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Age-related thymic involution, leading to reduced T cell production, is one of the major causes of immunosenescence. This results in an increased susceptibility to cancers, infections, and autoimmunity and in reduced vaccine efficacy. Here, we identified that the receptor activator of nuclear factor κB (RANK)–RANK ligand (RANKL) axis in the thymus is altered during aging. Using a conditional transgenic mouse model, we demonstrated that endothelial cells depend on RANK signaling for their cellularity and functional maturation. Decreased RANKL availability during aging resulted in a decline in cellularity and function of both endothelial cells and thymic epithelial cells, contributing to thymic involution. We then found that, whereas RANKL neutralization in young mice mimicked thymic involution, exogenous RANKL treatment in aged mice restored thymic architecture as well as endothelial cell and epithelial cell abundance and functional properties. Consequently, RANKL improved T cell progenitor homing to the thymus and boosted T cell production. This cascade of events resulted in peripheral T cell renewal and effective antitumor and vaccine responses in aged mice. Furthermore, we conducted a proof-of-concept study that showed that RANKL stimulates endothelial cells and epithelial cells in human thymic organocultures. Overall, our findings suggest that targeting the RANK-RANKL axis through exogenous RANKL administration could represent a therapeutic strategy to rejuvenate thymic function and improve T cell immunity during aging. Editor's summary: An immunologic feature of aging is thymic involution and decreased thymic output, resulting in fewer T cells able to respond to vaccines, infections, and cancer. Here, Santamaria et al. found that receptor activator of nuclear factor κB (RANK)–RANK ligand (RANKL) signaling decreased with age in mice, resulting in impaired thymic function. Exogenous administration of RANKL to aged mice restored their thymic architecture and function to nearly the same degree as young mice, enabling T cells in these aged mice to better respond to vaccination and implanted tumors. These data, coupled with human thymic organoculture data, suggest that targeting the RANK-RANKL axis may be an approach to alleviate the effects of aging on the thymus. —Courtney Malo [ABSTRACT FROM AUTHOR]