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

• 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
• 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

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.

项目摘要 衰老是一种高度个体化的现象，在时间上相同的人身上以不同的速度进行。这些 差异点燃了生物学年龄的概念，其中候选生物标志物包括血清分析物， 脆弱指数和最近的DNA甲基化。人类的纵向分析显示， 组织以不同的速度老化，导致高度个体化的年龄型。此外，在单个测量点处的测量结果 细胞分辨率显著提高了对人类衰老过程的洞察力。这些和其他研究强调， 需要在分子水平上预测衰老的生物标志物，优选具有单细胞分辨率， 揭示生物体衰老的复杂性，并提供功能性衰老的组织特异性定量特征， 年龄为了提供信息，此类分子特征必须锚定在衰老的功能读数中，例如 如代谢、身体、认知和免疫功能，优选地在个体生物体的水平上。的 Terskikh实验室已经开发出一种新的技术，该技术植根于对表观基因组拓扑结构的分析， 单细胞水平来定量染色质景观的变化。我们捕捉到了 表观遗传标记（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。将这种技术应用于老化，称为 生物年龄的显微成像（miBioAge），揭示了新分离的年轻人和老年人的稳健分离。 小鼠和人体组织，并与实足年龄无线性回归。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促进健康 在人类身上。我们建议利用源自U01 AG076941的一组独特的人类样本 临床试验，以关联（使用双曲线嵌入和机器学习）个体miBioAge签名， PBMC和骨骼肌，具有多个功能读数。