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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.

Background Brain age is a biomarker that predicts chronological age using neuroimaging features. Deviations of this predicted age from chronological age is considered a sign of age-related brain changes, or commonly referred to as brain ageing. The aim of this systematic review is to identify and synthesize the evidence for an association between lifestyle, health factors and diseases in adult populations, with brain ageing. Methods This systematic review was undertaken in accordance with the PRISMA guidelines. A systematic search of Embase and Medline was conducted to identify relevant articles using search terms relating to the prediction of age from neuroimaging data or brain ageing. The tables of two recent review papers on brain ageing were also examined to identify additional articles. Studies were limited to adult humans (aged 18 years and above), from clinical or general populations. Exposures and study design of all types were also considered eligible. Results A systematic search identified 52 studies, which examined brain ageing in clinical and community dwelling adults (mean age between 21 to 78 years, ~ 37% were female). Most research came from studies of individuals diagnosed with schizophrenia or Alzheimer’s disease, or healthy populations that were assessed cognitively. From these studies, psychiatric and neurologic diseases were most commonly associated with accelerated brain ageing, though not all studies drew the same conclusions. Evidence for all other exposures is nascent, and relatively inconsistent. Heterogenous methodologies, or methods of outcome ascertainment, were partly accountable. Conclusion This systematic review summarised the current evidence for an association between genetic, lifestyle, health, or diseases and brain ageing. Overall there is good evidence to suggest schizophrenia and Alzheimer’s disease are associated with accelerated brain ageing. Evidence for all other exposures was mixed or limited. This was mostly due to a lack of independent replication, and inconsistency across studies that were primarily cross sectional in nature. Future research efforts should focus on replicating current findings, using prospective datasets. Trial registration A copy of the review protocol can be accessed through PROSPERO, registration number CRD42020142817 .

Background Poor social health is associated with increased risk of cardiovascular disease (CVD). Recent research suggests that different social health domains should be considered separately as the implications for health and possible interventions may differ. Aim To assess social isolation, low social support and loneliness as predictors of CVD. Methods Secondary analysis of 11,486 community-dwelling, Australians, aged 70 years and over, free of CVD, dementia, or significant physical disability, from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Social isolation, social support (Revised Lubben Social Network Scale), and loneliness were assessed as predictors of CVD using Cox proportional-hazard regression. CVD events included fatal CVD, heart failure hospitalization, myocardial infarction and stroke. Analyses were adjusted for established CVD risk factors. Results Individuals with poor social health were 42 % more likely to develop CVD (p = 0.01) and twice as likely to die from CVD (p = 0.02) over a median 4.5 years follow-up. Interaction effects indicated that poorer social health more strongly predicted CVD in smokers (HR 4.83, p = 0.001, p-interaction = 0.01), major city dwellers (HR 1.94, p < 0.001, p-interaction=0.03), and younger older adults (70-75 years; HR 2.12, p < 0.001, p-interaction = 0.01). Social isolation (HR 1.66, p = 0.04) and low social support (HR 2.05, p = 0.002), but not loneliness (HR 1.4, p = 0.1), predicted incident CVD. All measures of poor social health predicted ischemic stroke (HR 1.73 to 3.16). Conclusions Among healthy older adults, social isolation and low social support may be more important than loneliness as cardiovascular risk factors. Social health domains should be considered in future CVD risk prediction models.

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 Physical function decline and depression are major challenges of the rapidly growing older population. This longitudinal study aimed to investigate the bidirectional longitudinal association between physical function and depressive symptoms, which are poorly understood in older adults. Methods We utilised data from the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial and extended follow‐up cohort between 2010 and 2022. The presence of depressive symptoms was defined as a score of ≥ 8 on the Center for Epidemiologic Studies Depression 10‐item scale. Physical function was assessed using gait speed for physical performance and handgrip strength for muscle strength. Gait speed and handgrip strength were categorised using the European Working Group on Sarcopenia in Older People (EWGSOP2) cut‐off points. The bidirectional association between physical function and depressive symptoms was estimated using generalised estimating equations models. The robustness of the longitudinal bidirectional relationship was assessed using random‐intercept cross‐lagged panel models. Results Among 19 114 ASPREE participants, 15 854 (56% females) older adults (mean age 75 years) were included in the analysis. During a median follow‐up of 8.4 years, participants with combined poor physical performance and weak muscle strength had 81% higher odds of developing depressive symptoms compared to those with good performance and strength (OR = 1.81, 95% CI: 1.55–2.11). Conversely, participants with depressive symptoms had 70% higher odds of reduced physical function (combined poor physical performance and weak muscle strength) compared to those with no depressive symptoms (OR = 1.70, 95% CI: 1.61–1.80). The random‐intercept cross‐lagged panel models verified the bidirectional longitudinal associations between physical function and depressive symptoms across the follow‐up waves. Conclusions Reduced physical function and depressive symptoms are associated bidirectionally over time of a similar magnitude. Understanding this reciprocal association is crucial for developing effective prevention and treatment strategies for physical and mental health conditions.

ASPirin in Reducing Events in the Elderly (ASPREE), a placebo-controlled prevention trial of low dose aspirin, provided the opportunity to establish a biospecimen biobank from initially healthy persons aged 70+ years for future research. The ASPREE Healthy Ageing Biobank (ASPREE Biobank) collected, processed and stored blood and urine samples at -80degC or under nitrogen vapour at two timepoints, three years apart, from a willing subset of Australian ASPREE participants. Written informed consent included separate opt-in questions for biomarker and genetic testing. Fractionated blood and urine were aliquoted into multiple low-volume, barcoded cryotubes for frozen storage within 4 hours of collection. Specially designed and outfitted mobile laboratories provided opportunities for participation by people in regional and rural areas. Detailed, high quality demographic, physiological and clinical data were collected annually through the ASPREE trial. 12,219 participants contributed blood/urine at the first timepoint, 10,617 of these older adults provided 3-year follow-up samples, and an additional 1,712 provided saliva for DNA. The mean participant age was 74 years, 54% were female and 46% lived outside major cities. Despite geographical and logistical challenges, nearly 100% of blood/urine specimens were processed and frozen within 4 hours of collection into >1.4 million aliquots. After a median of 4.7 years, major clinical events among ASPREE Biobank participants included 332 with dementia, 613 with cardiovascular disease events, 1259 with cancer, 357 with major bleeds and 615 had died. The ASPREE Biobank houses and curates a large number of biospecimens collected prior to the clinical manifestations of major disease, and 3-year follow-up samples, all linked to high quality, extensive phenotypic information. This provides the opportunity to identify or validate diagnostic, prognostic and predictive biomarkers, and potentially study biological effectors, of ageing-related diseases or maintenance of older-age good health.

BackgroundWe examined whether impaired kidney function, identified through elevated levels of urine albumin to creatinine ratio (UACR) or reduced estimated glomerular filtration rate (eGFR), is associated with hospitalisation or death due to heart failure (HF) in a large community-based cohort of older adults.MethodsWe included 17 834 participants from the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial and follow-up ASPREE eXTension observational study with complete baseline data on albuminuria and eGFR. HRs for hospitalisation due to HF (HHF), HF death, a composite outcome of HHF and HF death, and HF re-admission were calculated using Cox models adjusting for potential confounders.ResultsOver a median follow-up of 8.6 years, 354 (1.98%) participants had a first hospitalisation for HF and 147 (0.82%) died due to HF. Participants with albuminuria (UACR ≥3.0 mg/mmol; 11.3%) had higher risk for HHF, HF death and the combined HF outcome compared with those with no albuminuria (HRs 1.47 (95% CI 1.12 to 1.92), 1.55 (95% CI 1.04 to 2.33) and 1.33 (95% CI, 1.05 to 1.70), respectively). In participants with albuminuria, there was also an increased risk for re-admission due to HF (HR 1.30 (95% CI 1.03 to 1.65)), although there was no difference in risk of HF death. For eGFR, a U-shaped relationship was observed with increased risk of HHF, HF death and the HF composite outcome at both low (eg, <60 mL/min/1.73 m²) and high (eg, >90 mL/min/1.73 m²) eGFR levels. However, the association at high eGFR was not statistically significant and may reflect residual confounding. No association was observed between eGFR and HF re-admission.ConclusionsIn this large cohort of older adults, albuminuria was associated with increased risk of HF outcomes, supporting its role in HF risk assessment. Low eGFR was also linked to higher risk of HHF, HF death and the HF composite outcome. Associations with high eGFR were not conclusive and should be considered hypothesis-generating.

Purpose Physical health-related quality of life (HRQoL) is associated with adverse health outcomes, including hospitalizations and all-cause mortality. However, little is known about how physical HRQoL changes over time in older people and the predictors of this trajectory. This study (a) identified trajectories of physical HRQoL among older people and (b) explored whether economic factors, social health or stressful life events impact physical HRQoL trajectories. Method A cohort of 12,506 relatively ‘healthy’ community-dwelling Australians aged ≥ 70 years (54.4% females), enrolled in the ASPREE Longitudinal Study of Older Persons (ALSOP) study and was followed for six years. Economic factors, social health and life events in the last 12 months were assessed through a questionnaire at baseline. Physical HRQoL was measured by using the 12-item short form at baseline and annual follow-ups. Growth mixture and structural equation modelling were used to identify physical HRQoL trajectories and their predictors. Results Four physical HRQoL trajectories were identified—stable low (7.1%), declining (9.0%), stable intermediate (17.9%) and stable high (66.0%). Living in more disadvantaged areas, having a lower household income, no paid work, no voluntary work, loneliness and stressful life events (i.e. spousal illness, friend/family illness, financial problem) were associated with a 10%–152% higher likelihood of being in the stable low or declining physical HRQoL trajectory than the stable high group. Conclusion Specific stressful life events had a greater impact on adverse physical HRQoL trajectories in older people than other factors. Volunteering may prevent physical HRQoL decline and requires further investigation.

Background Longitudinal cohort studies across the lifespan suggest an association between ultra-processed food (UPF) and depression. However, the effect of UPF on depression and mental health in older adults has not been determined. Therefore, this study investigated the effect of UPF on depressive symptoms and mental health in community-dwelling older adults. Methods A pragmatic target trial was designed and emulated using the ASPirin in Reducing Events in the Elderly longitudinal data. Participants were community-dwelling older adults (≥ 70 years) in Australia. We specified and emulated the protocol of a two-arm randomised pragmatic clinical trial using the level of UPF consumption as the intervention. Greater than or equal to 4 servings of UPF per day was considered the intervention, with less than 4 servings per day the control. Dietary consumption was assessed using a mail-based diet screening questionnaire, and the level of food processing was classified based on the NOVA classification. The study outcomes were depressive symptoms, defined as a score of ≥ 8 on the Center for Epidemiological Studies Depression 10-item scale, and general mental health, defined by the mental component summary score of the Short Form-12. We applied inverse probability treatment weighting to balance confounders. Marginal structural models were employed to estimate the population-level average effect of intervention using generalised estimated equations. Results A total of 11,192 participants (3415 intervention and 7777 control) were eligible for the emulation. High UPF consumption at time zero was associated with an increased risk of depressive symptoms at follow-ups (RR: 1.10; CI: 1.04–1.18). The finding was consistent with sensitivity analyses; after excluding participants on antidepressants at time zero, the risk of depressive symptoms in the intervention group was increased by 11% compared to the control (RR: 1.11; 95% CI: (1.04–1.20)). Consumption of UPF adversely affected the mental component quality of life ( β : − 0.40; CI: − 0.65 to − 0.15). Conclusions A higher level of UPF consumption was associated with a higher risk of depressive symptoms and adversely affected mental health among older adults.

Background Older people experiencing depression and anxiety have higher rates of health service utilisation than others, but little is known about whether these influence their seeking of emergency care. The aim was to examine the associations between symptoms of depression and the use of emergency health care, in an Australian context, among a population of people aged 70 years and over initially free of cardiovascular disease, dementia or major physical disability. Methods We undertook secondary analyses of data from a large cohort of community-dwelling Australians aged 70 years. Multivariable logistic regression was used to compare the association of symptoms of depression (measured using the Center for Epidemiological Studies Depression Scale 10 question version, CESD at baseline) with subsequent episodes of emergency care, adjusting for physical and social factors of clinical interest. Marginal adjusted odds ratios were calculated from the logistic regression. Results Data were available for 10,837 Australian participants aged at least 70 years. In a follow-up assessment three years after the baseline assessment, 17.6% of people self-reported an episode of emergency care (attended an ED of called an emergency ambulance) in the last 12 months. Use of emergency healthcare was similar for men and women (17.8% vs. 17.4% p  = 0.61). A score above the cut-off on the CESD at baseline was associated with greater use of emergency health care (OR = 1.35, 95% CI 1.11,1.64). When modelled separately, there was a greater association between a score above the cut-off on the CESD and emergency healthcare for women compared with men. Conclusions This study is unique in demonstrating how depressive symptoms among healthy older persons are associated with subsequent increased use of emergency healthcare. Improved understanding and monitoring of mental health in primary care is essential to undertake effective healthcare planning including prevention of needing emergency care.