Overactivation of Cdc42 GTPase Impairs the Cytotoxic Function of NK Cells from Old Individuals towards Senescent Fibroblasts

Senescent fibroblasts accumulate in the connective tissue of all organs and promote organ aging and aging-related diseases. The underlying mechanisms for the accumulation of senescent fibroblasts are poorly understood. Natural killer (NK) cells of innate immunity play a critical role in the removal of tissue resident senescent cells. We here show that NK cells from old adults and old mice fail to efficiently remove senescent fibroblasts due to severely reduced efficiency of aged NK cells to induce perforin mediated membrane disruptions and granzyme B induced targeted death of senescent fibroblasts. We demonstrate elevated activation of the small Cdc42 Rho GTPase in aged NK cells to be responsible for the disruption of the microtubular organisation of aged NK cells. A correct microtubular organisation of NK cells is essential for cellular polarity, degranulation of perforin and granzyme B into the synaptic cleft between NK cells and senescent fibroblasts, and for a proper function of energy metabolism. Attenuation of the elevated activity of Cdc42 in aged human NK cells with CASIN, a small molecule Cdc42 inhibitor, rebalances Cdc42 activity to a young level, restores a proper perforin and granzyme B release and attenuates reduced ATP levels and mitochondrial dysfunction in aged NK cells to result in a youthful cytotoxicity of aged NK cells against senescent cells. Collectively, we identified a previously unreported molecular mechanism underlying functional impairment of NK cells from older adults. In perspective, our data hold promise to develop novel strategies against age-related disorders driven by tissue-resident senescent fibroblasts.