The Journals Of Gerontology. Series A, Biological Sciences And Medical Sciences[JOURNAL]
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200 papers
Updating and validating the Figueroa Frailty Index: transitioning from ICD-9 to ICD-10.
Huan T, Intrator O, Scott WJ … +3 more , Hall DE, Figueroa JF, Orkaby AR
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42271635 · Publisher ↗
BACKGROUND: The Figueroa Frailty Index (Figueroa-FI) is a claims-based frailty index developed using administrative Medicare claims data using International Classification of Disease (ICD) 9th revision. Updating to ICD-1...
BACKGROUND: The Figueroa Frailty Index (Figueroa-FI) is a claims-based frailty index developed using administrative Medicare claims data using International Classification of Disease (ICD) 9th revision. Updating to ICD-10 codes is essential for contemporary measurement. METHODS: ICD-9 codes were mapped to ICD-10 using Centers for Medicaid and Medicare Services (CMS) General Equivalence Mappings. Using a national cohort of Veterans aged ≥65 years, 2012-2019, annual prevalence trends for the 12 Figueroa-FI deficits were examined. Validity of Figueroa-FI was ascertained by examining adjusted annual HR of death and long-term institutionalization (LTI) for Veterans with 1 and ≥2 deficits vs 0, using Cox proportional hazards models. RESULTS: Annual cohorts of Veterans included 2.4 to 3.1 million Veterans, mean age 75 years, 97%-98% were male, 78%-80% White. Figueroa FI-ICD-10 includes 267 ICD-10 codes (vs 42 ICD-9 codes). Nine of the 12 Figueroa-FI deficits showed similar prevalence across the ICD-10 transition in 2016, while 3 displayed discontinuity. Veterans identified as frail were at increased risk of mortality and LTI. HR for death for FI of 1 vs 0 ranged from 1.97 to 2.02 over follow-up years, and HR of LTI from 2.75 to 2.92, while frail Veterans (FI ≥2) had hazards of death of 2.79 to 2.97 and hazards of LTI from 5.65 to 6.54. CONCLUSIONS: The updated Figueroa FI-ICD-10 maintains content validity, stability, and predictive validity for mortality and LTI in a contemporary cohort of Veterans aged ≥65 years, enabling frailty measurement using ICD-10 claims for clinical and research use.
Associations of obesity phenotypes with incident fall rates: results from the objective physical activity and cardiovascular disease health in older women study.
Jang H, Crandall CJ, Gore S … +9 more , Hu C, LaCroix AZ, LaMonte MJ, Liu L, Freeland KS, Cauley JA, Stefanick ML, Schumacher BT, Strotmeyer ES
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42271627 · Full text
BACKGROUND: Obesity and sarcopenia may influence fall risk through different mechanisms, but how different phenotypes affect fall rates is unclear, especially among older women. This study examined associations of whole-...
BACKGROUND: Obesity and sarcopenia may influence fall risk through different mechanisms, but how different phenotypes affect fall rates is unclear, especially among older women. This study examined associations of whole-body obesity, abdominal obesity, and sarcopenic obesity with incident fall rates among community-dwelling older women in the United States. METHODS: We analyzed data from 4654 ambulatory women aged ≥63 years in the Objective Physical Activity and Cardiovascular Health study, an ancillary study of the Women's Health Initiative. Whole-body overweight and obesity were defined as body mass index (BMI) 25 to <30 kg/m2 and ≥30 kg/m2, respectively; abdominal obesity as waist circumference >88 cm; and sarcopenia as grip strength <20 kg. Sarcopenic obesity was defined as the coexistence of obesity (either whole-body or abdominal) and sarcopenia. Falls were recorded using daily calendars over 13 months. Negative binomial regression models estimated associations between obesity phenotypes and monthly fall rates, adjusting for demographic, behavioral, and health-related covariates. RESULTS: Whole-body overweight and obesity were associated with lower fall rates compared to normal BMI (overweight incidence rate ratio [IRR] = 0.82, 95% confidence interval [CI] = 0.73, 0.92; obesity IRR = 0.76, 95% CI = 0.66, 0.87). Abdominal obesity showed a modest association with reduced fall rates (IRR = 0.87, 95% CI = 0.78, 0.96). In contrast, sarcopenia alone (IRR = 1.44, 95% CI = 1.24, 1.68), and sarcopenic obesity (IRR = 1.20, 95% CI = 1.03, 1.39) were associated with significantly higher fall rates. CONCLUSIONS: Our findings underscore the critical role of muscle strength loss, rather than excess adiposity, in fall risk among older women. Future interventions to reduce sarcopenia may reduce fall rates.
Associations of accelerometry-derived time in major activity intensities with cognitive outcomes: a compositional data analysis approach.
Callow D, Rabinowitz JA, Zhou X … +9 more , Chen X, Dougherty R, Crainiceanu C, Etzkorn L, Wanigatunga AA, Wanigatunga SK, Spira AP, Schrack JA, Zipunnikov V
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42268661 · Full text
BACKGROUND: Physical activity (PA), sedentary behavior (SB), and sleep are modifiable lifestyle factors linked to cognitive health. Prior research has largely relied on self-report to measure these constructs or ignored...
BACKGROUND: Physical activity (PA), sedentary behavior (SB), and sleep are modifiable lifestyle factors linked to cognitive health. Prior research has largely relied on self-report to measure these constructs or ignored the compositional nature of these data. We applied compositional data analysis (CoDA) to quantify the association between accelerometry-derived measures of time in major activity domains and cognitive outcomes among older adults. METHODS: Participants were 927 older adults (Mage = 82.71 years, SD = 3.99, range = 76-95) from the Atherosclerosis Risk in Communities (ARIC) study who wore wrist-worn accelerometers and completed cognitive assessments. Major activity domains were time in bed and time out of bed, which were divided into 4 categories: SB, low-light (low-LIPA), high-light (high-LIPA), and moderate-to-vigorous physical activity (MVPA). Cognitive outcomes included global cognition, memory, executive function, and language performance. RESULTS: Across all cognitive domains, greater time spent in MVPA relative to other activity domains, including out-of-bed time, SB, and low-LIPA, was associated with better cognitive performance. In contrast, greater time spent in low-LIPA relative to other activity domains was consistently associated with poorer performance across all cognitive domains, and these associations were attenuated, but remained statistically significant, after adjustment for gait speed. Sedentary behavior was negatively associated with executive function only. CONCLUSIONS: The trade-off between time spent in MVPA and in low-LIPA is the objectively measured PA that was most strongly associated with cognitive abilities. Time spent in low-LIPA may be an important biomarker of physical health and cognitive impairment.
MedADL: High-Throughput Information Extraction of Functional Status from Electronic Health Records to Advance Frailty Assessment in Older Adults.
Fu S, Yue Z, Nguyen JT … +7 more , Liu H, Ahn J, Ramirez V, des Bordes J, Liu H, Kwak MJ, Rianon NJ
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42267901 · Publisher ↗
BACKGROUND: Functional status is essential for assessing frailty and planning care in older adults but is often under-documented in the structured fields of electronic health records. Manual chart review can capture func...
BACKGROUND: Functional status is essential for assessing frailty and planning care in older adults but is often under-documented in the structured fields of electronic health records. Manual chart review can capture functional status information but is labor-intensive and time-consuming. In this study, we developed and validated a scalable natural language processing (NLP) model to extract functional status information from unstructured EHR notes. METHODS: This retrospective cohort study included 110 older adults seen at a geriatric osteoporosis clinic. An LLM-augmented symbolic NLP pipeline (MedADL) was developed to extract ADL and IADL impairments from 13,182 clinical notes and derive the Cumulative Functional Burden Index (CFBI), validated against grip strength, walking speed, balance score, and frailty status using ordinal logistic regression with 10-fold cross-validation. RESULTS: The NLP model demonstrated moderate to strong performance across 16 ADL and IADL categories, with an average precision of 0.868, sensitivity of 0.828, specificity of 0.937, and F1 score of 0.816. CFBI was significantly associated with frailty status (OR = 0.799, reciprocal OR = 1.25, p = 0.049, AUC = 0.66), indicating that each additional functional deficit was associated with approximately 25% higher odds of being classified in a less robust frailty category. CFBI was correlated with walking speed (r = 0.43, p < 0.001), balance (r = -0.42, p < 0.001), grip strength (r = -0.24, p = 0.019), and fall history (r = 0.21, p = 0.040). CONCLUSION: MedADL demonstrated moderate-to-strong performance across 16 bADL and iADL categories, and the derived Cumulative Functional Burden Index was significantly associated with frailty status and correlated with four objective physical performance measures. Future studies will prospectively evaluate long-term outcomes and integrate the model into the EHR to enable real-time clinical decision support.
The impact of upper gastrointestinal disorders on frailty: insights from the Baltimore Longitudinal Study of Aging.
Tegegne BS, Gupta T, Ferrucci L … +1 more , Tanaka T
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42262909 · Publisher ↗
BACKGROUND: Upper gastrointestinal (GI) disorders-including gastroesophageal reflux disorder, peptic ulcer disease, and gastritis-are common with aging, yet their contribution to frailty burden and progression is poorly...
BACKGROUND: Upper gastrointestinal (GI) disorders-including gastroesophageal reflux disorder, peptic ulcer disease, and gastritis-are common with aging, yet their contribution to frailty burden and progression is poorly understood. This study investigated whether upper GI disorders are independently associated with frailty in the Baltimore Longitudinal Study of Aging. METHODS: We analyzed data from 1353 participants (mean age 65.6 years; 47.7% men) with documented upper GI disorder status and Frailty Index (FI). Cross-sectional associations were examined using linear regression adjusted for age, sex, race, education, body mass index (BMI), and smoking. Longitudinal trajectories of FI were analyzed in a subset with ≥3 follow-up visits (n = 749) using linear mixed-effects models. Sensitivity analyses were conducted after excluding participants whose diagnosis occurred more than 1 year before FI assessment and for older adults. RESULTS: Upper GI disorders were significantly associated with higher frailty burden in cross-sectional analyses (β = 0.0303, p = 1.13 × 10-11). Older age, higher BMI, and lower educational attainment were also associated with higher FI. Longitudinal analyses further demonstrated that upper GI disorders were a significant predictor of FI throughout the follow-up period (β = 0.018, p = 4.3 × 10-9). However, the rate of frailty progression did not differ significantly between participants with and without GI disorders. Associations remained robust in all sensitivity analyses. CONCLUSIONS: Upper GI disorders were associated with higher frailty burden and greater degree of frailty that persisted over time, independent of covariates. Further research may be needed to explore the specific mechanisms through which upper GI disorders influence frailty.
Regulation of huntingtin-polyQ aggregation by glucose transporters and saccharide-binding receptors during aging in Drosophila.
Rai M, Coleman Z, Curley M … +1 more , Demontis F
J Gerontol A Biol Sci Med Sci · 2026 Jul · PMID 42249710 · Publisher ↗
Saccharides and responsive signaling pathways are important regulators of physiological and pathological processes. Saccharides can exert these functions via dedicated intracellular transporters and through binding to ce...
Saccharides and responsive signaling pathways are important regulators of physiological and pathological processes. Saccharides can exert these functions via dedicated intracellular transporters and through binding to cellular sensors, such as saccharide-binding receptors. Glucose homeostasis and saccharide signaling are emerging as important regulators of neurodegeneration. Here, we utilized a Drosophila model of Huntington's disease to examine the role of Glut1 (homologous to multiple human glucose transporters) and saccharide-binding receptors. We find that Glut1 knockdown increases the amount of huntingtin-polyQ protein aggregates during aging, whereas Glut1 upregulation has converse effects. RNAi screening identifies several saccharide-binding receptors that either increase or decrease the levels of huntingtin-polyQ protein aggregates. In particular, pathogenic polyglutamine aggregates are reduced by knockdown of the lectin domain-containing G-protein coupled receptor Cirl (Calcium-independent receptor for α-latrotoxin), orthologous to human ADGRL1 and ADGRL2. These findings indicate that glucose transporters and saccharide-binding receptors regulate proteostasis and neurodegeneration during aging.
Association between age-related musculoskeletal diseases and Parkinson disease: a population-based cohort study of UK Biobank.
Yang T, Huang J, Xiao Y … +6 more , Pang D, Cui Y, Cheng Y, Li C, Wei Q, Shang H
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42249707 · Publisher ↗
BACKGROUND: Age-related musculoskeletal diseases (ARMDs), including sarcopenia, osteoporosis, and osteoarthritis, may contribute to declines in intrinsic capacity and co-occur with neurodegenerative disorders such as Par...
BACKGROUND: Age-related musculoskeletal diseases (ARMDs), including sarcopenia, osteoporosis, and osteoarthritis, may contribute to declines in intrinsic capacity and co-occur with neurodegenerative disorders such as Parkinson disease (PD). We examined the association between ARMDs and PD risk. METHODS: In 362 656 UK Biobank participants (mean age: 56.48 years; median follow-up 13.65 years), ARMDs were assessed individually and cumulatively. Cox models estimated PD risk, adjusting for demographic, lifestyle, and genetic factors. Subgroup and sensitivity analyses were conducted to ensure robustness. A nested case-control analysis further explored the relationship between the duration of ARMDs exposure and the odds of PD diagnosis. Multivariable regression models assessed the associations between ARMDs and brain structure, including cortical, gray matter, and white matter integrity. RESULTS: During follow-up, 2057 participants developed PD. Sarcopenia (hazard ratio [HR]: 1.74, 95% confidence interval [CI]: 1.45-2.08, p < .001) and osteoporosis (HR: 1.76, 95% CI: 1.34-2.32, p < .001) were independently associated with higher PD risk. PD risk increased with the number of ARMDs (HR: 1.30, 95% CI 1.19-1.41; ptrend < .001) and the odds of PD diagnosis was highest within 5 years of the ARMDs diagnosis (odds ratio [OR] 2.19, 95% CI: 1.59-2.96, p < .001). Neuroimaging analysis indicated that ARMDs were associated with widespread and significant brain structural alterations, including in regions related to motor control. CONCLUSIONS: ARMDs are linked to elevated PD risk and brain structural changes. Interventions targeting musculoskeletal health may help preserve intrinsic capacity and delay or prevent PD onset in aging populations.
Multidomain functional dispersion and disability-free survival among community-dwelling older adults: an exploratory study.
Morikawa M, Harada K, Nishijima C … +5 more , Fujii K, Kakita D, Okuya T, Soma K, Shimada H
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42236294 · Publisher ↗
BACKGROUND: Physical, cognitive, and psychological functions contribute to disability risk and are interrelated. This study explored the association between multidomain functional dispersion and disability-free survival...
BACKGROUND: Physical, cognitive, and psychological functions contribute to disability risk and are interrelated. This study explored the association between multidomain functional dispersion and disability-free survival in community-dwelling older adults. METHODS: This cohort study used NCGG-SGS data. Functional dispersion was the within-person SD across standardized physical, cognitive, and psychological domain scores; higher values indicated greater between-domain differences. Disability-free survival was time to first certification under the Japanese Long-Term Care Insurance system. Adjusted cause-specific Cox models with restricted cubic splines examined dispersion and incident disability, including mean functional score. Robustness was assessed using bootstrap, Fine-Gray, and log-transformed sensitivity analyses. RESULTS: Among 13 746 participants (baseline 2011-2017), 2135 developed a disability during 5 years (15.5%). Dispersion was nonlinearly associated with disability risk (p for nonlinearity < .0001). Using the cohort median dispersion as the reference, adjusted hazard ratios were 0.94 (95% CI, 0.90-0.98) at the 25th percentile and 1.11 (95% CI, 1.03-1.20) at the 75th percentile. Below the median, hazard ratios decreased as dispersion declined but rose again at the extreme lower tail. Above the median, risk rose modestly and then declined at higher dispersion. Bootstrap and Fine-Gray analyses supported these patterns. CONCLUSIONS: Multidomain functional dispersion showed a nonlinear association with disability risk. Multidomain functional dispersion may be useful as an exploratory indicator of heterogeneity in disability risk beyond overall functional level.
Association of deep learning-derived temporalis sarcopenia with mortality in acute ischemic stroke.
Onichino JR, Zhang DY, Trottier M … +2 more , Rosenbloom L, Afilalo J
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42236280 · Full text
BACKGROUND: Sarcopenia is associated with mortality following acute ischemic stroke (AIS), but diagnosis is time-consuming. Computed tomography (CT) measures of temporal muscle volume (TMV) and density (TMD) can be autom...
BACKGROUND: Sarcopenia is associated with mortality following acute ischemic stroke (AIS), but diagnosis is time-consuming. Computed tomography (CT) measures of temporal muscle volume (TMV) and density (TMD) can be automatically extracted from existing scans using deep learning (DL). This study sought to demonstrate the incremental value of DL-derived TMV and TMD from CT scans on AIS mortality and length of stay (LOS). METHODS: In this retrospective, single-center cohort study, consecutive AIS patients admitted from 2014 to 2023 were included. TMV and TMD were quantified on admission CT scans by a novel DL model and represented as continuous or categorical variables. Patients were classified as non-sarcopenic, pre-sarcopenic (low TMV or TMD), or sarcopenic (low TMV and TMD) using 5th-percentile thresholds derived from 50 healthy adults. The primary outcome was 30-day all-cause mortality. Secondary outcomes were 365-day all-cause mortality and LOS. Multivariable logistic and linear regression were used. RESULTS: The cohort consisted of 2285 patients with 1151 (50%) females, and a mean (SD) age of 74.7 (13.7) years. There were 877 (38%) non-sarcopenic, 838 (37%) pre-sarcopenic, and 570 (25%) sarcopenic patients. Adjusted ORs (95% CIs) for 30-day mortality were 2.70 (1.64-4.46) and 2.91 (1.72-4.91) for pre-sarcopenia and sarcopenia. Findings were consistent across secondary outcomes. The association between sarcopenia and mortality was preserved after adding the Hospital Frailty Risk Score (HFRS) to the models. Findings were consistent in sensitivity analyses using cohort-derived threshold definitions. CONCLUSIONS: TMV and TMD extracted using a novel DL model were incrementally predictive of AIS mortality.
Using case-mixes to understand health resource utilization trajectories among older adults at high risk of falls who received baseline geriatrician-based Falls Prevention Clinic care.
Davis JC, Falck RS, Hsu CL … +10 more , Khan K, Chan P, Ghag C, Jacova P, Madden K, Dian L, Rice J, Parmar N, Mitton C, Liu-Ambrose T
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42226016 · Full text
BACKGROUND: We identified case-mixes among older adults at high risk of future falls, determined by longitudinal health resource utilization (HRU) cost trajectories, and examined baseline characteristics associated with...
BACKGROUND: We identified case-mixes among older adults at high risk of future falls, determined by longitudinal health resource utilization (HRU) cost trajectories, and examined baseline characteristics associated with these trajectories. METHODS: This descriptive secondary cohort analysis included 343 community-dwelling older adults at high risk of falls who participated in a randomized controlled trial. All participants received evidence-based falls prevention care at the Falls Prevention Clinic. The primary outcome was total healthcare resource utilization costs collected prospectively over 12 months using self-report questionnaires and monthly cost diaries. Case-mixes were identified using 12-month trajectories and latent class growth modeling. Baseline characteristics examined included intervention group, age, biological sex, cognitive function, and physical function. RESULTS: We identified 2 case-mixes. The "low-cost, stable" case-mix was characterized by low baseline HRU (∼$500 CAD) that remained stable over 12 months. The "low-cost, decreasing" case-mix had the lowest baseline HRU (<$500 CAD) and decreased over 12 months. Biological sex modified the trajectories. Specifically, males in the "low-cost, stable" case-mix demonstrated decreased HRU over 12 months, whereas female HRU remained unchanged. In the "low-cost, decreasing" case-mix, female HRU decreased at a greater rate than male HRU. CONCLUSIONS: Older adults at high risk of falls receiving Falls Prevention Clinic care demonstrated relatively low HRU characterized by stable and decreasing case-mixes. These findings provide descriptive insight into healthcare utilization patterns and may inform future evaluations of Falls Prevention Clinic models of care. These findings may assist future risk stratification and healthcare planning for older adults at elevated falls risk internationally.The trial was registered at clinicaltrials.gov (NCT01029171; NCT00323596).
Mitochondrial Dysfunction in Myoblasts: A TSPO-Dependent Mechanism of Sarcopenia.
Zhang P, Zheng H, Lin Z … +11 more , Dai H, Zhang M, Yang L, Deng Z, Song C, Su Y, Zhang R, Yu G, Luo J, Xu J, Luo F
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42226012 · Publisher ↗
Sarcopenia, the age-related loss of muscle mass and function, poses a significant health burden in aging societies. Although mitochondrial dysfunction is a recognized driver, the upstream molecular regulators remain poor...
Sarcopenia, the age-related loss of muscle mass and function, poses a significant health burden in aging societies. Although mitochondrial dysfunction is a recognized driver, the upstream molecular regulators remain poorly defined. Here, we identify the mitochondrial translocator protein (TSPO) as a novel negative regulator of myogenesis that is consistently upregulated in aged and sarcopenic muscle. Using gain- and loss-of-function approaches in C2C12 myoblasts, we show that TSPO overexpression disrupts mitochondrial homeostasis, impairs proliferation and differentiation, while TSPO knockdown produces opposite effects-establishing TSPO as a critical modulator of myogenic capacity. Mechanistically, TSPO suppresses the Wnt/β-catenin pathway, and this effect is partially mediated by ROS accumulation. Importantly, in vivo AAV9-mediated TSPO knockdown in aged mice not only restores mitochondrial integrity but also significantly improves muscle mass, strength, and exercise performance. Collectively, our findings uncover a TSPO-Wnt/β-catenin axis that links mitochondrial dysfunction to impaired muscle regeneration in aging. Targeting TSPO may offer a dual-action therapeutic strategy to combat sarcopenia by simultaneously enhancing mitochondrial bioenergetics and reactivating pro-myogenic signaling.
Effect of inactivation of the USP19 deubiquitinase gene in mice on important phenotypes of aging.
Sheng K, Coyne ES, Bédard N … +4 more , Lu E, Goltzman D, Haglund L, Wing SS
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42225593 · Publisher ↗
Aging is associated with many chronic conditions that increase morbidity and mortality. These include obesity, diabetes, sarcopenia, osteoporosis, and neurodegeneration. The deubiquitinase USP19 is involved in many of th...
Aging is associated with many chronic conditions that increase morbidity and mortality. These include obesity, diabetes, sarcopenia, osteoporosis, and neurodegeneration. The deubiquitinase USP19 is involved in many of these disorders suggesting that it may modulate common mechanism(s) that impact the aging process. Inactivation of USP19 is protective against muscle atrophy, obesity, and diabetes in young adult mice. Whether such protection persists in older adult mice remains unknown. In addition, the potential role of USP19 in osteoporosis remains unexplored. Here, we demonstrate that loss of USP19 is protective against loss of muscle mass and obesity in mice aged 22-24 months. Glucose tolerance was also improved in these older adult USP19 KO mice, but only in females. Bone mineral content was decreased in the USP19 KO bone, more evidently in cortical bone than in trabecular bone and only in males. This was associated with a reduced work-to-failure in the KO femurs. Osteoblasts derived from USP19 KO bone marrow cells demonstrated decreased ex-vivo mineralization compared to WT cells and the KO marrow cells showed enhanced differentiation into TRAP-positive multinucleated osteoclasts. These findings identify important potential benefits as well as risks of therapeutic targeting of USP19 for the prevention or treatment of key aging related disorders.
Untargeted metabolomics reveals effects of calorie restriction on skeletal muscle in older female and male rats.
Wang H, Hao J, Cartee GD
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42225590 · Full text
This study used untargeted metabolomics to investigate how calorie restriction (CR) affects skeletal muscle in older female and male rats. Fischer-344 Brown Norway rats of both sexes (22-23-month-old) were randomly assig...
This study used untargeted metabolomics to investigate how calorie restriction (CR) affects skeletal muscle in older female and male rats. Fischer-344 Brown Norway rats of both sexes (22-23-month-old) were randomly assigned to an ad libitum-fed (AL) group or a CR group, which received 65% of the daily food intake of their sex-matched AL counterparts for eight weeks. Epitrochlearis muscles were collected and analyzed using untargeted metabolomics and immunoblotting. CR altered the abundance of 554 out of the 999 detected muscle metabolites. Additionally, 521 metabolites differed between females and males. CR raised the levels of metabolites related to bile acids, with significantly greater CR-induced elevation of secondary bile acids in females, suggesting possible sex-dependent interactions involving the gut, liver, and muscle. Furthermore, CR increased the levels of five glycolytic metabolites. These changes occurred without increases in the abundance of phosphofructokinase (a rate-limiting glycolytic enzyme) or in key allosteric activators (AMP and ADP). There was no evidence for a CR-induced increase in NAD+/NADH ratio: NAD+ levels decreased and NADH levels increased for CR versus AL rats. Approximately 78% of dipeptides were lower in CR rats compared to AL rats, and 38% of dipeptides were greater for females versus males. Levels for 5-methyl-2'-deoxycytidine (a methylated DNA breakdown product and potential marker for changes in DNA remodeling) were significantly reduced by CR only in females. Together, these findings offer important insights for understanding both the shared and sex-specific mechanisms through which CR influences muscle metabolism, health, and function.
Cluster randomized trial of reablement strategies targeting sarcopenia (ReStart-S) in long-term care settings.
Kumar P, Umakanth S, Nayak K … +3 more , Bruyère O, Jaganathan V, Nandakumar G
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42218822 · Full text
BACKGROUND: Sarcopenia prevalence is high in long-term care settings (LTCS), yet existing guidelines often overlook this population. The Reablement Strategies targeting Sarcopenia (ReStart-S) program was developed to add...
BACKGROUND: Sarcopenia prevalence is high in long-term care settings (LTCS), yet existing guidelines often overlook this population. The Reablement Strategies targeting Sarcopenia (ReStart-S) program was developed to address this gap. This study evaluated its effects on muscle outcomes, physical performance, quality of life (QoL), and a blood biomarker. METHODS: A cluster-randomized trial was conducted in LTCS across Udupi and neighboring districts. Sarcopenic older adults (≥ 60 years, Barthel Index ≥ 60, Mini-Cog ≥ 3, AWGS-2019 criteria) were recruited. LTCS were randomized into intervention (IG) and control (CG) groups. IG received a 6-week ReStart-S program, while CG continued usual activities. Outcomes at baseline, 6, 12, and 18 weeks included handgrip strength (HGS, primary outcome), skeletal muscle index (SMI), Short Physical Performance Battery (SPPB), SarQoL, and C-terminal Agrin Fragment (CAF; not assessed at 12 weeks). Linear mixed models evaluated group*time interactions with Bonferroni correction. RESULTS: Of 12 LTCS screened, 7 were eligible; 78 participants enrolled (IG = 39; CG = 39). CG was older than IG (74.3 ± 9.4 vs 67.9 ± 6.0; p < .001). Significant group*time interaction was observed for HGS (F = 5.524; p = .001), improving at 12 (2.49; 95% CI, 1.16-3.82; p < .001) and 18 weeks (2.14; 0.79-3.48; p = .002). SPPB improved at 6, 12, and 18 weeks (all p < .001). SarQoL improved at all follow-ups (all p < .001). SMI improved at 18 weeks (0.20; p = .011). CAF decreased at 18 weeks (-61.77; p < .001). CONCLUSION: ReStart-S improved muscle strength, physical performance, and QoL, reduced CAF, and showed delayed muscle mass gains, supporting its role in sarcopenia care in LTCS. CLINICAL TRIAL REGISTRATION: The study was prospectively registered on October 20, 2022 on the Clinical Trial Registry-India (CTRI) platform. Trial registration number CTRI/2022/10/046680. The trial can be accessed at: https://ctri.nic.in/Clinicaltrials/showallp.php? mid1=71007&EncHid=&userName=CTRI/2022/10/046680.
Decoding the delirium proteome: linking clinical vulnerabilities to acute brain dysfunction.
Wang X, Liu K, Guo X … +2 more , Li N, Li Z
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42209428 · Publisher ↗
BACKGROUND: Delirium is an acute brain dysfunction syndrome with high morbidity and mortality, however its mechanisms remain poorly understood. Although multiple risk factors have been identified, directly targeting them...
BACKGROUND: Delirium is an acute brain dysfunction syndrome with high morbidity and mortality, however its mechanisms remain poorly understood. Although multiple risk factors have been identified, directly targeting them is challenging. Proteins may provide new insights into this challenge. METHODS: Using data from the UK Biobank, we explored associations between 18 established delirium risk factors and incident delirium using Cox proportional hazards models. Plasma proteomic profiling was conducted to identify proteins associated with delirium. Identified proteins underwent enrichment and mediation analyses to evaluate their potential involvement in the associations between risk factors and delirium. RESULTS: Over a median 13.5-year follow-up, 701 participants developed delirium. Among 2915 plasma proteins, 78 were significantly associated with delirium after Bonferroni correction, including Neurofilament light polypeptide (NEFL), Glial fibrillary acidic protein, WAP four-disulfide core domain protein 2 (WFDC2), Urokinase plasminogen activator surface receptor, and Growth/differentiation factor 15 (GDF15). Enrichment analysis suggested that these proteins were predominantly involved in immune, inflammatory, and metabolic processes. Mediation analysis indicated that some proteins may statistically mediate the associations between clinical risk factors and incident delirium; for example, NEFL (11.7%) and EDA2R (10.4%) for age, PLAUR (47.2%) and Mesothelin (MSLN; 40.1%) for smoking, GDF15 (40.6%) and C7 (16.3%) for diabetes, WFDC2 (13.4%) and PLAUR (13.1%) for frailty. Overall, 24 proteins statistically mediated the associations between at least 9 risk factors and delirium, with GDF15, PLAUR, Amphiregulin, Hepatitis A virus cellular receptor, Occludin, and, showing relatively higher statistical estimates. CONCLUSIONS: This large-scale study identifies plasma proteins that may help explain some of the observed associations between clinical risk factors and incident delirium, generating hypotheses about underlying mechanisms and potential avenues for further research.
Circulating biomarkers in older adults with and without sarcopenia: a systematic review and meta-analysis.
Prokopidis K, Deane CS, Baoubbou Z … +1 more , Beaudart C
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42202210 · Full text
BACKGROUND: Sarcopenia, the age-related loss of muscle mass and strength, poses a significant health and economic burden. This systematic review and meta-analysis evaluates circulating biomarkers (activin A, follistatin,...
BACKGROUND: Sarcopenia, the age-related loss of muscle mass and strength, poses a significant health and economic burden. This systematic review and meta-analysis evaluates circulating biomarkers (activin A, follistatin, growth differentiation factor (GDF-15), myostatin, growth hormone, insulin growth factor-1 (IGF-1), free and total testosterone) that may be associated with sarcopenia in community-dwelling older adults. METHODS: Following PRISMA 2020 guidelines, we searched PubMed, Scopus, Web of Science, and Cochrane Library from inception to June 2025. Studies included adults without major comorbidities aged >60 years with sarcopenia defined by established consensus. Standardized mean differences (SMDs) were calculated using a random-effects model. Heterogeneity was assessed via I2 and meta-regressions, while Egger's test was employed for publication bias. RESULTS: From 3488 records, 26 observational studies were included (n = 1345 adults with sarcopenia, 48.3% females, mean age 67.9-88.1 years). Adults with sarcopenia showed elevated GDF-15 (k = 5, SMD: 0.26, 95% confidence interval (95% CI), 0.03 to 0.50, I2 = 64%, p = .03) and reduced IGF-1 (k = 11, SMD: -0.40, 95% CI, -0.54 to -0.27, I2 = 36%, p < .01) compared to controls without sarcopenia. No significant differences were found between groups for the other circulating biomarkers. CONCLUSIONS: Elevated circulating IGF-1 and, to a lesser extent, GDF-15, may be promising biomarkers for sarcopenia. Larger, longitudinal studies are needed to address heterogeneity and causality.
A Bayesian network analysis of gait speed change upon transition to uneven surfaces in older adults.
Song Y, Rosano C, Chahine LM … +5 more , Rosso AL, Ambrosio F, Bohnen N, Chen Z, Kim S
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42184285 · Full text
BACKGROUND: Gait adaptability, defined as the ability to adjust walking performance to environmental challenges, likely reflects complex interactions among the central nervous system (CNS) and other physiological systems...
BACKGROUND: Gait adaptability, defined as the ability to adjust walking performance to environmental challenges, likely reflects complex interactions among the central nervous system (CNS) and other physiological systems. However, the drivers of lower gait adaptability in older adults are poorly understood. METHODS: We applied a Bayesian network framework to understand multisystem interactions contributing to percent change in gait speed (%GSC) on transition from even to uneven surface in 159 older adults. Neuroimaging measures include gray matter volume, white matter hyperintensities, striatal dopaminergic (DA) neurotransmission, and functional connectivity. Other measures were obtained for domains important for locomotor control: health history, lifestyle, psychological well-being, cognition, and musculoskeletal and peripheral nervous systems. The Bayesian network captured relationships among these variables as a network, quantifying their direct and indirect dependencies. The predictive accuracy of %GSC from the Bayesian network was compared with that of multivariate linear regression using 10-fold cross-validation. RESULTS: Participants exhibited slower gait on uneven compared to even surfaces (mean %GSC = -6.32%). The Bayesian network outperformed linear regression in predicting %GSC and identified four direct paths to %GSC from body mass index, muscle strength, striato-cortical sensorimotor connectivity, and purpose in life. Indirect paths to %GSC showed interrelations among CNS and non-CNS variables, including striatal DA neurotransmission, total grey matter volume, medications, proprioception, and sex. CONCLUSIONS: Gait adaptability in older adults is influenced by interactions among functional connectivity, body composition, muscle strength, and psychological well-being. Strengthening both neural and physical systems through targeted interventions may mitigate declines in gait instability and preserve mobility with aging.
Exercise-induced changes in physical performance and circulating acyl-CoA binding protein/diazepam binding inhibitor (ACBP/DBI) in older adults with and without HIV.
Sánchez-Conde M, Montégut L, Martín-Pedraza L … +7 more , Martins I, Luna L, Martínez M, Ryan P, López-Otín C, Kroemer G, Brañas F
J Gerontol A Biol Sci Med Sci · 2026 May · PMID 42179162 · Publisher ↗
Acyl-CoA binding protein (ACBP) is a tissue stress hormone with pro-senescent activity. Exercise promotes healthy ageing, but its relationship with circulating ACBP/DBI levels in older adults is unknown. We assessed the...
Acyl-CoA binding protein (ACBP) is a tissue stress hormone with pro-senescent activity. Exercise promotes healthy ageing, but its relationship with circulating ACBP/DBI levels in older adults is unknown. We assessed the association between exercise-induced functional changes and circulating ACBP/DBI levels in older adults with and without HIV. MOVIhNG is a prospective, longitudinal, multicentre controlled study including sedentary adults aged 50 years or older, with and without HIV. Participants undertook a personalised multicomponent exercise programme comprising strength, aerobic endurance, balance, and flexibility training. Assessments were performed at baseline and after 12, 24, and 48 weeks. Circulating ACBP/DBI levels were measured by ELISA. Physical performance was assessed using the Short Physical Performance Battery (SPPB), the chair stand test (lower-body strength); the biceps curl test (upper-body strength), and the 2-minute step test (aerobic endurance) Associations were analysed using generalized estimating equations adjusted for sex and body-mass index. Sixty participants were included (40 with HIV and 20 without HIV; median age 56·5 years). At 12 weeks, changes in circulating ACBP/DBI were significantly correlated with improvements in upper-body strength and aerobic endurance. Over 48 weeks, increases in aerobic endurance and SPPB scores were independently associated with significant reductions in circulating ACBP/DBI levels. Each one-point increase in SPPB score was associated with a 203 ng/mL decrease in plasma ACBP/DBI. HIV status did not influence overall ACBP/DBI trajectories across follow-up. Exercise-induced improvements in physical performance were associated with reduced circulating ACBP/DBI levels across follow-up in older adults, irrespective of HIV status.
Interventions that prolong multidimensional healthspan in humans: a systematic review of randomized controlled trials.
Zheng HT, Phyo AZZ, McCubbin C … +3 more , Wu Z, Bischoff-Ferrari HA, Ryan J
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42172592 · Full text
Maximizing healthspan, the period of life spent in good health, is a public health priority. This review aimed to summarize the current evidence from randomized controlled trials on interventions that can prolong healths...
Maximizing healthspan, the period of life spent in good health, is a public health priority. This review aimed to summarize the current evidence from randomized controlled trials on interventions that can prolong healthspan in humans. The specific focus was on multidimensional person-centered outcomes, which reflect functioning rather than disease, such as intrinsic capacity and quality of life. This review was registered (CRD420251015780) and conducted with adherence to the PRISMA guidelines. MEDLINE, EMBASE, and grey literature were systematically searched for studies evaluating interventions that improve intrinsic capacity or quality of life. The search included articles published up to October 16, 2025. Of 1960 publications identified, 15 articles (4656 participants) met the inclusion criteria. There was high heterogeneity between the included studies in terms of the interventions examined, which varied from exercise alone (7 studies) to multidomain interventions (6 studies, all of which included an exercise component), daily oral supplementation (2 studies), or caloric restriction (1 study). Overall, 11 studies reported that exercise or multidimensional intervention (which included an exercise component) improved intrinsic capacity and quality of life. However, due to the small number of studies and heterogeneity, no conclusion could be drawn regarding other interventions. Therefore there is some evidence that exercise could extend intrinsic capacity and quality of life, either aerobic or resistance training alone, or a combination of different types of exercise; but further research is required to evaluate the effect of other interventions that may prolong healthspan across more diverse populations.
Plasma myeloperoxidase predicts cognitive decline in mild cognitive impairment: a multicenter longitudinal cohort study.
Sun W, Shan A, Wang P … +5 more , Han X, Xu C, Luan H, Li S, Wei C
J Gerontol A Biol Sci Med Sci · 2026 Jun · PMID 42172591 · Publisher ↗
Mild cognitive impairment (MCI) is a key stage for early intervention in dementia, and its inflammatory mechanisms remain unclear. Myeloperoxidase (MPO), a key enzyme involved in inflammation and immune regulation, has n...
Mild cognitive impairment (MCI) is a key stage for early intervention in dementia, and its inflammatory mechanisms remain unclear. Myeloperoxidase (MPO), a key enzyme involved in inflammation and immune regulation, has not been fully studied in MCI. This multicenter longitudinal cohort study prospectively followed 133 patients with MCI for 12 months. Plasma MPO, Alzheimer's disease (AD)-related biomarkers (p-Tau181, p-Tau217, glial fibrillary acidic protein , neurofilament light chain, and Aβ42/40), inflammatory cytokines (IL-1β, IL-6, and TNF-α), neuropsychological performance, and APOE genotype were assessed at baseline and follow-up. During follow-up, 58 patients showed cognitive deterioration and 75 remained non-deteriorated. At both baseline and the 12-month follow-up, the cognitive deterioration group showed higher MPO, IL-1β, and IL-6 levels than the non-deterioration group. Within-group longitudinal changes from baseline to follow-up were modest and were not statistically significant. Cross-sectional analyses showed that MPO was associated with IL-1β, IL-6, Aβ42/40, Mini-Mental State Examination (MMSE), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) at different assessment time points. Longitudinal delta analyses showed that changes in MPO were significantly correlated with changes in MMSE, IL-1β, and IL-6, but not with changes in ADAS-Cog or Aβ42/40. After adjustment for potential confounders, MPO remained an independent predictor of cognitive deterioration in MCI (OR = 1.018, 95% CI, 1.00-1.03, p = .015). Nomogram analysis showed that MPO was the most prominent predictor in the model. These findings suggest that elevated plasma MPO may serve as a clinically accessible prognostic biomarker for risk stratification in patients with MCI.
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