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

项目总结/摘要 调节基本衰老机制的老年科学方法为产生 有效的新疗法，用于复杂的，多因素的衰老状况，如虚弱， 老年人的功能衰退、残疾和独立性丧失。虚弱综合征的概念 作为一种进行性功能衰退的条件，并增加了对压力源的脆弱性， 功能储备虚弱的病理生理学是复杂的，并没有得到很好的理解，但一般认为， 主要包括细胞能量产生缺陷沿着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， 酮体的内源性产生，作为向组织提供脂肪来源能量的一种手段。新进展 在了解酮体β-羟基丁酸酯（BHB）的生物活性方面， BHB的能量产生和信号传导活动可能在调节衰老中起机械作用， 特别是与虚弱的病理生理学有关。酮酯最近已成为一种药理学 输送酮体的方法。我们组建了一个多学科的老年科学专家小组， 老年与虚弱、酮体生物学、免疫衰老、酮体相关临床试验进行 一项多中心、概念验证的2a期临床试验，研究了酮酯（KE）在虚弱前期和轻度虚弱中的作用。 脆弱的老年人TAKEOFF是一项前瞻性、随机、双盲、12周研究，旨在比较酮体与 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的结果是否改善 在KE。目标2将确定每日KE在广泛代表性的虚弱前期和虚弱期患者中的安全性和耐受性。 老年人目的3将检验酮酯影响衰老的免疫系统、骨骼肌， 通过详细的机械免疫表型，肌肉代谢和生物标志物， 利用参与机构强大的专业知识进行研究。总的来说， 这项工作将提供关于越来越多的人使用的干预措施的安全性和有效性的重要信息。 尽管数据匮乏，但仍对公众产生影响，并有可能影响与衰老相关的重要条件，以改善健康状况。 老年人的健康和独立。

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.