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.

项目摘要 长期热量限制（CR）是扩展两者的最有效和研究的干预措施之一 从酵母到私人的各种物种中的平均寿命和最大寿命。来自 对减少能源摄入（Calerie）的长期影响的全面评估表明CR 通过应用于血液化学数据的算法来衡量的人类生物学老化。这 CR影响健康寿命的机制涉及一系列复杂的分子途径 炎症和氧化应激减少，线粒体功能的改善，自噬增强和 压力抗性增加。值得注意的是，近似机制暗示为端粒长度 规定。但是，尚未解决CR是否减慢生物学衰老，尚未解决， 以及感染和氧化应激在假设机制中的作用。了解 CR增加HealthSpan的分子途径可以查明抗衰老疗法的新靶标。 在这里，我们将在卡利亚中主张白细胞端粒长度（LTL），以测试CR是否与 与自发对照相比，LTL侵蚀。 LTL测定将使用T/S进行 比率和绝对qPCR分析，并根据由新的QPCR报告指南进行通信 端粒研究网络。此外，充分利用在整个跨过的LTL的重复度量 试验，我们将检查在两年范围内LTL出现的差异（例如，更早或更晚）。 利用卡利亚生物座位，我们将进一步测试假设的CR中的LTL侵蚀是否减少 手臂是通过降低的感染水平和氧化应激介导的。在AIM 1A中，意图对治疗分析将 与自重控制相比，CR是否在24个月内与LTL侵蚀减少有关。 AIM 1B将进行剂量反应分析，并研究干预效应是否由 体重减轻，并检查24个月试验的早期或晚期，CR对LTL变化的影响出现。 AIM 2将测试CR是否与LTL在24个月内通过降低的水平相关 12和24个月的炎症（CRP，ICAM1，IL1β，IL6，IL8，Leptin，MCP1和TNF-α的因子分析）， 以及12和24个月时氧化应激水平降低（F2-异丙烷的因子分析-IPF（2α）-III， 2,3-Dinor-IPF（2α）-III，IPF（2α）-VI和8,12-ISO-IPF（2α）-VI）。这项创新的工作将从第一个确定 随机试验设计如果人热量限制会减慢按端粒长度测量的细胞衰老。 发现将有助于在细胞水平上产生有关人类CR机制的新知识。数据 在完成调查人员使用的测定时，生成的生成将与卡尔利生物库共享。