Kidney Disease as a Driver of Immunosenescence: Mechanisms and Potential Interventions

Immunosenescence, a state marked by immune dysfunction, chronic low-grade inflammation, and impaired pathogen defense, is accelerated in CKD. CKD promotes systemic inflammation through the accumulation of uremic toxins, oxidative stress, and dysregulated immune signaling, all driving premature aging of both innate and adaptive immune cells. These mechanisms result in dysregulated immune activation and impaired surveillance, thereby aggravating kidney damage and increasing the risk for comorbidities. Despite removing uremic toxins, dialysis may further accelerate immunosenescence by exposing immune cells to oxidative and antigenic stress, inducing telomere shortening and T-cell exhaustion. Kidney transplantation can partially reverse CKD-induced immunosenescence by restoring kidney function. Commonly used immunosuppressive agents, however, may further promote immunosenescence by impairing thymic function, depleting naïve T cells, and suppressing natural killer cell activity. However, mammalian target of rapamycin (mTOR) inhibitors have shown anti-aging effects by promoting autophagy and inhibiting proinflammatory pathways. Therapeutic strategies targeting immunosenescence in CKD have been gaining momentum. Senotherapeutics can eliminate senescent cells and reduce senescence-associated secretory phenotype (SASP)-mediated inflammation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, caloric restriction, microbiome modulation, mesenchymal stem cell therapies, and KRTs also offer the potential to slow accelerated immunosenescence as a consequence of CKD. Here, we provide a comprehensive overview of the mechanisms linking CKD and immunosenescence, along with emerging therapeutic strategies that have the potential to target premature aging.