Sex differences in thyroid aging and their implications in thyroid disorders: insights from gene regulatory networks
Thyroid disorders are more prevalent in females than males, with sex differences in disease risk varying by age, e.g. although risk of anaplastic thyroid carcinoma (ATC) increases with age for both sexes, females are diagnosed at younger ages than males. In contrast, Hashimotos thyroiditis (HT) is more common in ages 30-50, with females having higher risk. These patterns suggest that in thyroid, gene regulatory processes evolve with age in a sex-specific manner. To characterize these sex differences in thyroid aging, we estimated and analyzed individual-specific gene regulatory networks using BONOBO and PANDA algorithms. We found that regulatory patterns of pathways involved in cell proliferation, immune response, and metabolic processes vary nonlinearly with age, with sex-specific differences in direction and rate. Females show two inflection points around ages 40 and 60, when regulatory patterns show significant change for most pathways, consistent with changes in targeting by estrogen and androgen receptors. Investigating gene regulatory patterns in HT and ATC, we observed that disease-relevant immune and metabolic pathways changed with age in the same direction as they change in ATC. In contrast, in HT, disease-related regulatory patterns are in the opposite direction of aging. In age groups where HT is most diagnosed, regulatory patterns in females more closely resembled disease states than males, highlighting sex-biased regulations role in elevated disease risk in females. Our findings demonstrate immune response and metabolic processes are regulated in age- and sex-specific manner, potentially driving variation in disease risk, emphasizing the need for tailored screening and prevention strategies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/684890v3_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@cd93aeorg.highwire.dtl.DTLVardef@9a913aorg.highwire.dtl.DTLVardef@1b4a862org.highwire.dtl.DTLVardef@19adca8_HPS_FORMAT_FIGEXP M_FIG C_FIG