Background: Systolic blood pressure (SBP) increases steadily with age. More than 50% of people aged 60+ are hypertensive. One suspected pathomechanism of SBP increase with age is aortic stiffness reflecting vascular aging. Oxidative stress contributes to aortic stiffness. An important regulator of oxidative stress is Toll-like receptor 4 (TLR4). We hypothesized that life-long TLR4 mediated oxidative stress increases aortic stiffness and contributes to SBP increase with age.

Methods: We investigated adult (3–6 months of age) aged (9–12 months of age) and advance aged (15–18 months of age) male C57Bl/6j and TLR4 null-mice mice. We assessed SBP, aortic stiffness (aortic pulse wave velocity, aPWV) and aortic oxidative burden with malondialdehyde (MDA) in aging. In a translational study we analyzed in a cohort of 2679 patients with myocardial infarction the effect of TLR4 896A/G single nucleotide polymorphism on SBP, pulse pressure and hypertension in dependency on age.

Results: C57Bl/6j and TLR4 null-mice had in adulthood similar SBP, aPWV and similar oxidative burden. During aging in C57Bl/6j mice SBP, aPWV and MDA increased (15mmHg, 2m/s, 30%, respectively). Aged TLR4 null-mice did not show these changes. In the upper age tertile of the patient cohort (age >70 years), patients with a TLR4 896A/G single nucleotide polymorphism had lower SBP and pulse pressure (7mmHg) and less hypertension (79% versus 60%). The TLR4 SNP remained a significant predictor for SBP in univariate and multivariate regression analysis.

Discussion: We propose that TLR4 signaling participates in SBP increase with age by inducing vascular aging.