen receptor. METHODOLOGY/PRINCIPAL FINDINGS: A prospective, population-based study of 5135 women aged 65 years and older who were recruited from three cities in France and followed over six years. Detailed information related to HT use was obtained and five estrogen receptor polymorphisms were genotyped. The total follow-up was 25,436 person-years and during this time 352 women died. Cancer (36.4%) and cardiovascular disease (19.3%) were the major causes of death. Cox proportional hazards models adjusted for age, education, centre, living situation, comorbidity, depression, physical and mental incapacities, indicated no significant association between HT and mortality, regardless of the type or duration of treatment, or the age at initiation. However, the association between HT and all-cause or cancer-related mortality varied across women, with significant interactions identified with three estrogen receptor polymorphisms (p-values = 0.004 to 0.03) in adjusted analyses. Women carrying the C allele of ESR1 rs2234693 had a decreased risk of all-cause mortality with HT (HR: 0.42, 95% CI: 0.18-0.97), while in stark contrast, those homozygous for the T allele had a significantly increased risk of cancer-related mortality (HR: 3.18, 95% CI: 1.23-8.20). The findings were similar for ESR1 rs9340799 and ESR2 rs1271572. CONCLUSIONS/SIGNIFICANCE: The risk of mortality was not associated with HT duration, type or age at initiation. It was however not equal across all women, with some women appearing genetically more vulnerable to the effects of HT in terms of their estrogen receptor genotype. These findings, if confirmed in another independent study, may help explain the differential susceptibility of women to the beneficial or adverse effects of HT