Testing the utility of miBioAge as a personalized aging biomarker

项目总结 衰老是在时间上相同的人中以不同速度进行的高度个性化的现象。这些 差异点燃了生物年龄的概念，候选生物标记物包括血清分析物和 脆弱指数和最近的DNA甲基化。人类的纵向分析显示，器官和 组织老化的速度不同，导致高度个体化的年龄类型。此外，在单项测量中， 细胞分辨率显著提高了对人类衰老过程的洞察力。这些研究和其他研究强调 需要在分子水平上预测衰老的生物标志物，最好是具有单细胞分辨率以 揭开生物衰老的复杂性，并提供组织特异性的功能定量标记 年龄。为了提供信息，这些分子签名必须锚定在衰老的功能读数中 作为代谢、身体、认知和免疫功能，最好是在个体有机体的水平上。这个 Terskikh实验室开发了一种新技术，该技术植根于 单细胞水平，以量化染色质景观的变化。我们捕捉到了核染色的模式 表观遗传标记(例如，乙酰化和甲基化的组蛋白)，并使用自动显微镜和机器 学习确定蜂窝状态的多参数特征。这项技术在老化中的应用，称为 生物年龄的显微成像(MiBioAge)，显示了新分离的年轻和老年的强大分离 小鼠和人的组织，并与年龄相关，没有线性回归。一个最近资助的 临床试验(U01 AG07694)将确定mTOR抑制剂伊维洛莫斯是否安全地促进健康 在人类身上。我们建议利用来自U01 AG076941的一组独特的人类样本 临床试验，将(使用双曲线嵌入和机器学习)个人miBioAge签名关联到 具有多功能读数的PBMC和骨骼肌。

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.