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Abstract The aging process is universal, and it is characterized by a progressive deterioration and decrease in physiological function leading to decline on the organismal level. Nevertheless, a number of genetic and nongenetic interventions have been described, which successfully extend healthspan and lifespan in different species. Furthermore, a number of clinical trials have been evaluating the feasibility of different interventions to promote human health. The goal of the annual Biological Sciences Section of the Gerontological Society of America meeting was to share current knowledge of different topics in aging research and provide a vision of the future of aging research. The meeting gathered international experts in diverse areas of aging research including basic biology, demography, and clinical and translational studies. Specific topics included metabolism, inflammaging, epigenetic clocks, frailty, senescence, neuroscience, stem cells, reproductive aging, inter-organelle crosstalk, comparative transcriptomics of longevity, circadian clock, metabolomics, and biodemography.

608 Background: Tinengotinib, a spectrum-selective multi-kinase inhibitor with unique binding properties to FGFR , potently inhibited FGFR2 fusion/rearrangement and acquired resistant/gatekeeper mutations in pre-clinical models and exhibited antitumor activity in cholangiocarcinoma (CCA) patients (pts) in phase 1/2 trials. Here we present the overall survival (OS) data and biomarker correlative analysis from a phase 2 clinical trial of tinengotinib in CCA. Methods: Eligible pts with advanced/metastatic CCA who had received ≥ 1 prior systemic chemotherapy with ECOG PS 0-1 were treated with tinengotinib 10 mg QD across four Cohorts: A1: FGFR2 fusion(s) with primary progression on previous FGFR inhibitor ( FGFR i); A2: FGFR2 fusion(s) with progression after prior response to FGFR i; B: FGFR alteration(s) without FGFR2 fusion(s); C: FGFR wild-type. Efficacy was evaluated per RECIST v1.1 and safety was assessed by CTCAE v5.0. Genomic alterations in circulating tumor DNA (ctDNA) were assessed by Foundation Medicine NGS panel at baseline, C3D1 and EOT. Planned correlative analyses of response (PR+SD>6 months) and PFS in pt subgroups based on ctDNA mutational status were performed. Results: 55 eligible pts were enrolled (18 in A1, 11 in A2, 13 in B, 13 in C) with median age 61.0 [range 24-81] years, ECOG PS 0 in 50.9% pts, 56.4% female, and 60.0% with ≥ 3 lines of prior therapy. Among 42 pts with FGFR alterations, 78.4% had ≥ 1 prior FGFR i, and 97.6% had prior chemotherapy. Median follow up time was 8.6 months (0.4-30.5). The median OS (months) was 17.1 (95%CI 7.5-19.5) in A1; not reached (95%CI 9.6, -) in A2; 18.0 (95%CI 9.6, -) in A1+A2; not reached (95%CI 8.0, -) in B; 6.5 (95%CI 4.8-16.4) in C. The OS rate in A, B and C was 100%, 91.7% and 75% at month 3; 83.7%, 83.3% and 66.7% at month 6, and 65.8%, 55.6% and 23.8% at month 12. Partial response was observed in 26% (10/39) of evaluable FGFR-altered pts (A1+A2+B). The safety profile was consistent with previous reports. The most common any-grade treatment-related AEs were hypertension (63.6%) and diarrhea (47.3%). Baseline ctDNA results were available in 46 pts, 35 in cohorts A+B and 11 in C. A positive correlation was shown in MED12 mutation vs response (P=0.03476). BCOR and ARID1A mutation were found to be negatively associated with PFS (P=0.01366 and P=0.0437). Acquired/secondary mutations at baseline were observed in cohort A, including V564F/I (3/24 and 5/24) and N549K/H (5/24 and 5/24); favorable anti-tumor activity was noted despite these resistant mutations, consistent with preclinical data. Conclusions: Tinengotinib has shown promising anti-tumor efficacy in CCA pts with FGFR fusion after prior FGFR i and in those with primary FGFR mutations. An ongoing randomized phase III study will investigate tinengotinib vs. chemotherapy in FGFR inhibitor refractory CCA (NCT05948475). Clinical trial information: NCT04919642 .

537 Background: A+B is the preferred first-line (1L) standard of care for uHCC, with emerging RW evidence supporting its use in a broad patient (pt) cohort. We evaluated pt characteristics, clinical and treatment outcomes in pts treated at five U.S. institutions: Mayo Clinic, Houston Methodist, Moffitt Cancer Center, Mays Cancer Center, and University of Arizona. Methods: This is a retrospective study of uHCC pts who initiated A+B after January 1, 2019. De-identified pt data were extracted by treating oncologists. Overall survival (OS) and real-world progression-free survival (rwPFS) were assessed using Kaplan-Meier methods for all pts and for a “trial-like” subgroup with characteristics similar to those in the IMbrave150 trial (ECOG performance status [PS] 0-1, Child-Pugh [CP] class A, albumin-bilirubin [ALBI] grade 1-2). HCC-related hospitalizations were evaluated within 1 year of A+B initiation. Results: A total of 300 eligible pts were treated with 1L A+B (median age 68 years, 79% male, 79% White, 82% BCLC C, 44% viral etiology,12% ECOG PS >1). Liver function was CP A in 73% (36% A5, 31% A6, 6% not reported), CP B in 26% pts (15% B7, 7% B8, 5% B9), and CP C in 2 (<1%) pts. Compared with CP A, more CP B pts had characteristics of compromised liver function (CP A vs B: cirrhosis: 61% vs 91%; ascites: 7% vs 46%; encephalopathy: 4% vs 17%; esophageal varices: 14% vs 32%), bile duct invasion (2% vs 11%), and ECOG PS>1 (8% vs 22%), all Ps<0.001. Over a median follow-up of 8.7 mos, 244 (81%) pts discontinued A+B, primarily due to disease progression. Toxicity-related treatment discontinuation and hospitalizations due to treatment-related adverse events (TRAE) were similar between the two groups (Table). Median OS (mOS) was 14.4 mos (95% CI: 12.3, 18.2) and median rwPFS was 6.8 mos (95% CI: 5.8, 8.4). In the trial-like subgroup (n=194), mOS was 19.5 mos (95%CI: 14.6, 24.7) and median rwPFS was 8.8 mos (95% CI: 7.6, 12.1). In the CP B subgroup, mOS was 5.6 mos (95% CI: 4.6, 11.3) and median rwPFS was 3.1 mos (95% CI: 2.4, 5.8). Conclusions: This study demonstrates the RW outcomes of 1L A+B in a diverse pt cohort. Results from the “trial-like” pts further confirm the reproducible efficacy of A+B in clinical practice. Although pts with CP-B had higher hospitalization rates due to disease progression or symptoms, consistent with their underlying liver complications, they had similar rates of toxicity-related treatment discontinuation and TRAE-related hospitalizations compared to CP-A. Further characterization of safety for A+B in CP B pts within a prospective, controlled trial is warranted. N (%) CP A (n=219) CP B (n=79) Treatment discontinuation* 167 (76) 75 (95) Atezolizumab-related toxicity 20 (12) 13 (17) Bevacizumab-related toxicity 26 (16) 16 (21) Hospitalization* 87 (40) 58 (73) Symptom-related 42 (48) 35 (60) Progression 8 (9) 11 (19) TRAE 7 (8) 6 (10) *P-value comparing CP A vs CP B <0.001.

Abstract There are ~100 genes or copy number variants (CNVs) used in genetic testing for Autism Spectrum Disorder (ASD, or autism). These genes are protein-coding, and the associated phenotypes often extend beyond socio-behavioral traits seen in autism including cognitive/medical complexities, epilepsy, and ADHD. Here, we characterize 27 males with ASD through whole genome sequencing (WGS), delineating X-chromosome microdeletions that implicate the long non-coding RNA (lncRNA) PTCHD1-AS as an ASD-susceptibility gene (OR=2.56, p=0.01). Two Ptchd1-as knockout (KO) murine models, created by removing the evolutionarily conserved exon-3, show ASD-like features in males, increasing repetitive behaviors and impairing typical social behavior and communication without overt cognitive comorbidities or ADHD-like behaviors. Hippocampus-dependent synaptic function, complex learning, and locomotor activity are unaffected in KO mice. Native nuclear-enriched mouse Ptchd1-as showed sustained expression from post-natal day-7 onward in the dorsal striatum, a predominantly GABAergic brain region implicated in ASD. Multi-omics revealed transcriptomic alterations in striatal oligodendrocyte, astrocyte and neurons impacting myelination and plasticity pathways. Disrupting Ptchd1-as led to reductions in conventional Protein Kinase-C, altered Src and GSK3α/β phosphorylation, and an enhancement of synaptic plasticity (long-term potentiation and long-term depression). Together, these findings implicate striatal molecular and circuit level dysregulation via Ptchd1-as in ASD etiology.

ImportanceAtrial fibrillation (AF) is the most common, chronic, cardiac arrythmia in older US adults. It is not known whether AF is independently associated with increased risk of retinal stroke (central retinal artery occlusion), a subtype of ischemic stroke that causes severely disabling visual loss in most cases and is a harbinger of further vascular events.ObjectiveTo determine whether there is an association between AF and retinal stroke.Design, Setting, and ParticipantsThis retrospective cohort study was performed between July 2023 and May 2024 using computerized inpatient, outpatient, emergency department, and skilled nursing facility claims files for a 5% sample of US fee-for-service Medicare beneficiaries aged 66 years and older between 2000 and 2020. Follow-up ended at death, conclusion of fee-for-service Medicare coverage, end of the study period, or loss to follow-up of 85% of the study cohort.ExposureAF, based on validated International Classification of Diseases, Ninth Revision, Clinical Modification and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes.Main Outcomes and MeasuresThe primary end point was incident retinal stroke in the primary diagnostic position of a single claim in any venue of care. Secondary end points included retinal stroke in any position of a single claim, 1 positive control end point (cerebral ischemic stroke), and 4 negative control end points (central retinal vein occlusion, urinary tract infection, humeral fracture, and cataract). Unadjusted and adjusted hazard ratios (HRs) and rate differences were computed across matched and overlap-weighted cohorts with and without AF (defined as 1 inpatient claim or 2 outpatient claims within a 365-day period).ResultsIn total, 1 090 144 patients (591 400 female [54.3%]; mean [SD] age, 76.92 [7.09] years) were included in the study; 545 072 patients had AF and 545 072 were matched controls. The median (IQR) follow-up was 45 (18 to 90) months. In total, 1333 patients with AF (rate, 0.55 per 1000 person-years) and 1082 AF-free matched controls (rate, 0.50 per 1000 person-years) experienced retinal stroke. The cause-specific, adjusted HR of retinal stroke after overlap weighting was 1.14 (95% CI, 1.02 to 1.28; adjusted rate difference, 0.05 [95% CI, −0.01 to 0.11]). AF was associated with cerebral ischemic stroke (adjusted HR, 1.73 [95% CI, 1.69 to 1.76]; adjusted rate difference, 10.11 [95% CI, 9.72 to 10.49]). Of 4 prespecified negative control end points, AF was not associated with central retinal vein occlusion but was associated with urinary tract infection, cataract, and humeral fracture.Conclusions and RelevanceIn this cohort study of Medicare beneficiaries aged 66 years and older, AF was independently associated with retinal stroke. The magnitude of the association was small, and a contribution from residual, unmeasured confounding could not be excluded.

AbstractBackgroundMayo Test DRIVE (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based multi‐device (smartphone, tablet, personal computer) platform optimized for remote self‐administered cognitive assessment that includes a computer‐adaptive word list memory test (Stricker Learning Span; SLS), a measure of processing speed/executive functioning (Symbols Test) and a score combining both the memory and processing speed/executive functioning measures (MTD Composite). We aimed to determine the reliability of MTD measures across follow‐up sessions.MethodIndividuals participating in this ancillary study who completed at least two and up to four complete MTD sessions were included, resulting in 1,293 participants (mean age = 70.6, SD = 11.6; mean education = 15.6, SD = 2.3; 48.6% male; 96.9% White; 99.1% non‐Hispanic; 97.1% cognitively unimpaired) from parent studies (see Table 1). MTD raw scores were winsorized at 1% and 99% to minimize the impact of outliers. Test‐retest reliability was assessed using single‐rating, absolute‐agreement, and two‐way mixed ICCs and results are described using descriptives from Koo et al. (2016). ICCs for in‐person‐administered traditional neuropsychological measures are also reported alongside MTD for a subset of participants newly enrolled into the MCSA (to ensure participants were test naïve to both MTD and in‐person tests).ResultReliability was good for the MTD Composite raw [total ICC = 0.78; see Table 2 for session‐to‐session ICCs and 95% CIs], and moderate‐to‐good for the primary outcome variables for each subtest [total ICC = 0.74 for both SLS and Symbols]. Weighting by accuracy negatively impacted reliability of Symbols and the Composite; without this weighting, MTD Composite and Symbols variables showed higher reliability (MTD Composite z total ICC = 0.80; Symbols response time total ICC = 0.84; see Table 2). Alternative methods of defining response time on Symbols showed nearly identical reliability values. SLS sum of trials (primary variable) had subtly higher reliability than separate measures of learning (1‐5 correct, max span) or delay. Reliability of remote MTD and in‐person‐administered measures and select comparisons are provided in Table 3.ConclusionMTD showed moderate to good reliability, similar to in‐person‐administered traditional neuropsychological tests. Future work will examine the effect of demographics, device type, and session interference on reliability.

AbstractBackgroundNeuritic plaques with fibrillar beta‐amyloid (Aβ) peptides and tau‐protein neurofibrillary tangles, hallmark features of Alzheimer’s disease (AD) pathology, have been concomitantly associated with white matter (WM) integrity loss, while a unique effect of each pathology on WM integrity in a more demographically diverse population remains unknown.MethodTo examine the degree to which each pathology affects WM integrity in a more diverse non‐demented cohort, Aβ and tau PET, diffusion‐weighted imaging (DWI), and cognition (memory and executive function composites) were examined from the U.S. POINTER neuroimaging participants (N=608; age=68.34±5.2; 61.8% females; 29% Aβ+) and a subset of Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants (N=291; age=72.85±7.3; 50% females; 39% Aβ+) (Table). Aβ‐positivity was determined using tracer‐specific standardized cut‐offs. Tau SUVR was estimated for each Braak stage. For WM integrity, voxel‐based GLMs were applied to FSL‐processed fractional anisotropy (FA) maps using Braak stage tau SUVR and Aβ‐positivity status, along with covariates of age, sex, and b‐value profiles.ResultIn U.S. POINTER, independent from Aβ‐positivity status, greater tau burden in Braak stages I and II was related to lower FA across the tracts including the superior longitudinal fasciculus, fornix (cres), corpus callosum, and anterior thalamic radiation (Figure). Average FA from supra‐threshold clusters for Braak I and II significantly predicted executive function but not episodic memory. No association between FA and tau burden in Braak stages III/IV or V/VI was found. In the ADNI sample, greater tau burden in Braak I was related to lower FA mostly in left inferior longitudinal fasciculus and left uncinate fasciculus, while negative associations with FA became more diffuse with tau load in Braak III/IV and V/VI. Average FA from supra‐threshold clusters significantly predicted both episodic memory and executive function scores. Across both samples, after accounting for tau burden in each Braak stage, there were no association between Aβ‐positivity status and WM integrity.ConclusionDistinct associations between tau burden, WM integrity, and cognition were found across the studies, indicating greater impact of early tau burden on WM integrity in U.S. POINTER, accounting for Aβ‐positivity status. Factors contributing to the distinct associations across studies need further investigation.

AbstractBackgroundNeuritic plaques with fibrillar beta‐amyloid (Aß) peptides and tau‐protein neurofibrillary tangles, hallmark features of Alzheimer’s disease (AD) pathology, have been concomitantly associated with white matter (WM) integrity loss, while a unique effect of each pathology on WM integrity in a more demographically diverse population remains unknown.MethodTo examine the degree to which each pathology affects WM integrity in a more diverse non‐demented cohort, Aß and tau PET, diffusion‐weighted imaging (DWI), and cognition (memory and executive function composites) were examined from the U.S. POINTER neuroimaging participants (N = 608; age = 68.34±5.2; 61.8% females; 29% Aß+) and a subset of Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants (N = 291; age = 72.85±7.3; 50% females; 39% Aß+) (Table). Aß‐positivity was determined using tracer‐specific standardized cut‐offs. Tau SUVR was estimated for each Braak stage. For WM integrity, voxel‐based GLMs were applied to FSL‐processed fractional anisotropy (FA) maps using Braak stage tau SUVR and Aß‐positivity status, along with covariates of age, sex, and b‐value profiles.ResultIn U.S. POINTER, independent from Aß‐positivity status, greater tau burden in Braak stages I and II was related to lower FA across the tracts including the superior longitudinal fasciculus, fornix (cres), corpus callosum, and anterior thalamic radiation (Figure). Average FA from supra‐threshold clusters for Braak I and II significantly predicted executive function but not episodic memory. No association between FA and tau burden in Braak stages III/IV or V/VI was found. In the ADNI sample, greater tau burden in Braak I was related to lower FA mostly in left inferior longitudinal fasciculus and left uncinate fasciculus, while negative associations with FA became more diffuse with tau load in Braak III/IV and V/VI. Average FA from supra‐threshold clusters significantly predicted both episodic memory and executive function scores. Across both samples, after accounting for tau burden in each Braak stage, there were no association between Aß‐positivity status and WM integrity.ConclusionDistinct associations between tau burden, WM integrity, and cognition were found across the studies, indicating greater impact of early tau burden on WM integrity in U.S. POINTER, accounting for Aß‐positivity status. Factors contributing to the distinct associations across studies need further investigation.