Assessing Thyroid Health: Phenotypic Age Compared to Chronological Age

Dongyu Yang¹Cihang Lu¹Haonan Zhang¹Xiaoguang Shi¹Ying Sun¹Ying Shao¹Shuting Fan¹Lijun Tian²Di Teng^2*

• ¹Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
• ²The Department of Endocrinology and Metabolism, National Health Commission Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, China

Background: Aging is associated with thyroid dysfunction, but the role of phenotypic age, a biological aging measure derived from nine clinical biomarkers and chronological age, remains unclear.Methods: This cross-sectional study included 6,681 adults from the National Health and Nutrition Examination Survey (NHANES, 2007–2012) with complete thyroid function and age data. Participants were grouped into quartiles based on chronological and phenotypic age. Weighted multinomial logistic regression was used to assess the association between aging and thyroid disorders, followed by the use of restricted cubic splines (RCSs) to explore potential nonlinear relationships. Subgroup and sensitivity analyses were conducted to test robustness. Mediation analysis assessed the role of phenotypic age components in the link between phenotypic age and thyroid dysfunction.Results: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) exhibited U-shaped relationships with both chronological and phenotypic age, while free triiodothyronine (FT3) showed a nonlinear association with chronological age and a negative linear correlation with phenotypic age. The age gap (phenotypic age minus chronological age) was positively associated with TSH and nonlinearly with FT4. Thyroid peroxidase antibody (TPOAb) exhibits a nonlinear association with both age types, and thyroglobulin antibody (TGAb) has a positive linear association with chronological age. Phenotypic age showed stronger linear associations with TGAb positivity (PTGAb), overt hyperthyroidism, and subclinical hypothyroidism than chronological age. Overt hypothyroidism demonstrated an inverted U-shaped association with both age metrics and a positive correlation with age gap. Mediation analysis revealed that mean cell volume mediated 10% of the association between phenotypic age and overt hypothyroidism, while lymphocyte percentage exhibited a negative mediation effect (−26%) in the association between phenotypic age and subclinical hypothyroidism.