Circadian Gene BMAL1 Regulation of Cellular Senescence in Thyroid Aging

ABSTRACT As global aging accelerates, the incidence of thyroid diseases, particularly hypothyroidism, is rising in the elderly. The thyroid‐stimulating hormone (TSH) levels increase in healthy elderly populations. However, whether the thyroid undergoes cellular senescence and how this relates to thyroid hormone (TH) synthesis remain unclear. To investigate the molecular and functional characteristics of thyroid aging, we performed scRNA‐seq on human thyroids from young, middle‐aged, and old groups, identifying thousands of aging‐related differentially expressed genes and revealing the early onset of aging in the middle‐aged group. As aging progresses, the expression levels of genes related to TH synthesis increase, suggesting that epithelial cells (EPI) adjust their gene expression in response to elevated TSH levels. Additionally, the senescence‐associated secretory phenotype (SASP) in EPI cells is progressively enhanced with aging. We identified a subgroup of epithelial cells (CDKN1A_EPI) characterized by reduced functionality and significantly elevated levels of cellular senescence. We found that the core circadian rhythm gene BMAL1 ( ARNTL ) is downregulated during aging. We further validated this finding using the thyroid‐specific Bmal1 knockout mouse model, showing that the downregulation of Bmal1 inhibits the expression of Nfkbia ( NF‐κB inhibitor alpha ), thereby accelerating cellular senescence and impairing hormone synthesis. Finally, through cell line experiments and transcriptome sequencing, we confirmed that BMAL1 knockout leads to decreased NFKBIA expression, promoting thyroid cellular senescence. Our study demonstrates that circadian rhythm disruption accelerates cellular senescence in the thyroid and exacerbates the decline of thyroid function, providing a novel theoretical foundation for understanding thyroid aging mechanisms and maintaining thyroid function stability.