Rescuing Age‐Related Vascular Dysfunction: The Impact of Tetrahydrobiopterin and Antioxidants
Authors: Garten Ryan , Lee Joshua , Groot Jonathan , Rossman Matthew , Clifton Heather , Wray Walter , Richardson Russell 
Published: November 2023

PURPOSEAging is associated with an increase in oxidant production that negatively impacts vascular function. This vascular dysfunction is, in part, mediated by a decrease in endothelial nitric oxide synthase (eNOS) activity. Tetrahydrobiopterin (BH4), an important co‐factor involved in eNOS coupling, is highly susceptible to oxidation and therefore less available in the vasculature of aged individuals. Therefore, this study sought to rescue vascular dysfunction in older adults with the acute oral supplementation of both BH4 and an antioxidant cocktail (AOC).METHODSEight healthy older subjects (O: 70±3 yrs) completed four testing sessions, each separated by at least 72 hours in a randomized, double‐blind cross‐over design. Prior to each visit, the older subjects ingested either placebo (PL), an AOC (600 IU α‐tocopherol, 1000 milligrams ascorbic acid, and 600 milligrams α‐lipoic acid), BH4 (10 mg/kg), or BH4+AOC. Vascular function was assessed by supine passive leg movement (PLM)‐induced vasodilation (leg vascular conductance, LVC). Central (heart rate, stroke volume, cardiac output, and mean arterial pressure, MAP) and peripheral hemodynamics (leg blood flow) were measured for 1 minute prior to PLM and then during 2 minutes of PLM with finger photoplethysmography and Doppler ultrasound, respectively. Twelve healthy young subjects (Y: 23±1 yrs) also completed the supine PLM protocol without supplementation, providing young reference data.RESULTSResting central hemodynamics were not different between the young and old with the exception of MAP that was significantly elevated in the old (O: 107±6; Y: 86±2 mmHg; p < 0.01). Compared to the young subjects, the old exhibited significantly lower PLM‐induced peak changes in LVC (O: 2.4±0.3; Y: 6.8±0.7; p < 0.01). Although not significantly lower than the PL condition, BH4 supplementation in the old lowered resting MAP such that there was no longer an age‐related difference (O: 93±6; Y: 86±2 mmHg; p = 0.29). There were no significant effects on resting MAP in the AOC (99±2 mmHg) or BH4+AOC (101±4 mmHg) conditions. The PLM‐induced peak change in LVC was augmented with BH4 (4.8±0.6) compared to all other conditions (PL: 2.4±0.3; AOC: 2.9±0.2; BH4+AOC: 1.8±0.4) in the old, such that the peak change in LVC in the BH4 condition was not different from that in the young (O: 4.8±0.6; Y: 6.8±0.7 ml·min−1·mmHg−1; p = 0.06). Surprisingly, the AOC alone and BH4+AOC conditions did not impact the peak change in LVC compared to PL condition in the older subjects.CONCLUSIONSThis study reveals that acute oral BH4 supplementation significantly improves leg vascular function in older adults when compared to PL, an AOC, or the combination of BH4 and an AOC. Furthermore, the substantial improvement in LVC in the older adults supplemented with BH4 meant that their vascular function was comparable to their younger counterparts and highlights the importance of BH4 in rescuing vascular function with advancing age.