Endothelial Sirtuins and Mitochondrial Function Are Associated With Testosterone Status: Implications for Accelerated Vascular Aging in Middle‐Age and Older Men With Low Testosterone

Middle-aged/older (MA/O) men with low testosterone have greater oxidative stress-mediated vascular endothelial dysfunction, a major risk factor for cardiovascular disease (CVD). Testosterone deficiency impairs mitochondria, a source and target of oxidative stress. Whether the greater vascular endothelial dysfunction in MA/O men with low testosterone is related to mitochondrial dysfunction is unknown. This cross-sectional study measured mitochondrial respiration in peripheral blood mononuclear cells (PBMCs), and regulators of mitochondrial function (i.e., sirtuins [SIRTs]), and oxidant burden in vascular endothelial cells from (1) young adult men with normal testosterone (18-40 years; serum testosterone ≥ 13.9 nmol/L [400 ng/dL]; n = 23); (2) MA/O men with normal testosterone (50-75 years; serum testosterone ≥ 13.9 nmol/L [400 ng/dL]; n = 57), and (3) MA/O men with low testosterone (50-75 years; serum testosterone < 10.4 nmol/L [300 ng/dL]; n = 21). PBMCs from MA/O men with low testosterone had reduced carbohydrate (2.96 ± 0.65 vs. 6.85 ± 0.77 pmol/s·million cells; p = 0.001) and lipid-supported (4.10 ± 0.67 vs. 6.23 ± 0.69 pmol/s·million cells; p = 0.047) state 2 respiration compared to young men, and lower carbohydrate-supported uncoupled respiration than age-matched men with normal testosterone (17.77 ± 2.91 vs. 24.9 ± 1.93 pmol/s·million cells; p = 0.046). SIRT3 arterial (0.64 ± 0.04 vs. 0.99 ± 0.08 FU; p = 0.003) and venous (0.61 ± 0.03 vs. 0.92 ± 0.07 FU; p = 0.003) expression was lower in endothelial cells from MA/O men with low testosterone compared to age-matched men with normal testosterone. This study highlights the potential role of mitochondrial respiration and regulation in accelerated vascular aging in hypogonadal MA/O men. Importantly, these findings provide promising evidence for clinical therapeutic interventions to target mitochondrial health and SIRT3 to mitigate accelerated vascular aging in hypogonadal MA/O men.