Hyperhomocysteinemia and Klotho in kidney-to-brain signaling: a metabolic stress-resilience framework for neurovascular dysfunction

Hyperhomocysteinemia (HHcy) and Klotho deficiency are commonly investigated in separate metabolic, renal, vascular, and neurological contexts, yet together they may illuminate how peripheral dysfunction is translated into cerebral vulnerability. This review develops a kidney-to-brain stress resilience framework in which HHcy represents a renal dysfunction-associated component of systemic metabolic and vascular stress, whereas α-Klotho represents a candidate indicator of biological resilience, supported mainly by experimental evidence and observational human studies. Declining renal function favors Hcy accumulation, reduces renal Klotho expression, and generates uremic, inflammatory, mineral, and hemodynamic disturbances that converge on the cerebral microvasculature. Experimental HHcy can additionally repress renal KL through HDAC9-dependent epigenetic regulation. At the brain-facing interface, circulating Hcy directly disrupts cerebral endothelial bioenergetics, redox homeostasis, inflammatory signaling, and tight-junction integrity, providing a plausible route from systemic metabolic disturbance to blood–brain barrier (BBB) and neurovascular-unit (NVU) dysfunction. Klotho-related mechanisms, in contrast, are associated with endothelial, antioxidant, mitochondrial, anti-inflammatory, and anti-senescent resilience, although circulating, renal, and CNS Klotho represent non-equivalent compartments and the causal contribution of circulating Klotho to human neurological disease remains uncertain. Clinical and imaging evidence from chronic kidney disease, cerebral small-vessel disease (CSVD), cognitive impairment, and ischemic stroke supports individual components of the proposed kidney circulation BBB/NVU brain continuum, but not a validated linear HHcy-Klotho molecular axis. We therefore define HHcy-high/Klotho-low status as a candidate metabolic stress-resilience phenotype and propose that the critical test is whether Klotho modifies the neurovascular consequences of a given Hcy burden. Establishing this framework will require cell-specific perturbation, compartment-resolved Klotho measurement, longitudinal neuroimaging, and prospective analyses linking renal dysfunction, BBB/NVU injury, CSVD progression, and cognitive decline.