Abstract Body (Do not enter title and authors here): Background: Aortic aneurysm (AA) is a fatal vascular disease that affects life expectancy. Theory predicts that biological processes of aging may better capture vascular aging than chronological age. Early-life tobacco exposure may induce lasting vascular injury and accelerate aging trajectories. However, the independent contributions of accelerated biological aging and early tobacco exposure to AA risk, as well as their potential synergistic interaction, remain fundamentally unknown.
Methods: A total of 268,491 participants from the UK Biobank study were included. We measured biological age from clinical traits using the KDM-BA and PhenoAge algorithms. Early-life tobacco exposure was assessed using self-reported questionnaires that included questions on utero tobacco exposure and age of smoking initiation. Cox proportional hazards models were used to analyse the association between biological ageing, early-life tobacco exposure and incident aortic aneurysm. Furthermore, multiplicative and additive interactions between accelerated biological aging and early-life tobacco exposure were formally tested. Disease subtype-specific analyses were conducted separately for incident thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA).
Results: Accelerated biological aging and early-life tobacco exposure were both significantly associated with increased risk of incident AA. Per standard deviation increase, PhenoAge and KDM-BA accelerations were associated with 26-35% and 27-41% higher AA risk, respectively. Participants in the highest quartile of aging acceleration showed markedly higher cumulative incidence of AA (P-trend <0.001). In utero smoke exposure increased AA risk by 21%. Compared to never-smokers, smoking initiation in adulthood, adolescence, and childhood was associated with progressively elevated AA risk (HRs=2.23, 2.26, and 2.57, respectively). Individuals with both highest quartile of biological aging and early-life exposure had markedly elevated AA risk, peaking for childhood smoking combined with high KDM-BA [5.65 (4.52-7.07) or PhenoAge [4.46 (3.61-5.52)]. Effects were stronger for AAA than TAA.
Conclusions: Exposure to tobacco smoke in early life markedly heightens the risk of AA when combined with accelerated biological aging. These findings underscore the need for early-life tobacco control policies and interventions targeting biological aging pathways to reduce AA burden across the lifespan.