This study plans to learn more about heart and vascular aging in men. In some men as they get older, testosterone levels fall below the normal range for young men. Also, as men get older cardiovascular health worsens. This can lead to high blood pressure and heart disease. In this study we want to find out what causes cardiovascular health to worsen in older men. Also we want to find out what happens when testosterone levels are lowered for a short time. Specifically, we want to see if the reduction in cardiovascular health in older men with low testosterone levels is because of damage to mitochondria. Mitochondria are the main power supply of the cells in our body. The results from this study will help to understand why cardiovascular health declines in older men with low testosterone levels compared to younger men and older men who have higher testosterone levels. Knowing this information will help to develop therapies to prevent heart disease in men.

Cardiovascular (CV) aging, featuring large artery stiffening, endothelial dysfunction, and impaired left ventricular (LV) diastolic function, is a major risk factor for the development of cardiovascular diseases (CVD). Male aging is associated with a gradual and variable decline in serum testosterone (T) and low T is associated with accelerated CV aging. The purpose of this research is to determine the key functional mechanisms underlying accelerated CV aging in older men with low T. The overall hypothesis is that mitochondrial dysfunction and oxidative stress are mechanisms underlying the apparent accelerated CV aging in older men with low T. To test this hypothesis Aim 1 will use cross-sectional comparisons of young and older men with normal T (≥400 ng/dl), and older men with chronically low T (<300 ng/dl). To better isolate the effects of low T from factors that change with aging and chronic low T, Aim 2 will expand on the cross-sectional comparisons by assessing measures of CV function, oxidative stress burden and mitochondrial function in older men with normal T before and after randomization to short-term (28 d) gonadal suppression (gonadotropin releasing hormone antagonist, GnRHant) + placebo (PL), GnRHant+T alone, or GnRHant+T+aromatase inhibitor (AI). AI will control for the effects of aromatization of T to estradiol (E2), and thereby isolate T effects while suppressing E2, a potent modulator of CV function. The results from this research should provide new mechanistic insight into the processes that mediate the impairment in CV function at the cellular and systemic level in older men with low T. These studies will lead to a better understanding of the independent role of T in age-related changes in CV function and the mechanisms of action, which will help guide future sex-specific therapies for the prevention of CVD.

Inclusion Criteria:

1. Men aged 18-40 years and 50-75 years
2. Chronically low testosterone group will have testosterone concentrations <300 ng/dl, and young and older normal testosterone groups will have testosterone levels 400-1000 ng/dl
3. No use of sex hormones for at least 1 year
4. Body mass index <40 kg/m2
5. Nonsmokers
6. Resting blood pressure <160/90 mmHg
7. Fasting plasma glucose <126 mg/dL
8. Healthy, as determined by medical history, physical examination, standard blood chemistries (chemistry panel, complete blood clot and circulating thyroid levels) and a graded exercise stress test with monitoring of blood pressure and electrocardiogram (ECG)
9. Sedentary or recreationally active (< 3 days/wk of vigorous aerobic exercise)
10. No use of medications that might influence cardiovascular function including anti-hypertensive, lipid lowering medications, and corticosteroids
11. No use of vitamin supplements or anti-inflammatory medications, or willing to stop 1 month prior and throughout the study.

Exclusion Criteria:

1. Contraindications to:

   1. Gonadotropin releasing hormone (GnRH) antagonist
   2. Testosterone gel and aromatase inhibitor including hypersensitivity to Acyline, Androgel®, Arimidex®
   3. Extrinsic peptide hormones, mannitol, GnRH or any other GnRH analogs

2. History of or active prostate or breast cancer or other sex hormone-dependent neoplasms

3. Pre-existing or active cardiac, renal or hepatic disease

4. History of stomach ulcer or bleeding

5. History of epilepsy or other seizure disorder

6. Diabetes

7. Active infection

8. Disease that affects the nervous system

9. Abnormal resting ECG

Additionally, men participating in the gonadal suppression intervention study will do so with the understanding that they will be randomly assigned to study groups that involve either GnRH antagonist plus testosterone gel plus placebo tablet (33% chance), GnRH antagonist plus testosterone gel plus aromatase inhibitor tablet (33% chance) or GnRH antagonist plus placebo gel plus placebo tablet (33% chance).