Aging, Klotho, and Mitochondrial Dysfunction in Cardiovascular–Kidney–Metabolic Syndrome: From Biological Mechanisms to Personalized Prevention and Treatment

Cardiovascular–kidney–metabolic (CKM) syndrome integrates three major chronic disease burdens — heart failure, chronic kidney disease, and metabolic dysfunction — into a unified pathophysiological framework. Accumulating evidence positions biological aging as the central substrate linking CKM risk factors to organ failure. Cardiac aging promotes mitochondrial dysfunction, diastolic stiffening, and impaired repair capacity; renal aging depletes tubular cell renewal, accelerates fibrosis, and reduces the production of the anti-aging hormone α-Klotho; pancreatic β-cell aging drives p16INK4a-mediated senescence and mitochondrial uncoupling that impair first-phase insulin secretion, constituting a primary metabolic driver of early CKM progression. Klotho, a kidney-derived endocrine factor whose circulating levels decline with CKD progression and metabolic disease, regulates cellular proliferation and mitochondrial homeostasis through the Sirt1–CHK2 signaling axis. Three-dimensional electron microscopy of aged renal tubular mitochondria reveals age-dependent loss of cristae structural integrity associated with reduced expression of the MICOS complex—the protein scaffold that maintains cristae junction architecture. Parallel volumetric electron microscopy of human failing myocardium demonstrates distinct mitochondrial structural phenotypes in heart failure with preserved ejection fraction (HFpEF) versus Heart Failure with Reduced Ejection Fraction (HFrEF), underscoring the specificity of mitochondrial remodeling in the CKM context. Measurement of circulating Klotho, senescence-associated secretory phenotype (SASP) markers, and urinary mitochondrial DNA provides a biological staging dimension that complements standard CKM clinical classification. The mitochondria-targeted peptide elamipretide (SS-31) — the most mature pharmacological intervention targeting inner mitochondrial membrane integrity — has demonstrated tremendous functional benefits in numerous pre-clinical models of heart failure, though the effect in HFpEF trial remains inconclusive. Together, these data outline a personalized medicine approach to CKM syndrome in which biological aging phenotype guides therapeutic strategy.