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Background Ageing is one of the principal risk factors for many chronic diseases. However, there is considerable between-person variation in the rate of ageing and individual differences in their susceptibility to disease and death. Epigenetic mechanisms may play a role in human ageing, and DNA methylation age biomarkers may be good predictors of age-related diseases and mortality risk. The aims of this systematic review were to identify and synthesise the evidence for an association between peripherally measured DNA methylation age and longevity, age-related disease, and mortality risk. Methods A systematic search was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using relevant search terms, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and PsychINFO databases were searched to identify articles meeting the inclusion criteria. Studies were assessed for bias using Joanna Briggs Institute critical appraisal checklists. Data was extracted from studies measuring age acceleration as a predictor of age-related diseases, mortality or longevity, and the findings for similar outcomes compared. Using Review Manager 5.3 software, two meta-analyses (one per epigenetic clock) were conducted on studies measuring all-cause mortality. Results Twenty-three relevant articles were identified, including a total of 41,607 participants. Four studies focused on ageing and longevity, 11 on age-related disease (cancer, cardiovascular disease, and dementia), and 11 on mortality. There was some, although inconsistent, evidence for an association between increased DNA methylation age and risk of disease. Meta-analyses indicated that each 5-year increase in DNA methylation age was associated an 8 to 15% increased risk of mortality. Conclusion Due to the small number of studies and heterogeneity in study design and outcomes, the association between DNA methylation age and age-related disease and longevity is inconclusive. Increased epigenetic age was associated with mortality risk, but positive publication bias needs to be considered. Further research is needed to determine the extent to which DNA methylation age can be used as a clinical biomarker.

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. 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. 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. 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.

Background The net benefit of aspirin cessation in older adults remains uncertain. This study aimed to use observational data to emulate a randomized trial of aspirin cessation versus continuation in older adults without cardiovascular disease (CVD). Methods Post hoc analysis using a target trial emulation framework applied to the immediate post-trial period (2017–2021) of a study of low-dose aspirin initiation in adults aged ≥ 70 years (ASPREE; NCT01038583). Participants from Australia and the USA were included if they were free of CVD at the start of the post-trial intervention period (time zero, T0 ) and had been taking open-label or randomized aspirin immediately before T0 . The two groups in the target trial were as follows: aspirin cessation (participants who were taking randomized aspirin immediately before T0 ; assumed to have stopped at T0 as instructed) versus aspirin continuation (participants on open-label aspirin at T0 regardless of their randomized treatment; assumed to have continued at T0 ). The outcomes after T0 were incident CVD, major adverse cardiovascular events (MACE), all-cause mortality, and major bleeding during 3, 6, and 12 months (short-term) and 48 months (long-term) follow-up. Hazard ratios (HRs) comparing aspirin cessation to continuation were estimated from propensity-score (PS) adjusted Cox proportional-hazards regression models. Results We included 6103 CVD-free participants (cessation: 5427, continuation: 676). Over both short- and long-term follow-up, aspirin cessation versus continuation was not associated with elevated risk of CVD, MACE, and all-cause mortality (HRs, at 3 and 48 months respectively, were 1.23 and 0.73 for CVD, 1.11 and 0.84 for MACE, and 0.23 and 0.79 for all-cause mortality, p  > 0.05), but cessation had a reduced risk of incident major bleeding events (HRs at 3 and 48 months, 0.16 and 0.63, p  < 0.05). Similar findings were seen for all outcomes at 6 and 12 months, except for a lowered risk of all-cause mortality in the cessation group at 12 months. Conclusions Our findings suggest that deprescribing prophylactic aspirin might be safe in healthy older adults with no known CVD.

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/m 2 [HR 25-29.9 vs 21–24.9 kg/m 2 : 0.85; 95% CI, 0.73–1.00] while the highest risk was in those who were underweight [HR BMI <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 (HR BMI <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.

Pharmaceuticals play an important role in clinical care. However, in community-based research, medication data are commonly collected as unstructured free-text, which is prohibitively expensive to code for large-scale studies. The ASPirin in Reducing Events in the Elderly (ASPREE) study developed a two-pronged framework to collect structured medication data for 19,114 individuals. ASPREE provides an opportunity to determine whether medication data can be cost-effectively collected and coded, en masse from the community using this framework. The ASPREE framework of type-to-search box with automated coding and linked free text entry was compared to traditional method of free-text only collection and post hoc coding. Reported medications were classified according to their method of collection and analysed by Anatomical Therapeutic Chemical (ATC) group. Relative cost of collecting medications was determined by calculating the time required for database set up and medication coding. Overall, 122,910 participant structured medication reports were entered using the type-to-search box and 5,983 were entered as free-text. Free-text data contributed 211 unique medications not present in the type-to-search box. Spelling errors and unnecessary provision of additional information were among the top reasons why medications were reported as free-text. The cost per medication using the ASPREE method was approximately USD $0.03 compared with USD $0.20 per medication for the traditional method. Implementation of this two-pronged framework is a cost-effective alternative to free-text only data collection in community-based research. Higher initial set-up costs of this combined method are justified by long term cost effectiveness and the scientific potential for analysis and discovery gained through collection of detailed, structured medication data.

High variability in long‐term blood pressure (BPV) independently predicts cardiovascular disease and cognitive decline. Increased BPV and declining physical performance may share mechanistic pathways. However, associations of BPV with gait speed and grip strength have not been examined. We completed a gender‐stratified analysis of 16 692 participants enrolled in ASPREE/ASPREE‐XT. Systolic and diastolic BPV were estimated from baseline‐year 2 (Y2); gait speed/grip strength were assessed every 1–2 years following this period. Linear mixed models examined gait speed/grip strength trajectories over a median of 7.3 years of follow‐up after Y2. Following adjustment, men with SBPV in tertile 3 (T3) versus T1 had slower gait speed at Y2 (0.021 m/s slower) and greater declines in gait speed (0.003 m/s greater decline/year, p < 0.001). Women with SBPV in T3 versus T1 had slower gait speed at Y2 (0.018 m/s slower), but similar rates of gait speed decline. Men with higher SBPV had weaker grip strength at Y2 (0.994 kg weaker for BPV T3 vs. T1) and greater declines in grip strength (0.016 kg greater decline/year/5 mmHg increase in BPV, p = 0.006). Women with BPV in T3 versus T1 had 0.486 kg weaker grip strength at Y2, but similar rates of grip strength decline. Associations of DBPV and SBPV with gait speed/grip strength were largely consistent. In summary, we found that higher BPV was independently associated with slower gait speed and weaker grip strength cross‐sectionally in men and women, but only associated with trajectories of gait speed and grip strength in men. Future studies should examine high BPV as a target to preserve physical performance. Trial Registration: ISRCTN number: ISRCTN83772183; ClinicalTrials.gov identifier: NCT01038583

High‐quality randomized trial evidence is lacking on whether low‐dose aspirin exerts significant effects on blood pressure (BP) in older adults. The authors assessed longitudinal BP changes in participants enrolled in ASPirin in Reducing Events in the Elderly (ASPREE), a randomized, placebo‐controlled trial of 100 mg daily aspirin in 19 114 community‐dwelling Australian and U.S. adults without cardiovascular disease (CVD), dementia, or independence‐limiting physical disability. Participants’ BP was recorded at baseline and annual study visits, and managed by their usual care provider. BP trajectories for aspirin versus placebo during 4.7 years of follow‐up were examined for systolic and diastolic BP separately, using linear mixed models to account for between and within‐individual variability in BP. Analyses by subgroups were also explored with inclusion of interaction terms in the models. The difference in mean change in systolic BP between aspirin and placebo during study follow‐up was −0.03 mm Hg (95% confidence interval [CI]: −0.13, 0.07; p = .541) (aspirin minus placebo), while the mean difference for change in diastolic BP was −0.05 mm Hg (95% CI: –0.11, 0.01; p = .094). These small, non‐significant differences in BP change between the aspirin and placebo groups were consistent across baseline levels of BP and antihypertensive treatment status (treated/untreated). Likewise, subgroups of age, sex, chronic kidney disease, diabetes, and frailty revealed no interaction effect between the subgroup, aspirin treatment, and time. Interval‐censored Cox proportional hazards regression showed no difference in rates of incident treated hypertension between aspirin and placebo‐treated participants. The authors conclude that daily low‐dose aspirin does not significantly affect BP in older adults when managed by usual care.

Background: Febuxostat, a nonpurine selective inhibitor of both the oxidized and reduced forms of xanthine oxidase, was approved in February 2009 by the US Food and Drug Administration for the management of hyperuricemia in adults with gout. Objective: The purpose of this review was to summarize available information about the clinical use of febuxostat, including its chemistry, pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety profile. Methods: A search of the medical literature using PubMed (1949–August 2009) and the Iowa Drug Information Service (1966–August 2009) was performed to identify all published articles about febuxostat. Key search terms included febuxostat, hyperuricemia, gout, TMX-67, and TEI-6720. Articles were limited to those published in English. Reference lists of the primary set of articles identified were reviewed for pertinent articles and scientific meeting abstracts not identified in the original search. Results: A total of 88 published articles (including 14 human studies) were identified in the original search. Review of the references of these 88 articles yielded 7 additional trials published in abstract form. Clinical trial data from this review were obtained from these 21 studies. Dose-dependent reductions from baseline in serum urate occur with febuxostat. Clinical trials found that 40 mg/d of febuxostat was noninferior to conventionally dosed allopurinol (300 mg/d) in the percentage of subjects achieving the primary end point of serum urate <6.0 mg/dL (45% for febuxostat vs 42% for allopurinol), whereas 80 mg/d of febuxostat was reported to be superior (67% vs 42%; P < 0.001). Febuxostat 40 and 80 mg/d appeared to be well tolerated in the populations studied, with adverse events mostly limited to liver enzyme elevations (6.6% and 4.6%, respectively), nausea (1.1% and 1.3%), arthralgias (1.1% and 0.7%), and rash (0.5% and 1.6%). Febuxostat does not require dosage adjustment in patients with mild to moderate renal impairment (creatinine clearance, 30–89 mL/min). Because of the risk of acute gout flares occurring when febuxostat treatment is initiated, concomitant therapy with colchicine or an NSAID for ≥8 weeks is recommended. Conclusions: Febuxostat is the first agent marketed in the United States to treat hyperuricemia of gout since allopurinol was approved in 1964. In English-language published clinical trials, it was found to be noninferior to allopurinol and generally well tolerated.

Polypharmacy is a major health issue for older adults. Entangled with several geriatric syndromes, including frailty, falls and cognitive decline, research focused on polypharmacy has been challenged by heterogeneity in its definition, confounding by comorbidities and limited prospective data. In this Review, we discuss varying definitions for polypharmacy and highlight the need for a uniform definition for future studies. We critically appraise strategies for reducing medication prescriptions and implementing deprescribing as a mechanism to reduce the potential harmful effects of polypharmacy. As we look to the future, we assess the role of novel analytics and high-throughput technology, including multiomics profiling, to advance research in polypharmacy and the development of new strategies for risk stratification in the age of precision medicine.

In a trial comparing 100 mg of aspirin with placebo in nearly 20,000 community-dwelling persons 70 years of age or older in Australia and the United States, aspirin use had no effect on the rate of survival free from dementia or physical disability.