Novel Strategy to Quantitate Delayed Aging by Caloric Restriction

通过热量限制来量化延迟衰老的新策略

• 批准号: 10355362
• 负责人: ALEXEY V TERSKIKH
• 金额: $ 29.87万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355362
• 关键词: ATAC-seq; Acceleration; Age; Aging; Animals; Biological; Biological Aging; Biology of Aging; Blood; CD3 Antigens; Calibration; Caloric Restriction; Cells; Chromatin; Chronology; Control Animal; DNA Methylation; Data Pooling; Data Set; Development; Diet; Dietary Intervention; Doxorubicin; Epigenetic Process; Gene Expression; Genetic; Genome; Genomics; Hepatocyte; Heterochromatin; Human; Individual; Intervention; Linear Regressions; Liver; Longevity; Machine Learning; Measures; Methods; Methylation; Microscopy; Mining; Molecular; Mus; Nuclear; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Plant Roots; Population; Process; Regimen; Research; Sampling; Serum; Site; Stains; Tissues; Training; Transcript; XCL1 gene; Yeasts; age related; base; candidate marker; cell type; cost effective; deep learning; dietary restriction; epigenetic marker; epigenome; experimental study; fascinate; frailty; genome sequencing; healthspan; indexing; man; microscopic imaging; mimetics; novel strategies; regression algorithm; screening; sex; small molecule; tool; transcriptome sequencing; whole genome

PROJECT SUMMARY Aging is associated with causal epigenetic changes that occur throughout the genome, as first shown in yeast and worms. DNA methylation clocks identify CpG sites in human blood and other tissues with age-dependent changes. All such clocks depend on linear regression algorithms or deep learning to select CpGs methylation sites with levels that best fit chronological age; the deviation from the linear regression prediction of chronologi- cal age for each individual is considered, by some, a measure of biological age. Such computation of biological age has several limitations. We developed novel approach “Microscopic Imaging of Epigenetic Landscapes” (MIEL)-clock, which is rooted in the analysis of epigenome topography at the single cell level to measure age- dependent signature of chromatin landscape. MIEL captures patterns of nuclear staining of epigenetic marks and employs automated microscopy and machine learning to determine multiparametric signature of cellular state. We provide preliminary evidence for the power of MIEL-clock to successfully distinguish several types of young and old cells in mice and man. Our preliminary experiments using Doxorubicin (DOX) treatment, and Caloric Restriction (CR) indicate that MIEL-clock successfully detects acceleration of aging after DOX treat- ment and slowdown of aging after CR diet. Because CR robustly and consistently increases maximum lifespan and delays biological aging in diverse species, successfully applied CR regimen serves as an incomparable research tool for understanding the biology of aging. Here we propose to employ CR regimens to determine the power of MIEL-clock to quantitate slowdown of aging process and to directly compare and contrast MIEL- clock, RNA-seq and ATAC-seq signatures of liver hepatocytes in CR and control mice. With the caveat that one-size does not fit all, a diet optimized for genetic background and sex can be applied to beneficially impact healthspan and longevity. Given the composition of our study, completion of Specific Aims will yield a unique dataset directly comparing MIEL-clock to the classical genomic readouts of CR paradigm. The latter constitute a rich data pool for molecular mining of age-associated changes and will serve to corroborate the utility of MIEL-clock as a simple, cost effective, high throughput single-cell readout and screening platform for evaluat- ing dietary interventions with potential to slow down the aging process and identifying small molecules mimet- ics of CR.

项目总结 衰老与整个基因组中发生的因果表观遗传变化有关，这首先在酵母中表现出来。 还有虫子。DNA甲基化时钟识别人类血液和其他组织中与年龄相关的CpG位点 改变。所有这些时钟都依赖于线性回归算法或深度学习来选择CPGS甲基化 最符合年代学年龄的地点；年代学的线性回归预测的偏差- 有些人认为，每个人的卡龄都是生物年龄的一种衡量标准。这样的生物计算 年龄有几个限制。我们开发了一种新的方法“表生景观的显微成像” (Miel)-CLOCK，它植根于单细胞水平上的表观基因组拓扑学分析，以测量年龄- 染色质景观的依赖签名。MIEL捕捉到表观遗传标记的核染色模式 并使用自动显微镜和机器学习来确定细胞的多参数特征 州政府。我们为miel-lock的能力提供了初步的证据，成功地区分了几种类型的 老鼠和人的年轻细胞和老年细胞。我们使用多柔比星(DOX)治疗的初步实验，以及 卡路里限制(CR)表明MIEL-CLOCK成功地检测到DOX治疗后衰老的加速。 CR饮食后衰老的减轻和延缓。因为CR有力且持续地延长了最长寿命 并延缓不同物种的生物衰老，成功应用CR方案是无与伦比的 了解衰老生物学的研究工具。在这里，我们建议使用CR方案来确定 MIEL-CLOCK定量老化过程减慢和直接比较MIEL-CLOCK的能力 CR和对照组小鼠肝细胞的CLOCK、RNA-SEQ和ATAC-SEQ特征但需要注意的是 一刀切并不适合所有人，针对遗传背景和性别进行优化的饮食可以应用于有益的影响 健康长寿。鉴于我们研究的构成，完成具体目标将产生一个独特的 直接将MIEL-CLOCK与CR范例的经典基因组读数进行比较的数据集。后者构成了 为年龄相关变化的分子挖掘提供丰富的数据库，并将用于证实 MIEL-CLOCK是一种简单、经济高效、高通量的单电池读出和筛选平台，用于评估- ING饮食干预有可能延缓衰老过程，并确定小分子模拟- CR的ICS。