The Lancet Healthy Longevity

Structured AbstractO_ST_ABSBACKGROUNDC_ST_ABSPatient reports are the standard when examining subjective cognitive decline (SCD). Recent research suggests that informant and clinician reports may also be associated with cognition. This study examined differences between patient, informant, and clinician definitions of SCD and their relationship to cognition. METHODSData from 4290 older adults (n=1690 normal controls, NC; n=840 mild cognitive impairment, MCI; n=1760 Alzheimers disease, AD) were examined from the National Alzheimers Coordinating Center. Linear models examined the relationships between SCD status using the three definitions and cognition at baseline and over time. RESULTSIn NC, informant and clinician SCD were associated with worse cognition at baseline, with patient and clinician SCD associated with worse cognition over time. All definitions were associated with worse cognition at baseline and over time in MCI and AD. DISCUSSIONOur findings suggest the importance of examining different SCD definitions, especially the inclusion of clinician SCD.

INTRODUCTIONAgitation is a common and burdensome neuropsychiatric symptom in dementia that fluctuates from day to day, but objective tools for short-term risk stratification are limited. We examined whether nocturnal physiological signals from unobtrusive under-mattress sensors predict next-day daytime agitation and whether associations differ for agitation occurrence versus severity. METHODSWe extracted cardiorespiratory, movement, and sleep-proxy features from two long-term care cohorts (N=55; 333 nights) and one external home-monitoring cohort (N=18; 803 nights). A two-part mixed-effects framework was used to model next-day agitation episodes. RESULTSLower nocturnal respiratory rate and greater activity instability independently predicted higher odds of next-day agitation occurrence. Associations were stronger for motor than verbal agitation. Respiration-related predictors were validated externally. Conversely, no nocturnal features significantly predicted agitation severity. DISCUSSIONPassive sleep monitoring identified reproducible, physiologically interpretable markers of next-day agitation occurrence, supporting the potential of under-mattress sensing for short-term risk stratification and more proactive dementia care.

Background Older adults' walking has so far been evaluated using standardised assessments of walking capacity within a clinical setting. By taking the evaluation out of the laboratory into the real world, this study provides first evidence of the ability of Digital Mobility Outcomes (DMOs) to detect changes over time and the Minimal Important Difference (MID) in patients after proximal femoral fracture (PFF). This will guide the implementation of DMOs in research and clinical care. Methods For this multicenter prospective cohort study, 381 community-dwelling older adults were included within one year after sustaining a PFF and assessed at two time points, separated by six months. Walking activity and gait DMOs were measured using a single wearable device worn on the lower back for up to seven days. A global impression of change question and three mobility-related outcome measures (Late-Life Function and Disability Instrument; Short Physical Performance Battery; 4m gait speed) were used as anchor variables. To assess each DMOs ability to detect changes, we calculated the standardized mean change as effect size. For estimating MIDs, both distribution-based and anchor-based methods were applied, followed by triangulation by experts if at least three anchor-based estimates were available per DMO, resulting in single-point estimates. Results All three anchor variables demonstrated substantial changes. Overall, 10 out of 24 available DMOs showed large and 7 DMOs moderate positive effects in the expected direction of the respective anchors. Seven DMOs showed no or only small effects. For 12 DMOs, at least three anchor-based estimates were available, enabling MID triangulation. MIDs for walking activity DMOs per day were: a walking duration of 10 minutes, a step count of 1,000 steps, 50 walking bouts (WB), and 15 WBs in WBs over 10 seconds. For gait DMOs, depending on the walking bout length, MIDs for walking speed were between 0.04 m/s and 0.08 m/s, and MIDs for cadence between 4 and 6 steps/minute. Almost all DMOs showed a strong ability to detect improvement in mobility, but rarely in detecting decline. Conclusions For the first time, MIDs are presented for real-world DMOs in PFF patients. These MIDs inform sample size requirements and interpretation of intervention effects for clinical trials, thereby providing guidance and reassurance for clinicians and regulatory bodies.

BackgroundDementia affects over 57 million people worldwide. UK and international policy position personalised, conversation-based care planning as central to post-diagnostic support. However, delivery in primary care is inconsistent, and many practitioners lack dementia-specific communication training. Existing evidence focuses on single roles or settings, leaving a gap in understanding how communication operates across the primary care workforce. AimsTo identify what helps and hinders effective communication for integrated dementia care planning and determine the support and training needs of the wider primary care workforce. MethodsO_LISemi-structured interviews - 11 people with dementia, 13 family carers, and 19 primary care practitioners from diverse roles, exploring experiences of care planning conversations C_LIO_LIReflexive thematic analysis C_LI ResultsThree themes were developed, progressing from micro-level communication practices (Theme 1: Beyond the tick-box), through triadic dynamics (Theme 2: Balancing voices in the conversation), to organisational influences (Theme 3: From silos to meaningful shared care planning). Time and Conversation as intervention cut across all themes, shaping trust and disclosure. Participants reported reliance on tick box approaches, inconsistent preparation, and uncertainty about care plan purpose and ownership. Non-clinical roles were commonly viewed as well placed to support meaningful conversations, but were often described as constrained by unclear remit and weak integration. ConclusionsA persistent gap remains between policy ambitions and everyday practice. Time-pressured, checklist-driven encounters and fragmented systems undermine shared decision-making. The expanded primary care workforce offers untapped potential to address these gaps, but this requires clearer roles, formal integration, and targeted investment in communicative skills.

BackgroundHigh-dose inactivated influenza vaccination (HD-IIV) demonstrates superior effectiveness versus standard-dose vaccination (SD-IIV) in adults aged [≥]60 years. A recent meta-analysis integrated complementary evidence sources of representing over 85 million individuals across 14 influenza seasons. MethodsA previously developed model was updated using life-time horizon and societal perspective. Updated parameters included demographics, costs, hospitalization rates, and relative vaccine effectiveness (rVE): RCT evidence (24% for ILI, 7% for cardiorespiratory hospitalizations) and RCT + real-world evidence (RWE) (15% for ILI, 8% for cardiorespiratory hospitalizations). ResultsHD-IIV resulted in incremental cost-effectiveness ratios of {euro}7,300/QALY (RCT evidence) and {euro}5,800/QALY (RCT+RWE evidence). Implementation would prevent 7,200 general practitioner visits, 6,300 cardiorespiratory hospitalizations, and 269 deaths, by using RCT evidence. Probabilistic sensitivity analysis demonstrated >99% probability of cost-effectiveness at {euro}20,000/QALY threshold for both RCT and RCT+RWE evidence. ConclusionsHD-IIV remains highly cost-effective for Dutch adults aged [≥]60 years under updated evidence scenarios, supporting implementation in the national immunization programme. HighlightsO_LIThe economic analysis of high-dose inactivated influenza vaccine was updated. C_LIO_LIRelative vaccine effectiveness of HD-IIV incorporating recent evidence was used. C_LIO_LIHD-IIV remains cost-effective in Dutch adults aged [≥]60. C_LI

ObjectivesNon-communicable diseases (NCDs) account for almost 90% of deaths in Europe, yet comparative estimates of the productivity costs associated with premature NCD mortality across diseases and countries remain limited. This study estimates and compares productivity losses attributable to cardiovascular disease (CVD) and cancer mortality among working-age populations across Europe. Population-based data were used to estimate productivity costs for CVD and cancer deaths across 30 European countries. Sex- and age-specific mortality data for 2021 were obtained from the World Health Organization Mortality Database. Economic data, including wages, unemployment rates, and labour force participation rates, were sourced from Eurostat. Productivity losses were valued using a human capital approach incorporating an age-transition lifecycle simulation model that adjusts for lifetime wage trajectories and labour market dynamics. Costs were discounted at 3.5%. Total productivity losses from cancer and CVD mortality in working-age populations were estimated at {euro}195.7 billion, equivalent to 1.24% of European GDP. Cancer accounted for 62.5% ({euro}122.2 billion) of total productivity losses, while CVD accounted for 37.5% ({euro}73.5 billion). Total CVD-related productivity costs exceeded cancer-related costs in Central and Eastern Europe, whereas cancer productivity costs were higher in Western, Northern, and Southern Europe. Mean productivity costs per death were higher for CVD ({euro}219,848; 95% CI 165,241-270,247) than for cancer ({euro}217,744; 95% CI 166,554-273,144). A larger gender gap was observed for CVD mortality, with a male-to-female cost ratio of 2.5 compared with 1.6 for cancer. Productivity losses associated with premature cancer and CVD mortality represent a substantial economic burden across Europe, with pronounced variation by disease, region, and sex. These findings provide comparative, cross-country estimates of the human capital costs associated with major NCD causes of death.

ObjectivesDigital biomarkers offer scalable screening for type 2 diabetes, yet adoption is stalled by uncertainty regarding economic viability. This study evaluates the cost-effectiveness and budget impact of digital screening compared to opportunistic screening from a Swiss payer perspective. MethodsA probabilistic Markov cohort model was developed to simulate at-risk Swiss adults (age [≥]45, BMI [≥]25 kg/m{superscript 2}) over a 40-year horizon. The model incorporates a digital attrition parameter, inputs derived from Swiss-specific sources (e.g., the CoLaus study and FSO life tables), and statutory tariffs. Costs and outcomes were discounted at 3.0%. ResultsIn the deterministic base-case, digital screening yielded an incremental cost-effectiveness ratio of CHF 2,912 per quality-adjusted life-year gained. Probabilistic sensitivity analysis indicated a 93.2% probability of cost-effectiveness at the CHF 50,000 threshold. The budget impact analysis estimated a Year 1 gross investment budget of CHF 27 million to identify prevalent cases, followed by long-term savings from averted complications. ConclusionsDigital screening can be highly cost-effective in Switzerland. While the required Year 1 gross investment poses a liquidity challenge, reimbursement via pathway-oriented models under the Swiss tariff could align incentives with long-term complication avoidance.

BackgroundQuadruple therapy, comprising an angiotensin receptor-neprilysin inhibitor (ARNI), {beta}-blocker, mineralocorticoid receptor antagonist (MRA), and sodium-glucose cotransporter 2 inhibitor (SGLT2i), is guideline-recommended for heart failure with reduced ejection fraction (HFrEF). However, uptake in Singapore remains low. This study evaluated the cost-effectiveness of scaling up quadruple therapy from the current 30% uptake to realistic (80%) and stretch (100%) targets. MethodsWe developed a decision-analytic model combining a decision tree and Markov structure to simulate clinical and economic outcomes over a 10-year horizon from the Singapore healthcare system perspective. Transition probabilities were estimated using local real-world data for current regimens, and published literature for quadruple therapy. Costs were derived from hospital billing data and drug utilisation patterns. A probabilistic sensitivity analysis (1,000 simulations) assessed uncertainty. The willingness-to-pay (WTP) threshold was S$45,000 per quality-adjusted life year (QALY) gained. ResultsBoth scale-up scenarios were cost-effective. Compared to current practice, the 80% uptake scenario resulted in an incremental cost of S$2.57M and 110 additional QALYs (ICER: S$23,392/QALY) for 1000 patients over 10 years, while the 100% uptake scenario yielded 137 QALYs at an incremental cost of S$2.88M (ICER: S$21,117/QALY). Under conservative assumptions, both scenarios remained cost-effective. The probability of being cost-effective was 92% (80% uptake) and 96% (100% uptake). InterpretationScaling up quadruple therapy for HFrEF in Singapore is highly cost-effective. Implementation strategies to close the treatment gap should be prioritised to improve outcomes and maximise value in heart failure care.

ObjectiveSevere infections have been implicated in dementia risk, but their associations with detailed patterns of cognitive performance, and whether poorer cognition in turn increases risk for certain infections, remain unclear. We examined bidirectional associations between hospital-treated infections and domain-specific cognitive function in a cohort of older adults. MethodsWe analysed data from the English Longitudinal Study of Ageing Harmonised Cognitive Assessment Protocol (ELSA-HCAP), conducted in 2018 and linked to national inpatient records. Pre-HCAP hospital-treated infections were identified from 1997 to 2018; post-HCAP incident infections were ascertained from 2018 to 2024. Cognitive performance was assessed at HCAP using 21 standardised neuropsychological tests summarised into general and four domain-specific scores (executive function, memory, language, and visuospatial ability). Linear regression assessed associations between pre-HCAP hospital-treated infections and standardised cognitive scores; Cox models estimated associations between cognition and risk of incident hospital-treated infections after HCAP. All models were adjusted for sociodemographic, lifestyle, and health covariates. ResultsOf 1,159 participants aged [≥]65 at HCAP (631 [54.1%] female; mean [SD] age, 75.6 [7.2] years), 351 (30.3%) had a hospital-treated infection before HCAP. Prior hospitalisation for any infection was associated with lower general cognition ({beta} = -0.11 SD, 95% CI -0.21 to -0.02) and poorer executive function ({beta} = -0.19, -0.28 to -0.09), with similar patterns across infection types. Lower respiratory tract infections were additionally associated with poorer memory ({beta} = -0.20, -0.36 to -0.04). Cognitive scores were progressively lower among individuals with more frequent or prolonged infection-related hospitalisations, sepsis, or cardiovascular disease. Prospectively, over a mean (SD) 4.8 (1.9) years of follow-up, 271 incident hospital-treated infections occurred. Each 1-SD higher general cognition was associated with a 36% lower risk of any subsequent hospital-treated infection (HR 0.64, 0.53 to 0.78), and with consistent associations across cognitive domains for all-cause and bacterial infections. Executive function alone showed a strong association with viral infections, especially COVID-19 (HR 0.59, 0.44 to 0.80). ConclusionSevere infections were primarily associated with poorer executive function. Conversely, cognitive vulnerability across multiple domains was associated with increased susceptibility to infections requiring hospital care, while poorer executive function was specifically associated with viral infection risk. These findings support a reinforcing infection-cognition cycle in later life and cognitively tailored infection-prevention strategies.

BackgroundEvidence from high-income countries suggests that COVID-19 may adversely affect cognitive functioning, yet population-based data from African countries remain scarce. Understanding how COVID-19 symptom burden, chronic disease, and mental health intersect to shape cognitive outcomes is critical in low-resource settings disproportionately affected by structural and health system constraints. MethodsCross-sectional data were collected from 3,058 adults (M_age = 27.2 years) in Botswana, Ghana, Nigeria, and Tanzania between April 2020 and November 2022 using the Sonde Health platform. Participants self-reported sociodemographic characteristics, COVID-19 symptoms, chronic disease diagnoses, mental health symptoms, physical activity, and sedentary behavior. Executive function was assessed using the Stroop Color-Word interference score. Multivariable linear regression models estimated adjusted mean differences in executive function associated with COVID-19 symptom burden and chronic disease, controlling for sociodemographic, health, mental health, and behavioral factors. Effect modification by country was evaluated using interaction terms (p < 0.10). ResultsExecutive function declined with increasing COVID-19 symptom burden, with Stroop scores decreasing from 0.14 among participants reporting no symptoms to 0.07 among those reporting three or more symptoms (p < 0.001). Being symptom-free was associated with better executive function in Ghana (adjusted mean difference = 0.06; 95% CI: 0.00, 0.11) and Nigeria (adjusted mean difference = 0.07; 95% CI: 0.02, 0.12), but not in Botswana or Tanzania. Lower chronic disease burden was associated with better executive function in Nigeria (adjusted mean difference = 0.16; 95% CI: 0.06, 0.26). Higher educational attainment was consistently associated with better executive function across countries. ConclusionsCOVID-19 symptom burden and chronic disease were associated with poorer executive function across the four African countries studied, with substantial cross-country variation. Education emerged as a consistent protective factor. These findings highlight the importance of integrated, context-sensitive approaches that address both physical and mental health to support cognitive well-being during and beyond public health crises.

ObjectivesTo examine associations between cardiometabolic conditions and health-related quality of life (HRQoL) and to evaluate whether condition-associated HRQoL changed from 2001 to 2022. MethodsWe analyzed nationally representative data from U.S. adults aged [&ge;]18 years in the Medical Expenditure Panel Survey, 2001-2022. Survey years without BMI data (2017, 2019, 2021) were excluded. EQ-5D utilities were mapped from SF-12 scores using a validated algorithm. For each survey year, survey-weighted multivariable regression models estimated associations of sociodemographic characteristics, BMI, and cardiometabolic conditions (diabetes, heart disease, high blood pressure, high cholesterol, obesity, stroke) with HRQoL measured by EQ-5D. Temporal changes in condition-associated HRQoL decrements were assessed using meta-regression across years. Associations in recent survey years were summarized using pooled estimates from 2015, 2016, 2018, and 2022. ResultsOverall HRQoL improved from 2001 to 2022 across age groups, with the largest improvement among older adults. In pooled analyses, stroke was associated with the largest adjusted HRQoL decrement (-0.0714), followed by heart disease (-0.0503), diabetes (-0.0427), high blood pressure (-0.0328), obesity (-0.0305), and high cholesterol (-0.0236). Additional adjustment for BMI attenuated condition-associated decrements, most notably for obesity (-0.0305 to -0.0183), diabetes (-0.0427 to -0.0414), and high blood pressure (-0.0328 to -0.0316). Over time, diabetes- and heart disease-associated decrements attenuated linearly (diabetes: - 0.0489 in 2001 to -0.0406 in 2022; heart disease: -0.0591 to -0.0493). High blood pressure (-0.0337 in 2001, -0.0415 in 2012, -0.0306 in 2022) and obesity (-0.0305 in 2001, -0.0283 in 2012, -0.0367 in 2022) showed nonlinear patterns. ConclusionsCondition-associated HRQoL decrements varied over time, and recent-year utility estimates are recommended for population health research. HRQoL decrements for diabetes and heart disease attenuated, consistent with improvements in treatment and survival. High blood pressure-associated were lowest around 2012, and obesity-associated became more negative after 2012, consistent with worsening blood pressure control and obesity severity.

BackgroundOlder age is widely considered a risk factor for post-acute sequelae of SARS-CoV-2 infection (PASC), typically attributed to immunosenescence and inflammaging. However, whether this association reflects intrinsic biological ageing or accumulated comorbidity burden remains unclear, with implications for clinical risk stratification. MethodsWe conducted a retrospective cohort study using the Precision PASC Research Cohort (P2RC) from Mass General Brigham, comprising 133,792 COVID-19 patients from 12 hospitals and 20 community health centres in Massachusetts (March 2020-May 2024). PASC was ascertained using a validated computational phenotyping algorithm. We used generalised estimating equations with cluster-robust variance to model PASC risk, causal mediation analysis to decompose age effects through comorbidity burden and acute severity, and specification curve analysis across 768 analytical specifications to assess robustness. FindingsAfter adjustment for comorbidity burden, each decade of age was associated with 6% lower odds of PASC (OR 0.94; 95% CI 0.93-0.95). Causal mediation analysis revealed that comorbidities accounted for 145% of the total age effect, indicating inconsistent mediation wherein ages direct protective effect was masked by its indirect harm through chronic disease accumulation. This protection was age-dependent: adults younger than 65 years retained robust resilience independent of comorbidities (ADE:-0.0042, p<0.001), whereas adults 65 years and older showed complete loss of this protection (ADE: +0.0020, p=0.14). InterpretationLong COVID susceptibility is driven by physiological reserve rather than chronological age until approximately age 65, beyond which age-related protective mechanisms become exhausted. Risk stratification should prioritise comorbidity burden over birth year in younger adults. FundingNational Institute of Allergy and Infectious Diseases (NIAID).

INTRODUCTIONDementia reflects vascular and neurodegenerative processes in late life, yet studies often examine risks and outcomes individually. This study tested whether the cumulative burden of risks relates to structural brain pathology and cognition, and whether brain markers mediate these associations. METHODSCross-sectional data were drawn from 38,414 older adults in the National Alzheimers Coordinating Center database. A composite score summed ten binary risk factors: hypertension, diabetes, hypercholesterolemia, alcohol misuse, smoking, depression, obesity, hearing loss, vision loss, and low education. Outcomes included white matter hyperintensities (WMH), infarcts, hippocampal atrophy, global cognition, cognitive status, delayed recall, and semantic fluency. RESULTSHigher burden was associated with poorer global cognition, greater clinical severity, worse memory and fluency, and higher odds of WMHs, infarcts, and hippocampal atrophy. Structural equation models identified hippocampal atrophy as the primary mediator, with smaller effects for WMHs and infarcts. DISCUSSIONFindings support multidomain prevention strategies targeting clustered modifiable risks.

BackgroundThe United Nations General Assembly High-level Meeting on Antimicrobial Resistance (UNGA HLM-AMR) committed to a target that 70% of global human antibiotic use (ABU) should be from the Access group of the WHO AWaRe system. MethodsWe used 2019 IQVIA MIDAS(R) global ABU Quarterly value sales, volumes (kg/SU) and average ex-manufacturer prices to evaluate price per daily defined dose (DDD) by AWaRe group across countries. IQVIA MIDAS volumes/value data reflect public, private, or mixed sectors. We estimated potential national pharmaceutical expenditure savings if i) the UNGA 70% Access target was met, and ii) national ABU aligned with the WHO Model List of Essential Medicines (EML). We evaluated 7-day treatment prices for common oral and parenteral antibiotics across AWaRe groups. We measured affordability in middle-income countries (MICs) by income group, as the percentage of the population at risk of falling below national poverty lines if paying out-of-pocket, using income distributions and generalised beta distributions of the second kind. Prices were reported in 2019 international dollars (I$). ResultsVolume-weighted ex-manufacturer prices per DDD were lower for Access (I$1{middle dot}2, IQR I$0{middle dot}7) than Watch (I$2{middle dot}6, IQR I$2{middle dot}1) and highest (I$83{middle dot}8, IQR I$80{middle dot}9) for Reserve antibiotics. Lower prices were seen in high-income countries for Access antibiotics. Meeting the 70% Access target could save countries I$0{middle dot}1 million-I$4{middle dot}9 billion annually. Global savings could reach I$10{middle dot}4 billion if only WHO EML-listed antibiotics were used. Seven-day parenteral meropenem could put 7% (IQR 9%) of the population in MICs at risk of impoverishment. ConclusionAntibiotic policies focused on achieving the UNGA-AMR 70% Access target could generate significant potential national and global expenditure savings. FundingThis work was supported by the Wellcome Trust (304681/Z/23/Z) as part of the Antibiotic Data to Inform Local Action (ADILA) project and the Global Antibiotic Policy initiative (GAPi) project (RES 2024-495).

BackgroundSmoking, unhealthy nutrition, alcohol consumption, and physical inactivity (SNAP behaviours) are major risk factors for multimorbidity but are often studied in isolation. Using longitudinal data, Suhag et al. identified clusters of older adults (aged [&ge;]50) with common SNAP behaviour patterns and distinct sociodemographic profiles and multimorbidity prevalence; whether and how these patterns generalise across adulthood remains unclear. AimTo conceptually replicate Suhag et al. across a wider age range using an independent panel study. MethodsWe used data from Waves 7-13 of the UK Household Longitudinal Study, analysing adults (aged [&ge;]16) participating across all seven waves (n=18,008). Repeated-measures latent class analysis identified clusters of adults with common SNAP behaviours at Waves 7, 9, 11 and 13. Multinomial and binomial logistic regression examined how clusters were associated with sociodemographic characteristics and disease status (six disease groups plus multimorbidity), respectively. FindingsSeven clusters were identified: Overall Low-risk (20% of the sample), Insufficiently active (18%), Poor diet and Insufficiently active (23%), Hazardous and Harmful drinkers (11%), Hazardous drinkers, Insufficiently active and Poor diet (14%), Smokers and Drinkers (5%), and Smokers (9%). Behavioural profiles within clusters were largely stable over time. Associations between clusters and disease outcomes were counterintuitive. The cluster labelled Overall Low-risk on the basis of SNAP behaviours had the highest prevalence of multimorbidity, whereas the Hazardous drinkers, Insufficiently active and Poor diet cluster showed lower prevalence across most conditions. These clusters also differed in sociodemographic composition: the Overall Low-risk cluster comprised mainly older women with lower education and income, while the Hazardous drinkers, Insufficiently active and Poor diet cluster was more likely to comprise individuals in the highest education and income groups. ConclusionCluster-analytic techniques can be used to identify population subgroups with distinct behavioural and disease profiles, underscoring the need to consider risk behaviours in conjunction with sociodemographic context.

BackgroundVestibular complaints are common in older adults and are linked to imbalance and falls. Some older adults show impaired vestibular perception despite preserved peripheral-reflex ("vestibular agnosia"). Yet it remains unclear if vestibular agnosia is independently linked to imbalance and falls in otherwise healthy older adults. We therefore investigated the prevalence of vestibular agnosia in community-dwelling older adults, and examined its association to balance and prospective falls. MethodsVestibular perceptual thresholds were measured during yaw-plane rotational chair testing. Postural sway and instrumented Timed-Up-and-Go were assessed using wearable sensors, and falls were recorded prospectively over six-month. Vestibular agnosia was identified using K-means clustering. Multivariable regressions examined associations between perceptual thresholds and balance outcomes; logistic and negative binomial regressions evaluated associations with prospective falls. ResultsAmong 166 participants (75.4 years; 81.9% female), 18.7% were classified as having vestibular agnosia. These individuals had worse cognition and somatosensation. Elevated (i.e. worse) vestibular perceptual thresholds were independently associated with greater sway velocity when standing on foam with eyes-open (adjusted {beta}=0.002, p=0.03). Associations with other balance outcomes were attenuated after adjustment. Vestibular perceptual thresholds were not associated with prospective falls (odds of [&ge;]1 fall: adjusted OR=0.99, p=0.65; fall counts: adjusted IRR=1.02, p=0.35). ConclusionsApproximately one-fifth of healthy older adults exhibit vestibular agnosia. While elevated perceptual thresholds are independently associated with poorer balance, they did not predict falls. Vestibular perceptual testing provides complementary insight into age-related balance impairment, although its utility in fall-risk prediction requires further investigation. Key PointsO_LIApproximately one-fifth of healthy older adults had vestibular agnosia (impaired vestibular perception despite intact peripheral function) C_LIO_LIOlder adults with vestibular agnosia have poorer cognition, reduced lower limb somatosensation, and higher anxiety. C_LIO_LIHigher (i.e. worse) vestibular perceptual thresholds were independently associated with greater sway velocity when standing on foam (eyes open). C_LIO_LIHigher vestibular perceptual thresholds were only associated with slower TUG performance and greater eyes-closed foam sway in unadjusted models. C_LIO_LIVestibular perceptual thresholds did not predict prospective falls over 6 months. C_LI

Adaptation to physiological stress is fundamental to health but varies widely among individuals. In humans, this heterogeneity is evident in markedly different gains in fitness in response to identical exercise training. The molecular determinants of this variable "trainability" remain poorly understood. Here we identify insulin-like growth factor binding protein-7 (IGFBP7), a senescence-associated secreted protein, as a circulating constraint on exercise adaptation. Plasma proteomics in older adults enrolled in a randomized exercise trial revealed that IGFBP7 levels inversely predicted fitness gains after one year of high-intensity interval training despite similar baseline fitness. In mice, genetic deletion of IGFBP7 markedly amplified training-induced gains in exercise capacity across distinct training protocols, whereas somatic overexpression abolished this advantage. In the UK Biobank, lower IGFBP7 levels were associated with reduced mortality and multiple incident age-related diseases, mirroring the breadth of ties between fitness and healthspan. Together, these findings identify circulating IGFBP7 as a molecular brake on physiological plasticity in response to exercise, linking training responsiveness, aging biology, and health outcomes.

ObjectiveTo examine adherence to COVID-19 public health measures among culturally and linguistically diverse (CALD) and low socio-economic status (SES) populations in Victoria using a unique longitudinal cohort. Study DesignThe Optimise Study was a mixed-methods longitudinal cohort and social networks study (September 2020 - December 2023) assessing the impact of COVID-19 and related public health measures in Victoria, Australia. We used a serial cross-sectional design to analyse adherence to public health recommendations, restrictions, and requirements. Settings, participantsThe study examines two 28-day periods during the COVID-19 pandemic in Victoria: April 23- May 20, 2021 ( non-lockdown), and September 13-October 10, 2021 ( lockdown). We explored adherence to three categories of COVID-19 public health measures -- Recommendations (non-enforced, longer-term), Restrictions (mandated during lockdown periods), and Requirements (mandated, longer-term) -- among participants who completed questionnaires during these periods. Participants were grouped as: 1) non-CALD high SES (did not meet CALD or low-SES criteria), 2) CALD, or 3) non-CALD low-SES. Main outcome measuresPrimary outcomes were adherence to Recommendations, Restrictions, and Requirements during the two study periods. ResultsOf 782 participants recruited, 579 (75%) completed a survey or diary during at least one study period and were included in the analysis. Of these, 275 (47%) were in the non-CALD high-SES group, 114 (20%) in the CALD group, and 190 (33%) in the non-CALD low-SES group. Across all groups, risk-reduction behaviours increased during the lockdown. CALD participants showed higher adherence to some Recommendations and Restrictions compared to the other groups. Overall, 28% left home while awaiting a COVID-19 test result, commonly due to work. ConclusionsHigh adherence among CALD and non-CALD low-SES groups suggest structural barriers, rather than behavioural non-compliance, contributed to higher COVID-19 impacts, highlighting the need for tailored support. During future public health emergencies, better supports are needed for individuals working outside of home to remain in isolation while awaiting a test result. Summary box O_TEXTBOXWhat is already known about this subject? In Australia, priority populations such as culturally and linguistically diverse (CALD) and low socio-economic status (SES) groups experienced higher COVID-19 infection, mortality and a disproportionate impact from public health restrictions. What does this study add? CALD populations had an overall higher level of adherence to public health behavioural measures during both lockdown and non-lockdown periods compared to non-CALD populations. Over 25% of participants did not comply with stay-at-home requirements while awaiting a COVID-19 test result, largely due to work responsibilities. How might this impact on clinical practice? Pandemic preparedness efforts should focus on understanding the reasons for non-adherence with isolation requirements and considering tailored support during future pandemics to address the diverse C_TEXTBOX

Advances in our understanding of the biology of skeletal muscle ageing are being made at pace, with great potential for these findings to inform the identification of novel treatments for sarcopenia. However, translation of findings from animal models to humans has been hampered by limitations of existing human muscle biopsy studies. Devised to directly address this challenge, the Muscle Ageing and Sarcopenia Study (MASS) Lifecourse is a unique resource for the study of human muscle ageing across adulthood. This deep-phenotyped observational study of 260 community-dwelling men and women aged 18 to 85 years living in North East England includes muscle biopsy samples and detailed characterisation of physical function, health status and sociodemographic and behavioural risk factors. Underpinned by broad interdisciplinary research and clinical expertise this study is catalysing cutting-edge translational research on human muscle ageing across the adult life course.

BackgroundIntrinsic capacity (IC) is a key marker of healthy ageing, which captures an individuals physical and mental capacities, measured across five domains: cognitive, locomotor, psychological, vitality, and sensory. Although genetic factors are known to influence both general IC and its individual domains, existing IC indices have been developed primarily using phenotypic data, without accounting for the underlying biological architecture across domains. In this study, we developed a multi-trait polygenic score (Mt-PGS) model for IC by integrating polygenic scores derived from a broad set of phenotypes spanning the five IC domains and examined its validity. MethodsUsing data from 13,085 participants of the Canadian Longitudinal Study on Aging (CLSA), we computed PGSs for 63 phenotypes related to IC domains. A supervised machine-learning model was applied to develop a mt-PGS model for IC and identify the optimal set of polygenic predictors. The validity of the mt-PGS IC score was evaluated by comparing it with a phenotype-based IC score and by examining its association with mortality. ResultsOur analysis identified PGSs for 33 phenotypes with non-zero coefficients, jointly explaining 2.23% of the variance in IC. Several of the strongest contributors were most closely aligned with vitality-related phenotypes in the literature (including body mass index, grip strength, fat-free mass, diastolic blood pressure, and chronic obstructive pulmonary disease), acknowledging cross-domain relevance, and that predictors from all five IC domains were represented. The mt-PGS IC score was consistent with the phenotype-based IC score, positively correlated with the phenotype-based IC score and was inversely associated with mortality (OR = 0.04; 95% CI: 0.005 - 0.379). ConclusionOur findings support the multisystem biological basis of IC, demonstrating that an mt-PGS model integrating diverse phenotypes is associated with the phenotype-based IC score. PGSs for the phenotypes frequently related to vitality in the literature were the strongest predictors, recognizing that several of these phenotypes may span multiple domains, and that all domains contributed to the model. If replicated across different ancestries and settings, these findings may serve as a foundation for future research for the potential integration of genetic information into IC frameworks.