San Diego Nathan Shock Center

项目总结--总体 由于老龄化是大多数人类疾病和个体整体功能衰退的最大风险因素， 人们对了解其生物学基础非常感兴趣，最终目标是增加 人的健康和生产年限(即健康跨度)。衰老和衰老的保守机制 长寿是通过对衰老的基本生物学进行研究而确定的。这些研究包括模型中的研究 生物体也表明衰老是柔韧的，这为促进健康的干预措施打开了大门。 然而，阻碍我们理解衰老和干预能力的一个主要复杂因素是 过程的内在异质性和诱致性异质性。不同的细胞类型具有本质上不同的老化 模式，甚至相同的细胞类型的衰老速度不同取决于生理环境或 暴露在环境中。这些和其他细胞异质性(例如，改变的表观遗传状态和基因 表达)可导致组织功能障碍和年龄相关的病理，最终影响健康寿命和 寿命。要在实验上解开这种复杂性，需要应用强大的单细胞和成像技术 迎头解决细胞老化异质性的方法，以及计算和数学 建模方法，以阐明涉及已知特征的衰老网络和途径相互作用 衰老。衰老研究中的另一个主要差距是需要新的和更好的人类细胞和组织模型来 允许与人类衰老直接相关的基础研究。因此，拟议的SAN的首要前提是 迭戈·内森休克中心(SD-NSC)是为了创建必要的基础设施，以促进和促进 系统研究衰老过程中的细胞异质性并为基础人类提供新的细胞和组织模型 老龄化研究。SD-NSC将建立尖端研究资源核心，专注于：1)新人 衰老的细胞和器官模型，包括来自一个独特的人类衰老队列，该队列被注释为物理 和生物年龄的功能测量，2)单细胞和高分辨率-组学和成像技术， 3)老化网络的计算模型。SD-NSC研究资源核心将提供 向国家科学委员会网络和老龄化研究界提供科学服务，并传播样本、数据集 协议和计算工具。这些资源将得到一个研究开发核心的补充 和中心外展活动，将提供：1)试点赠款和定制的指导计划，以 鼓励和支持早期和成熟的研究人员进入老龄化研究，2)创新- 在先进方法和技术方面进行人员和虚拟培训，以解决细胞异质性问题，以及3) 通过新的方案编制发挥智力领导作用，以鼓励合作和传播 与衰老的基本生物学相关的知识。SD-NSC将汇集互补的专业知识和 资源来自三个著名的圣地亚哥研究机构，他们的共同目标是了解 细胞异质性在衰老中的作用，最终使干预措施能够延长人类的健康寿命。

PROJECT SUMMARY – Overall Since aging is the biggest risk factor of most human diseases and the overall functional decline in individuals, there is great interest in understanding its biological underpinnings, with the ultimate goal of increasing the number of healthy and productive years of human life (i.e., healthspan). Conserved mechanisms of aging and longevity have been identified via investigations into the basic biology of aging. These include studies in model organisms that have also shown that aging is pliable, opening the door for healthspan-promoting interventions. However, a major complicating factor that impedes our understanding of aging and our ability to intervene is the intrinsic and induced heterogeneity of the process. Distinct cell types have intrinsically different aging modalities, and even identical cell types age at different rates depending on physiological context or environmental exposures. These and other cellular heterogeneities (e.g., altered epigenetic states and gene expression) can drive tissue dysfunction and age-related pathology that ultimately impact healthspan and lifespan. Unravelling this complexity experimentally requires application of robust single-cell and imaging approaches to address the heterogeneity of cellular aging head-on, as well as computational and mathematical modelling approaches to illuminate aging networks and pathway interactions that involve known hallmarks of aging. Another major gap in aging research is the need for new and better human cell and tissue models to allow basic research directly relevant to human aging. Thus, the overarching premise of the proposed San Diego Nathan Shock Center (SD-NSC) is to create the requisite infrastructure to facilitate and promote the systematic study of cellular heterogeneity in aging and to provide novel cell and tissue models for basic human aging studies. The SD-NSC will establish cutting-edge Research Resource Cores focused on: 1) novel human cell and organoid models of aging, including from a unique human aging cohort that is annotated for physical and functional measures of biological age, 2) single-cell and high resolution -omics and imaging techniques, and 3) computational modelling of aging networks. The SD-NSC Research Resource Cores will provide scientific services to the NSC Network and the aging research community, and disseminate samples, datasets protocols, and computational tools. These resources will be complemented by a Research Development Core and Center outreach activities that will provide: 1) pilot grants and customized mentoring programs to encourage and support early-stage and established investigators new to aging research, 2) innovative in- person and virtual training in advanced methods and technologies to address cellular heterogeneity, and 3) intellectual leadership through novel programming to encourage collaboration and the dissemination of knowledge related to the basic biology of aging. The SD-NSC will bring together complementary expertise and resources from three renowned San Diego research Institutions with the common goal of understanding the role of cellular heterogeneity in aging to ultimately enable interventions to extend human healthspan.