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.

项目摘要 衰老与整个基因组中发生的因果表观遗传变化有关，如酵母首先所示 和蠕虫。 DNA甲基化时钟与年龄有关 更改。所有此类时钟都取决于线性回归算法或深度学习选择CPG甲基化 具有最适合年代年龄的水平的站点；偏离了年表的线性回归预测 - 某些人认为每个人的年龄是生物年龄的量度。这种生物年龄计算 年龄有几个限制。我们开发了新的方法“表观遗传景观的微观成像” （MIEL） - Clock，它植根于单细胞水平的表观基因组地形的分析，以测量年龄 染色质景观的依赖特征。米尔捕获表观遗传标记的核染色模式 员工自动显微镜和机器学习以确定蜂窝的多参数签名 状态。我们提供了Miel-Clock成功区分几种类型的Miel-Clock的力量的初步证据 小鼠和人的年轻细胞和老细胞。我们使用阿霉素（DOX）治疗的初步实验，并 热量限制（CR）表明，Miel-Clock成功地检测到DOX治疗后的衰老加速度 - Cr饮食后的衰老和衰老放缓。因为CR强大而始终如一地增加了最大寿命 并延迟了潜水物种的生物衰老，成功地应用CR方案是无与伦比的 了解衰老生物学的研究工具。在这里，我们建议采用CR方案来确定 Miel-Clock量化衰老过程减慢的力量，并直接比较和对比Miel- CR和对照小鼠中肝细胞的时钟，RNA-SEQ和ATAC-SEQ特征。有警告 一种规模不合适，针对遗传背景和性别优化的饮食可用于受益影响 HealthSpan和longevity。鉴于我们研究的组成，特定目标的完成将产生独特的 数据集直接将Miel-Clock与CR范式的经典基因组读数进行比较。后者构成 丰富的数据库，用于与年龄相关的变化的分子开采，并将证实 Miel-clock是一个简单，具有成本效益，高吞吐量的单细胞读数和筛选平台，用于评估 - 进行饮食干预措施，可能会减慢衰老过程并确定小分子mimet- Cr的IC。