Aging increases circulating BH 2 without modifying BH 4 levels and impairs peripheral vascular function in healthy adults.

Little is known about the mechanisms of aging on vascular beds and its relationship with tetra and di-hydrobiopterin (BH ₄ and BH ₂ ) levels. This observational clinical study analyzed the impact of aging on plasma and platelet biopterins, cutaneous blood flow (CBF), and coronary flow reserve (CFR) in healthy adults. The study enrolled healthy adults in 3 age groups: 18-30, 50-59, and 60-70 years (n = 25/group). Biopterins were assessed by LC-MS/MS using newly defined pre-analytical conditions limiting BH ₄ oxidation and improving long-term stability. CBF was measured by Laser Speckle Contrast Imaging coupled with acetylcholine-iontophoresis and CFR by adenosine stress cardiac magnetic resonance. In healthy adults, aging (60-70 years vs 18-30 years) significantly increased platelet BH ₂ (+75%, P = 0.033) and BH ₂  + BH ₄ (+31%, P = 0.033), and to a lesser extent plasma BH ₂ (+29%, P = 0.009) without affecting BH ₄ and BH ₄ /BH ₂ . Simultaneously, CBF was decreased (-23%, P = 0.004) but not CFR, CBF being inversely correlated with platelet BH ₂ (r = -0.42, P = 0.001) and BH ₂  + BH ₄ (r = -0.41, P = 0.002). The proportion of adults with abnormal platelet BH ₂ increased with age (+28% in 60-70y). These abnormal BH ₂ levels were significantly associated with reduced CBF and CFR (-16%, P = 0.03 and -26%, P = 0.02). In conclusion, our study showed that age-related peripheral endothelial dysfunction was associated with an increase in circulating BH ₂ without decreasing BH ₄ , the effect being more marked in platelets, the most relevant blood compartment to assess biopterin bioavailability. Peripheral but not coronary vascular function is progressively impaired with aging in healthy adults. All these findings support biopterins as therapeutic targets to improve vascular function.
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