Discovery of a quinoline-based senomorphic agent for the treatment of chronic kidney disease

Area of Science:

• Gerontology and Regenerative Medicine
• Drug Discovery and Development
• Cellular Biology and Aging

Background:

• Cellular senescence is a key risk factor for age-related chronic diseases.
• Existing anti-aging compounds, like C1, face limitations due to cytotoxicity.
• Optimizing anti-aging strategies requires balancing efficacy with safety in mammalian systems.

Purpose of the Study:

• To structurally optimize C1, a lifespan-extending enrofloxacin derivative, to enhance safety while preserving anti-aging effects.
• To evaluate the efficacy of the optimized derivative, C36, in mitigating senescence and improving organ function in aging models.
• To explore the potential of C36 as a senomorphic therapeutic for age-related conditions, particularly chronic kidney disease (CKD).

Main Methods:

• Synthesized 37 derivatives of C1, focusing on structural modifications to reduce cytotoxicity.
• Assessed lifespan extension and cytotoxicity of derivatives in *Caenorhabditis elegans* (C. elegans) and mammalian cell lines.
• Utilized mouse models of induced senescence and kidney failure to evaluate C36's impact on senescence markers, SASP, renal function, and fibrosis.

Main Results:

• Derivative C36 demonstrated significant lifespan extension (11.49%) in C. elegans with low cytotoxicity (IC50 > 100 μM) in mammalian cells.
• C36 treatment attenuated the senescence-associated secretory phenotype (SASP), reduced cell cycle arrest, and lowered aging markers in kidneys of mice with induced senescence.
• In mice with kidney failure, C36 reduced SASP, alleviated kidney senescence, improved renal function, decreased renal fibrosis by ~50%, and lowered senescence markers (p21, p16, p53).

Conclusions:

• Structurally optimized derivative C36 exhibits potent anti-aging effects with improved safety profiles.
• C36 acts as a senomorphic agent, effectively reducing senescence and SASP in aging kidneys and improving renal function.
• C36 holds potential for therapeutic applications in age-related diseases, including chronic kidney disease, and warrants further investigation for drug repurposing.