Modifiable dementia risk factors associated with objective and subjective cognition.

INTRODUCTION: Early detection of both objective and subjective cognitive impairment is important. Subjective complaints in healthy individuals can precede objective deficits. However, the differential associations of objective and subjective cognition with modifiable dementia risk factors are unclear. METHODS: We gathered a large cross-sectional sample (N = 3327, age 18 to 84) via a smartphone app and quantified the associations of 13 risk factors with subjective memory problems and three objective measures of executive function (visual working memory, cognitive flexibility, model-based planning). RESULTS: Depression, socioeconomic status, hearing handicap, loneliness, education, smoking, tinnitus, little exercise, small social network, stroke, diabetes, and hypertension were all associated with impairments in at least one cognitive measure. Subjective memory had the strongest link to most factors; these associations persisted after controlling for depression. Age mostly did not moderate these associations. DISCUSSION: Subjective cognition was more sensitive to self-report risk factors than objective cognition. Smartphones could facilitate detecting the earliest cognitive impairments. HIGHLIGHTS: Smartphone assessments of cognition were sensitive to dementia risk factors. Subjective cognition had stronger links to most factors than did objective cognition. These associations were not fully explained by depression. These associations were largely consistent across the lifespan.

Which Components of the Haemodynamic Response to Active Stand Predict Cardiovascular Disease and Mortality? Data From The Irish Longitudinal Study on Ageing.

Background: An integrated haemodynamic response during standing may serve as an integrative marker of neuro-cardiovascular function. Individual components of both heart rate (HR) and blood pressure (BP) responses to active stand (AS) have been linked with cardiovascular disease (CVD) and mortality. We assessed longitudinal associations between entire HR/BP response curves during AS, incident CVD and mortality over 12 years. Methods: Beat-to-beat measurements of dynamic HR/BP responses to AS were conducted in 4,336 individuals (61.5±8.2 years; 53.7% female). Functional Principal Components Analysis was applied to HR/BP response curves and their association with CVD and mortality assessed. We hypothesised that integrating BP/HR information from the entire haemodynamic response curve may uncover novel associations with both CVD and mortality. Results: Higher systolic BP (SBP) before AS and blunted recovery of SBP during AS was associated with all-cause mortality over 12-years (Hazard Ratio [HR]: 1.14; 1.04, 1.26; p=0.007). Higher baseline/peak HR and lower HR from 30 seconds post stand onwards were associated with lower mortality due to circulatory causes (HR: 0.78; 0.64, 0.95; p = 0.013). Higher HR throughout AS was associated with mortality from other causes (HR: 1.48; 1.22, 1.80; p<0.001). Findings persisted on robust covariate adjustment. Conclusions: We observed distinct relationships between HR/BP responses to AS and 12-year incident CVD and mortality. Integrating the entire haemodynamic response may reveal more nuanced relationships between HR/BP responses to AS, CVD and mortality - serving as an integrative marker of neuro-cardiovascular health in midlife and beyond.

Mind versus body: Perceived stress and biological stress are independently related to cognitive decline.

Chronic stress may increase risk of age-related cognitive decline. 'Stress', however, is a multidimensional construct and few studies have investigated the inter-relationship of subjective stress and biological stress with cognitive decline. In this study, we examine the relationship between perceived stress and two measures of biological stress - allostatic load, indexing stress at the physiological level and leukocyte telomere length, indexing stress at the cellular level - with cognitive decline over a 12-year period in adults aged 50 and older. 3,458 participants (aged ≥ 50) from The Irish Longitudinal study on Ageing with measurements of allostatic load, telomere length and perceived stress at baseline and repeated measures of cognitive function were included. Hierarchical linear regression models with adjustment for multiple potential confounders were applied, and repeated stratified by sex in sensitivity analyses. Higher perceived stress at baseline was associated with lower cognitive function (ß = -0.10, 95 % CI -0.12, -0.07, p <.001), with similar strength of associations across waves. There were significant interactions between measures of biological stress and wave; higher allostatic load was associated (X2(18) = 64.4; p <.001), and telomere length was borderline (X2(18) = 9.4; p =.09) associated with cognitive decline from 4-year follow-up onward. Sex stratified analyses revealed that the association between telomere length and cognitive decline was present in women only. Mutual adjustment did not attenuate associations in either case. The interactions between allostatic load and telomere length with perceived stress were not significant. Our findings suggest that subjective measures of stress and biological metrics may be independently related to cognitive function over time in older adults, hinting at the potential for different underlying mechanisms.

Metabolic syndrome accelerates epigenetic ageing in older adults: Findings from The Irish Longitudinal Study on Ageing (TILDA).

Metabolic syndrome (MetS) is a risk factor for the development of diabetes, cardiovascular disease, and all-cause mortality. It has an estimated prevalence of 40 % among older adults. Epigenetic clocks, which measure biological age based on DNA methylation (DNAm) patterns, are a candidate biomarker for ageing. GrimAge is one such clock which is based on levels of DNAm at 100 Cytosine-phosphate-Guanine (CpG) sites. This study hypothesised that those with MetS have 'accelerated ageing' (biological age greater than their chronological age) as indexed by GrimAge. This study examined MetS's association with GrimAge age acceleration (AA) using data from a subsample of 469 participants of the Irish Longitudinal Study on Ageing (TILDA). MetS was defined by National Cholesterol Education Program Third Adult Treatment Panel (ATP III) and International Diabetes Foundation (IDF) criteria, operationalised using the conventional binary cut-off, and as a count variable ranging from 0 to 5, based on the presence of individual components. This study also explored inflammation (as measured by C reactive protein) and metabolic dysfunction (as measured by adiponectin) as possible mediating factors between MetS and GrimAge AA. We found that MetS as defined by IDF criteria was associated with GrimAge AA of 0.63 years. When MetS was treated as a count, each unit increase in MetS score was associated with over 0.3 years GrimAge AA for both ATP III and IDF criteria. Inflammation mediated approximately one third of the association between MetS and GrimAge AA, suggesting that chronic subclinical inflammation observed in MetS has a relationship with DNAm changes consistent with a faster pace of ageing. Metabolic dysfunction mediated the association between MetS and GrimAge AA to a lesser extent (16 %). These data suggest that chronic subclinical inflammation observed in MetS has a relationship with DNAm changes consistent with a greater pace of ageing.

Towards a consensus definition of allostatic load: a multi-cohort, multi-system, multi-biomarker individual participant data (IPD) meta-analysis.

BACKGROUND: Allostatic load (AL) is a multi-system composite index for quantifying physiological dysregulation caused by life course stressors. For over 30 years, an extensive body of research has drawn on the AL framework but has been hampered by the lack of a consistent definition. METHODS: This study analyses data for 67,126 individuals aged 40-111 years participating in 13 different cohort studies and 40 biomarkers across 12 physiological systems: hypothalamic-pituitary-adrenal (HPA) axis, sympathetic-adrenal-medullary (SAM) axis, parasympathetic nervous system functioning, oxidative stress, immunological/inflammatory, cardiovascular, respiratory, lipidemia, anthropometric, glucose metabolism, kidney, and liver. We use individual-participant-data meta-analysis and exploit natural heterogeneity in the number and type of biomarkers that have been used across studies, but a common set of health outcomes (grip strength, walking speed, and self-rated health), to determine the optimal configuration of parameters to define the concept. RESULTS: There was at least one biomarker within 9/12 physiological systems that was reliably and consistently associated in the hypothesised direction with the three health outcomes in the meta-analysis of these cohorts: dehydroepiandrosterone sulfate (DHEAS), low frequency-heart rate variability (LF-HRV), C-reactive protein (CRP), resting heart rate (RHR), peak expiratory flow (PEF), high density lipoprotein cholesterol (HDL-C), waist-to-height ratio (WtHR), HbA1c, and cystatin C. An index based on five biomarkers (CRP, RHR, HDL-C, WtHR and HbA1c) available in every study was found to predict an independent outcome - mortality - as well or better than more elaborate sets of biomarkers. DISCUSSION: This study has identified a brief 5-item measure of AL that arguably represents a universal and efficient set of biomarkers for capturing physiological 'wear and tear' and a further biomarker (PEF) that could usefully be included in future data collection.

Examining the Impact of Socioeconomic Position Across the Life Course on Cognitive Function and Brain Structure in Healthy Aging.

This study explores the relationship of life-course intergenerational social mobility with cognitive function and brain structure in older adults using Diagonal Reference Models. Data from the Irish Longitudinal Study on Ageing, a population-based cohort of adults aged 50 years and older (N = 4 620 participants; mean age: 66.1; standard deviation: 9.1; 55% female) was used for analysis. Brain magnetic resonance imaging data were available for 464 participants. Social mobility was characterized as the difference between childhood socioeconomic position (SEP; ie, father's occupation) and adulthood SEP (ie, own occupation). The Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), cortical thickness, and total gray matter volume (GMV) served as global cognitive and brain measures. Exploratory analyses included the volumes of the ventromedial prefrontal cortex (vmPFC), anterior cingulate (AC), hippocampus, and amygdala. A social gradient in cognitive function was observed among the intergenerationally stable; brain structure was not as clearly socially patterned. Adulthood SEP was significantly associated with MoCA (weight = 0.76; p < .001), MMSE (weight = 0.91; p < .001), GMV (weight = 0.77; p = .002), and AC volume (weight = 0.76; p < .001), whereas childhood SEP was associated with vmPFC volume (weight = 1.00; p = .003). There was no independent association of social mobility with any of the outcomes. Together our results suggest that both childhood and adulthood SEP are important in shaping later-life brain health, but that adulthood SEP predominates in terms of its influence. This is potentially an important insight as it suggests that brain health may be modifiable if socioeconomic circumstances change.

Life-course socioeconomic factors are associated with markers of epigenetic aging in a population-based study.

Adverse socioeconomic circumstances negatively affect the functioning of biological systems, but the underlying mechanisms remain only partially understood. Here, we explore the associations between life-course socioeconomic factors and four markers of epigenetic aging in a population-based setting. We included 684 participants (52 % women, mean age 52.6 ± 15.5 years) from a population and family-based Swiss study. We used nine life-course socioeconomic indicators as the main exposure variables, and four blood-derived, second generation markers of epigenetic aging as the outcome variables (Levine's DNAmPhenoAge, DunedinPoAm38, GrimAge epigenetic age acceleration (EAA), and the mortality risk score (MS)). First, we investigated the associations between socioeconomic indicators and markers of epigenetic aging via mixed-effect linear regression models, adjusting for age, sex, participant's recruitment center, familial structure (random-effect covariate), seasonality of blood sampling, and technical covariates. Second, we implemented counterfactual mediation analysis to investigate life-course and intermediate mechanisms underlying the socioeconomic gradient in epigenetic aging. Effect-size estimates were assessed using regression coefficients and counterfactual mediation parameters, along with their respective 95 % confidence intervals. Individuals reporting a low father's occupation, adverse financial conditions in childhood, a low income, having financial difficulties, or experiencing unfavorable socioeconomic trajectories were epigenetically older and had a higher mortality risk score than their more advantaged counterparts. Specifically, this corresponded to an average increase of 1.1-1.5 years for Levine's epigenetic age (ß and 95 %CI range, ß (minimum and maximum): 1.1-1.5 95 %CI[0.0-0.2; 2.3-3.0]), 1.1-1.5 additional years for GrimAge (ß: 1.1-1.5 95 %CI[0.2-0.6; 1.9-3.0]), a 1-3 % higher DunedinPoAm38 age acceleration (ß: 0.01-0.03 95 %CI[0.00; 0.03-0.04]), and a 10-50 % higher MS score (ß: 0.1-0.4 95 %CI[0.0-0.2; 0.3-0.4]) for the aforementioned socioeconomic indicators. By exploring the life-course mechanisms underlying the socioeconomic gradient in epigenetic aging, we found that both childhood and adulthood socioeconomic factors contributed to epigenetic aging, and that detrimental lifestyle factors mediated the relation between socioeconomic circumstances in adulthood and EAA (31-89 % mediated proportion). This study provides emerging evidence for an association between disadvantaged life-course socioeconomic circumstances and detrimental epigenetic aging patterns, supporting the "sensitive-period" life-course model. Counterfactual mediation analyses further indicated that the effect of socioeconomic factors in adulthood operates through detrimental lifestyle factors, whereas associations involving early-life socioeconomic factors were less clear.

Intergenerational Social Mobility and Allostatic Load in Midlife and Older Ages: A Diagonal Reference Modeling Approach.

OBJECTIVES: This study aims to understand the association of life-course intergenerational social mobility with allostatic load (AL) burden in midlife and older ages in Ireland. METHODS: The study involved biological data for 3,987 older adults participating in The Irish Longitudinal Study on Ageing (TILDA). Intergenerational social mobility was characterized using the cross-classification of origin socioeconomic position (SEP; i.e., father's occupation) and destination SEP (i.e., own occupation). AL was operationalized using 12 biomarkers tapping cardiovascular, metabolic, renal, and immune system dysregulation. Diagonal reference modeling (DRM) and ordinary least square regression techniques were applied to explore the effect of social mobility on AL burden. RESULTS: A total of 55.5% experienced intergenerational mobility: 37.5% were upwardly mobile, 18.0% were downwardly mobile. A social gradient in AL was observed among the socially non-mobile. Destination SEP (b = 0.74, 95% CI = 0.57, 0.92) predominated in influence over origin, although both life stages exerted significant influence on later-life AL. Social mobility in either direction was not associated with AL burden. Mobility coefficients were substantially small across a large variety of model specifications. DISCUSSION: Findings provide evidence for an accumulation model of social inequalities in which disparities in health are diluted rather than increased by social mobility (i.e., gradient constraint), with the socially mobile having an AL score that is intermediate between their origin class and destination class. This implies that the effects of origin SEP on health are not immutable, but are instead responsive to changing socioeconomic circumstances across the life course.

A blood DNA methylation biomarker for predicting short-term risk of cardiovascular events.

BACKGROUND: Recent evidence highlights the epidemiological value of blood DNA methylation (DNAm) as surrogate biomarker for exposure to risk factors for non-communicable diseases (NCD). DNAm surrogate of exposures predicts diseases and longevity better than self-reported or measured exposures in many cases. Consequently, disease prediction models based on blood DNAm surrogates may outperform current state-of-the-art prediction models. This study aims to develop novel DNAm surrogates for cardiovascular diseases (CVD) risk factors and develop a composite biomarker predictive of CVD risk. We compared the prediction performance of our newly developed risk score with the state-of-the-art DNAm risk scores for cardiovascular diseases, the 'next-generation' epigenetic clock DNAmGrimAge, and the prediction model based on traditional risk factors SCORE2. RESULTS: Using data from the EPIC Italy cohort, we derived novel DNAm surrogates for BMI, blood pressure, fasting glucose and insulin, cholesterol, triglycerides, and coagulation biomarkers. We validated them in four independent data sets from Europe and the USA. Further, we derived a DNAmCVDscore predictive of the time-to-CVD event as a combination of several DNAm surrogates. ROC curve analyses show that DNAmCVDscore outperforms previously developed DNAm scores for CVD risk and SCORE2 for short-term CVD risk. Interestingly, the performance of DNAmGrimAge and DNAmCVDscore was comparable (slightly lower for DNAmGrimAge, although the differences were not statistically significant). CONCLUSIONS: We described novel DNAm surrogates for CVD risk factors useful for future molecular epidemiology research, and we described a blood DNAm-based composite biomarker, DNAmCVDscore, predictive of short-term cardiovascular events. Our results highlight the usefulness of DNAm surrogate biomarkers of risk factors in epigenetic epidemiology to identify high-risk populations. In addition, we provide further evidence on the effectiveness of prediction models based on DNAm surrogates and discuss methodological aspects for further improvements. Finally, our results encourage testing this approach for other NCD diseases by training and developing DNAm surrogates for disease-specific risk factors and exposures.

The Role of Epigenetic Clocks in Explaining Educational Inequalities in Mortality: A Multicohort Study and Meta-analysis.

Educational inequalities in all-cause mortality have been observed for decades. However, the underlying biological mechanisms are not well known. We aimed to assess the role of DNA methylation changes in blood captured by epigenetic clocks in explaining these inequalities. Data were from 8 prospective population-based cohort studies, representing 13 021 participants. First, educational inequalities and their portion explained by Horvath DNAmAge, Hannum DNAmAge, DNAmPhenoAge, and DNAmGrimAge epigenetic clocks were assessed in each cohort via counterfactual-based mediation models, on both absolute (hazard difference) and relative (hazard ratio) scales, and by sex. Second, estimates from each cohort were pooled through a random effect meta-analysis model. Men with low education had excess mortality from all causes of 57 deaths per 10 000 person-years (95% confidence interval [CI]: 38, 76) compared with their more advantaged counterparts. For women, the excess mortality was 4 deaths per 10 000 person-years (95% CI: -11, 19). On the relative scale, educational inequalities corresponded to hazard ratios of 1.33 (95% CI: 1.12, 1.57) for men and 1.15 (95% CI: 0.96, 1.37) for women. DNAmGrimAge accounted for the largest proportion, approximately 50%, of the educational inequalities for men, while the proportion was negligible for women. Most of this mediation was explained by differential effects of unhealthy lifestyles and morbidities of the World Health Organization (WHO) risk factors for premature mortality. These results support DNA methylation-based epigenetic aging as a signature of educational inequalities in life expectancy emphasizing the need for policies to address the unequal social distribution of these WHO risk factors.

Early life adversity and age acceleration at mid-life and older ages indexed using the next-generation GrimAge and Pace of Aging epigenetic clocks.

OBJECTIVE: This retrospective cross-sectional study was designed to explore whether the experience of childhood adversity was associated with epigenetic age acceleration in mid-life and older ages using the next generation GrimAge and Pace of Aging DNA methylation clocks. METHOD: The study involved a sub-sample of 490 individuals aged 50-87 years of age participating in the Irish Longitudinal Study on Aging (TILDA); a large nationally representative prospective cohort study of aging in Ireland. Childhood adversity was ascertained via self-report using 5-items that were deemed to indicate potentially nefarious childhood exposures, including growing up poor, death of a parent, parental substance abuse in the family, childhood physical abuse, and childhood sexual abuse. RESULTS: Only childhood poverty was associated with significant epigenetic age acceleration according to the GrimAge and Pace of Aging clocks, hastening biological aging by 2.04 years [CI= 1.07, 3.00; p < 0.001] and 1.16 years [CI= 0.11, 2.21; p = 0.030] respectively. Analysis of the dose-response pattern revealed each additional adversity was associated with 0.69 years of age acceleration [CI= 0.23, 1.15; p = 0.004] according to the GrimAge clock. Mediation analysis suggested that lifetime smoking explains a substantial portion (>50%) of the excess risk of age acceleration amongst those who experienced childhood poverty. CONCLUSIONS: This study adds to the growing body of evidence which implicates early life adversity, particularly deprivation as a potential precipitant of earlier biological aging, and implicates smoking-related changes to DNA methylation processes as a candidate pathway and mechanism through which the social environment gets transduced at a biological level to hasten the aging process.

Comparisons of disease cluster patterns, prevalence and health factors in the USA, Canada, England and Ireland.

BACKGROUND: Identification of those who are most at risk of developing specific patterns of disease across different populations is required for directing public health policy. Here, we contrast prevalence and patterns of cross-national disease incidence, co-occurrence and related risk factors across population samples from the U.S., Canada, England and Ireland. METHODS: Participants (n = 62,111) were drawn from the US Health and Retirement Study (n = 10,858); the Canadian Longitudinal Study on Ageing (n = 36,647); the English Longitudinal Study of Ageing (n = 7938) and The Irish Longitudinal Study on Ageing (n = 6668). Self-reported lifetime prevalence of 10 medical conditions, predominant clusters of multimorbidity and their specific risk factors were compared across countries using latent class analysis. RESULTS: The U.S. had significantly higher prevalence of multimorbid disease patterns and nearly all diseases when compared to the three other countries, even after adjusting for age, sex, BMI, income, employment status, education, alcohol consumption and smoking history. For the U.S. the most at-risk group were younger on average compared to Canada, England and Ireland. Socioeconomic gradients for specific disease combinations were more pronounced for the U.S., Canada and England than they were for Ireland. The rates of obesity trends over the last 50 years align with the prevalence of eight of the 10 diseases examined. While patterns of disease clusters and the risk factors related to each of the disease clusters were similar, the probabilities of the diseases within each cluster differed across countries. CONCLUSIONS: This information can be used to better understand the complex nature of multimorbidity and identify appropriate prevention and management strategies for treating multimorbidity across countries.

Psychosocial adversity and allostatic load burden in midlife and older ages.

OBJECTIVE: To investigate the individual and cumulative impact of childhood and adulthood adversity on allostatic load (AL) burden. METHOD: Retrospective cross-sectional study design involving 4,165 participants from the first wave of The Irish Longitudinal study on Ageing (TILDA). AL was operationalized using 12 biomarkers across four physiological systems (cardiovascular, metabolic, renal, and immune). Measures of psychosocial adversity included poverty, abuse, loss, and illness. Negative binomial regression models estimated the relationship of individual adversities and a cumulative count of adversities with AL burden, controlling for age and sex. Multivariable models adjusted additionally for a range of other sociodemographic and lifestyle factors. RESULTS: Childhood poverty, childhood physical abuse, and having a spouse/partner/child experience a life-threatening illness/accident were associated with 10% (95% CI [1.04, 1,16]), 10% (95% CI [1.01, 1.18]), and 6% (95% CI [1.01, 1.11]) greater AL burden, respectively. Cumulative adversity was associated with 3% (95% CI [1.01, 1.04]) higher AL burden. Adjusting for sociodemographic and lifestyle covariates rendered the association of childhood poverty (IRR= 1.04, 95% CI [.98, 1.09]; p = .190) and childhood physical abuse (IRR= 1.07, 95% CI [.99, 1.15]; p = .081) with AL burden nonsignificant, while the association of having an ill spouse/partner/child on AL persisted (IRR= 1.06, 95% CI [1.01, 1.11]; p = .021). CONCLUSIONS: This study provided limited support for the idea that psychosocial stress leads to higher AL, with just three out of 11 adversities associated with AL. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

GrimAge Outperforms Other Epigenetic Clocks in the Prediction of Age-Related Clinical Phenotypes and All-Cause Mortality.

The aging process is characterized by the presence of high interindividual variation between individuals of the same chronical age prompting a search for biomarkers that capture this heterogeneity. Epigenetic clocks measure changes in DNA methylation levels at specific CpG sites that are highly correlated with calendar age. The discrepancy resulting from the regression of DNA methylation age on calendar age is hypothesized to represent a measure of biological aging with a positive/negative residual signifying age acceleration (AA)/deceleration, respectively. The present study examines the associations of 4 epigenetic clocks-Horvath, Hannum, PhenoAge, GrimAge-with a wide range of clinical phenotypes (walking speed, grip strength, Fried frailty, polypharmacy, Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), Sustained Attention Reaction Time, 2-choice reaction time), and with all-cause mortality at up to 10-year follow-up, in a sample of 490 participants in the Irish Longitudinal Study on Ageing (TILDA). HorvathAA and HannumAA were not predictive of health; PhenoAgeAA was associated with 4/9 outcomes (walking speed, frailty MOCA, MMSE) in minimally adjusted models, but not when adjusted for other social and lifestyle factors. GrimAgeAA by contrast was associated with 8/9 outcomes (all except grip strength) in minimally adjusted models, and remained a significant predictor of walking speed, .polypharmacy, frailty, and mortality in fully adjusted models. Results indicate that the GrimAge clock represents a step-improvement in the predictive utility of the epigenetic clocks for identifying age-related decline in an array of clinical phenotypes promising to advance precision medicine.

Patterning of educational attainment across inflammatory markers: Findings from a multi-cohort study.

BACKGROUND: Evidence suggests that the inflammatory reaction, an adaptive response triggered by a variety of harmful stimuli and conditions involved in the risk and development of many chronic diseases, is a potential pathway through which the socioeconomic environment is biologically embedded. Difficulty in interpreting the role of the inflammatory system in the embodiment dynamic arises because of heterogeneity across studies that use a limited but varied number of inflammatory markers. There is no consensus in the literature as to which inflammatory markers beyond the C-reactive protein and to a lesser extent interleukin 6 are related to the social environment. Accordingly, we aimed to investigate the association between educational attainment, and several markers of inflammation - C-reactive protein, fibrinogen, interleukin 6, interleukin 1ß and tumor necrosis factor α- in 6 European cohort studies. METHODS: Up to 17,470 participants from six European cohort studies with data on educational attainment, health behaviors and lifestyle factors, and at least two different inflammatory markers. Four sub-datasets were drawn with varying numbers of participants to allow pairwise comparison of the social patterning of C-reactive protein and any other inflammatory markers. To evaluate within each sub-dataset the importance of the context and cohort specificities, linear regression-based analyses were performed separately for each cohort and combined in a random effect meta-analysis to determine the relationship between educational attainment and inflammation. RESULTS: We found that the magnitude of the relationship between educational attainment and five inflammatory biomarkers (C-reactive protein, fibrinogen, interleukin 6 and 1ß and tumor necrosis factor α) was variable. By far the most socially patterned biomarker was C-reactive protein, followed by fibrinogen and to lesser extent interleukin 6, where a low educational attainment was associated with higher inflammation even after adjusting for health behaviours and body mass index. No association was found with interleukin 1ß and tumor necrosis factor α. CONCLUSIONS: Our study suggests different educational patterning of inflammatory biomarkers. Further large-scale research is needed to explore social differences in the inflammatory cascade in greater detail and the extent to which these differences contribute to social inequalities in health.

Physical activity partially mediates associations between "Big" personality traits and incident generalized anxiety disorder: Findings from the irish longitudinal study on ageing.

BACKGROUND: This study aimed to examine associations of personality with generalized anxiety disorder (GAD) and physical activity (PA), PA with GAD, and PA mediates associations between personality and incident GAD. METHODS: Participants aged ≥50 years completed the 60-item NEO-Five Factor Inventory questionnaire to assess personality and short-form International Physical Activity Questionnaire at baseline, and the Composite International Diagnostic Interview - Short Form to clinically assess GAD at baseline and 2, 4, and 6 years later. Participants who had GAD at baseline or reported having ever been told by a doctor that they had anxiety were excluded from analyses. Binary logistic regression quantified associations of the 'Big Five' personality traits with PA and incident GAD, and associations of PA with incident GAD (i.e., GAD at any point during follow-up). The 'counterfactual approach' identified potential mediating effects of PA in the associations between personality traits and incident GAD. RESULTS: Participants (n = 4582; 53.7% female) were aged 64.38±8.88 years. Incidence of GAD was 2.95% (n = 135). Extraversion (OR=1.160, 95%CI=1.087-1.237), openness (1.113, 1.043-1.188), and conscientiousness (1.083, 1.015-1.155) were positively associated with physical activity. Neuroticism was positively (2.335, 1.945-2.803), and extraversion (0.700, 0.563-0.797), conscientiousness (0.826, 0.693-0.985), and PA (0.655, 0.451-0.952) were inversely, associated with the incident GAD. Approximately 8.7% of the effect of extraversion and 8.8% of the effect of conscientiousness on GAD was due to mediation by PA only. LIMITATIONS: PA was self-reported Conclusions: Personality screening may help to identify older adults at-risk of anxiety who would benefit from participation in physical activity interventions.

Does the choice of Allostatic Load scoring algorithm matter for predicting age-related health outcomes?

Allostatic Load (AL) is posited to provide a measure of cumulative physiological dysregulation across multiple biological systems and demonstrates promise as a sub-clinical marker of overall health. Despite the large heterogeneity of measures employed in the literature to represent AL, few studies have investigated the impact of different AL scoring systems in predicting health. This study uses data for 4477 participants aged 50+ years participating in the Irish Longitudinal Study on Ageing (TILDA) to compare the utility of 14 different scoring algorithms that have been used to operationalise AL (i.e. count-based high-risk quartiles, deciles, two-tailed cut-points, z-scores, system-weighted indices, clinical cut-points, sex-specific scores, and incorporating medication usage). Model fit was assessed using R2, Bayesian Information Criterion (BIC), and the area under the Receiver Operating Characteristic curve (AUC). The measure incorporating medications predicted walking speed and SRH marginally better than others. In general, AL was not predictive of grip strength. Overall, the results suggest that the choice of AL scoring algorithm exerts a relatively modest influence in predicting a number of important health outcomes.

Special Report: The Biology of Inequalities in Health: The Lifepath Consortium.

Funded by the European Commission Horizon 2020 programme, the Lifepath research consortium aimed to investigate the effects of socioeconomic inequalities on the biology of healthy aging. The main research questions included the impact of inequalities on health, the role of behavioral and other risk factors, the underlying biological mechanisms, the efficacy of selected policies, and the general implications of our findings for theories and policies. The project adopted a life-course and comparative approach, considering lifetime effects from childhood and adulthood, and pooled data on up to 1.7 million participants of longitudinal cohort studies from Europe, USA, and Australia. These data showed that socioeconomic circumstances predicted mortality and functional decline as strongly as established risk factors currently targeted by global prevention programmes. Analyses also looked at socioeconomically patterned biological markers, allostatic load, and DNA methylation using richly phenotyped cohorts, unraveling their association with aging processes across the life-course. Lifepath studies suggest that socioeconomic circumstances are embedded in our biology from the outset-i.e., disadvantage influences biological systems from molecules to organs. Our findings have important implications for policy, suggesting that (a) intervening on unfavorable socioeconomic conditions is complementary and as important as targeting well-known risk factors, such as tobacco and alcohol consumption, low fruit and vegetable intake, obesity and a sedentary lifestyle, and that (b) effects of preventive interventions in early life integrate interventions in adulthood. The report has an executive summary that refers to the different sections of the main paper.

Impaired orthostatic heart rate recovery is associated with smaller thalamic volume: Results from The Irish Longitudinal Study on Aging (TILDA).

The thalamus is a central hub of the autonomic network and thalamic volume has been associated with high-risk phenotypes for sudden cardiac death. Heart rate response to physiological stressors (e.g., standing) and the associated recovery patterns provide reliable indicators of both autonomic function and cardiovascular risk. Here we examine if thalamic volume may be a risk marker for impaired heart rate recovery in response to orthostatic challenge. The Irish Longitudinal Study on Aging involves a nationally representative sample of older individuals aged ≥50 years. Multimodal brain magnetic resonance imaging and orthostatic heart rate recovery were available for a cross-sectional sample of 430 participants. Multivariable regression and linear mixed-effects models were adjusted for head size, age, sex, education, body mass index, blood pressure, history of cardiovascular diseases and events, cardiovascular medication, diabetes mellitus, smoking, alcohol intake, timed up-and-go (a measure of physical frailty), physical exercise and depression. Smaller thalamic volume was associated with slower heart rate recovery (-1.4 bpm per 1 cm3 thalamic volume, 95% CI -2.01 to -0.82; p < .001). In multivariable analysis, participants with smaller thalamic volumes had a mean heart rate recovery -2.7 bpm slower than participants with larger thalamic volumes (95% CI -3.89 to -1.61; p < .001). Covariates associated with smaller thalamic volume included age, history of diabetes, and heavy alcohol consumption. Thalamic volume may be an indicator of the structural integrity of the central autonomic network. It may be a clinical biomarker for stratification of individuals at risk of autonomic dysfunction, cardiovascular events, and sudden cardiac death.