This study investigated the role of α-melanocyte-stimulating hormone (α-MSH) signaling in modulating sex-specific and inflammatory processes in aging related osteoarthritis (OA) models in vitro and in vivo. We aimed to determine if α-MSH elicits sex-dependent molecular effects on doxorubicin-induced senescence in OA and non-OA human chondrocytes in vitro, and to examine analogous sex-specific differences in senescence and inflammation in wild-type (WT) versus melanocortin receptor 1 (MC1R) signaling-deficient (MC1Re/e) mice during aging. In vitro, human articular chondrocytes (hCh) from OA- and non-OA donors were subjected to doxorubicin-induced senescence and treated with Nle4-D-Phe7 (NDP)-α-MSH. Senescence markers (senescence‑associated β‑galactosidase (SA-β-gal), CDKN2A, CDKN1A), oxidative stress (reactive oxygen-, nitrogen species (ROS/RNS)), metabolic activity, secretion of matrix metalloproteinases (MMPs) and pro-inflammatory cytokine IL-6 were assessed. In parallel, in in vivo experiments, knee joint chondrocyte MC1R expression and apoptosis, as well as subchondral bone architecture, and synovial immune cell populations were analyzed in male and female WT and MC1Re/e mice aged up to 18 months. NDP-α-MSH partly mitigated doxorubicin-induced senescence markers and significantly reduced ROS/RNS levels in hCh. Effects were sex-specific and different between OA- and non-OA hCh in vitro. NDP-α-MSH also attenuated the secretion of pro-inflammatory IL-6 without affecting MMP secretion. In vivo, MC1R signaling deficiency in mice exacerbated spontaneous age-related processes in a sex-dependent manner, particularly in female mice, and influenced subchondral bone parameters and synovial immune cell profiles. α-MSH signaling plays a protective role during joint aging and OA associated cartilage and subchondral bone alterations by mitigating senescence, oxidative stress, and inflammation, with notable sex-specific differences. These findings emphasize the need for personalized and sex-based approaches and identify the α-MSH - MC1R axis as a potential therapeutic target for age-related disease-modifying interventions in OA.