Testing the utility of miBioAge as a personalized aging biomarker

测试 miBioAge 作为个性化衰老生物标志物的实用性

基本信息

批准号：
10728233
负责人：
ALEXEY V TERSKIKH
金额：
$ 56.98万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10728233
关键词：
Acceleration Acetylation Age Aging Biological Biological Markers Blood Calibration Caloric Restriction Cell Nucleus Cells Chromatin Chronology Clinical Research Clinical Trials DNA Methylation Data Set Doctor of Philosophy Doxorubicin Epigenetic Process Exclusion Funding Future Human Individual Internet Intervention Laboratories Letters Life Linear Regressions Link Longevity Machine Learning Measurement Measures Metabolic Methods Methylation Microscopy Molecular Molecular Profiling Mus Nuclear Organ Organism Participant Pathology Pattern Peripheral Blood Mononuclear Cell Persons Physical Function Physiological Placebos Process Reproducibility Resolution SDZ RAD Sampling Serum Skeletal Muscle Speed Spiders Stains Stratification Techniques Testing Tissues Training age related candidate marker cognitive function epigenome frailty healthspan heart function histone methylation human tissue immune function improved indexing insight mTOR Inhibitor mTOR inhibition microscopic imaging middle age novel peripheral blood pharmacologic placebo group predictive marker response response biomarker young adult

项目摘要

PROJECT SUMMARY Aging is highly individual phenomenon proceeding at different speed in chronologically identical people. These differences kindle the notion of biological age for which candidate biomarkers include serum analytes and frailty indices and more recently DNA methylation. Longitudinal profiling in humans revealed that organs and tissues age with different speeds resulting in highly individual ageotype. Further, measurements at the single cell resolution significantly improve the insights into human aging process. These and other studies underscore the need for predictive biomarkers of aging at the molecular level preferably with single cell resolution to unravel the complexity of organismal aging and to provide tissue-specific quantitative signatures of functional age. To be informative such molecular signatures must be anchored in the functional readouts of aging such as metabolic, physical, cognitive, and immune functions preferably at the level of individual organisms. The Terskikh laboratory has developed a novel technique rooted in the analysis of epigenome topography at the single cell level to quantitate changes in chromatin landscape. We capture patterns of nuclear staining of epigenetic marks (e.g. acetylated and methylated histones) and employ automated microscopy and machine learning to determine multiparametric signature of cellular state. Application of this technique to aging, termed microscopic imaging of Biological Age (miBioAge), revealed robust separation of young and old freshly isolated mouse and human tissues, and correlated with chronological age without linear regression. A recently funded clinical trial (U01 AG07694) will determine whether the mTOR inhibitor everolimus safely promotes healthspan in humans. We propose to take advantage of a unique set of human samples originating from U01 AG076941 clinical trial, to associate (using hyperbolic embedding and machine learning) individual miBioAge signatures in PBMC and skeletal muscles with multiple functional readouts.

项目概要衰老是一种高度个体化的现象，在时间顺序相同的人中以不同的速度进行。这些差异引发了生物年龄的概念，其候选生物标志物包括血清分析物和衰弱指数和最近的 DNA 甲基化。人体的纵向分析表明，器官和组织以不同的速度老化，导致高度个体化的年龄型。此外，单次测量细胞分辨率显着提高了对人类衰老过程的了解。这些和其他研究强调需要在分子水平上预测衰老生物标志物，最好是单细胞分辨率揭示有机体衰老的复杂性并提供功能的组织特异性定量特征年龄。为了提供信息，这些分子特征必须锚定在衰老的功能读数中，例如代谢、身体、认知和免疫功能，最好是在个体生物体水平上。这 Terskikh 实验室开发了一种植根于表观基因组拓扑分析的新技术单细胞水平来定量染色质景观的变化。我们捕获的核染色模式表观遗传标记（例如乙酰化和甲基化组蛋白）并采用自动显微镜和机器学习确定细胞状态的多参数特征。将该技术应用于衰老，称为生物年龄 (miBioAge) 的显微成像，揭示了新鲜分离的年轻人和老年人的牢固分离小鼠和人体组织，并与实际年龄相关，没有线性回归。最近资助的临床试验 (U01 AG07694) 将确定 mTOR 抑制剂依维莫司是否安全地延长健康寿命在人类中。我们建议利用源自 U01 AG076941 的一组独特的人类样本临床试验，将个体 miBioAge 签名关联（使用双曲嵌入和机器学习）具有多种功能读数的 PBMC 和骨骼肌。