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: 9973115
• 负责人: Daniel Walker Belsky
• 金额: $ 53.71万
• 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/9973115
• 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 全球人口老龄化使得延长健康寿命（healthspan）的干预措施成为一项公共卫生 优先事项。针对衰老基本生物过程的疗法在动物身上进行了概念验证：早期到 中年干预可以延缓疾病的发生并延长健康寿命。但翻译这些老年保护 人类疗法面临中年老年保护疗法的人体临床试验将面临的障碍 需要数十年的随访来衡量健康寿命的延长。另一种选择是短期加速 老年保护试验，测试老年保护干预是否可以减缓生物衰老的速度。生物 老化是指随着时间的推移，系统完整性逐渐下降。 年龄。这一过程被认为是晚年发病率和残疾增加的根本原因。新的 研究表明，生物衰老可以在人类中测量，并且生物衰老的测量 预测人类的健康寿命。针对衰老基本生物过程的老年保护疗法是 假设可以减缓生物衰老的速度。但这还没有经过测试。我们的研究将测试是否最好- 在动物中建立了老年保护干预措施，长期限制热量，减缓了生物衰老的速度 中年人类的衰老，他们仍然年轻，可以推迟或预防与年龄相关的疾病。 我们将对国家衰老研究所最近存储的生物样本进行新的分析—— 完成 CALERIE 试验，随机将 220 名非肥胖成年人纳入 25% 的热量限制（CR，N=145） 或随意正常饮食（AL，N=75）2年。我们已经证明 CR 可以延缓衰老—— 器官系统完整性的相关恶化。现在，我们建议将该测试扩展到基因组测量 生物老化。我们将检测全基因组 DNA 甲基化（使用 Illumina 芯片）和基因表达 （使用 RNA 测序）来自 CALERIE 基线、12 个月和 24 个月时收集的血液样本 后续行动。我们将使用这个 3 时间点重复测量多组学数据集来测试 (i) CR 是否会变慢 通过 DNA 甲基化测量的生物衰老速度？ (ii) CR是否会引起基因改变 已知在动物体内介导 CR 延长健康寿命作用的途径中的表达，例如这 mTOR通路？ (iii) DN​​A 甲基化和基因表达的变化是否介导 CR 对器官的影响 系统运行正常吗？我们将与 CALERIE Biorepository 共享我们生成的多组学数据， 向所有感兴趣的研究人员免费提供该资源。拟议的项目将产生新的 关于热量限制对人类生物衰老影响的知识并测试概念证明 加速老年保护剂试验设计，可以加速新的延缓衰老疗法的转化 动物对人类。通过 CALERIE Biorepository 的开放数据共享将使研究超越 该项目的范围是提高对热量限制的理解并推进老年科学领域。