Association of plasma high-density lipoprotein cholesterol level with risk of incident dementia: a cohort study of healthy older adults.

Background: Recent studies have reported associations between high plasma high-density lipoprotein cholesterol (HDL-C) levels and risk of all-cause mortality, age-related macular degeneration, sepsis and fractures, but associations with dementia risk remain unclear. To determine whether high plasma HDL-C levels are associated with increased incident dementia risk in initially-healthy older people. Methods: We conducted a post-hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial; a double-blind, randomized, placebo-controlled trial of daily low-dose aspirin in healthy older people. ASPREE recruited 16,703 participants aged ≥70 years (from Australia) and 2411 participants aged ≥65 years (from the US) between 2010 and 2014. Participants had no diagnosed cardiovascular disease, dementia, physical disability, or life-threatening illness at enrolment and were cognitively healthy (3MS score ≥78). All-cause dementia was a primary trial endpoint, and determined by DSM-IV criteria. Cox regression was used to examine hazard ratios between HDL-C categories <40 mg/dL, 40-60 mg/dL (reference category), 60-80 mg/dL, and >80 mg/dL and dementia. Restricted cubic spline curves were used to determine nonlinear associations. Data analysis was performed from October 2022 to January 2023. Findings: Of the 18,668 participants, 850 (4.6%) cases of incident dementia were recorded over 6.3 (SD 1.8) years. Participants with high HDL-C (>80 mg/dL) had a 27% higher risk of dementia (HR 1.27, 95% CI 1.03, 1.58). Age stratified analyses demonstrated that the risk of incident dementia was higher in participants ≥75 years compared to participants <75 years (HR 1.42, 95% CI 1.10, 1.83 vs HR 1.02, 95% CI 0.68, 1.51). Associations remained significant after adjusting for covariates including age, sex, country of enrolment, daily exercise, education, alcohol consumption, weight change over time, non-HDL-C, HDL-C-PRS, and APOE genotype. Interpretation: In a population of initially-healthy older adults aged ≥75 years, high HDL-C levels were associated with increased risk of all-cause dementia. Funding: National Institutes of Health, USA; National Health and Medical Research Council Australia; Monash University (Melbourne, VIC, Australia); and the Victorian Cancer Agency (Australia).

Association of serum phosphate, calcium and alkaline phosphatase with risk of incident fractures in healthy older adults.

BACKGROUND: Aging increases fracture risk through bone loss and microarchitecture deterioration due to an age-related imbalance in bone resorption and formation during bone remodelling. We examined the associations between levels of phosphate, calcium, and alkaline phosphatase, and fracture risk in initially-healthy older individuals. METHODS: A post-hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial recruited 16,703 Australian participants aged ≥70 years and 2,411 US participants aged ≥65 years. Analyses were conducted on ASPREE-Fracture substudy participants from Australia with serum calcium, phosphate, and alkaline phosphatase measurement. Fracture data were collected post-randomization. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CIs). Phosphate, calcium, and alkaline phosphatase were analysed in deciles (D1-D10), with deciles 4-7 (31-70%) as the reference category. Restricted cubic spline curves were used to identify nonlinear associations. RESULTS: Of the 9915 participants, 907 (9·2%) persons had incident fractures recorded over 3·9 (SD 1·4) years. In the fully adjusted model, males in the top decile (D10) of phosphate had 78% higher risk of incident fracture (HR 1·78, 95% CI 1·25-2·54). No such association was observed for females (HR 1·09, 95% CI 0·83-1·44). The population attributable fraction in men within the D10 phosphate category is 6·9%. CONCLUSION: This result confirms that, high-normal serum phosphate levels are associated with increased fracture risk in older men.

Adiposity associates with lower plasma resolvin E1 (Rve1): a population study.

BACKGROUND: Inadequate inflammation resolution may contribute to persistent low-grade inflammation that accompanies many chronic conditions. Resolution of inflammation is an active process driven by Specialized Pro-resolving Mediators (SPM) that derive from long chain n-3 and n-6 fatty acids. This study examined plasma SPM in relation to sex differences, lifestyle and a broad range cardiovascular disease (CVD) risk factors in 978, 27-year olds from the Australian Raine Study. METHODS: Plasma SPM pathway intermediates (18-HEPE, 17-HDHA and 14-HDHA), and SPM (E- and D-series resolvins, PD1, MaR1) and LTB4 were measured by liquid chromatography-tandem mass spectrometry (LCMSMS). Pearson correlations and multiple regression analyses assessed relationships between SPM and CVD risk factors. Unpaired t-tests or ANOVA assessed the effect of sex, smoking, unhealthy alcohol consumption and obesity on SPM. RESULTS: Women had higher 17-HDHA (p = 0.01) and lower RvE1 (p < 0.0001) and RvD1 (p = 0.05) levels compared with men. In univariate analysis, obesity associated with lower RvE1 (p = 0.002), whereas smoking (p < 0.001) and higher alcohol consumption (p < 0.001) associated with increased RvE1. In multiple regression analysis, plasma RvE1 was negatively associated with a range of measures of adiposity including BMI, waist circumference, waist-to-height ratio, abdominal subcutaneous fat volume, and skinfold thicknesses in both men and women. CONCLUSION: This population study suggests that a deficiency in plasma RvE1 may occur in response to increasing adiposity. This observation could be relevant to ongoing inflammation that associates with CVD and other chronic diseases.

Genome-Wide Interaction Analysis With DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.

BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet score lowers blood pressure (BP). We examined interactions between genotype and the DASH diet score in relation to systolic BP. METHODS: We analyzed up to 9 420 585 single nucleotide polymorphisms in up to 127 282 individuals of 6 population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (n=35 660) and UK Biobank (n=91 622) and performed European population-specific and cross-population meta-analyses. RESULTS: We identified 3 loci in European-specific analyses and an additional 4 loci in cross-population analyses at Pinteraction<5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency, 0.03) and the DASH diet score (Pinteraction=4e-8; P for heterogeneity, 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (Pinteraction=9.4e-7) and 0.20±0.06 mm Hg (Pinteraction=0.001) in Cohorts for Heart and Aging Research in Genomic Epidemiology and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P=4e-273) and cis-DNA methylation quantitative trait loci variants (P=1e-300). Although the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by single nucleotide polymorphisms potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. CONCLUSIONS: We demonstrated gene-DASH diet score interaction effects on systolic BP in several loci. Studies with larger diverse populations are needed to validate our findings.

Sex-dependent associations of plasma high-density lipoprotein cholesterol and mortality risk in healthy older men and women: two prospective cohort studies.

The relationship between high plasma high-density lipoprotein cholesterol (HDL-C) and cause and mortality are not well established in healthy older people. This study examined the associations between HDL-C levels and mortality in initially healthy older men and women. This analysis included participants from the Aspirin in Reducing Events in the Elderly (ASPREE; n=18,668) trial and a matched cohort from the UK Biobank (UKB; n=62,849 ≥65 years). Cox regression was used to examine hazard ratios between HDL-C categories <1.03 mmol/L, 1.03-1.55 mmol/L (referent category), 1.55-2.07 mmol/L, and >2.07 mmol/L and all-cause, cancer, cardiovascular disease (CVD), and "non-cancer non-CVD" mortality. Genetic contributions were assessed using a polygenic score for HDL-C. Among ASPREE participants (aged 75±5 years), 1836 deaths occurred over a mean follow-up of 6.3±1.8 years. In men, the highest category of HDL-C levels was associated with increased risk of all-cause (HR 1.60, 95% CI 1.26-2.03), cancer (HR 1.37, 95% CI 0.96-2.00), and "non-cancer non-CVD" mortality (HR 2.35, 95% CI 1.41-3.42) but not CVD mortality (HR 1.08, 95% CI 0.60-1.94). The associations were replicated among UKB participants (aged 66.9±1.5 years), including 8739 deaths over a mean follow-up of 12.7±0.8 years. There was a non-linear association between HDL-C levels and all-cause and cause-specific mortality. The association between HDL-C levels and mortality was unrelated to variations in the HDL-C polygenic score. No significant association was found between HDL-C levels and mortality in women. Higher HDL-C levels are associated with increased risk from cancer and "non-cancer non-CVD" mortality in healthy older men but no such relationship was observed in women.

Relationship between TV Watching during Childhood and Adolescence, and Artery Function in Adulthood.

PURPOSE: Artery dysfunction is an early, integral stage in atherogenesis that predicts future cardiovascular events. Sedentary behavior, such as TV watching, is highly prevalent and associated with increased risk of developing cardiovascular diseases. This study investigated whether patterns of TV watching throughout childhood and adolescence were associated with artery function in adulthood. METHODS: TV watching data were collected when participants of the Raine Study were aged 5, 8, 10, 14, 17, and 20 yr. Previous latent class analysis indicated three trajectory groups of TV watching: low TV (<14 h·wk -1 ), high TV (>14 h·wk -1 ), and increasing TV (change from low TV to high TV). At age 28 yr, participants were invited to undergo tests of brachial and femoral artery function by flow-mediated dilation (FMD). General linear models examined differences in artery function between TV trajectory groups for men and women. RESULTS: Five hundred sixty participants (n = 261 women, n = 299 men) were included in the study. In women, the low TV group had significantly greater femoral artery FMD (10.8 ± 1.6%) than both High TV (9.0 ± 1.3%, P = 0.005) and Increasing TV groups (8.5 ± 1.3%, P < 0.001); these results were maintained following mediation analysis, including contemporaneous risk factors. There were no significant differences in femoral artery FMD between TV trajectory groups in men ( P = 0.955). CONCLUSIONS: This study suggests that TV watching behaviors during childhood and adolescence may have legacy impacts on artery function at age 28 yr, particularly in women. This may increase the risk of atherosclerotic vascular pathologies in later life.

Long-term blood pressure variability and frailty risk in older adults.

INTRODUCTION: In healthy older adults, the relationship between long-term, visit-to-visit variability in blood pressure (BP) and frailty is uncertain. METHODS: Secondary analysis of blood pressure variability (BPV) and incident frailty in >13 000 participants ≥65-70 years enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial and its observational follow-up (ASPREE-XT). Participants were without dementia, physical disability, or cardiovascular disease at baseline. BPV was estimated using standard deviation of mean BP from three annual visits (baseline through the second annual follow-up). Frailty was defined using Fried phenotype and a frailty deficit accumulation index (FDAI). Participants with frailty during the BPV estimation period were excluded from the main analysis. Adjusted Cox proportional hazards regression evaluated the association between BPV and incident frailty, and linear mixed models for change in frailty scores, through a maximum of 9 years of follow-up. RESULTS: Participants in the highest systolic BPV tertile were at higher risk of frailty compared to those in the lowest (referent) tertile of systolic BPV [Fried hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.04-1.31; FDAI HR 1.18, 95% CI 1.07-1.30]. Findings were consistent when adjusted for multiple covariates and when stratified by antihypertensive use. Linear mixed models showed that higher systolic BPV was associated with increasing frailty score over time. Diastolic BPV was not consistently associated. CONCLUSIONS: High systolic BPV, independent of mean BP, is associated with increased risk of frailty in healthy older adults. Variability of BP across visits, even in healthy older adults, can convey important risk information beyond mean BP. TRIAL REGISTRATION: ClinicalTrials.gov NCT01038583 and ISRCTN83772183.

Low-Density-Lipoprotein Cholesterol and Mortality Outcomes Among Healthy Older Adults: A Post Hoc Analysis of ASPREE Trial.

BACKGROUND: The prognostic implication of cholesterol levels in older adults remains uncertain. This study aimed to examine the relationship between low-density-lipoprotein cholesterol (LDL-c) and mortality outcomes in older individuals. METHODS: This post hoc analysis examined the associations of LDL-c levels with mortality risks from all-cause, cardiovascular disease (CVD), cancer, and combined non-CVD/noncancer conditions in a cohort of individuals aged ≥65 years from the ASPirin in Reducing Events in the Elderly trial (NCT01038583). At baseline, participants had no diagnosed dementia, physical disability, or CVD, and were not taking lipid-lowering agents. Outcome analyses were performed using multivariable Cox models. RESULTS: We analyzed 12 334 participants (mean age: 75.2 years). Over a median 7-year follow-up, 1 250 died. Restricted cubic splines found a U-shaped relation for LDL-c and all-cause mortality, cancer mortality, and noncancer/non-CVE mortality (nadir: 3.3-3.4 mmol/L); the risk of CVD mortality was similar at LDL-c below 3.3 mmol/L and increased above 3.3 mmol/L. Similar trends were observed in analyses modeling LDL-c by quartiles. When modeling LDL-c as a continuous variable, the risk of all-cause mortality, cancer mortality, and noncancer/non-CVD mortality was decreased by 9%, 16%, and 18%, respectively, per 1-mmol/L higher LDL-c, and the risk of CVD mortality was increased by 19% per 1-mmol/L higher LDL-c. Reduced all-cause and non-CVD/noncancer mortality risks were only significant in males but not females (pinteraction < .05). CONCLUSIONS: There were U-shaped relationships between LDL-c and all-cause mortality, cancer mortality, and noncancer/non-CVD mortality in healthy older adults. Higher LDL-c levels were associated with an increased risk of CVD mortality. Future studies are warranted to confirm our results.

Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.

Objective: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP). Methods: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses. Results: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P = 4e-273) and cis-DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. Conclusion: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.

Association Between Triglycerides and Risk of Dementia in Community-Dwelling Older Adults: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: It has been suggested that higher triglyceride levels were associated with a lower risk of Alzheimer disease. This study aimed to examine the association of triglycerides with dementia and cognition change in community-dwelling older adults. METHODS: This prospective longitudinal study used data from the Aspirin in Reducing Events in the Elderly (ASPREE) randomized trial of adults aged 65 years or older without dementia or previous cardiovascular events at enrollment. The main outcome was incident dementia. Other outcomes included changes in composite cognition and domain-specific cognition (global cognition, memory, language and executive function, and psychomotor speed). The association between baseline triglycerides and dementia risk was estimated using Cox proportional hazard models adjusting for relevant risk factors. Linear mixed models were used to investigate cognitive change. The analysis was repeated in a subcohort of participants with available APOE-ε4 genetic data with additional adjustment for APOE-ε4 carrier status and an external cohort (UK Biobank) with similar selection criteria applied. RESULTS: This study included 18,294 ASPREE participants and 68,200 UK Biobank participants (mean age: 75.1 and 66.9 years; female: 56.3% and 52.7%; median [interquartile range] triglyceride: 106 [80-142] mg/dL and 139 [101-193] mg/dL), with dementia recorded in 823 and 2,778 individuals over a median follow-up of 6.4 and 12.5 years, respectively. Higher triglyceride levels were associated with lower dementia risk in the entire ASPREE cohort (hazard ratio [HR] with doubling of triglyceride: 0.82, 95% CI 0.72-0.94). Findings were similar in the subcohort of participants with APOE-ε4 genetic data (n = 13,976) and in the UK Biobank cohort (HR was 0.82 and 0.83, respectively, all p ≤ 0.01). Higher triglycerides were also associated with slower decline in composite cognition and memory over time (p ≤ 0.05). DISCUSSION: Older adults with higher triglyceride levels within the normal to high-normal range had a lower dementia risk and slower cognitive decline over time compared with individuals with lower triglyceride levels. Higher triglyceride levels may be reflective of better overall health and/or lifestyle behaviors that would protect against dementia development. Future studies are warranted to investigate whether specific components within the total circulating pool of plasma triglycerides may promote better cognitive function, with the hope of informing the development of new preventive strategies.

Association of a healthy lifestyle with mortality in older people.

BACKGROUND: Unhealthy lifestyle behaviours such as smoking, high alcohol consumption, poor diet or low physical activity are associated with morbidity and mortality. Public health guidelines provide recommendations for adherence to these four factors, however, their relationship to the health of older people is less certain. METHODS: The study involved 11,340 Australian participants (median age 7.39 [Interquartile Range (IQR) 71.7, 77.3]) from the ASPirin in Reducing Events in the Elderly study, followed for a median of 6.8 years (IQR: 5.7, 7.9). We investigated whether a point-based lifestyle score based on adherence to guidelines for a healthy diet, physical activity, non-smoking and moderate alcohol consumption was associated with subsequent all-cause and cause-specific mortality. RESULTS: In multivariable adjusted models, compared to those in the unfavourable lifestyle group, individuals in the moderate lifestyle group (Hazard Ratio (HR) 0.73 [95% CI 0.61, 0.88]) and favourable lifestyle group (HR 0.68 [95% CI 0.56, 0.83]) had lower risk of all-cause mortality. A similar pattern was observed for cardiovascular related mortality and non-cancer/non-cardiovascular related mortality. There was no association of lifestyle with cancer-related mortality. CONCLUSIONS: In a large cohort of initially healthy older people, reported adherence to a healthy lifestyle is associated with reduced risk of all-cause and cause-specific mortality. Adherence to all four lifestyle factors resulted in the strongest protection.

The association between frailty and incident cardiovascular disease events in community-dwelling healthy older adults.

Study objective: This study examined the association between frailty and incident cardiovascular disease (CVD) events, major adverse cardiovascular events (MACE), and CVD-related mortality. Design: Longitudinal cohort study. Setting: The ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial in Australia and the United States. Participants: 19,114 community-dwelling older adults (median age 74.0 years; 56.4 % females). Interventions: Pre-frailty and frailty were assessed using a modified Fried phenotype and a deficit accumulation Frailty Index (FI) at baseline. Main outcome measures: CVD was defined as a composite of CVD death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure; MACE included all except heart failure. Cox proportional hazards regression was used to analyze the association between frailty and CVD outcomes over a median follow-up of 4.7 years. Results: Baseline pre-frail and frail groups had a higher risk of incident CVD events (Hazard Ratio (HR): 1.31; 95 % Confidence Interval (CI): 1.14-1.50 for pre-frail and HR: 1.63; 95 % CI: 1.15-2.32 for frail) and MACE (pre-frail HR: 1.26; 95 % CI: 1.08-1.47 and frail HR: 1.51; 95 % CI: 1.00-2.29) than non-frail participants according to Fried phenotype after adjusting for traditional CVD risk factors. Effect sizes were similar or larger when frailty was assessed with FI; similar results for men and women. Conclusion: Frailty increases the likelihood of developing CVD, including MACE, in community-dwelling older men and women without prior CVD events. Screening for frailty using Fried or FI method could help identify community-dwelling older adults without prior CVD events who are more likely to develop CVD, including MACE, and may facilitate targeted preventive measures to reduce their risk.

Fetal Growth Trajectories and Measures of Insulin Resistance in Young Adults.

CONTEXT: Events during gestation greatly influence the risk of cardiometabolic diseases including diabetes in offspring during later life. OBJECTIVE: This study aimed to investigate relationships between serial ultrasound-derived fetal growth trajectories and markers of insulin resistance in young adults in the Raine Study, an Australian pregnancy cohort. METHODS: Linear mixed modeling examined the relationship between fetal growth trajectory groups, constructed using serial ultrasound-based abdominal circumference (AC), femur length (FL), and head circumference (HC) from 1333 mother-fetal pairs, and offspring Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), as a marker of diabetes risk, at 20 (n = 414), 22 (n = 385), and 27 (n = 431) years. Analyses were adjusted for age, sex, ethnicity, socioeconomic status, adult lifestyle factors, and maternal factors during pregnancy. RESULTS: The study identified 7 AC, 5 FL, and 5 HC growth trajectory groups. Compared to the average-stable (reference) group, a low-falling AC growth trajectory (26%; P = .005) and 2 low HC growth trajectories (20%; P = .006% and 8%; P = .021) were associated with higher adult HOMA-IR. Trajectories representing a high-stable FL and a rising HC were associated with 12% (P = .002) and 9% (P = .021) lower adult HOMA-IR, respectively, compared to the reference group. CONCLUSION: Restricted fetal HC and AC from early pregnancy are associated with higher relative insulin resistance in the offspring during adulthood. These data strengthen our understanding of the importance of the intrauterine environment and its effect on the risk of predisposition to adult diabetes and related metabolic disorders.

Longitudinal association between handgrip strength, gait speed and risk of serious falls in a community-dwelling older population.

OBJECTIVE: Both grip strength and gait speed can be used as markers of muscle function, however, no previous study has examined them in the same population with respect to risk of falls. METHODS: In this prospective cohort study, utilising data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial and ASPREE-Fracture substudy, we analysed the association of grip strength and gait speed and serious falls in healthy older adults. Grip strength was measured using a handheld dynamometer and gait speed from 3-metre timed walks. Serious falls were confined to those involving hospital presentation. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for associations with falls. RESULTS: Over an average of 4.0±1.3 years, amongst 16,445 participants, 1,533 had at least one serious fall. After adjustment for age, sex, physical activity, body mass index, Short Form 12 (state of health), chronic kidney disease, polypharmacy and aspirin, each standard deviation (SD) lower grip strength was associated with 27% (HR 1.27, 95% CI 1.17-1.38) higher risk of falls. The results remained the same for males and females. There was a dose-response relationship in the association between grip strength and falls risk. The higher risk of falls was observed in males in all body mass index (BMI) categories, but only in obese females. The association between gait speed and falls risk was weaker than the association between grip strength and falls risk. CONCLUSIONS: All males and only obese females with low grip strength appear to be at the greatest risk of serious falls. These findings may assist in early identification of falls.

Statins for extension of disability-free survival and primary prevention of cardiovascular events among older people: protocol for a randomised controlled trial in primary care (STAREE trial).

INTRODUCTION: The world is undergoing a demographic transition to an older population. Preventive healthcare has reduced the burden of chronic illness at younger ages but there is limited evidence that these advances can improve health at older ages. Statins are one class of drug with the potential to prevent or delay the onset of several causes of incapacity in older age, particularly major cardiovascular disease (CVD). This paper presents the protocol for the STAtins in Reducing Events in the Elderly (STAREE) trial, a randomised double-blind placebo-controlled trial examining the effects of statins in community dwelling older people without CVD, diabetes or dementia. METHODS AND ANALYSIS: We will conduct a double-blind, randomised placebo-controlled trial among people aged 70 years and over, recruited through Australian general practice and with no history of clinical CVD, diabetes or dementia. Participants will be randomly assigned to oral atorvastatin (40 mg daily) or matching placebo (1:1 ratio). The co-primary endpoints are disability-free survival defined as survival-free of dementia and persistent physical disability, and major cardiovascular events (cardiovascular death or non-fatal myocardial infarction or stroke). Secondary endpoints are all-cause death, dementia and other cognitive decline, persistent physical disability, fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, heart failure, atrial fibrillation, fatal and non-fatal cancer, all-cause hospitalisation, need for permanent residential care and quality of life. Comparisons between assigned treatment arms will be on an intention-to-treat basis with each of the co-primary endpoints analysed separately in time-to-first-event analyses using Cox proportional hazards regression models. ETHICS AND DISSEMINATION: STAREE will address uncertainties about the preventive effects of statins on a range of clinical outcomes important to older people. Institutional ethics approval has been obtained. All research outputs will be disseminated to general practitioner co-investigators and participants, published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT02099123.

Associations of Change in Body Size With All-Cause and Cause-Specific Mortality Among Healthy Older Adults.

Importance: The association between weight change and subsequent cause-specific mortality among older adults is not well described. The significance of changes in waist circumference (WC) has also not been compared with weight change for this purpose. Objective: To examine the associations of changes in body weight and WC with all-cause and cause-specific mortality. Design, Setting, and Participants: This cohort study is a post hoc analysis of data from the Aspirin in Reducing Events in the Elderly (ASPREE) randomized clinical trial, which recruited participants between March 1, 2010, and December 31, 2014. The study included community-based older adults (16 703 Australian participants aged ≥70 years and 2411 US participants aged ≥65 years) without evident cardiovascular disease (CVD), dementia, physical disability, or life-limiting chronic illness. Data analysis was performed from April to September 2022. Exposures: Body weight and WC were measured at baseline and at annual visit 2. Analysis models were adjusted for baseline body mass index because height and weight were measured at baseline, allowing for calculation of body mass index and other variables. Both body weight and WC changes were categorized as change within 5% (stable), decrease by 5% to 10%, decrease by more than 10%, increase by 5% to 10%, and increase by more than 10%. Main Outcomes and Measures: All-cause, cancer-specific, CVD-specific, and noncancer non-CVD-specific mortality. Mortality events were adjudicated by an expert review panel. Cox proportional hazards regression and competing risk analyses were used to calculate hazard ratios (HRs) and 95% CIs. Results: Among 16 523 participants (mean [SD] age, 75.0 [4.3] years; 9193 women [55.6%]), 1256 deaths were observed over a mean (SD) of 4.4 (1.7) years. Compared with men with stable weight, those with a 5% to 10% weight loss had a 33% higher (HR, 1.33; 95% CI, 1.07-1.66) risk of all-cause mortality, and those with more than a 10% decrease in body weight had a 289% higher (HR, 3.89; 95% CI, 2.93-5.18) risk. Compared with women with stable weight, those with a 5% to 10% weight loss had a 26% higher (HR, 1.26; 95% CI, 1.00-1.60) risk of all-cause mortality, and those with more than a 10% decrease in body weight had a 114% higher (HR, 2.14; 95% CI, 1.58-2.91) risk. Weight loss was associated with a higher cancer-specific mortality (>10% decrease among men: HR, 3.49; 95% CI, 2.26-5.40; 5%-10% decrease among women: HR, 1.44; 95% CI, 1.46-2.04; >10% decrease among women: HR, 2.78; 95% CI, 1.82-4.26), CVD-specific mortality (>10% decrease among men: HR, 3.14; 95% CI, 1.63-6.04; >10% decrease among women: HR, 1.92; 95% CI, 1.05-3.51), and noncancer non-CVD-specific mortality (>10% decrease among men: HR, 4.98; 95% CI, 3.14-7.91). A decrease in WC was also associated with mortality. Conclusions and Relevance: This cohort study of healthy older adults suggests that weight loss was associated with an increase in all-cause and cause-specific mortality, including an increased risk of cancer, CVD, and other life-limiting conditions. Physicians should be aware of the significance of weight loss, especially among older men.

Associations of body size with all-cause and cause-specific mortality in healthy older adults.

In the general population, body mass index (BMI) and waist circumference are recognized risk factors for several chronic diseases and all-cause mortality. However, whether these associations are the same for older adults is less clear. The association of baseline BMI and waist circumference with all-cause and cause-specific mortality was investigated in 18,209 Australian and US participants (mean age: 75.1 ± 4.5 years) from the ASPirin in Reducing Events in the Elderly (ASPREE) study, followed up for a median of 6.9 years (IQR: 5.7, 8.0). There were substantially different relationships observed in men and women. In men, the lowest risk of all-cause and cardiovascular mortality was observed with a BMI in the range 25.0-29.9 kg/m2 [HR25-29.9 vs 21-24.9 kg/m2: 0.85; 95% CI, 0.73-1.00] while the highest risk was in those who were underweight [HRBMI <21 kg/m2 vs BMI 21-24.9 kg/m2: 1.82; 95% CI 1.30-2.55], leading to a clear U-shaped relationship. In women, all-cause mortality was highest in those with the lowest BMI leading to a J-shaped relationship (HRBMI <21 kg/m2 vs BMI 21-24.9 kg/m2: 1.64; 95% CI 1.26-2.14). Waist circumference showed a weaker relationship with all-cause mortality in both men and women. There was little evidence of a relationship between either index of body size and subsequent cancer mortality in men or women, while non-cardiovascular non-cancer mortality was higher in underweight participants. For older men, being overweight was found to be associated with a lower risk of all-cause mortality, while among both men and women, a BMI in the underweight category was associated with a higher risk. Waist circumference alone had little association with all-cause or cause-specific mortality risk.Trial registration ASPREE https://ClinicalTrials.gov number NCT01038583.

Association of a Healthy Lifestyle with Mortality in Older People.

Background: Unhealthy lifestyle behaviours such as smoking, high alcohol consumption, poor diet or low physical activity are associated with morbidity and premature mortality. Public health guidelines provide recommendations for adherence to these four factors, however, their impact on the health of older people is less certain. Methods: The study involved 11,340 Australian participants (median age 7.39 [Interquartile Range (IQR) 71.7, 77.3]) from the ASPirin in Reducing Events in the Elderly study, followed for a median of 6.8 years (IQR: 5.7, 7.9). We investigated whether a point-based lifestyle score based on adherence to guidelines for a healthy diet, physical activity, non-smoking and moderate alcohol consumption was associated with all-cause and cause-specific mortality. Results: In multivariable adjusted models, compared to those in the unfavourable lifestyle group, individuals in the moderate lifestyle group (Hazard Ratio (HR) 0.73 [95% CI 0.61, 0.88]) and favourable lifestyle group (HR 0.68 [95% CI 0.56, 0.83]) had lower risk of all-cause mortality. A similar pattern was observed for cardiovascular related mortality and non-cancer/non-cardiovascular related mortality. There was no association of lifestyle with cancer-related mortality. Stratified analysis indicated larger effect sizes among males, those ≤ 73 years old and among those in the aspirin treatment group. Conclusions: In a large cohort of initially healthy older people, reported adherence to a healthy lifestyle is associated with reduced risk of all-cause and cause-specific mortality.

Effect of Oral Contraception on Screening Tests for Primary Aldosteronism: A 10-Year Longitudinal Study.

CONTEXT: Primary aldosteronism (PA) and oral contraception (OC) can both cause hypertension in young women. However, the effect of OC on the screening test for PA, the aldosterone to renin ratio (ARR), is not clear. OBJECTIVE: We evaluated the impact of OC on the screening test for PA. METHODS: In this retrospective cohort study, we analyzed data from the female offspring (Gen2) of women enrolled in the Raine Study, a population-based birth cohort, who had blood pressure (BP) measurements, blood samples, and information about OC use at age 17 years (N = 484) and/or age 27 years (N = 486). RESULTS: Aldosterone concentration was significantly higher in OC users than nonusers at 17 years (median 486 pmol/L vs 347 pmol/L, P < 0.001). Renin concentration was significantly lower in OC users at both 17 years (13.4 mU/L vs 20.6 mU/L) and 27 years (9.2 mU/L vs 11.8 mU/L), hence the ARR was significantly higher in OC users compared to nonusers at both 17 years (31.5 vs 18.3) and 27 years (27.3 vs 21.1). The proportion of participants with ARR > 70 pmol/mU (current threshold for PA detection) was significantly higher in OC users at both 17 years (12.6% vs 2.1%) and 27 years (6.4% vs 0.4%); however, they had comparable BP to those with ARR < 70. OC use at any age abolished the relationship between ARR and BP that is observed in nonusers. CONCLUSION: OC can increase the ARR and cause a false positive PA screening result. Until more reliable criteria for PA screening in OC users are established, alternative contraception should be considered during screening.

Association of Plasma High-Density Lipoprotein Cholesterol Level With Risk of Fractures in Healthy Older Adults.

Importance: Increased levels of high-density lipoprotein cholesterol (HDL-C) have been associated with osteoporosis. Preclinical studies have reported that HDL-C reduces bone mineral density by reducing osteoblast number and function. However, the clinical significance of these findings is unclear. Objective: To determine whether higher HDL-C levels are predictive of an increased fracture risk in healthy older adults. Design, Setting, and Participants: This cohort study is a post hoc analysis of data from the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial and the ASPREE-Fracture substudy. ASPREE was a double-blind, randomized, placebo-controlled primary prevention trial of aspirin that recruited participants between 2010 and 2014. These comprised community-based older adults (16 703 Australians aged ≥70 years, 2411 US participants ≥65 years) without evident cardiovascular disease, dementia, physical disability, and life-limiting chronic illness. The ASPREE-Fracture substudy collected data on fractures reported postrandomization from Australian participants. Cox regression was used to calculate hazard ratio (HR) and 95% CI. Data analysis for this study was performed from April to August 2022. Exposure: Plasma HDL-C. Main Outcomes and Measures: Fractures included were confirmed by medical imaging and included both traumatic and minimal trauma fractures. Fractures were adjudicated by an expert review panel. Results: Of the 16 262 participants who had a plasma HDL-C measurement at baseline (8945 female participants [55%] and 7319 male [45%]), 1659 experienced at least 1 fracture over a median (IQR) of 4.0 years (0.02-7.0 years). In a fully adjusted model, each 1-SD increment in HDL-C level was associated with a 14% higher risk of fractures (HR, 1.14; 95% CI, 1.08-1.20). The results remained similar when these analyses were stratified by sex. Sensitivity and stratified analyses demonstrated that these associations persisted when the analyses were repeated to include only (1) minimal trauma fractures, (2) participants not taking osteoporosis medications, (3) participants who were never smokers and reported that they did not drink alcohol, and (4) participants who walked outside for less than 30 minutes per day and reported no participation in moderate/vigorous physical activity and to examine only (5) statin use. No association was observed between non-HDL-C levels and fractures. Conclusions and Relevance: This study suggests that higher levels of HDL-C are associated with an increased fracture risk. This association was independent of common risk factors for fractures.