FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged
Chi Zhang1,2, Yun Xie1,3, Haicheng Chen1
1Department of Andrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China.
Abstract:
Male late-onset hypogonadism is an age-related disease, the core mechanism of which is dysfunction of senescent Leydig cells. Recent studies have shown that elimination of senescent cells can restore proper homeostasis to aging tissue. In the present study, we found that the fork head box O (FOXO) transcription factor FOXO4 was specially expressed in human Leydig cells and that its translocation to the nucleus in the elderly was related to decreased testosterone synthesis. Using hydrogen peroxide-induced senescent TM3 Leydig cells as an in vitro model, we observed that FOXO4 maintains the viability of senescent Leydig cells and suppresses their apoptosis. By disrupting the FOXO4-p53 interaction, FOXO4-DRI, a specific FOXO4 blocker, selectively induced p53 nuclear exclusion and apoptosis in senescent Leydig cells. In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency. These findings reveal the therapeutic potential of FOXO4-DRI for the treatment of male late-onset hypogonadism.
Insights
Targeting FOXO4 with FOXO4-DRI eliminates senescent Leydig cells, improving testosterone production in aging males. This offers a potential treatment for late-onset hypogonadism.
Area of Science:
- Endocrinology
- Cell Biology
- Gerontology
Background:
- Male late-onset hypogonadism is linked to aging Leydig cell dysfunction.
- Senescent cell clearance can restore tissue homeostasis in aging.
- FOXO4 is expressed in Leydig cells and its nuclear translocation correlates with reduced testosterone in elderly males.
Purpose of the Study:
- To investigate the role of FOXO4 in senescent Leydig cells.
- To evaluate the therapeutic potential of FOXO4 inhibition for male late-onset hypogonadism.
Main Methods:
- Utilized hydrogen peroxide-induced senescent TM3 Leydig cells as an in vitro model.
- Employed FOXO4-DRI, a specific FOXO4 blocker, to disrupt the FOXO4-p53 interaction.
- Administered FOXO4-DRI to naturally aged mice.
Main Results:
- FOXO4 inhibition (FOXO4-DRI) induced apoptosis in senescent Leydig cells by promoting p53 nuclear exclusion.
- FOXO4-DRI treatment improved the testicular microenvironment in aged mice.
- FOXO4-DRI alleviated age-related testosterone secretion insufficiency in aged mice.
Conclusions:
- FOXO4 plays a role in maintaining senescent Leydig cell viability.
- FOXO4-DRI selectively eliminates senescent Leydig cells and restores testosterone levels.
- FOXO4-DRI demonstrates therapeutic potential for treating male late-onset hypogonadism.
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