Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway.

backgroundImmunosenescence, characterized by progressive immune dysfunction accompanied by chronic low-grade inflammation (inflammaging), is a key driver of systemic ageing. Senescent T cells are central to this process, yet effective interventions remain limited. Kaempferol is a natural flavonoid with diverse bioactivities, but its potential to counteract T-cell immunosenescence is largely unexplored. Here, we investigated whether kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice and delineated the underlying mechanism.

methodsNineteen-month-old C57BL/6 J mice were fed standard chow or chow supplemented with kaempferol (50 or 100 mg/kg/day). Depressive-like behavior and neuromuscular performance were evaluated using the tail suspension, rotarod, and grip strength tests. Senescence and senescence-associated secretory phenotype (SASP) markers were quantified by RT–qPCR across multiple organs. Immune profiling and circulating cytokines were assessed by flow cytometry and Luminex assays, respectively. Ex vivo studies in senescent T cells examined mitochondrial function, reactive oxygen species (ROS), mitochondrial mass, and mitophagy. Proteomic analysis was performed to identify candidate pathways, and CRISPR/Cas9-mediated SIRT3 knockout was used to test pathway necessity.

resultsKaempferol did not significantly extend lifespan but improved depressive-like behavior and neuromuscular function without detectable toxicity. It restored peripheral T-cell homeostasis, increasing the CD4 + /CD8 + ratio and naïve T-cell frequency while reducing effector memory T cells and PD-1 expression. These improvements occurred predominantly in the periphery, with no significant rejuvenation of the aged thymus. Kaempferol also reduced systemic inflammatory burden and directly suppressed proinflammatory cytokine secretion from senescent T cells. Mechanistically, kaempferol activated the SIRT3-LKB1-AMPK axis, inducing mitophagy to eliminate damaged mitochondria, reduce ROS, restore mitochondrial function, and attenuate the inflammatory senescent phenotype. Notably, SIRT3 knockout abolished kaempferol-induced mitophagy and cytokine suppression.

conclusionKaempferol alleviates T-cell immunosenescence and inflammaging by activating the SIRT3-LKB1-AMPK-mitophagy pathway, thereby restoring mitochondrial quality control and restraining inflammatory secretion in senescent T cells. These findings position kaempferol as a promising candidate for interventions targeting age-related immune decline.