Genomic Analysis of the CALERIE Trial to Generate New Knowledge for Geroscience

CALERIE 试验的基因组分析，为老年科学产生新知识

• 批准号: 10378000
• 负责人: Daniel Walker Belsky
• 金额: $ 32.63万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378000
• 关键词: Activities of Daily Living; Adult; Advanced Development; Affect; Age; Aging; Animals; Basic Science; Biological; Biological Aging; Biological Assay; Biological Process; Biology; Biology of Aging; Blood; Blood specimen; Body Weight decreased; Caloric Restriction; Caloric Tests; Cell Aging; Cessation of life; Chronology; Clinical Trials; DNA; DNA Methylation; Data; Data Analyses; Data Set; Databases; Deterioration; Diet; Disease; Dose; Elderly; Epigenetic Process; FRAP1 gene; Face; Gene Expression; Genes; Genetic Transcription; Genomics; Geroscience; Goals; Health; Human; Individual; Intervention; Knowledge; Life; Link; Long-Term Effects; Longevity; Measurement; Measures; Mediating; Methylation; Morbidity - disease rate; Multiomic Data; Mus; National Institute on Aging; Non obese; Observational Study; Onset of illness; Participant; Pathway interactions; Persons; Physiology; Plant Roots; Population; Process; RNA; Randomized; Randomized Controlled Trials; Research; Research Personnel; Resources; Running; Specimen; Speed; Surrogate Endpoint; System; Testing; Time; Translating; Translations; Tube; Whole Blood; age related; arm; biobank; body system; body-mind; data resource; data sharing; disability; disorder risk; experience; experimental study; fly; follow-up; genomic data; healthspan; improved; interest; intervention effect; middle age; multiple omics; novel; novel strategies; open data; peer; prevent; randomized trial; rate of change; response; targeted treatment; transcriptome; transcriptome sequencing; translation to humans; trial design; whole genome

SUMMARY The graying global population makes interventions to extend healthy lifespan (healthspan) a public heath priority. Therapies targeting basic biological processes of aging show proof-of-concept in animals: early-to- midlife intervention can delay disease onset and prolong healthspan. But translating these geroprotective therapies to humans faces the barrier that human clinical trials of midlife geroprotective therapy would require decades of follow-up to measure healthspan extension. An alternative is a short-term accelerated geroprotector trial that tests if geroprotective intervention can slow the rate of biological aging. Biological aging is the gradual and progressive decline in system integrity that occurs with advancing chronological age. This process is thought to be the root cause of increases in morbidity and disability in later life. New research shows that biological aging can be measured in humans and that measures of biological aging predict human healthspan. Geroprotective therapies that target basic biological processes of aging are hypothesized to slow the rate of biological aging. But this has not been tested. Our study will test if the best- established geroprotective intervention in animals, long-term caloric restriction, slows the rate of biological aging in midlife humans, who are still young enough for age-related disease to be delayed or prevented. We will conduct new assays of stored biospecimens from the National Institute on Aging's recently- completed CALERIE Trial, which randomized 220 non-obese adults to 25% caloric restriction (CR, N=145) or ad libitum normal diet (AL, N=75) for a period of 2 years. We have already shown that CR slows aging- related deterioration in organ-system integrity. Now, we propose to extend this test to genomic measures of biological aging. We will assay whole-genome DNA methylation (using Illumina chips) and gene expression (using RNA sequencing) from blood samples collected at CALERIE baseline, and at 12-, and 24-month follow-ups. We will use this 3-time-point repeated-measures multi-omics dataset to test (i) Does CR slows the rate of biological aging as measured from DNA methylation? (ii) Does CR cause changes to gene expression in the pathways known to mediate healthspan-extending effects of CR in animals, e.g. the mTOR pathway? (iii) Do changes to DNA methylation and gene expression mediate effects of CR on organ system functioning? We will share the multi-omics data we generate with the CALERIE Biorepository, making the resource freely available to all interested researchers. The proposed project will generate new knowledge about effects of caloric restriction on biological aging in humans and test proof of concept for an accelerated geroprotector trial design that can speed translation of new age-delaying therapies from animals to humans. Open data sharing through the CALERIE Biorepository will enable research beyond the scope of this project to improve understanding of caloric restriction and advance the field of geroscience.

概括 灰色的全球人口进行了干预措施，以延长健康的寿命（HealthSpan）公共荒地 优先事项。针对衰老基本生物学过程的疗法显示动物的概念证明：早期至早期 中年干预会延迟疾病发作并延长健康状态。但是翻译这些老年保护 对人类的疗法面临的障碍是，中等生活的细胞保护疗法的人类临床试验将 需要数十年的随访来衡量健康范围的扩展。替代方案是短期加速 测试是否会降低生物衰老的速度，测试是否会降低生物衰老的速度。生物 衰老是系统完整性的逐渐下降，随着时间顺序排列 年龄。人们认为这一过程是后来生活中发病率和残疾增加的根本原因。新的 研究表明，可以在人类中测量生物衰老，并测量生物衰老 预测人类HealthSpan。针对基本衰老的基本生物学过程的细胞保护疗法是 假设可以减慢生物衰老的速度。但这尚未进行测试。我们的研究将测试是否最好 建立的对动物的老年保护干预，长期热量限制，减慢了生物学的速度 中年人类的衰老，他们还足够年轻，可以延迟或预防与年龄有关的疾病。 我们将对美国国家衰老的最近 - 完成的热量试验，该试验随机220个非肥胖成年人至25％的热量限制（CR，n = 145） 或随意的正常饮食（Al，n = 75）2年。我们已经表明，CR会减慢衰老 - 器官系统完整性的相关恶化。现在，我们建议将此测试扩展到基因组测量 生物衰老。我们将测定全基因组DNA甲基化（使用Illumina Chips）和基因表达 （使用RNA测序）来自在卡利亚基线收集的血液样本，在12个月和24个月中 后续行动。我们将使用此3点重复测量多摩尼斯数据集进行测试（i）确实会减慢 通过DNA甲基化测量的生物衰老速率？ （ii）CR会导致基因变化 在已知介导CR的延伸效应的途径中的表达，例如这 mtor途径？ （iii）对DNA甲基化和基因表达的变化介导了Cr对器官的影响 系统功能？我们将与Calerie Biorepository共享我们生成的多摩斯数据， 使所有感兴趣的研究人员免费提供资源。拟议的项目将产生新的 关于热量限制对人类生物衰老的影响的知识，以及测试概念证明 加速的老师试验设计可以加快从 动物到人类。通过Calerie BioreSository开放数据共享将使研究能够超越 该项目的范围旨在提高对热量限制的理解并推进Geroscience领域。