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

Aging (Albany NY). 2020 Jan 20;12(2):1272-1284. doi: 10.18632/aging.102682. Epub 2020 Jan 20.


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.

Keywords: FOXO4-DRI; Leydig cell; male late-onset hypogonadism; senescence; senolytics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cellular Senescence* / genetics
  • DNA Copy Number Variations
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation
  • Leydig Cells / metabolism*
  • Male
  • Mice
  • Mitochondria / metabolism
  • Testis / metabolism
  • Testosterone / biosynthesis*


  • Biomarkers
  • Cell Cycle Proteins
  • Forkhead Transcription Factors
  • FoxO4 protein, mouse
  • Testosterone