Female mice generated significantly stronger antibody responses to influenza vaccination than males through estradiol-driven metabolic reprogramming of B cells. The hormone activated mTOR signaling pathways in germinal center B cells and plasmablasts, shifting cellular metabolism toward lipid pathways rather than central carbon metabolism seen in males. When researchers depleted estradiol in females, vaccine responses declined, while estradiol replacement restored enhanced immunity. Crucially, aged female mice with declining estrogen showed weakened vaccine responses, but treatment with estradiol or selective estrogen receptor α agonists restored robust antibody production. This discovery illuminates why premenopausal women consistently show superior vaccine responses compared to men, and why this advantage diminishes with menopause. The mTOR-estrogen axis represents a previously unrecognized mechanism linking hormonal status to immune function. For aging populations, particularly postmenopausal women with compromised vaccine responses, targeted estrogen receptor modulation could potentially restore more youthful immune competence. However, translating these mouse findings to humans requires careful consideration of hormone therapy risks and benefits, especially given that sustained estrogen exposure carries cardiovascular and cancer implications that weren't assessed in this short-term study.