Brianna Jane Stubbs

Background: Biological systems exhibit dynamic patterns over multiple temporal scales—from minutes to months—that are poorly captured by conventional cross-sectional or low-frequency longitudinal studies. These patterns, including diurnal variations and underlying continuous rhythms, may be critical determinants of health, resilience, and disease risk in aging. Existing longitudinal studies in older adults lack high-frequency, multimodal measurements that integrate molecular, physiological, and digital health data streams. Objectives: The TIME Study aims to: (i) Characterize temporal patterns in molecular, physiological, and digital health measures in healthy older adults; (ii) determine how these patterns vary across biological domains and relate to each other; and (iii) assess how physiological systems respond to defined perturbations (oral glucose tolerance and maximal exercise). Methods: TIME is a single-site, observational, longitudinal study enrolling up to 150 adults aged ≥55 years. Over an 11-week main phase, participants complete seven weekly low-frequency visits, two perturbation challenge visits, and two, two-day high-frequency sampling epochs. Biospecimens, clinical measures, cognitive and physical performance tests, and continuous digital health data are collected. Follow-up visits occur at 6 and 12 months. Expected impact: By integrating multimodal, temporally resolved data, TIME will provide a foundational dataset for understanding the role of biological rhythms in aging and inform future precision health strategies. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT07107386 , identifier NCT07107386.

Acoustic droplet ejection (ADE) enables nanoliter-scale liquid handling for complex microplate assays, yet translating experimental designs into validated, instrument-ready instructions remains a bottleneck. We present PickliPy, an open-source framework that converts spreadsheet-based assay designs into validated ADE picklists. PickliPy.Assay supports combinatorial, dose-response, and multi-addition time-course dispensing, while PickliPy.Screen extends to high-throughput workflows, including library reformatting and shortlisting. Across biological contexts, the framework generated reproducible, assay-ready plates and standardized execution in human cohort studies. Acoustic pre-dispensing deepened bioenergetic phenotyping of human skeletal muscle mitochondria, capturing substrate switching and sharpened dose-response precision in human pancreatic β-cells, revealing an age-associated change in succinate dehydrogenase kinetics. We benchmarked a wash-free, live-cell screen of mitochondrial function and morphology, in which deep-learning image analysis widened the assay window, and ADE enabled integrative dose-response co-response analysis. These tools, including their agentic use, make complex ADE experiments easier to design and scale from single benches to screening campaigns.

Advanced glycation end products (AGEs) drive metabolic dysfunction, inflammation, and age-related disease, and their accumulation accelerates after menopause. Preclinical studies show that GLYLO, a five-compound glycation-lowering formulation (alpha-lipoic acid, nicotinamide, pyridoxine, benfotiamine, and piperine), reduces AGE burden and improves metabolic health, but its translational relevance in humans is unknown. The Glycation Reduction and Aging: a Clinical Evaluation (GRACE) trial is a randomized, double-blind, placebo-controlled pilot study testing whether six months of GLYLO supplementation lowers circulating AGEs and methylglyoxal (MGO) in postmenopausal women (45–65 years) with elevated adiposity (BMI ≥ 25 kg/m² or waist circumference ≥88 cm) and elevated HbA1c (5.5–6.4%). Secondary and exploratory endpoints include HOMA-IR, body composition, and reproductive hormones, cognitive and physical function, retinal aging, and systemic inflammation. GRACE is designed to address a critical gap in geroscience by evaluating whether targeting glycation can mitigate early metabolic and functional decline in postmenopausal women. ClinicalTrials.gov identifier NCT06813261.

Introduction: Cognitive function is closely linked to brain energy metabolism and may be compromised by aging, metabolic stress, and neuropsychiatric disease. Ketone bodies can serve as an alternative cerebral fuel and may also exert signaling effects relevant to cognition. Exogenous ketones (EK) offer a practical means of increasing circulating ketone concentrations without dietary carbohydrate restriction. However, the overall effect of EK supplementation on cognitive performance in humans has not been systematically quantified. Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. PubMed, Web of Science, and Embase were searched through October 2025 for randomized controlled trials investigating the effects of EK on cognitive outcomes in healthy adults or individuals with neuropsychiatric conditions. Data extraction and quality assessment were performed independently by multiple reviewers using the PEDro scale. Standardized mean differences (SMD) were calculated using random-effects models. Subgroup and meta-regression analyses examined the influence of ketone formulation, intervention duration, dose, population type, and presence of acute cognitive stressors. Results: 38 studies comprising 41 protocols (1,602 participants) were included in the systematic review, with 29 protocols (1,117 participants) eligible for meta-analysis. EK supplementation was associated with a statistically significant improvement in cognitive performance compared with placebo (SMD = 0.29, 95% CI 0.16–0.41; p < 0.001). Sub-group analyses did not show statistically significant differences between the type of supplementation ( p = 0.083), study duration (acute vs. intermediate; p = 0.11), population type (healthy vs. Alzheimer’s disease; p = 0.077), or the presence of acute cognitive stressors ( p = 0.89). Meta-regression revealed a positive association between daily EK dose and cognitive improvement. Discussion: EK supplementation is associated with modest improvements in cognitive performance across diverse populations and study designs. These findings support EK as a flexible nutritional strategy for cognitive support and warrant further investigation in well-powered, long-term trials to clarify optimal dosing, formulation, and clinical applicability. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD42023471727 , CRD42023471727.

Importance: Impaired cognitive function is a hallmark of neuropsychiatric disease, posing a significant challenge to patients, clinicians and healthcare systems. Emerging research on ketone bodies suggests they may function as an alternative fuel for the brain, potentially enhancing cognitive function through both metabolic and signaling pathways. An alternative to inducing ketosis by lowering dietary carbohydrate intake is consumption of exogenous ketones (EK). Objective: It is unknown whether the existing literature collectively supports a beneficial effect of EK on cognitive function; this systematic review and metanalysis aims to aggregate available data and address this gap. Data Sources: PubMed, Web of Science, and EMBASE databases were searched in October 2023 for key words and free words referring to ketone bodies, cognition, and health-related conditions. Study Selection: Multiple reviewers selected 29 studies for inclusion in the analysis from the initial 1678 search results, which included randomized control studies of healthy participants and patients with neuropsychiatric conditions, using exogenous ketones as an intervention alongside a placebo, that included outcomes assessing cognitive function. Data Extraction and Synthesis: A PRISMA model was used for abstracting data, and the PEDRo scale was used to assess study quality. Data was extracted and verified by independent investigators. Main Outcome: Cognitive function measures. Results: 29 studies (1,347 participants) were included, with 18 studies (875 participants) in the meta-analysis. Results indicate that EK administration has a modest but statistically significant positive effect on cognitive performance (SMD = 0.26, 95% CI: 0.11 – 0.40, p = 0.0007). Sub-group analyses showed no significant differences between study duration (acute vs. intermediate; p = 0.50), ketone form (mono-esters vs. medium-chain triglycerides; p = 0.06), population type (healthy vs. Alzheimer’s disease; p = 0.21), or the presence of acute cognitive stressors (p = 0. 25). Conclusions: The findings suggest that EK could be a promising adjunctive strategy in dementia management, offering potential benefits even in patients who maintain sufficient carbohydrate intake. EK may provide psychiatrists with an innovative, non-invasive approach to supporting cognitive resilience in patients with neuropsychiatric disorders. Further clinical trials should refine the therapeutic application of EK and integrate them into comprehensive neuropsychiatric care protocols. Key points: Question: Does the consumption of exogenous ketones improve cognitive function, and what are the variables that influence efficacy. Finding: Exogenous ketones have a modest but significant effect on overall cognitive performance outcomes, with no clear effect of study duration or population, ketone form or dose, or the presence of a stressor. Meaning: These findings strongly support further research to determine the ideal administration strategy for exogenous ketones to improve cognitive function.

Bis-octanoyl-(R)-1,3-butanediol (BO-BD) is a novel ketone ester (KE) ingredient which increases blood beta-hydroxybutyrate (BHB) concentration rapidly after ingestion. KE is hypothesized to improve function in older adults. Whilst many studies have investigated KE in young adults, they have not been studied in healthy older adults (HOA), for whom age-related differences in metabolism may alter the effects. This randomized, observational, open-label study in HOA (n = 30, 50% male, age = 76.5y) aimed to elucidate tolerance, blood BHB and glucose concentrations for 4h following consumption of either 12.5 or 25 g of BO-BD formulated in ready-to-drink beverage (n = 30), and re-constituted powder (n = 21) with a meal. All study interventions were well tolerated, and increased blood BHB, inducing nutritional ketosis (≥0.5 mM) until the end of the study. Peak BHB concentration (C_max) and incremental area under the curve (iAUC) were significantly greater with 25 vs 12.5 g of BO-BD in both formulations. There were no significant differences in C_max or iAUC between formulations. Blood glucose increased in all conditions following the meal, with no consistent significant differences between conditions. These results demonstrate that both powder and beverage formulations of the KE, BO-BD, induce ketosis in HOA adults, facilitating future research on functional effects of KE in aging.

Background: Ketone bodies are metabolites produced during fasting or on a ketogenic diet that have pleiotropic effects on the inflammatory and metabolic aging pathways underpinning frailty in in vivo models. Ketone esters (KEs) are compounds that induce hyperketonemia without dietary changes and that may impact physical and cognitive function in young adults. The functional effects of KEs have not been studied in older adults. Objectives: Our long-term goal is to examine if KEs modulate aging biology mechanisms and clinical outcomes relevant to frailty in older adults. Here, we report the exploratory functional and quality-of-life outcome measures collected during a 12-week safety and tolerability study of KE ( NCT05585762 ). Design: Randomized, placebo-controlled, double-blinded, parallel-group, pilot trial of 12-weeks of daily KE ingestion. Setting: The Clinical Research Unit at the Buck Institute for Research on Aging, California. Participants: Community-dwelling older adults (≥ 65 years), independent in activities of daily living, with no unstable acute medical conditions (n = 30). Intervention: Subjects were randomly allocated (1:1) to consume 25 g daily of either KE (bis-octanoyl (R)-1,3-butanediol) or a taste, appearance, and calorie-matched placebo (PLA) containing canola oil. Measurements: Longitudinal change in physical function, cognitive function and quality of life were assessed as exploratory outcomes in n = 23 completers (n = 11 PLA, n = 12 KE). A composite functional outcome to describe the vigor-frailty continuum was calculated. Heart rate and activity was measured throughout the study using digital wearables. Results: There were no statistically significant longitudinal differences between groups in exploratory functional, activity-based or quality of life outcomes. Conclusion: Daily ingestion of 25 g of KE did not affect exploratory functional or quality-of-life end points in this pilot cohort of healthy older adults. Future work will address these endpoints as primary and secondary outcomes in a larger trial of pre-frail older adults.

Background: Frailty is a geriatric syndrome characterized by chronic inflammation and metabolic insufficiency that creates vulnerability to poor outcomes with aging. We hypothesize that interventions which target common underlying mechanism of aging could ameliorate frailty. Ketone bodies are metabolites produced during fasting or on a ketogenic diet that have pleiotropic effects on inflammatory and metabolic aging pathways in laboratory animal models. Ketone esters (KEs) are compounds that induce ketosis without dietary changes, but KEs have not been studied in an older adult population. Our long-term goal is to examine if KEs modulate aging biology mechanisms and clinical outcomes relevant to frailty in older adults. Objectives: The primary objective of this randomized, placebo-controlled, double-blinded, parallel-group, pilot trial is to determine tolerability of 12-weeks of KE ingestion in a broad population of older adults (≥ 65 years). Secondary outcomes include safety and acute blood ketone kinetics. Exploratory outcomes include physical function, cognitive function, quality of life, aging biomarkers and inflammatory measures. Methods: Community-dwelling adults who are independent in activities of daily living, with no unstable acute medical conditions (n = 30) will be recruited. The study intervention is a KE or a taste, appearance, and calorie matched placebo beverage. Initially, acute 4-hour ketone kinetics after 12.5g or 25g of KE consumption will be assessed. After collection of baseline safety, functional, and biological measurements, subjects will randomly be allocated to consume KE 25g or placebo once daily for 12-weeks. Questionnaires will assess tolerability daily for 2-weeks, and then via phone interview at bi-monthly intervals. Safety assessments will be repeated at week 4. All measures will be repeated at week 12. Conclusion: This study will evaluate feasibility, tolerability, and safety of KE consumption in older adults and provide exploratory data across a range of aging-related endpoints. This data will inform design of larger trials to rigorously test KE effects on aging mechanisms and clinical outcomes relevant to frailty.