AbstractThe immune system plays a central role in many processes of age‐related disorders and it remains unclear if the innate immune system may play roles in shaping extreme longevity. By an integrated analysis with multiple bulk and single cell transcriptomic, so as DNA methylomic datasets of white blood cells, a previously unappreciated yet commonly activated status of the innate monocyte phagocytic activities is identified. Detailed analyses revealed that the life cycle of these monocytes is enhanced and primed to a M2‐like macrophage phenotype. Functional characterization unexpectedly revealed an insulin‐driven immunometabolic network which supports multiple aspects of phagocytosis. Such reprogramming is associated to a skewed trend of DNA demethylation at the promoter regions of multiple phagocytic genes, so as a direct transcriptional effect induced by nuclear‐localized insulin receptor. Together, these highlighted that preservation of insulin sensitivity is a key to healthy lifespan and extended longevity, via boosting the function of innate immune system in advanced ages.