Comment on “Combination of biological aging and genetic risk helps identify at-risk population of thoracic aortic aneurysms: insight from a prospective cohort study of UK Biobank”

Dear Editor, Xu et al address a key unmet need in thoracic aortic aneurysm (TAA) prevention: unlike abdominal aneurysm, TAA lacks a widely adopted population screening strategy, largely because “who to image” remains uncertain[1]. In >400 000 UK Biobank participants followed for >13 years, the authors show that phenotypic age acceleration (PhenoAgeAccel) captures risk beyond chronological age, and that combining PhenoAgeAccel with a polygenic risk score (PRS) materially enriches an at-risk subgroup[1]. This commentary was prepared in accordance with the TITAN 2025 guideline to promote transparent and responsible reporting[2]. The clinical appeal is the “two-axis” architecture: a stable lifelong genetic signal plus a biomarker-derived biological aging signal that plausibly reflects accumulated cardiometabolic and inflammatory burden. PhenoAge (and by extension PhenoAgeAccel) is grounded in prior work showing that routine clinical biomarkers can quantify aging-related mortality and morbidity risk more informatively than chronological age alone[3]. On the genetic side, recent UK Biobank–based work has demonstrated that polygenic scoring can improve detection of thoracic aortic dilation/aneurysm phenotypes, supporting the premise that PRS can help select individuals for targeted imaging rather than broad population screening[4]. From a translation perspective, the most important question is how such stratification could be operationalized within guideline-based care. The 2022 ACC/AHA Aortic Disease Guideline emphasizes diagnosis, genetic evaluation/family screening, and longitudinal surveillance once disease is identified, but does not endorse general population imaging for TAA[5]. Xu et al’s approach is therefore potentially valuable as an “enrichment layer” that might bridge the gap between no screening and indiscriminate imaging – provided it demonstrates net benefit (earlier detection of clinically meaningful dilation) without excessive incidental findings and downstream testing[1,5]. Key cautions remain. UK Biobank’s healthy-volunteer selection and ancestry composition mean calibration and thresholds may not transport to more diverse or higher-risk populations[1]. Biomarkers were assessed at baseline only, so it is unknown whether changes in PhenoAgeAccel track aneurysm growth or respond to risk-factor modification. Finally, risk enrichment must be tied to an actionable pathway – what imaging modality, at what interval, and what intervention thresholds – aligned with guideline surveillance and repair triggers[5]. Overall, this study provides a persuasive proof-of-concept that integrating biological aging with polygenic susceptibility can improve TAA risk enrichment. The next step is external validation with standardized imaging endpoints and pragmatic decision-curve/cost-effectiveness analyses to define where “age + PRS + biological aging” can safely guide targeted thoracic imaging[1].