Abstract
The female reproductive system is one of the first to age in humans, resulting in infertility and endocrine disruptions. The aging ovary assumes a fibro-inflammatory milieu which negatively impacts gamete quantity and quality as well as ovulation. Here, we tested whether the systemic delivery of anti-inflammatory (Etanercept) or anti-fibrotic (Pirfenidone) drugs attenuates ovarian aging in mice. We first evaluated the ability of these drugs to decrease the expression of fibro-inflammatory genes in primary ovarian stromal cells treated with a pro-fibrotic or a pro-inflammatory stimulus. Whereas Etanercept did not block Tnf expression in ovarian stromal cells, Pirfenidone significantly reduced Col1a1 expression. We then tested Pirfenidone in vivo where the drug was delivered systemically via mini-osmotic pumps for 6 weeks. Pirfenidone mitigated the age-dependent increase in ovarian fibrosis without impacting overall health parameters. Ovarian function was improved in Pirfenidone-treated mice as evidenced by increased follicle and corpora lutea number, AMH levels, and improved estrous cyclicity. Transcriptomic analysis revealed that Pirfenidone treatment resulted in an upregulation of reproductive function-related genes at 8.5 months and a downregulation of inflammatory genes at 12 months of age. These findings demonstrate that reducing the fibroinflammatory ovarian microenvironment improves ovarian function, thereby supporting modulating the ovarian environment as a therapeutic avenue to extend reproductive longevity.
| Original language | English (US) |
|---|---|
| Journal | GeroScience |
| DOIs | |
| State | Accepted/In press - 2024 |
Funding
We would like to acknowledge all members of the Duncan laboratory for their support and insightful discussion regarding this work. We thank Karen Velez for her help monitoring the mice. We would like to thank Dr. Hernan E. Lara from the Universidad de Chile for his advice on implanting the osmotic pump. Surgical services were provided by Jiao-Jing Wang from the Northwestern University Comprehensive Transplant Center Microsurgery Core. The RNAseq analysis was supported by the Northwestern University NUSeq Core Facility. The microCT analysis was performed at the CAMI facility, and the multiplex assay was supported by the Comprehensive Metabolic Core at Northwestern University. The ovarian hormone analysis was performed by the Ligand Assay & Analysis Core at the Center for Research in Reproduction from the University of Virginia. Finally, we also thank Dr. John Varga for his critical comments on this work. Figures were done using BioRender. This work was supported by the Global Consortium for Reproductive Longevity and Equality postdoctoral grant 1720 (F.A), the K99/R00 pathway to independence award K99HD108424 (F.A), the pilot funds from the Northwestern University Center for Advanced Molecular Imaging (CAMI) (F.A, F.E.D), and Northwestern University Department of Obstetrics and Gynecology start-up funds (F.E.D). Additionally, the CAMI facility is supported by NCI CCSG P30 CA060553 award to the Robert H Lurie Comprehensive Cancer Center.
Keywords
- Fibrosis
- Healthspan
- Inflammation
- Ovarian function
- Reproductive aging
ASJC Scopus subject areas
- Aging
- veterinary (miscalleneous)
- Complementary and alternative medicine
- Geriatrics and Gerontology
- Cardiology and Cardiovascular Medicine