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

总结 老龄化的全球人口使延长健康寿命（healthspan）的干预措施成为公共卫生 要务针对衰老的基本生物过程的治疗显示了动物的概念验证： 中年干预可以延迟疾病发作和延长健康寿命。但是翻译这些保护老人的 中年老年保护疗法的人类临床试验面临着障碍， 需要几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 老化是随着时间的推移而发生的系统完整性的逐渐和渐进的下降 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 研究表明，生物衰老可以在人类身上测量， 预测人类的健康寿命针对衰老的基本生物过程的老年保护疗法是 被认为可以减缓生物衰老的速度。但这还没有经过测试。我们的研究将测试最好的- 在动物中建立的老年保护干预措施，长期的热量限制，减缓了生物降解率， 中年人的衰老，他们仍然年轻，可以推迟或预防与年龄有关的疾病。 我们将对国家衰老研究所最近储存的生物样本进行新的分析- 已完成的CALERIE试验，将220名非肥胖成人随机分配至25%热量限制组（CR，N=145） 或随意正常饮食（AL，N=75），持续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， 生物老化我们将分析全基因组DNA甲基化（使用Illumina芯片）和基因表达 CALERIE基线时以及12个月和24个月时采集的血样（使用RNA测序） 后续行动。我们将使用这个3时间点重复测量的多组学数据集来测试（i）CR是否减慢 从DNA甲基化来衡量生物衰老的速度(ii)CR是否会导致基因改变 在已知介导CR在动物中的健康延长作用的途径中的表达，例如， mTOR通路？(iii)DNA甲基化和基因表达的改变是否介导CR对器官的影响 系统功能？我们将与CALERIE Biorepository共享我们生成的多组学数据， 使资源免费提供给所有感兴趣的研究人员。该项目将产生新的 关于热量限制对人类生物衰老的影响的知识，以及 加速geroprotector试验设计，可以加速新的延缓衰老疗法的翻译， 动物到人类通过CALERIE生物储存库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，推进老年科学领域。

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.