DHT ameliorates cardiac aging in progeroid mice by XRCC4-mediated genome stabilization.

Rui Jiang, Hao Wang, Weina Zhang, Jiaxi Li, Shiqi Huang, Lingjiang Chen, Yuhan Min, Zhaohui Ouyang, Ying Jiang, Zhiyong Mao, Guizhu Wu, Ke Wei, Yu Chen

Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. · pubmed

Paper

Abstract

Cardiovascular compromise is the primary cause of death in Hutchinson-Gilford Progeria Syndrome (HGPS), a lethal segmental premature aging disorder; however, no therapies directly target its underlying cardiac pathology. Our prior work established that non-homologous end joining (NHEJ)-the dominant pathway for double-strand break repair and genomic stabilization in cardiomyocytes-is impaired in HGPS mice, triggering cardiac atrophy via a CHK2-AMPKα-FOXO3A signaling axis. While forced cardiac hypertrophy can ameliorate pathology, whether restoring DNA repair capacity constitutes a viable therapeutic strategy remains unknown. Here, utilizing dihydrotestosterone (DHT), we demonstrate that NHEJ activation stabilizes the cardiomyocyte genome, increases cardiomyocyte size, and enhances contractile function. Furthermore, DHT administration reduces DNA damage accumulation and promotes structural and functional recovery in HGPS hearts. Transcriptome analysis further demonstrates that DHT treatment rejuvenates HGPS hearts, upregulates pathways linked to heart function and downregulates inflammatory responses, a key driver of cardiac aging and disease. Collectively, our findings support NHEJ activation as a promising therapeutic approach for mitigating HGPS-associated cardiac degeneration and ameliorating cardiac aging.

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Research summary

DHT treatment activates NHEJ, stabilizes the cardiomyocyte genome, and ameliorates cardiac aging in progeroid mice. The paper addresses a potential therapeutic strategy targeting the underlying mechanisms of cardiac aging, specifically through DNA repair pathways, which is directly relevant to longevity research.

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