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Introduction Age is a major risk factor for cardiovascular disease, with chronic inflammation and immunosenescence contributing to atherosclerosis and pathological cardiac remodelling. Macrophages are central to pathogen clearance, arterial lipid handling and tissue homeostasis but exhibit functional decline with age including reduced phagocytosis, chemotaxis, and migration. We identified age-associated downregulation of master transcriptional regulators, MYC and USF1, which drive functional decline in human and murine macrophages. Knockdown of MYC or USF1 in macrophages from younger donors recapitulates an aged phenotype, establishing a role in immunosenescence. However, restoring these transcription factors to reverse age-associated dysfunction remains unexplored. We hypothesise that fisetin, a senolytic flavonoid, restores macrophage function through restoration of MYC or USF1.Methods Transgenic Drosophila with macrophage-specific Myc overexpression served as an in vivo ageing model and were assessed for lifespan and climbing-fitness over 9 weeks. Monocyte-derived macrophages (MDMs) were isolated from younger and older donors and treated with fisetin over 14 days. Aged mice received fisetin-supplemented diets in three 2-week cycles over 12 weeks, after which bone marrow-derived macrophages (BMDMs) were isolated. MYC, USF1 and target gene expression was quantified by RT-qPCR. Macrophage function was assessed using phagocytosis and chemotaxis assaysResults Drosophila with macrophage-specific Myc overexpression showed enhanced physical performance aged 7-8 weeks, compared to control, while lifespan was unaffected. Fisetin treatment restored MYC expression in aged human MDMs and murine BMDMs, while USF1 remained unaffected. This restoration improved age-related dysregulation of MYC-regulated target genes and reversed decline in phagocytosis and chemotaxis in MDMs from older donors. Murine BMDMs from fisetin-fed mice showed restored Myc and improved phagocytosis. Fisetin treated aged mice demonstrated improved muscle strength, motor coordination, and significantly reduced frailty index at 20 months.Conclusion Fisetin improves expression of MYC and its target genes, and age-associated functional decline in macrophages, supporting the hypothesis that MYC-driven transcriptional programmes are central to immunosenescence. Myc restoration improves healthspan but not lifespan in Drosophila, suggesting systemic benefits of targeting macrophage senescence. These results position MYC as a critical target and fisetin as a promising intervention for mitigating immunosenescence and reducing age-related cardiovascular disease risk.