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

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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.