Research

The proposed research addresses the molecular origins of female reproductive aging, which impacts fertility, endocrine function, and overall health. We will test the hypothesis that ovarian aging is fueled by damaged DNA inthe oocyte which stimulates an inflammatory response in the surrounding somatic follicular cells that is further amplified by spatial cues within the broader microenvironment. This project provides a novel paradigm for female reproductive aging, a major reproductive transition, and thus aligns with NICHD priorities. This is a joint project between Dr. Francesca Duncan (contact PI) and Dr. Jennifer Gerton (co-PI) (R01HD105752).

Aging in women is associated with diminished ovarian responses to follicle-stimulating hormone (FSH) as well as the oocyte quality. Our studies using novel genetic models expressing different age-specific FSH glycoforms will not only provide mechanistic insights but unequivocally test the role of FSH-mediated signaling pathways in vivo in the ovary which produces estrogen and eggs. Thus, our studies may lead to developing novel FSH-based therapies to preserve and enhance ovarian function in women. This is a joint project between Dr. T. Rajendra Kumar (PI) and Dr. Francesca Duncan (co-I) (R01HD103384).

The female reproductive system ages decades prior to other organs and results in infertility, miscarriages, and birth defects - with such adverse consequences of particular concern as women worldwide are delaying childbearing. We recently identified fibrosis and inflammation as a hallmark of the aging ovarian microenvironment in which eggs grow and develop, and in this project we seek to investigate the underlying mechanism to ultimately counteract this phenomenon and improve reproductive longevity and outcomes. We will test the hypothesis that age-associated loss and fragmentation of a key extracellular matrix molecule (hyaluronan) in the mammalian ovary converts the microenvironment into a reactive matrix that drives fibrosis and inflammation. This is a joint project with Dr. Michele Pritchard and Dr. Mary Ellen Pavone (R01HD093726).

In women, reduced fertility, increased risk of aneuploidy and miscarriage rise dramatically starting in the early thirties. Mechanisms that drive reproductive aging are poorly understood, and because women in the U.S. are delaying childbearing until older ages, there is an urgent need to develop innovative approaches and animal models to address this growing problem. In this project, we will develop the naked mole-rat, the longest-living rodent, which does not display reproductive aging, as a model to study factors that determine reproductive longevity. This project is a collaboration between Drs. Ned Place (PI), Francesca E. Duncan (Co-I), Vera Gorbunova (Co-I), and Melissa Homes (Co-I) (NSF Award: 2005919)

Ovarian cancer is the fifth leading cause of cancer deaths in the US and disproportionately affects Non-Hispanic Black (NHB) women. Even among patients with equal access to care, the all-cause mortality rate of NHB ovarian cancer patients is 1.3 times higher than non-Hispanic White (NHW) counterparts. This project will provide unprecedented insight into whether differences exist in the aging of the ovarian ECM between NHB and NHW women and how differential ovarian aging may promote increased ovarian cancer pathogenesis. Funding source: H Foundation Core Usage Pilot Project Award.

Cellular senescence is a multi-faceted cell fate that arrests cell proliferation and activates the synthesis and secretion of numerous cytokines, chemokines, growth factors, proteases and lipids, termed the Senescence Associated Secretory Phenotype (SASP). The SASP can influence tissue microenvironments, locally and distally, and thus senescent cells can strongly affect tissue function. Senescent cells (SnCs) increase with age in most vertebrate organisms, including mice and humans, and it is increasingly clear through both genetic and pharmacological manipulations that they can drive a growing list of age-related pathologies, ranging from neurodegeneration to cancer. At present, there are no invariant biomarkers of SnCs and the molecular characteristics of SnCs are remarkably heterogeneous and variable, depending on cell and tissue type, microenvironment, senescence inducer, and timing. Our overall goal is to determine, molecularly and spatially, when and where senescent cells occur in humans, and also how their patterns of gene expression and SASPs vary with tissue physiology and age in three human tissues: ovary, breast and skeletal muscle and three biofluids: follicular fluid, plasma and urine. This work is part of the Common Fund’s Cellular Senescence Network (SenNet) and is a collaboration with Dr. Judy Campisi (PD/PI), Dr. Birgit Schilling (PD/PI), Dr. Chris Benz (Biospecimen Core co-PI) and Dr. Mary Ellen Pavone (subcontract co-I) (U54AG075932).

Cellular senescence is a multi-faceted cell fate that arrests cell proliferation, essentially irreversibly, and activates the production and secretion of pro-inflammatory cytokines, chemokines, growth factors, proteases and lipids, termed the Senescence Associated Secretory Phenotype (SASP). The SASP can influence tissue microenvironments, and thus senescent cells can strongly affect tissue function and likely the systemic milieu. Senescent cells increase with age and can drive a growing list of age-related pathologies, ranging from neurodegeneration to cancer, in part through the SASP. There is increasing evidence that there are no universal markers for senescent cells. Instead, senescent cells, while sharing certain characteristics and biomarkers, are remarkably heterogeneous, varying in characteristics with genotype, cell and tissue type, senescence inducer, tissue (and cell culture) microenvironment, and chronology (time after initial senescence induction). While some of the more commonly employed senescence markers have utility in superficially identifying senescent cells de novo, the onus remains on the investigator to demonstrate why a cell should be considered senescent, rather than relying on historical markers such as p16INK4a or p21Cip1. Thus, new technologies designed to identify novel senescent cells and phenotypes are necessary that will require validation both in culture and in tissue. The ultimate goal of this proposal is to develop new technologies to map senescent signatures back to intact human tissue.  Specifically, we will develop a microphysiologic ex vivo tissue-on-a-chip to model ovarian senescence and human tissue-tissue interactions via the SASP. This project is part of the Common Fund’s Cellular Senescence Network (SenNet) and is a collaboration with Dr. Simon Melov (MPI) and Dr. Mary Ellen Pavone (subcontract co-I) (UH3CA268105). 

The major goals of the research team at Northwestern University are to propose to test the hypothesis that lifelong PAI-1 deficiency provides multifaceted protection against aging-related multimorbidity and is sufficient to promote healthy longevity in mice and in man. This project is led by Dr. Douglas Vaughan (PI) and Dr. Francesca Duncan serves as a co-I (1R56AG077278).

The goal of this work is to use a mouse model to test the efficacy and safety of using novel biological platforms to cryopreserve and recover small numbers of mammalian sperm to restore fertility. This work is funded by a Daniel Manela Research Grant through the Pediatric Oncofertility Research Foundation.

This project aims to bring further understanding to the biological mechanisms impaired in pre-pubertal oocytes. Using our developed mouse model, we are investigating the specific genetic pathways that are dysregulated in pre-pubertal oocyte and determining if this can be improved via hormonal treatments. We will are also examining whether the phenomena uncovered in mouse oocytes may be conserved in human oocytes.  This is a joint project between Dr. Michael Klutstein (PI) at the Hebrew University of Jerusalem and Dr. Francesca Duncan (co-I) (Project 2021180).

Aging occurs universally and is characterized by a general deterioration of cellular and tissue function.  However, the female reproductive system is unique in that it ages decades prior to other organ systems in the body.  Fertility begins to decline in women in their mid-30s and reproductive function ceases completely at the time of menopause around age 50. In the ovary, reproductive aging is characterized by a loss of follicles which produce eggs along with a decrease in the quality of those that remain.  This reproductive aging has clinical ramifications because decreased egg quality can lead to miscarriages, birth defects, and infertility, and this is increasingly relevant as women globally are delaying childbearing.  In addition, ovarian follicles produce the hormone estrogen as they grow and develop, and estrogen is important for heart, bone, immune, brain, and sexual health.  Therefore, the decline in follicles and, thereby, estrogen that occurs in women with advanced reproductive age has general adverse health consequences. Female reproductive aging is important beyond fertility in the consideration of overall healthspan especially as women are living longer post menopause due to medical interventions that are extending average lifespan. Thus, there is an urgent need to better understand the mechanisms that underlie ovarian aging.  Our lab made the critical discovery that the ovarian environment in which eggs develop, which is known as the stroma, undergoes prominent age-related changes.  In particular, the aging ovarian environment becomes inflamed and fibrotic due to the accumulation of fibrous tissue, similar to what occurs with scarring. Fibrosis changes the properties of the aging ovary such that it is physically stiffer or tougher compared to ovaries from young individuals. Increased stiffness can negatively impact ovarian function, compromising the ability of follicles to grow, develop, produce hormones, and even undergo ovulation. Thus, rejuvenating the ovary through therapies that reverse or prevent tissue stiffness, such as use of anti-fibrotic drugs, hold tremendous promise for extending reproductive longevity and improving healthspan for women.  The goal of this application is to use shear wave elastography, a cost effective and non-invasive method that can be combined with routine gynecological ultrasound, to measure, monitor, and track human ovarian stiffness and determine its relationship to age.  This technology will ultimately enable the broad use of ovarian stiffness as a novel clinical biomarker of reproductive longevity and will lay the foundation for translating our research into clinical trials to test therapeutic interventions that target ovarian stiffness. This work is funded by the Global Consortium for Reproductive Longevity and Equality and is a collaboration with Dr. Elnur Babayev (Co-Investigator).

In this project, we are validating whether a conserved inflammatory cytokine profile increases with age in human cumulus cells and whether it directly correlates with embryo outcomes in ART procedures. If successful, these studies will define a non-invasive reproductive aging signature that could provide a clinically relevant non-invasive readout of embryo potential. Such knowledge will thus have the dual benefit of improving reproductive health and offspring outcomes in women of advanced reproductive age. This work is a joint project with Dr. Mary Ellen Pavone and is funded through a Friends of Prentice grant through the Northwestern Memorial Foundation.

Aging is associated with cellular and tissue deterioration and is a prime risk factor for chronic diseases and declining health, with the female reproductive system being the first to show overt manifestations of aging (i.e. decreased fertility, miscarriages, and birth defects). A key hallmark of aging in many tissues is loss of protein homeostasis or quality control mechanisms that protect the cellular proteome. In this project, we will open new avenues of discovery through the use of state-of-the-art mass spectrometry and imaging approaches to identify, visualize, and quantify a unique population of extremely long lived proteins in the oocyte and ovary that persist through the entire reproductive lifespan and likely fuel reproductive aging through accumulated damage. This is a collaboration with Dr. Jeffrey Savas (R21HD098498).

The average age of menopause remains constant despite drastic increases in global life expectancy; consequently, women are living longer in the post-menopausal state with increases in cardiovascular disease, osteoporosis, depression, and sexual dysfunction. In parallel, the average age of a woman's first birth continues to rise, resulting in a shortened reproductive window and impaired fertility. A major aging pathway (mTOR) may be a key link between reproductive and total lifespan as mTOR activity increases with age in multiple organs, and mTOR inhibitors promote longevity in animals. This research will interrogate the impact of mTOR inhibitors on reproductive lifespan and offspring health in mice, as well investigate the relationship between advancing age and mTOR in human ovaries. Dr. Kara N. Goldman (PI) and Dr. Francesca E. Duncan (Co-I) are seeking to gain a clearer understanding of the role of this critical aging pathway in reproductive aging, thereby providing important therapeutic value that may lead to the development of useful clinical markers for aging and health. This work is funded through a Friends of Prentice grant through the Northwestern Memorial Foundation.