Overactivation of Cdc42 <scp>GTPase</scp> Impairs the Cytotoxic Function of <scp>NK</scp> 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. This is due to severely reduced perforin and granzyme B release from aged NK cells where perforin is responsible for inducing holes in the membrane of senescent fibroblasts through which granzyme B enters enforcing cell 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 organization which is essential for the proper release of perforin and granzyme B and for energy homeostasis. 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. Rebalancing of Cdc42 restores proper perforin and granzyme B release and attenuates reduced ATP levels in aged NK cells resulting in an attenuated "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.