Natural Products as Geroprotective Modulators in Diabetic Nephropathy: A Mechanistic Framework Integrating Aging Hallmarks and the AMPK–SIRT1–Nrf2 Axis

Abstract

ABSTRACT Diabetic nephropathy (DN) is not merely a metabolic complication, it is an age‐accelerated kidney disorder in which biological aging pathways amplify hyperglycemic injury. Mounting evidence implicates cellular senescence, mitochondrial dysfunction, chronic inflammation (“inflammaging”), and epigenetic drift as central drivers of DN progression. However, current therapies fail to address these aging mechanisms. This review introduces a geroscience‐based framework in which natural products are conceptualized as geroprotective modulators capable of reprogramming age‐related molecular damage in the diabetic kidney. We integrate preclinical evidence showing that compounds such as resveratrol, quercetin, curcumin, ginsenosides, and berberine restore the AMPK–SIRT1–Nrf2 regulatory triad, thereby rejuvenating mitochondrial bioenergetics, suppressing inflammasome activation, and mitigating fibrosis. A new mechanistic classification model is proposed, categorizing natural products by the specific hallmarks of aging they target; cellular senescence, mitochondrial decline, inflammaging, and epigenetic alterations rather than by chemical class. Finally, we advance a unifying hypothesis: simultaneous activation of the AMPK–SIRT1–Nrf2 axis represents the central mechanism through which diverse natural products confer renoprotection and longevity signaling in DN. By linking geroscience to phytotherapy, this review provides a novel conceptual and mechanistic roadmap for developing multi‐targeted interventions to slow kidney aging and improve outcomes in diabetic patients.