Skin advanced glycation end-products are independently associated with endothelial function in a sample of predominantly young and healthy adults

Background Advanced glycation end-products (AGEs) accumulate irreversibly in body tissues throughout life and are associated with impaired vascular function via pro-atherogenic mechanisms, including RAGE-mediated oxidative stress and impaired nitric oxide bioavailability. Skin autofluorescence (SAF), measured non-invasively using an AGE Reader, estimates long-term tissue AGE accumulation. As AGE accumulation is influenced by ageing and diet, it represents a potentially modifiable cardiovascular risk marker. Inverse associations between SAF and endothelial function have been reported in populations with chronic disease. However, this relationship had not been examined in predominantly young, healthy adults prior to the emergence of classic cardiovascular disease (CVD) risk factors. Purpose To quantify the association between skin AGE accumulation (SAF) and endothelial function, measured via brachial artery flow-mediated dilation (FMD), and to identify independent predictors of endothelial function in a predominantly young, healthy population. Methods A cross-sectional study was conducted in 2021-2022 with 125 participants (median age: 28.5 years [IQR: 24.4-36.0]; 54% women). Endothelial function was assessed via fasting brachial artery FMD using high-resolution ultrasound. Skin AGEs were measured as SAF in triplicate using an AGE Reader. Anthropometry, blood pressure, and fasting blood biomarkers, including glucose, insulin, lipids, glycated haemoglobin (HbA1c), high-sensitivity C-reactive protein (hsCRP), and soluble receptor for AGEs (sRAGE), were assessed. Multivariable linear regression identified independent predictors of FMD, with allometrically scaled FMD examined as a sensitivity analysis. Results FMD was inversely correlated with SAF (ρ = -0.50, P < 0.001) and chronological age (ρ = -0.51, P < 0.001). In multivariable analysis (N = 113), SAF and chronological age were independently and inversely associated with FMD (B [95% CI]: -2.60 [-4.40, -0.80]; -0.10 [-0.16, -0.03]), and females exhibited higher FMD than males (B = 1.40 [0.14, 2.67]; adjusted R² = 0.31, overall model P < 0.001). For every 1 arbitrary unit (AU) increase in SAF, FMD decreased by 2.60 percentage points. Findings were consistent following allometric scaling and after excluding participants with medical conditions or those aged over 50 years (ρ = -0.31, P < 0.01, N = 92). Conclusions For the first time in a predominantly young, healthy cohort, increased skin AGE accumulation was associated with lower FMD, independent of traditional CVD risk factors. SAF is a simple, non-invasive marker that could complement FMD for early detection of vascular risk to inform lifestyle and dietary intervention.