QUANTITATIVE ASSESSMENT OF BIOLOGICAL AGE AND ITS APPLICATIONS

生物年龄的定量评估及其应用

• 批准号: 10833859
• 负责人: Vadim N. Gladyshev
• 金额: $ 22.5万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10833859
• 关键词: Address; Age; Aging; Animals; Basic Science; Behavior Therapy; Biological; Biological Aging; Biological Markers; Biology; Biology of Aging; Blood specimen; Caloric Restriction; Categories; Cell Aging; Cell Culture Techniques; Cells; Chronology; Communities; Consensus; Cultured Cells; DNA Damage; DNA Methylation; Data; Development; Epigenetic Process; Exhibits; Future; Gene Expression; Generations; Genetic; Geroscience; Goals; Health; Human; In Vitro; Individual; Intervention; Link; Longevity; Measures; Methylation; Mitochondria; Modeling; Molecular; Monitor; Mus; Organ; Organism; Outcome; Phenotype; Physiological; Process; Reaction; Recommendation; Reporting; Research; Research Personnel; Resources; Sampling; Series; Signal Transduction; System; Testing; Therapeutic; Time; Tissues; Training; Validation; age related; cohort; dietary; dietary restriction; healthspan; in vivo; intervention effect; mimetics; mitochondrial dysfunction; molecular marker; mortality; mouse model; novel; novel therapeutics; pharmacologic; phenotypic data; practical application; prognostic; response; screening; senescence; tool

ABSTRACT Quantifying aging is a major goal in Geroscience research as the availability of a reliable marker of aging can facilitate understanding of the fundamental biology of aging, enable tracking of the aging process in different tissues and cell systems, and support identification and validation of interventions that extend lifespan and healthspan. Traditionally, aging has been monitored by following chronological age, mortality, age-related changes in gene expression, and/or other molecular features, however, there is currently no consensus on the best practices for quantitatively tracking progression through aging. The recent advent of biomarkers based on advanced omics approaches, such as DNA methylation, have provided some hope to support development of precise estimates of age, both in humans and mice. Nevertheless, the majority of such measures are trained as chronological age predictors, with little to no integration of biological, functional, or phenotypic data. Further, the modifiability of aging measures based on DNA methylation in response to lifespan and healthspan extending interventions is almost entirely unknown. We propose to address these challenges by developing a series of novel DNA methylation clocks by integrating information on phenotypic and functional aging, investigating links between DNA methylation and aging hallmarks, and evaluating DNA methylation responses to longevity interventions. We suggest that these clocks will offer a much-needed resource for the Geroscience community. We will develop these clocks using three general approaches. First, we will use cultured cells (MEFs) to induce or establish models of three well-known hallmarks of aging—cellular senescence, DNA damage, and mitochondrial dysregulation. We will then train epigenetic predictors of these hallmarks and validate them in vivo. We will also establish epigenetic alterations in response to novel and established longevity interventions. In doing so, we will develop biomarkers of intervention response that can be used to test mimetics, and/or optimize aging biomarkers. Finally, building on the highly characterized SLAM colony of C57Bl/6 and UM-HET3 animals, we will produce longitudinal methylation data across the lifespan that can be used to develop an epigenetic clock that can serve as a robust predictor of healthspan. We hypothesize that these new clocks will better capture biological age than chronological age trained clocks. Given that they were developed to capture different facets associated with the aging process, they can be combined to create a single aging measure that is more biologically informed and characterized compared to existing epigenetic clocks.

抽象的 量化衰老是Geroscience Research的主要目标 促进对衰老的基本生物学的理解，启用不同的衰老过程 组织和细胞系统，并支持延长寿命和延长寿命的干预措施的识别和验证 HealthSpan。传统上，衰老是通过按年代年龄，死亡率，与年龄相关的年龄来监测的 但是，基因表达和/或其他分子特征的变化，但是目前尚无共识 通过衰老来定量跟踪进展的最佳实践。基于生物标志物的最近冒险 先进的OMICS方法，例如DNA甲基化，为支持开发的希望 在人类和小鼠中，年龄的精确估计。然而，大多数此类措施都被培训为 年代年龄预测因子，几乎没有生物学，功能或表型数据的整合。此外， 基于DNA甲基化的衰老测量可修改性，以响应寿命和健康范围延长 干预几乎完全未知。我们建议通过开发一系列 新型DNA甲基化时钟通过整合表型和功能衰老的信息，研究联系 在DNA甲基化和衰老标志之间，并评估DNA甲基化对寿命的反应 干预措施。我们建议这些时钟将为Geroscience社区提供急需的资源。 我们将使用三种一般方法开发这些时钟。首先，我们将使用培养的细胞（MEF）诱导 或建立三个著名衰老标志的模型 - 细胞感应，DNA损伤和 线粒体失调。然后，我们将训练这些标志的表观遗传预测因子，并在体内验证它们。 我们还将建立对新颖和确定的寿命干预措施的表观遗传改变。做 因此，我们将开发出干预响应的生物标志物，可用于测试模仿和/或优化衰老 生物标志物。最后，建立在C57BL/6和UM-HET3动物的高度特征的大群落上，我们将 在整个寿命中产生纵向甲基化数据，可用于开发表观遗传时钟 可以用作健康范围的强大预测指标。我们假设这些新时钟将更好地捕获生物学 年龄大于年龄训练的时钟。鉴于它们是为了捕获相关的不同方面而开发的 随着衰老过程，它们可以组合起来，以创建一个单一的衰老度量，该度量更加生物学上 与现有的表观遗传钟相比。

项目成果

Rapamycin treatment during development extends life span and health span of male mice and Daphnia magna.

• DOI: 10.1126/sciadv.abo5482
• 发表时间: 2022-09-16
• 期刊: Science advances
• 影响因子: 13.6

Causality-enriched epigenetic age uncouples damage and adaptation.

因果关系丰富的表观遗传年龄将损伤和适应分开。

• DOI: 10.1038/s43587-023-00557-0
• 发表时间: 2024
• 期刊: Nature aging
• 作者: Ying,Kejun;Liu,Hanna;Tarkhov,AndreiE;Sadler,MarieC;Lu,AkeT;Moqri,Mahdi;Horvath,Steve;Kutalik,Zoltán;Shen,Xia;Gladyshev,VadimN
• 通讯作者: Gladyshev,VadimN

Intersection clock reveals a rejuvenation event during human embryogenesis.

• DOI: 10.1111/acel.13922
• 发表时间: 2023-10
• 期刊: Aging cell
• 影响因子: 7.8