Association of early-life tobacco exposure with Cardiovascular-Kidney-Metabolic (CKM) syndrome risk : is accelerated biological aging a mediating pathway?

Early-life tobacco exposure, including in utero exposure and early smoking initiation, is a well-established risk factor for age-related diseases, but its associations with proteomic aging and Cardiovascular-Kidney-Metabolic (CKM) syndrome severity, and whether optimal modifiable risk factors can attenuate the aging associations, remain unclear. In this cross-sectional study using baseline data (2006-2010) from the UK Biobank, we examined the associations of early-life tobacco exposure (in utero exposure and age of smoking initiation) with accelerated biological aging, measured by Phenotypic Age acceleration (PhenoAgeAccel) and Proteomic Age gap (ProtAgeGap), and with CKM syndrome stage, including whether optimal modifiable risk factors (BMI, smoking, alcohol, physical activity, sleep, diet) modified the aging associations and whether biological aging mediated the CKM associations. In utero tobacco exposure was associated with 0.24-year higher PhenoAgeAccel and 0.17-year higher ProtAgeGap; childhood smoking initiation (vs. never smokers) was associated with 1.60-year and 0.64-year accelerations, respectively, with dose-response trends. The combined exposure showed the strongest associations (PhenoAgeAccel: 1.73 years; ProtAgeGap:0.75 years). The association with PhenoAgeAccel was attenuated from 0.48 years among those with zero optimal factors to null with 5-6 factors (P interaction = 0.009), while no significant interaction was observed for ProtAgeGap. For CKM syndrome, in utero exposure was modestly associated with higher stage odds (OR 1.03), and earlier smoking initiation showed a graded association (OR 1.40 adulthood; 1.50 adolescence; 1.71 childhood); combined in utero and childhood initiation was associated with an OR of 1.86. Both PhenoAgeAccel and ProtAgeGap partially mediated these associations, with stronger indirect associations for childhood initiators. These findings suggest that early-life tobacco exposure, particularly combined in utero and childhood initiation, is associated with accelerated biological aging and more severe CKM syndrome in adulthood, that a higher number of optimal modifiable risk factors may attenuate the phenotypic aging association, though proteomic aging associations appear resistant, and that accelerated biological aging is a potential mediating pathway warranting prospective evaluation.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Doctoral

Grantor

Baylor University.

Year dc:date.issued

2026

Author dc:creator

• Zhang, Huihui, 1989-

Advisor dc:contributor.advisor

• Bowden, Rodney G., 1966-

• Early-life tobacco exposure.
• Biological aging.
• Proteomic age gap.
• Phenotypic age acceleration.
• UK Biobank.
• Cardiovascular-Kidney-Metabolic (CKM) syndrome.

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/2104/15117

OAI record oai:identifier

https://baylor-ir.tdl.org/server/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Abaylor-ir.tdl.org%3A2104%2F15117