Association of LOY with Other Forms of Genome Instability

Summary/Abstract Loss of the Y chromosome (LOY) in hematopoietic cells is a prevalent age-related phenomenon with significant health implications, including increased risks of cancer, neurodegeneration, cardiovascular diseases, and overall mortality. While recent genomic studies have linked LOY to disease risk, the mechanistic connections, particularly in the context of aging, remain unclear. Emerging evidence from cancer research suggests that LOY may contribute to genomic instability, potentially due to defects in DNA repair mechanisms and cell cycle regulation in Y-chromosome-lacking tumor cells. This area of research in aging is relatively unexplored and warrants further investigation. Leveraging the unique aging biobank at the Albert Einstein College of Medicine, where we have determined LOY status, this study aims to rigorously examine the causal relationship between LOY and genomic instability using cutting-edge genomic and molecular techniques. We hypothesize that LOY is associated with increased genome instability, possibly through elevated somatic mutation rates, chromosomal aberrations, or shared genetic determinants. Our study comprises two aims: Aim 1 will assess whether aging men with high LOY exhibit a higher burden of other types of mutations. Using the Einstein Longevity Cohort, we will apply advanced methodologies, including single-molecule and single-cell studies, to evaluate genomic instability in 40 individuals with varying LOY status. In aim 2 we will induce LOY and study its effect on genome stability using induced pluripotent stem cells (hiPSCs) differentiated into T cells. By elucidating the mechanistic basis of the correlation between LOY and genomic instability, this project may offer insights relevant to similar phenomena in women, such as the genetic determinants of aneuploidy or LOX, which have also been reported in aging women. This understanding could facilitate the exploration of molecular pathways, identification of biomarkers, and development of targeted interventions. Ultimately, this novel research may lead to personalized medical approaches and improved health outcomes, particularly in the context of healthy aging.