Amino acid metabolism modulates chronic kidney disease progression by mediating the aging process: Mechanistic insights and therapeutic interventions.

Abstract

The kidneys play a vital role in maintaining systemic homeostasis by eliminating waste products, modulating metabolic homeostasis, and performing endocrine functions. Aging, characterized by hallmarks including oxidative stress, chronic inflammation, and metabolic dysregulation, constitutes a major predisposing factor for the pathogenesis of renal diseases. Amino acids serve as critical regulators of cellular metabolism, stress responses, and immune regulation, rendering amino acid metabolism intimately linked to the aging process. This review focuses on the multifaceted interplay between amino acid metabolism and renal aging, with particular emphasis on its implications in chronic kidney disease and related disorders: In senescent cells, accumulated branched-chain amino acids activate the mammalian target of rapamycin complex 1 (mTORC1), while tryptophan metabolites activate the aryl hydrocarbon receptor (AhR). Taurine deficiency impairs mitochondrial function and antioxidant defenses. Glutamine metabolism regulates the clearance of senescent cells through mechanisms including modulation of lysosomal pH and apoptosis. Glycine enhances glutathione synthesis and mitigates oxidative and inflammatory damage. In addition to modulating the aging process, urea cycle amino acids exhibit altered levels in kidney diseases and frequently serve as indicators of disease severity. Furthermore, we propose several promising therapeutic strategies, including nutritional interventions directed at specific amino acids and pharmacological therapies that target the modulation of amino acid metabolism. The relationship between amino acid availability and aging in kidney disease is not merely linear but involves a complex and dynamic interplay. Elucidating these mechanisms with advanced methods is key to developing novel clinical interventions and building a theoretical foundation for translational research.