Improvement of fertility in female mice by treatment with novel telomerase-increasing compounds

Pharmaceutical approaches to enhance female fertility are especially important for women who delay childbearing and experience age-related fertility decline. Previous studies have highlighted the potential role of telomerase in female reproductive health and fertility. Infertility in fourth-generation telomerase knockout mice, which have critically shortened telomeres, highlights the importance of both telomere length and telomerase in reproductive health. Increasing telomerase levels in the ovary shows promise for enhancing fertility by influencing folliculogenesis, oocyte maturation, and ovulation. AGS compounds, designed by us, transiently increase telomerase reverse transcriptase (TERT) expression and telomerase activity in vitro and in vivo. We therefore examined, for the first time, the effects of AGS compounds on female fertility. Young (3–5 months), older (12 months), and TERT-knockout (TERT-KO) female mice were treated with subcutaneous injections of AGS compounds. We then evaluated the effects on ovarian TERT levels, folliculogenesis, ovulation, blood hormone levels, number of embryos and offspring, fertility-related gene expression, and key signaling pathways. In both age groups, treatment with AGS increased TERT mRNA levels and telomerase activity in the mouse ovary, leading to faster oocyte maturation and ovulation, as well as higher expression of fertility-related genes. Treatment also elevated plasma levels of progesterone, estrogen, and gonadotropins. Consequently, the number of embryos and offspring increased, with all showing normal development and growth. However, in telomerase-knockout (TERT-KO) mice, AGS treatment did not affect ovarian stage or the expression of certain genes, indicating a TERT-dependent mechanism. Additionally, AGS exert their effects partially through TERT-dependent activation of the Wnt-β-catenin pathway. These findings demonstrate that transient telomerase activation in the ovary through pharmaceutical compounds may improve female fertility.