Validation of Nuclear Morphology as a Biomarker of Aging and Aging-Related Phenotypes

摘要 细胞核中核蛋白层蛋白及其相关结构的变化 被确定为显著影响整体细胞的核形态变化的来源 功能。这些核形态的变化被认为是推动分子变化的原因 影响一系列与衰老相关的表型和慢性病状态。重要的是，我们 最近使用了高通量的核形态测量来确定突出的 年代顺序的生物标志物。我们假设这些与年龄相关的核变化 在健康个体中，形态与实际年龄高度相关，并且特定的 层粘连蛋白与年龄相关的生物学变化是这种现象的基础。建立在我们之前的基础上 这些高通量和精确的核形态测量的发展，我们建议 在此进一步发展这一生物发现和技术作为有效和可靠的生物标志物 与衰老相关的生物学机制。我们假设原子核形态的变化可以 快速测量，年龄相关的改变与衰老相关的表型和 疾病状态与实际年龄无关，与细胞生物学的衡量标准一致 年龄。为了测试这些假设并将结果推向临床应用，我们已经组装了一个高度 协同、跨学科团队提出了以下具体目标： 目标1.使用我们经过验证的单细胞技术，我们将发展一种机械性的理解 人皮肤成纤维细胞和B淋巴细胞的核形态指标是怎样的 健康个体衰老的强健生物标志物。目标2.建立准确度和精密度 我们建议的生物标记物用来识别患有不同疾病的人的年龄 人口统计、行为和健康特征。目标3.我们将用以下方法检验实力 哪些形态生物标记物可以区分具有不良表型和结局的个体 老龄化的风险，以及以上健康的老年人的风险 按时间顺序排列的年龄。

Abstract Alterations in the nuclear protein lamin and associated structures in the nucleus have been identified as a source of nuclear morphology changes that markedly impact overall cellular function. These changes in nuclear morphology are thought to drive molecular changes that influence a wide range of aging-related phenotypes and chronic disease states. Importantly, we have recently used high-throughput measurements of nuclear morphology to identify outstanding biomarkers of chronological age. We hypothesize that these age-related changes in nuclear morphology are highly correlated with chronological age in healthy individuals, and that a specific age-related biological change in lamin underlies this phenomenon. Building on our prior development of these high-throughput and accurate measures of nuclear morphology, we propose here to further develop this biological discovery and technology as a valid and reliable biomarker of aging-related biological mechanisms. We hypothesize that changes in nuclear morphology can be rapidly measured and that age-related alterations correlate with aging-related phenotypes and disease states independently of chronological age, consistent with a measure of cellular biological age. To test these hypotheses and move results toward clinical utility, we have assembled a highly synergistic, interdisciplinary team propose the following specific aims: Aim 1. Using our validated single-cell technologies, we will develop a mechanistic understanding of how descriptors of nuclear morphology in human dermal fibroblasts and B-lymphocytes are robust biomarkers of aging in healthy individuals. Aim 2. Establish the accuracy and precision with which our proposed biomarkers identify chronological age for individuals with varying demographic, behavioral, and health characteristics. Aim 3. We will examine the strength with which morphological biomarkers discriminate individuals with adverse phenotypes and outcomes of aging, and at risk for the development of these, from healthy older adults, above and beyond chronological age.