TAKEOFF: Targeting Aging with Ketone Ester in Older adults for Function in Frailty

起飞：用酮酯对抗老年人的衰老，改善虚弱功能

• 批准号: 10640024
• 负责人: John C Newman
• 金额: $ 75.52万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640024
• 关键词: Adult; Adverse event; Affect; Aging; Atrophic; Attenuated; Biological; Biological Aging; Biological Markers; Biology; Biopsy; Blood; Brain; Calories; Catabolism; Chronic; Clinical; Clinical Research; Clinical Trials; Complex; Data; Disease; Double-Blind Method; Drug Kinetics; Elderly; Elements; Esters; Fasting; Fatty acid glycerol esters; Foundations; Frail Elderly; Functional disorder; Gait speed; Geriatrics; Geroscience; Goals; Health; Heart; Heart failure; Immune System Diseases; Immune system; Immunity; Immunophenotyping; Inflammation; Inflammatory; Institution; Intervention; Ketone Bodies; Ketones; Leg; Link; Lipids; Liver; Longevity; Measures; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular; Mus; Muscle; Muscle Fatigue; Muscular Atrophy; Nutritional; Ohio; Oral; Organ; Outcome; Phase; Physical Function; Physiological; Placebo Control; Placebos; Population; Pre-Clinical Model; Production; Quality of life; Randomized; Role; Safety; Scheme; Signal Transduction; Site; Skeletal Muscle; Specialist; Symptoms; Syndrome; System; T-Lymphocyte; Taste Perception; Testing; Therapeutic; Time; Tissues; Translating; Treatment Efficacy; Universities; Wild Type Mouse; actigraphy; age related; beta-Hydroxybutyrate; clinical application; cognitive function; cognitive testing; dietary; dietary restriction; disability; frailty; functional decline; heart function; human data; immune function; immunosenescence; improved; improved outcome; instrument; interest; ketogenic diet; ketogentic; multidisciplinary; muscle metabolism; muscle strength; novel therapeutics; pharmacologic; pre-clinical; primary outcome; prospective; reduced muscle strength; secondary outcome; small molecule; standard measure; stressor; trial enrollment; young adult

PROJECT SUMMARY/ABSTRACT The geroscience approach of modulating fundamental aging mechanisms holds great promise for generating effective new therapeutics for complex, multifactorial conditions of aging such as frailty which contribute so much to functional decline, disability, and loss of independence in older adults. The frailty syndrome is conceptualized as a condition of progressive functional decline and increased vulnerability to stressors resulting from decreased functional reserve. The pathophysiology of frailty is complex and not well understood, but is generally thought to prominently include cellular energy production deficits along with chronic inflammation and immune dysfunction. Dietary restriction and fasting, interventions closely linked to fundamental mechanisms of aging, promote the endogenous production of ketone bodies as a means of supplying fat-derived energy to tissues. New advances in understanding the biological activities of the ketone body beta-hydroxybutyrate (BHB) suggest that both energy production and signaling activities of BHB may have a mechanistic role in modulating aging, and may be particularly relevant to the pathophysiology of frailty. Ketone esters have recently emerged as a pharmacological means of delivering ketone bodies. We have assembled a multidisciplinary team of experts in geroscience, geriatrics and frailty, ketone body biology, immunosenescence, and ketone body-related clinical trials to carry out a multi-site, proof-of-concept Phase 2a clinical trial of a ketone ester (KE) targeting frailty in prefrail and mildly frail older adults. TAKEOFF is a prospective, randomized, double-blind, 12-week study of ketone ester vs. matched placebo. Aim 1 will test if muscle strength and other clinical frailty- and aging-related outcomes improve with KE. Aim 2 will determine the safety and tolerability of daily KE in broadly representative pre-frail and frail older adults. Aim 3 will test the hypothesis that ketone ester impacts the aging immune system, skeletal muscle, and biomarkers of aging via detailed mechanistic immunophenotyping, muscle metabolism, and biomarker studies that leverage the strong specialist expertise at the participating institutions. Altogether, this translational effort will provide crucial information on the safety and efficacy of interventions increasingly being used by the public despite a paucity of data, and with potential to impact important aging-related conditions to improve the health and independence of older adults.

项目总结/文摘