Telomere length analysis in the CALERIE trial

CALERIE 试验中的端粒长度分析

• 批准号: 10364945
• 负责人: Idan Shalev
• 金额: $ 7.91万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10364945
• 关键词: Address; Adult; Affect; Aging; Algorithms; Animal Model; Autophagocytosis; Biological; Biological Aging; Biological Assay; Biological Markers; Birth length; Blood Chemical Analysis; Body Weight decreased; C-reactive protein; CCL2 gene; Caloric Restriction; Caloric Tests; Cell Aging; Chromosomes; Complex; DNA; DNA Damage; Data; Data Analyses; Databases; Diet; Dose; Energy Intake; F2-Isoprostanes; Factor Analysis; Guidelines; Human; ICAM1 gene; IL6 gene; IL8 gene; Inflammation; Intercellular adhesion molecule 1; Interleukin-1 beta; Interleukin-6; Interleukin-8; Intervention Studies; Isoprostanes; Knowledge; Length; Leptin; Leukocytes; Link; Long-Term Effects; Longevity; Measurement; Measures; Mediating; Methodology; Mitochondria; Molecular; Mus; Names; National Institute of Environmental Health Sciences; Non obese; Nucleoproteins; Oxidative Stress; Participant; Pathway interactions; Persons; Physiological; Population Study; Primates; Process; Randomized; Randomized Controlled Trials; Rattus; Regulation; Reporting; Reproducibility; Research; Research Personnel; Resistance; Robotics; Role; Sampling; Specimen; Stress; System; TNF gene; Telomerase; Testing; Time; Tissues; Variant; Whole Blood; Work; Yeasts; aged; anti aging; arm; base; biobank; factor A; healthspan; human old age (65+); improved; innovation; intervention effect; member; middle age; mitochondrial dysfunction; molecular array; novel; randomized trial; response; synergism; telomere; trial design

PROJECT SUMMARY Long-term caloric restriction (CR) is one of the most effective and well-studied intervention to extend both average and maximum life spans in a variety of species, from yeast to primates. Recent evidence from the Comprehensive Assessment of Long term Effects of Reducing Intake of Energy (CALERIE) suggests CR slows biological aging in humans, as measured by an algorithm applied to blood chemistry data. The mechanisms through which CR affects healthy lifespan involve a complex array of molecular pathways, from reduced inflammation and oxidative stress, improved mitochondrial function, enhanced autophagy and increased stress resistance. Notably, the aforementioned mechanisms are implicated in telomere length regulation. Yet, whether CR slows biological aging as indicated by telomere length, has not been addressed, as well as the role of inflammation and oxidative stress in the hypothesized mechanism. Understanding the molecular pathways by which CR increases healthspan could pinpoint new targets for anti-aging therapies. Here we will assay leukocyte telomere length (LTL) in CALERIE to test whether CR is associated with decreased LTL erosion as compared to the ad libitum control. LTL assays will be conducted using both the T/S ratio and the absolute qPCR assay, and communicated based on new qPCR reporting guidelines set by the Telomere Research Network. Further, making full use of the repeated measures of LTL obtained across the trial, we will examine when, during the two-year span, the differences in LTL emerge (e.g., earlier or later). Utilizing CALERIE biorepository, we will further test whether the hypothesized reduced LTL erosion in the CR arm is mediated by reduced level of inflammation and oxidative stress. In Aim 1a, intent-to-treat analysis will test whether CR is associated with reduced LTL erosion over 24 months, compared to the ad libitum control. Aim 1b will conduct dose-response analyses and investigate whether intervention effects are mediated by weight loss, and examine when, earlier or later in the 24-month trial, the CR effects on LTL change emerge. Aim 2 will test whether CR is associated with LTL changes over 24 months through reduced levels of inflammation at 12 and 24 months (factor analysis of CRP, ICAM1, IL1β, IL6, IL8, Leptin, MCP1, and TNF-α), and reduced levels of oxidative stress at 12 and 24 month (factor analysis of F2‐isoprostanes—iPF(2α)‐III, 2,3‐dinor‐iPF(2 α)‐III, iPF(2 α)‐VI, and 8,12‐iso‐iPF(2α)‐VI). This innovative work will determine from a first-ever randomized trial design if human caloric restriction slows cellular aging as measured by telomere length. Findings will help generate new knowledge about CR mechanisms in humans at the cellular level. The data generated will be shared with the CALERIE Biorepository upon completion of assays for investigators use.

项目概要 长期热量限制 (CR) 是最有效且经过充分研究的干预措施之一，可延长 从酵母到灵长类动物的最新证据显示了各种物种的平均和最大寿命。 减少能量摄入的长期影响 (CALERIE) 的综合评估建议 CR 通过应用于血液化学数据的算法测量，可以减缓人类的生物衰老。 CR 影响健康寿命的机制涉及一系列复杂的分子途径，从 减少炎症和氧化应激，改善线粒体功能，增强自噬和 值得注意的是，上述机制与端粒长度有关。 然而，CR 是否可以通过端粒长度来减缓生物衰老尚未得到解决。 以及炎症和氧化应激在已发展机制中的作用。 CR 延长健康寿命的分子途径可以确定抗衰老疗法的新靶标。 在这里，我们将在 CALERIE 中检测白细胞端粒长度 (LTL)，以测试 CR 是否与 与自由采食对照相比，LTL 侵蚀将使用 T/S 进行。 比率和绝对 qPCR 检测，并根据新的 qPCR 报告指南进行沟通 此外，充分利用在整个范围内获得的 LTL 的重复测量。 在试验中，我们将检查在两年的时间里零担差异何时出现（例如，提前或推迟）。 利用CALERIE生物样本库，我们将进一步测试捕获的CR中的LTL侵蚀是否减少 在目标 1a 中，意向治疗分析将通过降低炎症和氧化应激水平来介导。 测试与随意控制相比，CR 是否与 24 个月内 LTL 侵蚀减少相关。 目标 1b 将进行剂量反应分析，并调查干预效果是否由以下因素介导： 体重减轻，并检查在 24 个月的试验中，CR 对 LTL 变化的影响何时出现。 目标 2 将通过降低 CR 水平来测试 CR 是否与 24 个月内的 LTL 变化相关。 12 个月和 24 个月时的炎症（CRP、ICAM1、IL1β、IL6、IL8、瘦素、MCP1 和 TNF-α 的因子分析）， 12 个月和 24 个月时氧化应激水平降低（F2-异前列腺素 -iPF(2α)-III 的因子分析， 这项创新工作将由首次确定。 随机试验设计，如果人类热量限制减缓细胞衰老（通过端粒长度测量）。 研究结果将有助于在细胞水平上产生关于人类 CR 机制的新知识。 分析完成后，生成的数据将与 CALERIE 生物存储库共享，供研究人员使用。