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

15 April 2026

Nguyen Branden L., Kehmeier Mackenzie N., Babcock Matthew C., DuBose Lyndsey E., Hildreth Kerry L., Stauffer Brian L., Rosenberry Ryan, Keller Amy C., Steinke Kira, Miles Kaleb, Guerrero Lucas, Kohrt Wendy M., Reusch Jane, Clayton Zachary S., Moreau Kerrie L.

Summary

This study investigated the link between low testosterone in middle-aged and older men and their vascular health, focusing on cellular energy production. It found that men with low testosterone had reduced mitochondrial function—the "powerhouses" of our cells—and lower levels of a key protective protein called SIRT3, which is vital for mitochondrial health. These findings suggest that impaired mitochondrial function and reduced SIRT3 may contribute to accelerated vascular aging in men with low testosterone.

Key Findings:

  • Middle-aged and older men with low testosterone showed reduced mitochondrial energy production in their immune cells (PBMCs) compared to younger men and age-matched men with normal testosterone.
  • Their cells exhibited impaired ability to use both carbohydrates and fats efficiently for energy.
  • Blood vessel lining cells (endothelial cells) from men with low testosterone had significantly lower levels of SIRT3, a protein crucial for mitochondrial maintenance and protection against cellular stress.
  • These results highlight a potential pathway where compromised mitochondrial health and SIRT3 levels contribute to accelerated vascular aging in men with low testosterone.

Practical Takeaways for Nutrition and Longevity:

  • Support Mitochondrial Health: Emphasize a diet rich in antioxidants from diverse fruits, vegetables, and whole grains, along with healthy fats, to support mitochondrial function. Regular exercise, particularly a mix of aerobic and resistance training, is also crucial for boosting mitochondrial health.
  • Maintain Hormonal Balance: If you are a middle-aged or older man, discuss symptoms of low testosterone with your doctor. Maintaining healthy testosterone levels through lifestyle or, if medically indicated, other interventions, may have benefits for vascular and mitochondrial health.
  • Lifestyle for Cellular Resilience: Lifestyle choices like balanced nutrition, regular physical activity, and adequate sleep can positively influence sirtuin activity, including SIRT3, which is important for cellular repair and longevity.

Study Limitations: As a cross-sectional study, this research identifies associations rather than direct cause-and-effect relationships. Further long-term and intervention studies are needed to confirm these findings and explore therapeutic strategies.

Abstract

ABSTRACT 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.
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