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Background: Accumulation of advanced glycation end-products (AGEs) is one of pathophysiological processes, responsible for progressive stiffening of vessel wall. In contrast, soluble isoform of receptor for AGEs (sRAGE) act as “decoy” and physiological defense against circulating AGEs. We hypothesized that low levels of sRAGE might be associated with accelerated age-dependent arterial stiffening. Methods: We followed 429 population-based subjects (mean age 50.8 (±11.7) years, 41.5% males) in prospective study. Aortic pulse wave velocity (aPWV) was measured using a Sphygmocor device. sRAGE concentrations were assessed in frozen samples by ELISA methods (R&D Systems). Baseline examination was done in 2008/9, while follow-up visit in 2016/17 (median time of follow-up was 7.6 years) Results: Mean intra-individual increase of aPWV during follow-up was 1.37 (±1.88) m/sec and was inversely associated with baseline sRAGE concentration – the aPWVV difference [follow-up minus baseline] across its quintiles was 2.08((±1.89), 1.51(±2.16), 1.20(±2.10), 0.99(±1.70), 1.13(±1.21) in 1st–5th quintiles of sRAGE, resp.; p = 0.003 (adjusted for age, gender and baseline mean arterial pressure) Baseline concentration of sRAGE <917 pg/mL (1st quintile) was associated with about two-fold higher risk, that aPWV increased by more than 0.8 m/sec (expectable “secular“ age- dependent increase) even if adjusted for baseline risk profile and pharmacotherapy [fully adjusted odds ratio was 1.95 (95%CI: 1.12–3.39, p = 0.018]. Conclusions: Low concentration of circulating sRAGE was in our sample of generally healthy subjects associated with markedly accelerated age-dependent arterial stiffening, probably as a consequence of higher deposition of AGEs in vessel wall (supported by SVV 02684, PROGRES Q39 and AZV 15-27109 grants).