Itaconate Attenuates Aging-Related Kidney and Extrarenal Organ Damage by Inhibiting Senescence-Associated Secretory Phenotype

Background: Aging is a high-risk factor for many chronic diseases, imposing a huge burden on modern society. Cellular senescence is an important hallmark of aging. SASP ,one of the important features of cellular senescence, is a collection of inflammatory factors and growth-promoting proteins secreted by senescent cells. Senescent cells release inflammatory factors through SASP, and recruit inflammatory cells thus accelerating organism aging, so targeting SASP is an effective means to attenuate aging-related kidney and extrarenal organ damage. Itaconate, which has potent anti-inflammatory effects, is a negative regulator of inflammation. However, the role of itaconate in aging-related diseases is unknown. The aim of this study is to explore the role and mechanism of itaconate in aging-related diseases and to provide an important theoretical basis for healthspan. Methods: To investigate the role of itaconate in aging, we implemented a multi-modal experimental strategy. First, Irg1 expression in renal and extrarenal tissues of aged mice were assessed. Subsequently, macrophage-specific Irg1 knockout mice were were generated and established to aging models by radiotherapy. To evaluate therapeutic potential, both chronologically aged (24-month-old) animals and radiation-induced senescent cell models received 4-octyl itaconate (4-OI) administration through in vivo and in vitro paradigms. Comprehensive aging assessments were performed using molecular profiling, functional testing, and histopathological analyses. Finally, the downstream mechanism of itaconate in aging was investigated by single-cell sequencing. Results: Elevated Irg1 mRNA levels were observed in renal and multiple extrarenal organs of aged mice. Macrophage-specific Irg1 deficiency exacerbated aging phenotypes, increasing SASP factors senescence markers,and multi-organ damage. 4-OI treatment can supress SASP factors,alleviate aging in vivo and in vitro. Single-cell analysis and further experiments revealed apolipoprotein E mediated the effect of itaconate in aging. Conclusion: This study reveals the inhibitory and therapeutic effects of itaconate on SASP in aging-related kidney and extrarenal organ damage and elucidates that this process is mediated by APOE. These findings provide new targets for the prevention and treatment for aging-related diseases. Funding: Government Support – Non-U.S.