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Knockout of the transcription factor Nrf2: Effects on testosterone production by aging mouse Leydig cells
Haolin Chen1, Shiying Jin2, Jingjing Guo3
1Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205; The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Abstract:
Aging in rodents and men is associated with reduced serum levels of testosterone and Leydig cell testosterone productions. To further investigate the mechanism by which Leydig cell testosterone production declines, the effect of knocking out Nrf2, a master regulator of phase 2 antioxidant genes, was examined. In wild-type mice, testosterone production and serum testosterone levels remained unchanged through middle age (8 months), but then were reduced significantly by old age (21-24 months). In contrast, serum testosterone levels and Leydig cell testosterone production were reduced significantly in the Nrf2-/- mice as early as middle age, and were reduced further in the aged mice. Reduced steroidogenesis in the knockout mice was associated with reduced antioxidant capacity, and increased expression of protein nitrotyrosine residues, a marker of ROS. These results support the hypothesis that, over time, increases in oxidative stress contribute to or cause the reduced testosterone production that characterizes Leydig cell aging.
Insights
Aging reduces testosterone production, with Nrf2 knockout mice showing earlier declines due to increased oxidative stress. This study highlights the role of oxidative stress in Leydig cell aging and declining testosterone levels.
Area of Science:
- Endocrinology
- Aging Research
- Molecular Biology
Background:
- Testosterone levels and Leydig cell production decline with age in rodents and humans.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of antioxidant responses.
Purpose of the Study:
- To investigate the role of Nrf2 in age-related decline of testosterone production.
- To determine if Nrf2 deficiency exacerbates age-associated reductions in Leydig cell function.
Main Methods:
- Comparison of testosterone levels and Leydig cell production in wild-type and Nrf2 knockout mice at different ages.
- Assessment of oxidative stress markers, including protein nitrotyrosine and antioxidant capacity.
Main Results:
- Wild-type mice showed reduced testosterone production in old age (21-24 months).
- Nrf2 knockout mice exhibited significantly reduced testosterone levels and Leydig cell production by middle age (8 months), worsening with age.
- Nrf2 deficiency was linked to decreased antioxidant capacity and increased oxidative stress markers.
Conclusions:
- Oxidative stress contributes to the age-related decline in Leydig cell testosterone production.
- Nrf2 plays a protective role against age-related oxidative stress in Leydig cells.
