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The endocannabinoid system (ECS) participates in regulating whole body energy balance. Overactivation of the ECS has been associated with the negative consequence of obesity and type 2 diabetes. Since activators of the ECS rely on lipid-derived ligands, an investigation was conducted to determine whether dietary PUFA could influence the ECS to affect glucose clearance by measuring metabolites of macronutrient metabolism. C57/blk6 mice were fed a control or DHA-enriched semi-purified diet for a period of 112 d. Plasma, skeletal muscle, and liver were collected after 56 d and 112 d of feeding the diets for metabolomics analysis. Key findings characterized a shift in glucose metabolism and greater catabolism of fatty acids in mice fed the DHA diet. Glucose use and promotion of fatty acids as substrate were found based on levels of metabolic pathway intermediates and altered metabolic changes related to pathway flux with DHA feeding. Greater levels of DHA-derived glycerol lipids were found subsequently leading to the decrease of arachidonate-derived endocannabinoids (eCB). Levels of 1- and 2-arachidonylglcerol eCB in muscle and liver were lower in the DHA diet group compared to controls. These findings demonstrate that DHA feeding in mice alters macronutrient metabolism and may restore ECS tone by lowering arachidonic acid derived eCB.

Bistability is a fundamental biological phenomenon associated with “switch-like” behavior reflecting the capacity of a system to exist in either of two stable states. It plays a role in gene regulation, cell fate switch, signal transduction and cell oscillation, with relevance for cognition, hearing, vision, sleep, gait and voiding. Here we consider a potential role for bistability in the existence of specific frailty states or phenotypes as part of disablement pathways. We use mathematical modeling with two frailty biomarkers (insulin growth factor-1, IGF-1 and interleukin-6, IL-6), which mutually inhibit each other. In our model, we demonstrate that small variations around critical IGF-1 or IL-6 blood levels lead to strikingly different mobility outcomes. We employ deterministic modeling of mobility outcomes, calculating the average trends in population health. Our model predicts the bistability of clinical outcomes: the deterministically-computed likelihood of an individual remaining mobile, becoming less mobile, or dying over time either increases to almost 100% or decreases to almost zero. Contrary to statistical models that attempt to estimate the likelihood of final outcomes based on probabilities and correlations, our model predicts functional outcomes over time based on specific hypothesized molecular mechanisms. Instead of estimating probabilities based on stochastic distributions and arbitrary priors, we deterministically simulate model outcomes over a wide range of physiological parameter values within experimentally derived boundaries. Our study is “a proof of principle” as it is based on a major assumption about mutual inhibition of pathways that is oversimplified. However, by making such an assumption, interesting effects can be described qualitatively. As our understanding of molecular mechanisms involved in aging deepens, we believe that such modeling will not only lead to more accurate predictions, but also help move the field from using mostly studies of associations to mechanistically guided approaches.

Additional file 2: Supplemental Table 2. Subjects who discontinued treatment during the study. Four participants chose to discontinue treatment during the study and the reasons given were recorded. No clear pattern was noted for metformin discontinuation.

Additional file 6: Supplemental Figure 4. Frequency of CD57+ CD4 and CD8 T cells. Frequency of CD57+ A) CD4 T cells and B) CD8 T cells prior to and following 20 weeks of treatment with either placebo or metformin was analyzed and fold change in frequency of CD57+ cells were calculated. Statistical significance was calculated by t-test and significance set at p

Additional file 3: Supplemental Figure 1. MFI of PDI and ICOS expression on circulating Tfh. Peripheral blood mononuclear cells (PBMCs) were analyzed for circulating T follicular helper cells. Mean fluorescence intensity of the activation markers ICOS and PD1 was analyzed. Fold change was calculated from A-B) pre-vaccination and C-D) pre-treatment levels to determine the effect of metformin on cTfh activation prior to and following vaccination, respectively. Statistical significance was calculated by two-way repeated measures ANOVA with Šídák’s posthoc corrections and significance set at p

Additional file 5: Supplemental Figure 3. T and B Cell phenotypes. Peripheral blood mononuclear cells (PBMCs) were gated on CD4 and CD8 T cells and analyzed for naïve (CCR7+CD45RA+), central memory (CCR7+CD45RA-), effector memory (CCR7-CD45RA-), and terminally differentiated effector memory cells re-expressing CD45RA (TEMRA, CCR7-CD45RA+). Fold change was calculated from pre-treatment to determine the effect of metformin on these populations prior to vaccination. No differences between placebo and metformin group were observed in A-D) CD4 or E-H) CD8 T cells for these populations. PBMCs were also analyzed for B cell populations via gating on CD19+ cells and then phenotyping for I) naïve (IgD+CD27-), J) non-switched memory B cells (IgD+CD27+), K) switched memory B cells (IgD-CD27+), and L) double negative B cells (IgD-CD27-). Fold change was calculated from pre-treatment to determine the effect of metformin on populations prior to vaccination. Statistical significance was calculated by two-way repeated measures ANOVA with Šídák’s posthoc corrections and significance set at p

Additional file 7: Supplemental Figure 5. Flow cytometric gating strategy for T cell populations. Peripheral blood mononuclear cells (PBMCs) were stained with antibodies as indicated in Table 2. Samples were analyzed on the ZE5 Cell Analyzer (Bio-Rad Laboratories, Hercules, CA), and data were analyzed with FlowJo software (BD Biosciences, Woburn, MA). Samples were first gated on lymphocytes (FSC-A x SCA-A), singularity (FSC-A x FSC-H), and identified as live with Carboxylic acid, succinimidyl ester (live/dead) staining prior to gating strategy illustrated.

Additional file 1: Supplemental Table 1. Adverse effects by treatment group. Adverse events were monitored by staff inquiry at all study visits and biweekly telephone calls throughout the study. Safety blood chemistry labs were performed following approximately 15 weeks of treatment. Adverse events were recorded and broadly classified.

Additional file 8: Supplemental Figure 6. Flow cytometric gating strategy for B cell populations. Peripheral blood mononuclear cells (PBMCs) were stained with antibodies as indicated in Table 2. Samples were analyzed on the ZE5 Cell Analyzer (Bio-Rad Laboratories, Hercules, CA), and data were analyzed with FlowJo software (BD Biosciences, Woburn, MA). Samples were first gated on lymphocytes (FSC-A x SCA-A), singularity (FSC-A x FSC-H), and identified as live with Carboxylic acid, succinimidyl ester (live/dead) staining prior to gating strategy illustrated.

Additional file 4: Supplemental Figure 2. Raw frequency of cTfh and ASC. Peripheral blood mononuclear cells (PBMCs) were analyzed for circulating T follicular helper cells (cTfh), activated ICOS+PD1+ cTfh, and Antibody Secreting Cells (ASCs). Frequency of A) cTfh, B) activated cTfh, and C) ASCs. D-F) Fold change was calculated from pre-treatment to determine the effect of metformin on these populations prior to vaccination. Statistical significance was calculated by two-way repeated measures ANOVA with Šídák’s posthoc corrections and significance set at p

Additional file 1: Table S1. Summary of antibody and cell-mediated immune responses pre- and 4-weeks post-influenza vaccination. Table S2. Results from multivariable analysis of vaccine antibody responses in older adults where plasma TNF, IL-6 and CRP were simultaneously included as fixed effects. Table S3. Summary of participants enrolled in the follow-up cohort, including pre-vaccination levels of inflammatory mediators and antibody responses pre- and 4-weeks post-influenza vaccination. Figure S1. Associations between inflammatory mediator levels and antibody responses of high-dose vaccine recipients are independent of frailty. Figure S2. Joint effects of TNF and IL-6 in the association with post-vaccination antibody titres in standard- dose (SD) and high-dose (HD) older recipients. Figure S3. Sex-stratified models of systemic inflammation and the response to influenza vaccination in young (YA) and older (OA) adults vaccinated with either standard (SD) or high (HD) dose vaccine. Figure S4. ILT2+CD57+ Dim NK-cells mediate a significant proportion of the effect of frailty on post-vaccination A/H3N2 antibody titres in older high-dose recipients.

Additional file 1: Supplementary Table 1. Regression table describing the association between standardized, natural-log 4-week antibody titres and ΔBA in high-dose recipients, including a two-way interaction between ΔBA and CMV serostatus. Supplementary Table 2. KDM training parameters derived from the CLSA and used calculate biological aging in the vaccination cohort. Supplementary Figure 1. Characteristics of KDM biological age (BA) in the CLSA training cohort and associations with the frailty index (FI). A) Pearson’s correlation (R) for BA with chronological age and significance (p) for females (red asterisk) and males (blue dots). B) Distribution of ΔBA in females and males, including the mean and standard deviation. C) Differences in years for ΔBA (and 95% confidence interval) for pre-frail (0.10=FI

Additional file 2. Review history.

ObjectiveTo determine whetherCYP2C19loss-of-function (LoF) alleles increase risk of ischaemic stroke and myocardial infarction (MI) in UK primary care patients prescribed clopidogrel.DesignRetrospective cohort analysis.SettingPrimary care practices in the UK from January 1999 to September 2017.Participants7483 European-ancestry adults from the UK Biobank study with genetic and linked primary care data, aged 36–79 years at time of first clopidogrel prescription.InterventionsClopidogrel prescription in primary care, mean duration 2.6 years (range 2 months to 18 years).Main outcome measureHospital inpatient-diagnosed ischaemic stroke, MI or angina while treated with clopidogrel.Results28.7% of participants carried at least one CYP2C19LoF variant. LoF carriers had higher rates of incident ischaemic stroke while treated with clopidogrel compared with those without the variants (8 per 1000 person-years vs 5.2 per 1000 person-years; HR 1.53, 95% CIs 1.04 to 2.26, p=0.031). LoF carriers also had increased risk of MI (HR 1.14, 95% CI 1.04 to 1.26, p=0.008). In combined analysis LoF carriers had increased risk of any ischaemic event (stroke or MI) (HR 1.17, 95% CI 1.06 to 1.29, p=0.002). Adjustment for aspirin coprescription produced similar estimates. In lifetables using observed incidence rates, 22.5% (95% CI 14.4% to 34.0%) ofCYP2C19LoF carriers on clopidogrel were projected to develop an ischaemic stroke by age 79 (oldest age in the study), compared with 15.4% (95% CI 11.4% to 20.5%) in non-carriers, that is, 7.1% excess stroke incidence in LoF carriers by age 79.ConclusionsA substantial proportion of the UK population carry genetic variants that reduce metabolism of clopidogrel to its active form. In family practice patients on clopidogrel,CYP2C19LoF variants are associated with substantially higher incidence of ischaemic events. Genotype-guided selection of antiplatelet medications may improve outcomes in patients carryingCYP2C19genetic variants.

Varied physiological functions demonstrate increased heterogeneity with aging. Variability in force exertion and motor performance is higher in old age, with increased step-to-step gait variability indicating greater risk of falls and cognitive decline. Even in healthy older adults, renal function may show no change, slight decline, or marked decline. In contrast, heart rate variability declines with age, with decreased complexity and a higher risk of cardiac events. The risk of death, disease and disability varies among individuals with increasing heterogeneity with aging. As a result, frailty has been conceptualized as both as a phenotype and an accumulation deficit index, offering strong predictive validity when seeking to understand the heterogeneity of aging from the perspective of risk of mortality and physiologic dysregulation across different systems. Physical resilience defined as ability to maintain or restore function following exposure to stressors also demonstrates increased heterogeneity with aging.

OBJECTIVES: To estimate outcomes according to attained blood pressure (BP) in the oldest adults treated for hypertension in routine family practice. DESIGN: Cohort analysis of primary care inpatient and death certificate data for individuals with hypertension. SETTING: Primary care practices in England (Clinical Practice Research Datalink). PARTICIPANTS: Individuals aged 80 and older taking antihypertensive medication and free of dementia, cancer, coronary heart disease, stroke, heart failure, and end-stage renal failure at baseline. MEASUREMENTS: Outcomes were mortality, cardiovascular events, and fragility fractures. Systolic BP (SBP) was grouped in 10-mmHg increments from less than 125 to 185 mmHg or more (reference 145-154 mmHg). RESULTS: Myocardial infarction hazards increased linearly with increasing SBP, and stroke hazards increased for SBP of 145 mmHg or greater, although lowest mortality was in individuals with SBP of 135 to 154 mmHg. Mortality of the 13.1% of patients with SBP less than 135 mmHg was higher than that of the reference group (Cox hazard ratio=1.25, 95% confidence interval=1.19-1.31; equating to one extra death per 12.6 participants). This difference in mortality was consistent over short- and long-term follow-up; adjusting for diastolic BP did not change the risk. Incident heart failure rates were higher in those with SBP less than 125 mmHg than in the reference group. CONCLUSION: In routine primary care, SBP less than 135 mmHg was associated with greater mortality in the oldest adults with hypertension and free of selected potentially confounding comorbidities. Although important confounders were accounted for, observational studies cannot exclude residual confounding. More work is needed to establish whether unplanned SBPs less than 135 mmHg in older adults with hypertension may be a useful clinical sign of poor prognosis, perhaps requiring clinical review of overall care.

The American Geriatrics Society, with support from the National Institute on Aging and other funders, held its eighth Bedside-to-Bench research conference, entitled "Sleep, Circadian Rhythms, and Aging: New Avenues for Improving Brain Health, Physical Health and Functioning," October 4 to 6, 2015, in Bethesda, Maryland. Part of a conference series addressing three common geriatric syndromes-delirium, sleep and circadian rhythm (SCR) disturbance, and voiding dysfunction-the series highlighted relationships and pertinent clinical and pathophysiological commonalities between these three geriatric syndromes. The conference provided a forum for discussing current sleep, circadian rhythm, and aging research; identifying gaps in knowledge; and developing a research agenda to inform future investigative efforts. The conference also promoted networking among developing researchers, leaders in the field of SCR and aging, and National Institutes of Health program personnel.

BackgroundAlthough vitamin D has been mechanistically linked to insulin secretion and sensitivity, it remains unclear whether low 25-hydroxyvitamin D levels confer an increased risk of impaired glucose metabolism. We evaluated the relationship between vitamin D insufficiency (25-hydroxyvitamin D < 20ng/mL) and abnormal hemoglobin A1c (A1c) (≥6.5%) in community-dwelling older persons and examined whether this relationship differed according to race.MethodsParticipants were 2,193 persons of age 70-79 years at Year 1 (52% women; 37% black) in the Health, Aging, and Body Composition study who had clinic visits at Years 2 and 4. Logistic regression analyses, adjusted for potential confounders, were used to evaluate the association between vitamin D insufficiency and abnormal A1c 2 years later. Interaction of race and vitamin D insufficiency was tested.ResultsA total of 665 (30%) and 301 (14%) of the participants had vitamin D insufficiency at Year 2 and abnormal A1c at Year 4, respectively. After controlling for demographics, other potential confounders, and diabetes status at Year 4 (n = 477 diabetics), we found that vitamin D insufficiency was associated with an increased likelihood of having abnormal A1c (odds ratio = 1.56; 95% CI: 1.03-2.37). We also found that this relationship persisted among the 1,765 participants without diabetes in Year 2 (odds ratio = 2.33; 95% CI: 1.00-5.40). Findings did not differ by race.ConclusionsVitamin D insufficiency was associated with abnormal A1c levels among black and white older persons independent of diabetes status. Future studies are needed to establish the temporal relationship between vitamin D and A1c in diverse samples of older persons.

Prevalence of any and long-term high risk medications in 2003/4, 2007/8 and 2011/12. (DOCX 59 kb)

Weighted prevalence of patients receiving one or more potentially harmful drugs in 2011/12 by specific chronic disease. (DOCX 46 kb)

Logistic regression models for the predictors of high risk medication exposure at least once a year (any prescribing) or all quarters of the year (long-term prescribing) in 2011/12. (DOCX 43 kb)

High Risk Medications to avoid in older people according to Beers Criteria after UK adaptation. (DOCX 43 kb)

Beers 2012 Criteria filtering conditions (recommendations) and their operationalization in the CPRD sample. (DOCX 44 kb)

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10−17), arthritis (GDF5 p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing., Muscle weakness has been associated with morbidity and mortality in older people. Here, the authors have investigated this trait further by performing a genome-wide meta-analysis of grip strength and Mendelian randomization to discover causal relationships between muscle weakness and other diseases.