Mechanical Insights into the Distinct Effects of Ovariectomy Versus Adrenalectomy on Age-Related Thymic Atrophy in Female Mice

Age-related thymic atrophy, a hallmark of immunosenescence linked to age-related diseases, involves gonadal and adrenal steroid hormones, but their distinct roles and mechanisms in this process remain unclear. Through biochemical, histological, and RNA-seq analyses, we comprehensively explored the mechanisms underpinning age-related thymic atrophy in response to ovariectomy (OVX) versus adrenalectomy (ADX) in female mice. Compared to the sham controls, OVX overtly ameliorated age-related thymic atrophy, as evidenced by increased thymus mass, a larger gross thymus area, and denser cortex cellularity. In contrast, ADX evidently accelerated age-related thymic atrophy, characterized by increased adipose infiltration and decreased cortex/medulla ratio, obscure cortico-medullary junctions, and sparser thymic cortical cells. Unexpectedly, combined OVX and ADX displayed a more pronounced effect than OVX alone in ameliorating age-related thymic atrophy. Mechanistically, OVX decreased while ADX increased the circulating 17β-estradiol levels in female mice, which drove these opposing outcomes potentially by promoting <i>Pparg</i>-mediated thymic fat deposition and blocking <i>Cdk1</i>-dependent thymocyte cell cycle progression. Although OVX eliminated gonadal 17β-estradiol production, it appeared to trigger a compensatory adrenal-dependent estrogen biosynthesis, whereas combined OVX and ADX nearly eliminated all estrogen sources, thus leading to a more pronounced effect than OVX alone in ameliorating age-related thymic atrophy in female mice. Notably, OVX increased while ADX decreased serum corticosterone levels, but these alterations exerted minimal impacts on age-related thymic atrophy, highlighting a pivotal role of estrogens over glucocorticoids in accelerating age-related thymic atrophy in females. Undesirably, although OVX ameliorated age-related thymic atrophy, it appeared to simultaneously increase autoimmune susceptibility by downregulating thymic <i>Cd74</i> expression. Taken together, our results indicate that OVX ameliorates while ADX accelerates age-related thymic atrophy in females. Estrogens rather than glucocorticoids act as the predominant regulator of this process, potentially via promoting <i>Pparg</i>-dependent fat deposition and blocking <i>Cdk1</i>-dependent thymocyte cycle progression. However, OVX-induced estrogen depletion also elevated autoimmune risk, emphasizing the need to balance benefits and risks in regulating thymic aging.