Circadian Gene BMAL1 Regulation of Cell Senescence in Thyroid aging [scRNA-Seq]

As the global aging society intensifies, the incidence of thyroid diseases among the elderly is increasing annually, with hypothyroidism being particularly common. Studies have shown that in healthy elderly individuals, thyroid-stimulating hormone (TSH) levels are significantly elevated, while thyroid hormone (TH) levels are notably normal or decreased. However, the molecular mechanisms underlying thyroid aging and function remain unclear. To understand thyroid aging, it is essential to study the molecular and functional characteristics of various thyroid cell types during the aging process. We conducted single-cell sequencing of thyroids from different age groups and identified eight typical cell types and five thyroid epithelial cell subtypes (EPI). During aging, the expression levels of thyroid hormone synthesis-related genes (TSHR, TG, TPO) increased, suggesting that EPI cells adjust their gene expression patterns in response to elevated TSH. With advancing age, rhythmic disruption and cellular senescence signals accumulated in thyroid. Further analysis indicated that the senescent EPI cell subpopulation (CDKN1A_EPI) exhibited functional decline. Additionally, we unexpectedly found that the expression of the core circadian gene BMAL1 (ARNTL) was downregulated in the CDKN1A_EPI cells of elderly individuals. To verify this finding, we used a thyroid-specific knockout mouse model and found that BMAL1 downregulation inhibited NFKBIA expression, exacerbating cellular senescence. Finally, cell line knockout experiments and transcriptome sequencing further confirmed that BMAL1 knockout led to decreased expression of NF-kB Inhibitor Alpha (NFKBIA), a key mechanism driving thyroid cell senescence. This discovery not only reveals the relationship between thyroid cell aging and circadian rhythm disruption but also enriches our understanding of the mechanisms underlying thyroid aging.