Five specific polyphenols—bergamot, curcumin, quercetin, catechins, and resveratrol—demonstrate remarkable ability to interrupt the destructive feedback loops driving cardiorenal syndrome through three critical molecular pathways. They activate the Nrf2/HO-1 antioxidant system, suppress NLRP3 inflammasome-driven inflammation, and enhance SIRT1/PINK1/Parkin-mediated mitophagy for mitochondrial quality control. This represents a sophisticated understanding of how natural compounds can simultaneously address oxidative stress, chronic inflammation, and cellular energy dysfunction—the trinity of pathological processes underlying accelerated aging and organ failure. The gut-kidney-heart axis modulation adds another dimension, suggesting these compounds work systemically rather than just locally. However, this remains preclinical evidence with the persistent challenge of bioavailability limiting real-world application. The mention of nano-delivery systems and synthetic analogs indicates researchers recognize this translational gap. For health-conscious adults, this research reinforces the potential of a polyphenol-rich diet, though therapeutic dosing likely requires supplementation. The multitarget approach represents exactly what aging biology demands—compounds that address multiple pathways simultaneously rather than single-target interventions.