Androgen signaling stabilizes genomes to counteract senescence by promoting XRCC4 transcription

Aging is accompanied by a decreased DNA repair capacity, which might contribute to age-associated functional decline in multiple tissues. Disruption in hormone signaling, associated with reproductive organ dysfunction, is an early event of age-related tissue degeneration, but whether it impacts DNA repair in nonreproductive organs remains elusive. Using skin fibroblasts derived from healthy donors with a broad age range, we show here that the downregulation of expression of XRCC4, a factor involved in nonhomologous end-joining (NHEJ) repair, which is the dominant pathway to repair somatic double-strand breaks, is mediated through transcriptional mechanisms. We show that the androgen receptor (AR), whose expression is also reduced during aging, directly binds to and enhances the activity of the XRCC4 promoter, facilitating XRCC4 transcription and thus stabilizing the genome. We also demonstrate that dihydrotestosterone (DHT), a powerful AR agonist, restores XRCC4 expression and stabilizes the genome in different models of cellular aging. Moreover, DHT treatment reverses senescence-associated phenotypes, opening a potential avenue to aging interventions in the future.

Automated summary

Aging is accompanied by decreased DNA repair capacity, which contributes to age-associated functional decline in multiple tissues. Hormone signaling disruption, associated with reproductive organ dysfunction, is an early event of tissue degeneration, but its impact on DNA repair in nonreproductive organs is unclear. This study shows that the downregulation of XRCC4 expression, involved in DNA repair, is mediated through transcriptional mechanisms. The androgen receptor directly binds to and enhances the activity of the XRCC4 promoter, stabilizing the genome. DHT treatment reverses senescence-associated phenotypes, providing a potential avenue for aging interventions.