Clinical Kidney Journal · 8 authors, 8 centres
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Chronic kidney disease (CKD) drives premature aging and early vascular aging through oxidative stress, inflammation, and gut dysbiosis. Key molecular pathways (Nrf-2, AMPK, SIRT1, klotho) are implicated, and targeting them may offer therapeutic strategies. Premature vascular aging, marked by arterial stiffness, is an independent predictor of cardiovascular and all-cause mortality in CKD patients.
**Background:** Chronic kidney disease (CKD) affects approximately 15% of the US population and is associated with premature aging, characterized by frailty, vascular disease, osteoporosis, and muscle wasting. Premature vascular aging, including arterial stiffening, is a key prognostic marker for mortality and cardiovascular morbidity in CKD. This narrative review summarizes the mechanisms, molecular pathways, and potential therapeutic targets for early aging and premature vascular aging in CKD.
**Methods:** This is a narrative review synthesizing evidence from preclinical and clinical studies on the pathophysiology of early aging in CKD, with a focus on oxidative stress, cellular senescence, inflammation, gut microbiota, advanced glycation end products (AGEs), and fructose consumption. It also reviews the molecular pathways of Nrf-2, AMPK, SIRT1, and klotho, and discusses potential therapeutic strategies.
**Key Results:** Oxidative stress in CKD arises from intravenous iron, RAAS activation, decreased antioxidants, dialysis-related factors, and mitochondrial dysfunction. Cellular senescence, immunosenescence, and inflammaging contribute to sterile inflammation and CKD progression. Altered gut microbiota increases uremic toxins (e.g., indoxyl sulfate, p-cresyl sulfate) and systemic inflammation. AGEs accumulate due to reduced renal excretion and dietary intake, triggering oxidative stress and inflammation. High fructose intake induces tubular injury and accelerates aging in animal models. Premature vascular aging is characterized by medial vascular calcification and increased aortic stiffness, measured by carotid-femoral pulse wave velocity (PWV). Aortic PWV is an independent predictor of all-cause and cardiovascular mortality; a PWV >12 m/s has prognostic value in ESRD patients younger than 60 years. Cardiovascular mortality is 10–30 times higher in ESRD patients versus the general population, and up to 500 times higher in young patients. Key molecular pathways include Nrf-2, which upregulates antioxidant enzymes and inhibits vascular calcification; AMPK, which decreases oxidative stress and improves endothelial function; SIRT1, which reduces oxidative stress, inflammation, and vascular calcification; and klotho, which protects against vascular aging and calcification. Klotho levels decline with age and in CKD, and klotho deficiency is linked to arterial stiffness and hypertension. Several drugs (RAAS inhibitors, statins, metformin, SGLT2 inhibitors, vitamin D) and experimental therapies (recombinant klotho, gene therapy) can increase klotho levels.
**Clinical Implications:** Premature vascular aging is a critical prognostic marker in CKD, especially in younger patients. Clinicians should consider early cardiovascular assessment in younger or early-stage CKD patients. Targeting Nrf-2, AMPK, SIRT1, and klotho pathways may offer therapeutic opportunities. Resveratrol, metformin, and other agents are under investigation. Future large-scale studies are needed to validate these strategies and translate them into clinical practice.