Work

Resistant hypertension and accelerated vascular aging: evidence for PTEN–AKT-associated cellular senescence

Year: 2026

Type: article

Abstract: Resistant hypertension (RH) is increasingly linked to accelerated vascular aging and is particularly prevalent among older and obese individuals. Cellular senescence has emerged as a potential driver of vascular aging, but its contribution to RH remains unclear. We examined age and body mass index (BMI) in the WalkByLab cohort and assessed whether RH was associated with vascular features consistent with accelerated aging. Obesity-related transcriptomic datasets were integrated with a curated senescence-associated gene set to identify candidate regulators, followed by validation in an independent RH dataset, PBMCs, and human endothelial cells. An exploratory clinical-molecular nomogram was also developed. BMI and age increased progressively from normotension to RH. RH was characterized by reduced flow-mediated dilation, increased pulse wave index, and unchanged ankle-brachial index, consistent with endothelial dysfunction and arterial stiffness. Transcriptomic analyses identified enrichment of inflammatory, PI3K-AKT, and senescence-associated pathways. In PBMCs from RH patients, PTEN expression was reduced, AKT phosphorylation was increased, and p16/p21 levels were elevated, indicating a systemic senescence-associated molecular profile. In human endothelial cells, exposure to obese serum or pharmacological PTEN inhibition induced AKT activation and cellular senescence, whereas AKT inhibition attenuated these effects. Together, transcriptomic, clinical, and experimental findings indicate that RH is associated with vascular and molecular features consistent with accelerated vascular aging. Human data indicate a systemic senescence-associated molecular profile, whereas endothelial cell experiments support endothelial senescence as a mechanistically relevant cellular component. PTEN-AKT-associated cellular senescence may represent one mechanistically relevant component linking obesity to vascular dysfunction in RH.

Source: GeroScience

DOI: 10.1007/s11357-026-02627-8