Significance The pituitary is our master endocrine gland. Local damage and aging present important threats. We started to decrypt the ill-defined regulation of the gland’s stem cells, typically dormant but acutely activated upon damage. Single-cell transcriptomics uncovered interleukin-6 as a pituitary stem cell activator upon local damage, corroborated in vivo and in vitro using stem cell–derived organoids. This competence extinguishes at aging, concurrent with a raised inflammatory state in the older gland (inflammaging). However, the aging pituitary’s stem cells retain intrinsic activatability, resurfacing once released from their impeding tissue milieu. Our insights may instigate tactics to refrain the pituitary from aging or rejuvenate the aging gland. The single-cell transcriptomic database provides a powerful resource to decipher pituitary damage and aging.