# Role of Cholesterol in Age-related Decline in Steroidogenesis

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2020 · —

## Abstract

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-regula...

## Key facts

- **NIH application ID:** 9814677
- **Project number:** 5I01BX001923-08
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** Salman Azhar
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-10-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9814677

## Citation

> US National Institutes of Health, RePORTER application 9814677, Role of Cholesterol in Age-related Decline in Steroidogenesis (5I01BX001923-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9814677. Licensed CC0.

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