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

摘要 核蛋白核纤层蛋白和细胞核中相关结构的改变已经被发现。 被鉴定为核形态变化的来源，其显著影响整体细胞 功能核形态的这些变化被认为会驱动分子变化， 影响广泛的衰老相关表型和慢性疾病状态。重要的是我们 最近使用核形态的高通量测量来识别突出的 生理年龄的生物标志物。我们假设这些与年龄相关的核变化 形态学与健康个体的实足年龄高度相关， 核纤层蛋白中与年龄相关的生物学变化是这种现象的基础。根据我们之前 发展这些高通量和准确的测量核形态，我们建议 在这里进一步发展这一生物学发现和技术，作为有效和可靠的生物标志物 与衰老有关的生物学机制。我们假设细胞核形态的变化可以 可以快速测量，年龄相关的变化与衰老相关的表型相关， 疾病状态独立于实际年龄，与细胞生物学指标一致， 年龄为了验证这些假设并将结果推向临床应用，我们组装了一个高度 协同、跨学科小组提出以下具体目标： 目标1。使用我们经过验证的单细胞技术，我们将开发一个机械的理解 人类皮肤成纤维细胞和B淋巴细胞的核形态描述符是如何 健康个体衰老的生物标志物。目标2.确定准确度和精密度 我们提出的生物标志物可以识别具有不同年龄的个体的实际年龄， 人口、行为和健康特征。目标3：我们将检查强度， 哪些形态学生物标志物区分具有不良表型和结果的个体 从健康的老年人身上， 实际年龄

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.