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.

项目概要/摘要 调节基本衰老机制的老年科学方法为产生 针对复杂、多因素的衰老状况（例如虚弱）的有效新疗法，其贡献如此之大 导致老年人功能衰退、残疾和丧失独立性。虚弱综合症的概念化 作为进行性功能衰退和因功能下降而增加的对压力源的脆弱性的一种情况 功能储备。衰弱的病理生理学很复杂且尚未被充分理解，但通常认为 主要包括细胞能量产生缺陷以及慢性炎症和免疫功能障碍。 饮食限制和禁食，与衰老的基本机制密切相关的干预措施，促进 酮体的内源性产生作为向组织提供脂肪来源的能量的一种手段。新进展 在了解酮体β-羟基丁酸（BHB）的生物活性时，表明两者 BHB 的能量产生和信号活动可能在调节衰老方面具有机械作用，并且可能是 与虚弱的病理生理学特别相关。酮酯最近作为一种药理学出现 传递酮体的方式。我们组建了一支由老年科学专家组成的多学科团队， 老年医学和衰弱、酮体生物学、免疫衰老和酮体相关的临床试验 进行了一项酮酯 (KE) 的多中心概念验证 2a 期临床试验，该试验针对先衰和轻度衰弱患者 体弱的老年人。 TAKEOFF 是一项针对酮酯与酮酯的前瞻性、随机、双盲、为期 12 周的研究。 匹配的安慰剂。目标 1 将测试肌肉力量和其他临床虚弱和衰老相关结果是否有所改善 与 KE.目标 2 将确定每日 KE 在具有广泛代表性的前衰弱和衰弱中的安全性和耐受性 老年人。目标 3 将检验酮酯影响衰老免疫系统、骨骼肌、 通过详细的机械免疫表型、肌肉代谢和生物标志物来确定衰老的生物标志物 利用参与机构强大的专业知识的研究。总而言之，这个翻译 努力将提供有关越来越多地使用的干预措施的安全性和有效性的重要信息 尽管缺乏数据，但有可能影响重要的与老龄化相关的状况，以改善 老年人的健康和独立性。