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

摘要 全球人口老龄化使延长健康寿命的干预措施成为公共健康 优先考虑。针对衰老基本生物学过程的治疗方法在动物身上显示出概念验证：早期到 中年干预可以延缓疾病的发病，延长健康寿命。但将这些齿轮保护转化为 对人类的治疗面临着人类中年保护疗法的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的 基因保护剂试验，测试基因保护性干预是否可以减缓生物衰老的速度。生物学 老化是随着时间顺序的推进而发生的系统完整性的逐渐下降 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身上测量，而生物衰老的衡量标准 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有 假设是为了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- 在动物中建立了保护动物的干预措施，长期限制卡路里，减缓了生物 中年人类的老龄化，他们仍然足够年轻，可以推迟或预防与年龄相关的疾病。 我们将对国家老龄化研究所最近储存的生物标本进行新的分析- 完成CALERIE试验，220名非肥胖成年人随机接受25%卡路里限制(CR，N=145) 或随意正常饮食(AL，N=75)，疗程2年。我们已经证明了CR可以延缓衰老-- 器官系统完整性的相关恶化。现在，我们建议将这项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 (使用RNA测序)从CALERIE基线、12个月和24个月时采集的血液样本 后续行动。我们将使用这个3个时间点的重复测量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 在已知的介导CR延长动物健康跨度效应的途径中的表达，例如 MTOR路径？(Iii)DNA甲基化和基因表达的变化在CR对器官的影响中起中介作用 系统运行正常吗？我们将与CALERIE生物库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资源。拟议的项目将产生新的 关于卡路里限制对人类生物衰老影响的认识和一个概念的测试验证 加速齿轮保护剂试验设计，可以加快新的延缓衰老疗法的翻译速度 从动物到人类。通过CALERIE生物库共享开放数据将使研究超越 该项目的范围是提高对卡路里限制的理解，促进老年科学领域的发展。

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.