Numerous cross-sectional and longitudinal studies have established that circulating levels of testosterone decline with age in men, and this decline has been associated with parallel age-related metabolic and pathophysiological changes such as increased fat mass, cardiovascular risk, and incidence of frailty, depression, osteopenia, osteoporosis, insulin resistance and type 2 diabetes and decreased muscle/bone mass, and sexual function. Likewise, aging of the human ovary also results in a gradual decline in ovarian steroid production, followed by an abrupt and complete cessation of both progesterone and estrogen production at the onset of menopause. Similarly, human aging is accompanied by a dramatic decline in adrenal androgens (DHEA, DHEAS) and alterations in cortisol and aldosterone production and secretion. Similar to humans, aging in experimental rodents is also associated with profound changes in the synthesis and secretion of steroid hormones, particularly testosterone. Moreover, most of the age-induced alterations in the testicular (testosterone) and adrenal steroid responses in experimental rodents are reflective of the response in humans. Although the various cellular and molecular mechanisms controlling this aging defect in rodents have not been unequivocally identified, recent studies mainly from this laboratory have established a causal link between increased ROS formation/excessive oxidative stress and oxidative damage (especially from life-long continued processing of cholesterol for steroid production) to the cellular machinery involved in cholesterol transport to mitochondria, resulting in attenuated cholesterol transport with consequent impairment of steroidogenesis during aging. The cytosolic Sod1peroxiredoxins (Prdx) and mitochondrial Sod2 peroxiredoxins are the most potent anti-oxidant defense systems in steroid producing cells. Our preliminary data demonstrate that the functional expression of both cytosolic and mitochondrial Sod-Prdx antioxidant axes is coordinately and robustly downregulated most likely via excessive oxidative damage during aging. Using the above information, we propose the following 3 specific aims to investigate our hypothesis that increased ROS formation/excessive oxidative stress and ensuing oxidative damage to cytosolic and mitochondrial Sod-Prdx antioxidant axes, leads to downregulation of functional expression of crucial proteins involved in cholesterol transport to (SNAREs) and within the mitochondria (StAR) for side- chain cleavage (Cyp11a1), resulting in impaired cholesterol transport to mitochondria and failed steroidogenesis. In addition, we will test the hypothesis that genetic ablation or pharmacological inhibition of oxidant-sensitive p38 MAPK will attenuate or prevent age-related decline in steroid hormone synthesis and secretion.
Specific Aim 1 : Examine a functional link between ROS induced impairment of expression of components of the Sod-Prdx axes and oxidative stress-induced down-regulation of SNAREs and StAR, resulting in loss of steroidogenic response during aging;
Specific Aim 2 : Assess the contribution of Sods and Prdx proteins in ROS-mediated inhibition/inactivation of specific SNAREs and StAR, impaired cholesterol transport to mitochondria, and inhibition of steroidogenesis in aging;
and Specific Aim 3 : Determine whether pharmacological inhibition or genetic ablation of p38 MAPK reverses impaired steroidogenesis during aging or in antioxidant-deficient mouse models. The planned studies involve a multi- level approach including use of state-of-the art biochemical, cell biology, and molecular biology techniques, several metabolic aging mouse and rat models, and genetically altered mice with increased or decreased expression of specific antioxidant enzymes and pharmacological intervention strategies to achieve the stated goals.

Public Health Relevance

Steroid hormones are mainly produced by the adrenal gland and gonads. They regulate a diverse array of physiological processes including the maintenance of carbohydrate, lipid and protein metabolism, salt and water balance, immunity, blood pressure, muscle and bone growth, reproduction and secondary sex characteristics. It is well-established that aging in Veterans, like the general population, leads to a decline in testosterone production and alterations in adrenal steroid production in both sexes. The goal of this project is to examine the role of cytosolic and mitochondrial superoxide dismutase-peroxiredoxin axes in age- related and oxidative stress-mediated decline in steroid synthesis in experimental rodent models. Successful completion of the proposed studies may identify the novel target(s) that can be exploited in the management of clinical conditions such as hypogonadism, sexual dysfunction, fragility, dyslipidemia and other steroid metabolic disorders seen in older Veterans and the general aging population.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001923-06
Application #
9397416
Study Section
Endocriniology A (ENDA)
Project Start
2012-10-01
Project End
2020-09-30
Budget Start
2017-10-01
Budget End
2018-09-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Veterans Admin Palo Alto Health Care Sys
Department
Type
DUNS #
046017455
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
Li, Jiaxin; Zhou, Qian; Ma, Zhuang et al. (2017) Feedback inhibition of CREB signaling by p38 MAPK contributes to the negative regulation of steroidogenesis. Reprod Biol Endocrinol 15:19
Hu, Zhigang; Shen, Wen-Jun; Kraemer, Fredric B et al. (2017) Regulation of adrenal and ovarian steroidogenesis by miR-132. J Mol Endocrinol 59:269-283
Zaidi, Syed Kashif; Shen, Wen-Jun; Bittner, Stefanie et al. (2014) p38 MAPK regulates steroidogenesis through transcriptional repression of STAR gene. J Mol Endocrinol 53:1-16
Kraemer, Fredric B; Khor, Victor K; Shen, Wen-Jun et al. (2013) Cholesterol ester droplets and steroidogenesis. Mol Cell Endocrinol 371:15-9
Hu, Zhigang; Hu, Jie; Zhang, Zhonghua et al. (2013) Regulation of expression and function of scavenger receptor class B, type I (SR-BI) by Na+/H+ exchanger regulatory factors (NHERFs). J Biol Chem 288:11416-35
Hu, Zhigang; Shen, Wen-Jun; Cortez, Yuan et al. (2013) Hormonal regulation of microRNA expression in steroid producing cells of the ovary, testis and adrenal gland. PLoS One 8:e78040
Azhar, Salman (2013) MicroRNA-122: a new player in the negative regulation of LH receptor expression by the LH receptor mRNA binding protein (LRBP). Endocrinology 154:4439-42
Shen, Wen-Jun; Zaidi, Syed Kashif; Patel, Shailja et al. (2012) Ablation of vimentin results in defective steroidogenesis. Endocrinology 153:3249-57