Reduced serum testosterone (T), or hypogonadism, is estimated to affect about 5 million American men and to be associated with reductions in lean body mass, bone mineral density, muscle mass and libido. In studies supported by the Merit Award that this revised R01 application seeks to renew, we found that decline in serum T levels in aging Brown Norway rats, as in many aging men, results largely from the reduced ability of Leydig cells to produce testosterone in response to luteinizing hormone (LH). In Brown Norway rats, reduced T is associated with reductions in Leydig cell production of cAMP, cholesterol transport from intracellular sources into the mitochondria (the rate-determining step in T formation), steroidogenic acute regulatory protein (STAR), translocator protein (18-kDa; TSPO), and downstream steroidogenic enzymes. Decreases in the antioxidant molecules superoxide dismutase-1 and -2, glutathione peroxidase and glutathione (GSH), and increases in superoxide production, also are seen. We hypothesize that, over time, changes in the Leydig cell oxidant/anti-oxidant environment cause altered LH signal transduction, reduced cholesterol transport into the mitochondria, and ultimately decreased T production. We further hypothesize that maintaining a ?young? redox environment in aged Leydig cells, using biological and/or pharmacological means, will block such changes in steroidogenesis. To address these hypotheses, we will determine the intracellular deficits and molecular mechanisms that cause age-related reductions in T formation, focusing on the molecular consequences of imbalance in the intracellular redox environment that result from steroidogenesis itself or from pharmacologic or genetic manipulation. We will determine whether age-related reductions in Leydig cell T production can be delayed, prevented or reversed. We will compare the changes in Leydig cells of aging rodents to those of aging men by analysis of testicular biopsies, and through the use of testis xenografts. Finally, we will test the hypothesis that Leydig cell T production can be restored to higher (?young?) levels by pharmacological means that by-pass LH signal transduction. The potential impact of this latter approach to T elevation could be paradigm shifting for the clinical treatment of primary hypogonadism in aging (and young) men.

Public Health Relevance

Reduced serum testosterone occurs commonly in aging men, and often is associated with altered mood, fatigue, and decreased lean body mass, bone mineral density and libido. The overarching hypothesis of this proposal is that changes in the balance between reactive oxygen accumulation and the antioxidant defense system cause reduced cAMP production by aged cells, and that this leads to reduced cholesterol transport into the mitochondria and ultimately to reduced testosterone production. We will compare the changes and mechanisms in Leydig cells of aging rodents to those in aging men with the ultimate goal to develop therapeutic approaches to delay, prevent or reverse age-related androgen deficiency.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG021092-17
Application #
9701082
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Fuldner, Rebecca A
Project Start
2002-09-01
Project End
2021-04-30
Budget Start
2019-06-01
Budget End
2021-04-30
Support Year
17
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Zirkin, Barry R; Papadopoulos, Vassilios (2018) Leydig cells: formation, function, and regulation. Biol Reprod 99:101-111
Musicki, B; Karakus, S; Akakpo, W et al. (2018) Testosterone replacement in transgenic sickle cell mice controls priapic activity and upregulates PDE5 expression and eNOS activity in the penis. Andrology 6:184-191
Papadopoulos, V; Fan, J; Zirkin, B (2018) Translocator protein (18 kDa): an update on its function in steroidogenesis. J Neuroendocrinol 30:
Nanjappa, M K; Medrano, T I; Prins, G S et al. (2017) Transdifferentiation of adult rat stem Leydig cells into prostatic and uterine epithelium, but not epidermis. Andrology 5:1165-1173
Chen, Haolin; Wang, Yiyan; Ge, Renshan et al. (2017) Leydig cell stem cells: Identification, proliferation and differentiation. Mol Cell Endocrinol 445:65-73
Wang, Yiyan; Chen, Fenfen; Ye, Leping et al. (2017) Steroidogenesis in Leydig cells: effects of aging and environmental factors. Reproduction 154:R111-R122
Chen, Haolin; Jin, Shiying; Huang, Shengsong et al. (2016) Transplantation of alginate-encapsulated seminiferous tubules and interstitial tissue into adult rats: Leydig stem cell differentiation in vivo? Mol Cell Endocrinol 436:250-8
Aghazadeh, Yasaman; Zirkin, Barry R; Papadopoulos, Vassilios (2015) Pharmacological regulation of the cholesterol transport machinery in steroidogenic cells of the testis. Vitam Horm 98:189-227
Salehi, Sajad; Adeshina, Ikeoluwa; Chen, Haolin et al. (2015) Developmental and endocrine regulation of kisspeptin expression in mouse Leydig cells. Endocrinology 156:1514-22
Chen, Haolin; Jin, Shiying; Guo, Jingjing et al. (2015) Knockout of the transcription factor Nrf2: Effects on testosterone production by aging mouse Leydig cells. Mol Cell Endocrinol 409:113-20

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