Age

Handgrip strength (HGS) is recognized as the primary characteristic of sarcopenia. Low HGS is strongly associated with morbidity, disability, and mortality. However, the neural mechanisms underlying age-related declines in HGS have not been fully elucidated. The multi-finger force deficit (MFFD), which reflects the central nervous system’s capacity to coordinate finger activation during a power grip, provides an innovative approach to assess these neural contributions. Prior MFFD studies have inferred neural contributions to grip force, but this assumes that multi-finger dynamometry captures coordination processes relevant to conventional HGS. Because prior paradigms used non-standard hand/forearm postures and generally studied younger-old, high-functioning adults, the clinical relevance of MFFD to age-related weakness remains uncertain. Therefore, we tested younger (n = 12; 23.7 ± 1.7 years) and markedly older (n = 10; 80.3 ± 8.8 years) adults using a biomimetic setup that replicated traditional HGS assessment and examined whether HGS is altered under cognitively demanding dual-task conditions. Older adults exhibited 48.8

Retinal pigment epithelium (RPE) senescence acts as a core driver of subretinal fibrosis, a major irreversible pathological feature that exacerbates age-related macular degeneration (AMD). Mitophagy is essential for maintaining RPE homeostasis during aging. However, the upstream molecular mechanisms underlying mitophagy impairment in senescent RPE remain poorly defined. Here, we show that lysosomal-associated transmembrane protein 5 (LAPTM5) is significantly upregulated in human AMD specimens and D-galactose (D-gal)–induced aging mouse model, with its overexpression correlating with transcriptomic signatures of RPE senescence and fibrogenesis. Gain- and loss-of-function assays validate that LAPTM5 acts as an important regulator of RPE senescence and senescence-associated secretory phenotype (SASP) production. Mechanistically, LAPTM5 physically interacts with and promotes the lysosome-dependent degradation of WW domain-containing E3 ubiquitin protein ligase 2 (WWP2), which in turn diminishes optineurin (OPTN) polyubiquitination and ablates OPTN-mediated mitophagy. The resulting mitophagy deficiency is associated with cytoplasmic mitochondrial DNA leakage and sustained cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) innate immune activation, stimulating robust senescence-associated secretory phenotype (SASP) release that promotes RPE epithelial-mesenchymal transition (EMT) and exacerbates subretinal fibrotic scarring. Notably, AAV-mediated RPE-specific Laptm5 knockdown efficiently alleviates subretinal fibrotic lesions in the aged mouse model, while pharmacological STING inhibition with H-151 markedly attenuates EMT progression. Collectively, our findings identify a previously uncharacterized LAPTM5-WWP2-OPTN mitophagy cascade and reveal a new pathogenic circuit linking impaired mitophagy to RPE senescence and age-related retinal fibrosis, offering translational prospects for treating senescence-associated fibrotic diseases. This graphical abstract depicts the LAPTM5-associated pathological signaling cascade underlying subretinal fibrosis in neovascular age-related macular degeneration (nAMD). In senescent retinal pigment epithelial (RPE) cells, upregulated LAPTM5 accelerates the lysosomal degradation of WWP2, disrupting K48- and K63-linked OPTN polyubiquitination. Impaired OPTN-dependent mitophagy leads to cytosolic mitochondrial DNA (mtDNA) accumulation and robust activation of the cGAS-STING axis, which markedly boosts the production of senescence-associated secretory phenotype (SASP) factors. Released SASP factors act in a paracrine manner on neighboring RPE cells, fibroblasts, choroidal endothelial cells (CECs) and macrophages, driving their transdifferentiation into myofibroblasts. This process initiates epithelial-mesenchymal transition (EMT) in RPE cells, promoting excessive extracellular matrix (ECM) deposition and subsequent subretinal fibrosis. (Note: Dashed arrows denote paracrine signaling and fibrotic events inferred from published literature, which are not experimentally validated in this study.) Overall, LAPTM5 functions as a pivotal regulator bridging RPE senescence and retinal fibrogenesis, offering a viable therapeutic target for nAMD. (Graphical abstract created by Figdraw2.0)

Accurate preoperative prediction of postoperative neurobehavioral instability remains an important unmet need in perioperative medicine. Existing prediction models often rely on intraoperative variables, specialized biomarkers, or limited validation, reducing their usefulness during routine preoperative assessment. We developed and temporally validated a multivariable prediction model for postoperative Richmond Agitation-Sedation Scale alterations (RASSa) using routinely available preoperative variables. We conducted a retrospective observational cohort study including consecutive adults undergoing elective orthopedic surgery (EOS) at a tertiary referral hospital between 2018 and 2024. The model was developed in a chronological derivation cohort using routinely collected demographic and laboratory variables and evaluated by tenfold cross-validation, 2000 bootstrap resamples, and independent temporal validation. Model performance was assessed through discrimination, calibration, prediction error, precision-recall analysis, and decision curve analysis. Among 46,804 screened procedures, 41,010 patients met the eligibility criteria. The development cohort comprised 34,271 patients and the temporal validation cohort 6739 patients. RASSa occurred in 377 patients. The final model included age, sex, preoperative hemoglobin, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, systemic immune-inflammation index, systemic inflammation response index, and a two-component representation of the basophil-to-lymphocyte ratio. Internal validation showed minimal optimism, whereas temporal validation demonstrated good discrimination (AUROC 0.892), satisfactory calibration (intercept 0.132; slope 0.861), low prediction error (Brier score 0.013), and consistent utility. A prediction model based exclusively on routinely available preoperative variables provided individualized estimation of postoperative RASSa after EOS. It demonstrated stable temporal performance and may support perioperative risk stratification. External validation is required before routine implementation.

Older adults with mild cognitive impairment (OAwMCI) fall 2 × more than cognitively intact older adults (CIOA), possibly due to impaired reactive stepping. However, most studies in OAwMCI have focused on slip-like perturbations (backward loss of balance), rather than trip-like perturbations (forward loss of balance). This study examined reactive stepping strategies following a novel support surface perturbation during treadmill walking, and compared fall rate, margin of stability (MOS), step length, and trunk angle between OAwMCI and CIOA during unperturbed walking (i.e., pre-trip) and recovery stepping (i.e., post-trip). As an exploratory analysis, muscle synergies were also extracted from bilateral lower limb EMG data from perturbation onset to recovery touchdown. After trip onset, most participants took a lowering-like step with the swing limb, followed by a forward recovery step with the contralateral (43

Infections remain a major cause of mortality and may threaten healthy aging. Previous studies have focused on isolated severe infections rather than longitudinal infection burden. We aimed to examine associations of infection trajectories with biological age acceleration (BAA) and assessed infection severity and genetic susceptibility. We included adults aged 20–74 years from the Shanghai Suburban Adult Cohort and Biobank, China, enrolled between 2016 and 2019 with valid biological age (BA) measurements at baseline and follow-up. Infection-related episodes were identified from linked local health information systems and summarized quarterly between baseline and first follow-up. Group-based trajectory modeling identified infection trajectories. BA was estimated using the Klemera-Doubal method and BAA was defined as the residual from regressing BA on chronological age. Linear mixed-effects models assessed associations with annual BAA change. Polygenic risk scores and Cox models evaluated genetic susceptibility and all-cause mortality. Among 7614 participants, four infection trajectories were identified: infrequent (71.15

Workplace stress is an increasingly recognized determinant of both workforce well-being and healthy aging. However, few longitudinal studies have systematically integrated stress assessment into large occupational cohorts with an explicit focus on aging processes. The Semmelweis Study, launched in 2024, addresses this gap by embedding validated stress assessment tools into a comprehensive, multidisciplinary framework designed to explore the biological, psychological, and social determinants of healthy and unhealthy aging in a university workforce. This paper presents the conceptual foundation, methodology, and early applications of workplace stress assessment within the Semmelweis Study. We outline research hypotheses linking stress to aging outcomes and describe a pilot investigation among a high-risk subgroup-conductors trained at the András Pető Faculty of Semmelweis University. Stress is assessed using validated psychometric tools, including the Perceived Stress Scale, Effort-Reward Imbalance Questionnaire, Maslach Burnout Inventory, resilience measures, and social support scales. These are integrated with biological aging markers, cognitive assessments, mental health indicators, lifestyle factors, and detailed occupational data. A pilot study applying this framework was conducted among conductors, a professional group known for high emotional demands and role strain. Preliminary findings indicate elevated stress levels and burnout symptoms among conductors, with workload, perfectionism, and emotional burden identified as key stressors. Participants expressed strong interest in workplace-based stress management resources, informing plans for targeted interventions within this group. The integration of workplace stress assessment into the Semmelweis Study offers a novel platform for advancing healthy aging research and informing real-world prevention strategies. By systematically linking stress measurement to aging outcomes, and by addressing occupational stress through targeted interventions, Semmelweis University exemplifies how academic institutions can act as both research leaders and models of healthy workplace practices. These efforts align with the Semmelweis-EUniWell Workplace Health Promotion Model Program and contribute to broader European efforts to promote resilience, well-being, and healthy longevity across the working life course.

Language impairment is increasingly recognized as an early marker of neurodegeneration in mild cognitive impairment (MCI). L5, an electronegative subfraction of low-density lipoprotein cholesterol, has been implicated in both vasculopathy and neurodegenerative processes, positioning it as a potential contributing factor to MCI pathology. This study investigates alterations in the connectivity and dynamics of core language networks and aims to elucidate the diverse pathophysiological processes underlying language decline. We enrolled 22 patients with clinically defined MCI and 30 cognitively normal individuals. Cognitive function was assessed using the Cognitive Abilities Screening Instrument. Serum L5 levels were quantified by anion-exchange chromatography. Resting-state functional magnetic resonance imaging (MRI) was used to evaluate functional connectivity and Granger causal interactions within predefined language-related regions. Correlation analyses and prespecified multivariable linear regression models were performed to examine the independent associations among serum L5 percentage (L5

Alzheimer's disease (AD) is increasingly recognized as a neurodegenerative disorder associated with chronic low-grade inflammation and age-related immune dysregulation. Microglial-derived extracellular vesicles (MDEVs) are emerging as important mediators of neuroimmune communication and potential biomarkers reflecting pathological processes occurring within the central nervous system (CNS). However, how EV-associated inflammatory signalling changes across different stages of AD remains poorly understood. In this study, we characterized the inflammatory molecular profile of serum-derived MDEVs in 22 AD patients, 19 prodromal AD subjects, and 23 healthy controls (HC). Cytokine concentrations were also evaluated in paired serum and cerebrospinal fluid (CSF) samples to compare vesicle-associated and soluble inflammatory signals across biological compartments. MDEVs were isolated by size exclusion chromatography followed by TMEM119-based immunoenrichment. Cytokine quantification was performed using the Ella Simple Plex automated immunoassay platform. MDEVs from AD patients showed a generalized reduction in both pro- and anti-inflammatory cytokines compared to HC, including IL-1β, TNF-α, IL-2, IFN-γ, IL-6, IL-12p70, IL-10, and IL-4. Notably, several alterations were already detectable at the prodromal stage. In contrast, soluble cytokines in serum and CSF displayed a predominantly pro-inflammatory profile in AD patients, with increased levels of IL-1β, TNF-α, and IL-12p70. No significant correlations were observed between cytokine levels measured in MDEVs and those detected in serum or CSF. Overall, these findings support the presence of a compartment-specific reorganization of inflammatory signalling during AD progression. Early alterations in MDEV inflammatory cargo may reflect disrupted EV-mediated neuroimmune communication and highlight the potential of MDEVs as accessible peripheral biomarkers of neuroinflammatory processes in AD.

Excessive alcohol consumption accelerates cardiovascular aging by promoting oxidative stress, inflammation, lipid dysregulation, fibrotic remodeling, and loss of ventricular-vascular reserve. PCSK9, a key regulator of cholesterol metabolism, has emerged as a mediator of age-related cardiovascular dysfunction and alcohol-associated liver and neurovascular injury. We investigated whether PCSK9 inhibition protects against alcohol-induced cardiovascular dysfunction and associated cardiac-hepatic injury in rats. Male Sprague–Dawley rats were assigned to pair-fed control or 35

Chemotherapy-induced bone loss represents a major clinical challenge, particularly in aging populations, yet the contribution of cellular senescence to this process and its therapeutic potential remain incompletely understood. Here, we investigated the role of chemotherapy-induced cellular senescence in mediating skeletal deterioration following chemotherapy and evaluated the therapeutic potential of senolytic treatment. Young (3-month-old) and aged (20-month-old) male and female mice were treated with doxorubicin (DX), a chemotherapeutic agent, dasatinib/quercetin (DQ), senolytic agents, or their combination (DX/DQ). Chemotherapy-induced hallmark features of accelerated skeletal aging, including trabecular bone loss, increased marrow adiposity, and upregulation of senescence-associated and inflammatory gene expression. These effects were sex- and age-dependent and were more pronounced in females. Senolytic treatment with DQ partially restored osteogenic gene expression, including Alpl, Runx2, and Dmp1, and reduced marrow adiposity, particularly in aged females, indicating preservation of bone marrow niche function. Proteomic analysis of cortical bone revealed that DX-induced cellular senescence was associated with extracellular matrix remodeling and a metabolic shift toward glycolysis, characterized by increased inflammatory collagen isoforms and glycolytic enzymes. DQ treatment partially reversed these molecular signatures, including restoration of several extracellular matrix proteins associated with bone architecture and mineralization. Despite these molecular improvements, recovery of trabecular bone architecture remained modest, suggesting that senolytic-mediated molecular remodeling precedes detectable skeletal recovery. Collectively, these findings support a model in which chemotherapy-induced bone loss is driven by both early osteoblast suppression and senescence-driven microenvironmental dysfunction, identifying cellular senescence as a potential therapeutic target for preserving skeletal health following chemotherapy.

Aging is a multifaceted process where physiological metrics, such as brain age and muscle age (MA), provide deeper insights than chronological age alone. These nonlinear trajectories are heavily influenced by exogenous factors like lifestyle and nutrition. In older populations, muscle age acceleration (MAA) critically impacts functional autonomy and cognitive health, necessitating research into its link with brain network organization to refine assessments and, based on these, integrated motor and cognitive rehabilitation strategies. In this study, eyes-closed resting-state electroencephalography (EEG) was recorded from 101 healthy, neurologically intact older adults. MA and MAA were quantified using a regression model incorporating the functional assessments recommended by the European Working Group on Sarcopenia in Older People (EWGSOP-2) consensus (anthropometrics, muscle strength, and motor functional tests). Participants were stratified into three groups based on their MAA: decelerated MA, normal MA, and accelerated MA. Brain connectivity was assessed through magnitude-squared coherence (MSCoh) and node strength analyses. The results demonstrated that decelerated MA subjects exhibit significantly lower MSCoh compared to the normal and accelerated groups in the Alpha 1, Alpha 2, and Beta 1 bands. Furthermore, node strength analysis revealed that the decelerated MA group possessed lower values in the right frontal area across Alpha 1, Beta 1, and Beta 2 bands. Conversely, the normal MA group exhibited lower values in the right temporal region compared to the accelerated MA group. These findings may suggest that divergent muscle aging trajectories significantly modulate brain network topography. This brain–body interconnection highlights the potential for personalized interventions designed to redirect muscle aging trajectories, ultimately enhancing global functioning and quality of life of older people.

Dietary isoleucine restriction improves metabolic health and lifespan in animal models. It is hypothesized that shifts in branched-chain amino acid catabolism drive longevity. We investigated dietary isoleucine restriction on organismal branched-chain amino acid catabolism and its association with longevity and reproduction. In two main experiments, adult female Lubber grasshoppers were assigned to a high-quality diet (Bal ile) or diets with two levels of isoleucine content (moderate isoleucine restriction [Mod ile-R] or severe isoleucine restriction [Sev ile-R]). In Experiment 2, we used a low-energy (Low Lett) group as a positive control for catabolism. In Experiment 3, we used an ad libitum lettuce (Ad Lib Lett) control to show the reproduction-longevity trade-off. Nutrient-specific, organismal catabolism was measured by tracking 13C in an ingested amino acid through catabolism to breath CO2. The Bal ile, Mod ile-R, and Sev ile-R diets extended lifespan and increased leucine catabolism relative to the Ad Lib Lett group. The Sev ile-R and Low Lett groups showed the highest leucine catabolism but greatly reduced reproduction. The Bal ile group showed intermediate leucine catabolism while sustaining reproduction. The Mod ile-R group had intermediate leucine catabolism but delayed reproduction. There was no compensatory feeding on low isoleucine diets. Valine catabolism did not show statistical significance but tended to show similar trends to leucine catabolism. Weak leucine catabolism is linked to a short lifespan, while excessive leucine catabolism is linked to impaired reproduction. Intermediate levels of leucine catabolism were associated with longevity and sustained reproduction.

Naturally aged mice provide an important platform for studying frailty because functional decline emerges during biological aging rather than through acute injury or artificial manipulation. This review critically examines major frailty assessment tools used in aged mice, including the mouse frailty index, mouse frailty phenotype, physical function score/vitality score, mouse social frailty index, and mouse cognitive frailty index. We compare their conceptual foundations, scoring procedures, dimensional coverage, reproducibility, mortality associations, intervention responsiveness, and translational correspondence with clinical models such as the Fried phenotype and deficit accumulation frailty index. We also discuss how biological mechanisms linked to the hallmarks of aging, including inflammaging, immunosenescence, mitochondrial dysfunction, cellular senescence, altered nutrient sensing, and impaired stress resilience, may contribute to frailty development. Current instruments capture complementary aspects of frailty but differ in their dependence on subjective observation, cohort-specific thresholds, testing conditions, and validation across sex, strain, laboratory, and outcome. Digital phenotyping, longitudinal trajectories, secondary prognostic models, and measures of latent vulnerability may extend current approaches, but these strategies remain exploratory. Alternative weighting systems and the proposed distinction between pre-frailty and subclinical frailty require prospective validation before they can be considered standardized methods. Clear separation of established instruments from conceptual future directions will improve methodological rigor and translational relevance.

Although motor and cognitive functions are closely interconnected in daily life, they are typically assessed separately in fall assessments. This dual-center cross-sectional, observational study examined the discriminative performance of agility and motor-cognitive assessments to distinguish between community-dwelling older adults with and without a history of falls, compared with established motor and cognitive tests. A total of 231 participants (103 with a history of falls; age 71.9 ± 7.5 years) completed a SKILLCOURT test battery, including the Random Star Run (unplanned, reactive changes of direction; agility) and motor-cognitive stepping tasks involving reactive responses while standing to simple and choice reaction, task-switching, 2-back, and Stroop word-color stimuli. Motor tests included the Timed-Up-and-Go (TUG), Sit-to-Stand, and walking speed, each performed under both single- and dual-task conditions. Seated PC-based cognitive tests assessed reaction speed and executive functions corresponding to the SKILLCOURT tasks. Age- and study location-adjusted general linear models identified significant group effects after Holm adjustment for the Random Star Run (η2p = 0.04, p = .050) and the simple stepping reaction task (η2p = 0.03, p = .048), with faster completion and response times for participants without a history of falls, whereas established assessments showed no relevant group differences (η2p = 0.001–0.013, p > .05). Z-standardised adjusted logistic regression analyses revealed significant associations between Random Star Run performance and fall history (Odds Ratio; OR = 1.82 per 1 SD increase, p = .009), with longer completion times associated with higher odds of having a history of falls. The adjusted model yielded an AUC value of 0.73, with 70

Pulmonary hypertension (PH) frequently complicates heart failure with reduced ejection fraction (HFrEF), worsening prognosis despite limited therapeutic options. Whether sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve PH beyond their established hemodynamic effects remains unclear. Seventy-four patients with ischemic HFrEF after acute myocardial infarction and a high echocardiographic probability of PH were prospectively enrolled in a single-center, non-randomized study. Patients received either an SGLT2i (dapagliflozin or empagliflozin, 10 mg/day; n = 42) plus guideline-directed medical therapy or guideline-directed medical therapy alone (n = 32). Untargeted plasma proteomics (pooled samples), microRNA profiling, and selected biomarkers of senescence and oxidative stress were performed. Candidate findings were validated by ELISA and qRT-PCR. Complementary in vivo and in vitro experiments evaluated empagliflozin in ischemia/reperfusion injury and hypoxic human pulmonary artery endothelial cells and cardiomyocytes. SGLT2i therapy was associated with lower circulating activin A and miR-1306-5p levels, improved World Health Organization functional class, fewer signs of right-heart failure, reduced echocardiographic probability of PH, and enhanced right ventricle–pulmonary artery coupling. In experimental models, empagliflozin reduced activin A, increased BMPR2 expression, and improved post-ischemic ventricular function. Similar molecular changes were observed in hypoxic endothelial cells and cardiomyocytes. Chloroquine partially attenuated these effects, suggesting a possible involvement of autophagy. Across complementary clinical and experimental models, SGLT2i treatment was consistently associated with reduced activin A signaling. Modulation of the BMP/activin/TGFβ pathway represents a biologically plausible mechanism associated with SGLT2 inhibitor therapy that may contribute to the observed phenotype in ischemic HFrEF with a high echocardiographic probability of PH.

To investigate associations between body roundness index (BRI) and progression of cardio-renal-metabolic diseases (CRMDs). This study included 442,489 UK Biobank participants aged ≥ 40 years without CRMDs at baseline. BRI was analyzed continuously and by tertiles. Primary outcomes were first CRMD (FCRMD), cardio-renal-metabolic multimorbidity (CRMM), and all-cause mortality. Hazard ratios (HRs) and population attributable fractions (PAFs) were estimated using Cox and multistate models. Higher BRI was consistently associated with increased risks of CRMD onset and all-cause mortality, with strongest associations in the highest tertile for T2D (HR 6.94, 95

Early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD) have different clinical and neuroimaging characteristics, and non-cognitive deficits usually observed are suggestive of hypothalamic dysfunctions. Here, we assessed in vivo the hypothalamic volumetry in EOAD and LOAD and explored its association with cognitive and non-cognitive features. The hypothalamus and its subunits were segmented on T1-weighted MRIs from 14 younger and 23 elderly controls (EC), 14 EOAD, and 28 LOAD. Amyloid or fluid biomarker confirmation was not available for all participants, and diagnostic classification was primarily based on clinical criteria. Volumes were correlated with cognitive (global cognition, memory) and non-cognitive (mood, body mass index) features. Lower bilateral volumes of the whole and posterior hypothalamus were observed in LOAD compared with EC (p < 0.010), while lower right anterior-inferior subunit was a common feature in patients than in controls (p = 0.007). These alterations were associated with abnormal cognition (rho ranging from −0.35 to −0.30, p < 0.041), as well as with memory (rho = 0.30, p = 0.041) and depressive mood (rho ranging from −0.82 to −0.68, p < 0.031) in the LOAD-EC pooled group. Our study provided a valuable insight into the heterogeneity of EOAD and LOAD, extending current understanding of the differential involvement of brain regions and highlighting the importance of hypothalamic involvement as a potential target for further investigation in conjunction with clinical assessment.

The planet is experiencing an unprecedented growth in its human population aged 65 years and older, underscoring the urgent need for comprehensive aging-centered biobehavioral data to guide public health interventions. The Arlington Study of Healthy Aging (ASHA) is a multidisciplinary community cohort study designed to investigate the biological, psychological, and social mechanisms underlying age-related functional decline. Here, we present the study’s rationale, design, and methodological framework. Utilizing a comprehensive, multi-modal assessment strategy—including whole-body MRI, vascular function testing, venous blood biomarkers, cognitive and physical function evaluations, DEXA scans, and continuous remote monitoring of activity, sleep, blood pressure, and glucose—the study captures both quantitative and qualitative dimensions of aging across multiple organ systems (brain, heart, muscle, liver, adipose tissue). A central aim is to identify modifiable risk factors and protective mechanisms that influence aging trajectories. Through interdisciplinary collaboration, ASHA seeks to generate actionable insights to enhance longevity, independence, and quality of life among older adults. NCT 06857877, 2024-09-24.

The locus coeruleus (LC), the earliest site of tau accumulation in Alzheimer’s disease, directly influences pupillary and vergence oculomotor systems. Whether task-evoked oculomotor dynamics can non-invasively differentiate AT(N) profiles, A+T+ (biological Alzheimer’s disease) and A−T+ (suspected non-Alzheimer’s tauopathy), remains unexamined despite their differential impact on LC-mediated modulation and cortical network integrity. Thirty-eight MCI individuals (12 A−T+, 26 A+T+), classified using validated CSF biomarker thresholds, completed a visual oddball paradigm under binocular eye-tracking. Linear mixed-effects models examined profile × condition interactions across full time series and six trial-level features; participant-level associations were tested using Firth-penalized logistic regression to account for the small and imbalanced sample. Profiles did not differ in oculomotor magnitude but diverged in temporal organization. Profile × condition interactions were significant for vergence global slope, vergence time to peak, and pupillary time to peak (all p-Holm ≤ 0.048). Timing differences were condition-dependent: A−T+ showed later responses during distractor trials, while A+T+ showed the most delayed timing during target trials. Subject-level associations were significant for vergence and pupillary time to peak, with greater condition-dependent modulation predicting higher A+T+ probability (ORs = 0.43 and 0.35; both p < 0.05); vergence global slope delta did not reach significance at the subject level. A−T+ showed superior target detection accuracy (89.7

Premature ovarian insufficiency (POI) is a leading cause of female infertility. Its mechanisms are poorly understood, and effective therapies are lacking. In this study, we aimed to identify novel druggable targets and repurposable drugs for POI through an integrated multiomics and computational pharmacology approach. We integrated large-scale proteomic data from two independent cohorts (deCODE, N = 35,559; UK Biobank, N = 54,219) using Mendelian randomization, Bayesian colocalization, and single-cell RNA sequencing. Seven high-confidence targets were identified: EPHA4, FSTL3, NUCB2, OXT, SERPINA12, TNFRSF6B, and FABP1. Among these genes, EPHA4, FSTL3, and NUCB2 were significantly dysregulated in cisplatin-induced mouse and human granulosa cell models (P < 0.05 to P < 0.001) and exhibited high diagnostic accuracy (AUC = 0.92–0.96), supporting their potential as both biomarkers and therapeutic targets. Molecular docking revealed strong binding affinities, notably for cycloheximide binding to EPHA4 (−7.8 kcal/mol), with molecular dynamics confirming stable interactions (root mean square deviation, RMSD < 2.0 Å), providing a structural basis for drug repurposing or lead optimization. The functional enrichment results suggested that fibrosis, inflammation, and metabolic dysregulation are involved in POI pathogenesis. Collectively, our findings establish a multiomics-to-therapy pipeline that not only prioritizes causal targets for POI but also provides translational opportunities, from biomarker-guided diagnosis to computationally driven drug repositioning, paving the way for mechanism-based interventions in ovarian aging.