FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice.

Chi Zhang,Yanqing Li,Xiaoyan Liang,Jiahui Yao,Min Zhang,Xiangzhou Sun,Haicheng Chen,Chunhua Deng,Yun Xie,Linyan Lv,Guihua Liu,Kai Xia,Xin Feng

doi:10.18632/aging.102682

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.

Highlights

Male late-onset hypogonadism (LOH) is a clinical and biochemical syndrome associated with advancing age
The forkhead box O 4 (FOXO4)+ cells expressed the Leydig cell markers StAR and CYP11A1, as confirmed by triple immunofluorescent staining (Figure 1B). These results indicate that FOXO4 is expressed in Leydig cells within human testes
These results suggest that nuclear localization of FOXO4 may contribute to Leydig cell senescence and the downregulation of testosterone synthesis

Summary

Introduction

Male late-onset hypogonadism (LOH) is a clinical and biochemical syndrome associated with advancing age It is characterized by a deficiency in serum testosterone levels and symptoms such as low sexual desire, erectile dysfunction, muscle mass loss, obesity, osteoporosis, and depression [1,2,3]. The number of Leydig cells per testis remains unchanged, but these cells may exhibit a reduced capacity for testosterone synthesis, resulting in an age-related decline of serum testosterone levels [8, 9]. These dysfunctional senescent Leydig cells play a core role in the pathogenesis of LOH

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