Mechanisms of DNA helicase b in ovarian and systemic aging

The National Institute on Aging awarded The Trustees of Columbia University in the City of New York $227,652 on August 6, 2026, under the Aging Research program (CFDA 93.866) to investigate mechanisms of DNA helicase B in ovarian and systemic aging.

The research examines how reduced DNA helicase B (HELB) expression or function extends reproductive lifespan in women. The project integrates genome-wide association study analysis and functional genomic experiments to understand the relationship between HELB, DNA damage response, and ovarian aging. The work explores how HELB suppresses DNA double-strand break repair by homologous recombination during meiosis, which impacts both female gamete quantity and quality, and investigates how genetic variants affecting HELB expression associate with delayed age at natural menopause. The research aims to identify mechanistic pathways underlying ovarian aging that could inform interventions to extend female healthspan.

Work is performed at Columbia University's Health Sciences Division in New York, New York. The performance period runs through July 31, 2029.

Abstract

The ovary is unique in that IT is the first organ in the body to exhibit an age-related functional decline. Ovarian aging is characterized by decreased gamete quantity and quality, resulting in infertility and endocrine dysfunction. Moreover, ovarian aging has consequences on overall health because reproductive hormones have extra- ovarian targets including the cardiovascular, skeletal, and neurocognitive systems. Therefore, understanding the mechanisms underlying ovarian aging is an essential first step in the development of interventions to extend female healthspan. There is a strong relationship between genetic factors and ovarian aging. Thus, human genetics can provide mechanistic insight into the biological processes dictating reproductive lifespan. Genome wide association studies (gwas) have uncovered hundreds of common variants associated with age at natural menopause (ANM), which serves as a proxy for the rate of ovarian aging. These ANM-associated variants are enriched in genetic loci associated with DNA damage response, including the DNA helicase b (helb) gene. Through integrative post-gwas analysis and functional genomic follow-up experiments, our lab identified a causal regulatory variant that decreases helb expression, which is associated with delayed ANM. Together with data from whole exome sequencing studies which have identified rare deleterious helb coding variants in women with extremely delayed ANM, this suggests that reduced helb expression or function extends reproductive lifespan. Helb is a conserved 5'-3' helicase that suppresses DNA double-strand break repair by homologous recombination. Homologous recombination during meiosis impacts both female gamete quantity and quality. Genetic models that impair meiotic recombination result in increased oocyte attrition during the formation of the primordial follicle pool in fetal development. The primordial follicle pool is non-renewable and is gradually depleted each cycle, thus serving as a determinant for female reproductive lifespan. Moreover, meiotic recombination forms physical linkages between homologous chromosomes, called chiasmata, which are required for accurate chromosome segregation. With advance age, oocytes exhibit an increase in chromosome segregation errors and a decrease in chiasmata frequency. Therefore, our overarching hypothesis is that helb deficiency delays ovarian aging by enhancing meiotic recombination, in turn improving post-reproductive health. We will test this hypothesis by evaluating meiotic recombination, age-associated oocyte competence, ovarian aging, and systemic aging using a recently generated global helb knockout mouse model. These studies will uncover mechanisms by which modulation of homologous recombination promotes ovarian longevity and may inform therapeutic strategies to extend reproductive function and systemic health in aging women. This project along with rich intellectual infrastructure of columbia university, my interdisciplinary mentoring team, and strong training plan will provide me with the support and skill sets needed to develop into an independent investigator.