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

项目摘要/摘要 调整基本衰老机制的老年科学方法为产生 有效的新疗法用于治疗复杂的、多因素的衰老状况，如虚弱，这些因素对衰老有很大影响 导致老年人的功能衰退、残疾和丧失独立性。虚证是概念化的 作为一种进行性功能衰退和对应激源的易感性增加的状况 功能储备。虚弱的病理生理学很复杂，也不是很清楚，但人们普遍认为 突出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 内源性生产酮体，作为向组织提供脂肪衍生能量的一种手段。新进展 在了解酮体的生物活性时，β-羟基丁酸酯(BHB)表明两者都 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，并可能是 尤其与虚弱的病理生理学有关。酮酯最近已成为一种药理物质。 运送酮体的方法。我们已经组建了一个多学科的老年科学专家团队， 老年病与衰弱、酮体生物学、免疫衰老、酮体相关临床试验 针对早衰和轻度脆弱的酮酯(KE)的2a期多点概念验证临床试验 身体虚弱的老年人。腾飞是一项前瞻性、随机、双盲、为期12周的酮酯与... 匹配的安慰剂。目标1将测试肌肉力量和其他临床上与虚弱和衰老相关的结果是否有所改善 和柯一起。目标2将确定具有广泛代表性的虚弱前期和虚弱患者每日KE的安全性和耐受性 上了年纪的人。目标3将验证酮酯影响衰老免疫系统、骨骼肌、 以及通过详细的机械性免疫表型、肌肉代谢和生物标记物预测衰老的生物标记物 利用参与机构的强大专业知识进行研究。总而言之，这一翻译 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关键信息 公众，尽管数据匮乏，并有可能影响与老龄化相关的重要状况，以改善 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.