Ovarian aging through the novel lens of the 3D lymphatic network

The National Institute of Child Health and Human Development awarded the Buck Institute for Research on Aging $194,000 on September 1, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to investigate ovarian aging through the three-dimensional lymphatic network.

The research examines how the lymphatic vasculature contributes to ovarian function across adulthood and aging, with focus on three-dimensional lymphatic structure and function and interactions between lymphatic vasculature and ovarian follicles. The project addresses a critical gap in understanding the ovarian microenvironment's evolution with age—specifically, how a dysfunctional lymphatic system contributes to the inflammatory signature observed in aged ovaries and subsequent reproductive decline.

Work is performed in Novato, California. The period of performance runs from September 1, 2026, through August 31, 2028.

Abstract

Reduced reproductive capacity with aging predominantly affects women, as the female reproductive system ages first, losing function decades before other organs. Beyond infertility, the cessation of ovarian function and the resulting decline in gonadal hormones negatively impact various organs, including the heart, bones, and brain, ultimately diminishing the quality of life in women. Therefore, uncovering the mechanisms underlying female reproductive aging is crucial. Our long-term objective is to elucidate the factors driving ovarian aging within the broader ovarian microenvironment, ultimately improving reproductive lifespan. Thus, our application closely aligns with the mission of eunice kennedy shriver national institute of child health and human development. Despite extensive research on age-related changes in oocytes, the evolution of their surrounding microenvironment with aging remains poorly understood, a critical GAP given the constant communication between oocytes and their environment. Pioneering studies in the field have revealed that aged ovaries exhibit an inflammatory signature, which is broadly linked to a dysfunctional lymphatic system in most organs. The lymphatic vasculature drains interstitial fluid, regulates immune cell trafficking, and maintains tissue homeostasis. Over the past decades, a series of landmark discoveries has significantly advanced our understanding of the lymphatic system, contributing to new knowledge in medicine. Despite these advances, the ovarian lymphatic vasculature remains underexplored, especially in the context of aging. The objective of this proposal is to define how the lymphatic network contributes to ovarian function across adulthood and aging by examining three- dimensional (3D) lymphatic structure and function, as well as the interactions between lymphatic vasculature and ovarian follicles in the ovary. Our central hypothesis is that altered lymphatic network density and function in aged ovaries contribute to a reduced drainage by lymphatic vessels, thereby contributing to the aging phenotype of the ovary. To address our hypothesis, we will first establish a comprehensive 3D map of the lymphatic network in the ovary throughout the reproductive cycle and aging (aim 1). These studies will be performed using state-of-art imaging and analysis tools to generate a valuable resource, a detailed 3D map of lymphatic vessels and their relationship with ovarian follicles. We will then investigate the lymphatic system function in young and aged ovaries (aim 2). To achieve this goal, we will assess the structural organization of lymphatic vessels as a key indicator of their functionality and develop a unique assay to monitor the transport capacity of lymphatic vessels in young and aged ovaries and using live imaging to assess their lymphatic function. These findings will illuminate ovarian lymphatic vessel function, advancing therapies to enhance reproductive potential and healthspan.