Age-Related Enhancement of HPT Axis Sensitivity to Thyroid Hormones Protects Metabolic and Cardiovascular Health

Background The regulation and secretion of hormones in the endocrine system change with aging, including a decline in serum free triiodothyronine (fT3) and an increase in thyroid-stimulating hormone (TSH) within their reference ranges. While these changes may influence age-related disease risks, the role of hypothalamic-pituitary-thyroid (HPT) axis sensitivity in metabolic and cardiovascular health remains unclear. Methods This study enrolled 13,646 participants (6,221 males, 7,425 females). Metabolic (BMI, SUA, FPG, lipoproteins) and cardiovascular (ECG, CK-MB, NT-proBNP) indices were measured. HPT sensitivity was quantified using Thyroid Feedback Quantile-Based Index (TFQI). Multivariable logistic regression adjusted for age (per 10-year increment), sex, and outcome-specific confounders (BMI, SUA, FPG, non-HDL for ST-segment analysis). Nonlinear relationships between age and TFQI were analyzed using restricted cubic splines (RCS). Result Metabolic indicators were generally elevated in participants with decreased HPT axis sensitivity to fT3 (Q4) compared to the reference group (Q1). Restricted cubic spline analysis revealed a significant age-dependent decline in TFQI-fT3 values, with an inflection point at 48 years (p < 0.001); TFQI-fT4 showed a similar but attenuated trend. For metabolic outcomes, increased fT3 sensitivity (TFQI-fT3 Q1) was associated with lower MetS risk in older adults (> 48 years) (OR 0.79, 95% CI 0.65–0.97, p = 0.023), whereas no significant association was observed in younger adults (≤ 48 years) (all p > 0.05). For cardiovascular outcomes, higher fT3 sensitivity was significantly associated with reduced risk of abnormal ST segments in both age groups (younger: OR 0.57, 95% CI 0.32–0.97, p = 0.046; older: OR 0.68, 95% CI 0.48–0.95, p = 0.027). Conversely, decreased fT4 sensitivity (TFQI-fT4 Q4) specifically increased ST-segment risk in older adults (OR 1.43, 95% CI 1.04–1.96, p = 0.025), with no significant effect in younger adults (OR 1.11, 95% CI 0.65–1.82, p = 0.693). Conclusion Enhanced HPT axis sensitivity to fT3 increased with age (inflection at 48 years) and was associated with reduced risks of metabolic syndrome (in > 48-year-olds) and ST-segment abnormalities (all adults). These findings suggest age-specific TH regulation influences metabolic and cardiovascular health, warranting further research into underlying mechanisms.