Proteomic investigation of thyroid aging and pathogenesis reveals health and disease in thyroid cancers.

Understanding thyroid aging is essential for deciphering its physiological and pathological alterations, yet the causal relationship between aging and thyroid disease remains poorly characterized. We conducted a comprehensive proteomic analysis of 6109 thyroid tissues across ages 8-87 from 22 clinical centers (retrospective and prospective cohorts). Using a machine learning-based biological aging clock, we quantified accelerated aging phenotypes in pathological tissues, including benign and malignant nodules. We identified linear and non-linear age-associated proteins and pathways related to metabolism, immune response, and extracellular matrix organization remodeling, with critical transitions observed during the third, sixth, and eighth decades. Cross-species analysis of mouse and monkey tissues uncovered conserved aging markers. Intervention studies suggested that low-protein diets delay thyroid aging in mice, and therapeutic drug screening identified potential anti-tumor candidates. This study establishes the first organ-specific thyroid aging clock, linking tumorigenesis to accelerated aging, and proposing dietary interventions for thyroid longevity.