Longevity Factor Klotho and Resistance to Cognitive Deficits in Individuals with Parkinson's Disease and in an α-Synuclein Mouse Model.

Aging is the primary risk factor for Parkinson's disease (PD), and PD-related cognitive impairment remains a major unmet biomedical challenge. Klotho, a pleiotropic protein, extends lifespan and enhances cognition, but whether it confers resilience to cognitive impairments in PD is unclear. Here, we show that in humans, the KL-VS genetic variant of <i>KLOTHO</i>, linked to higher circulating klotho levels, associated with better executive cognition in individuals with PD across two independent cohorts. To test causality and explore mechanisms, we turned to mouse models. Transgenic elevation of klotho in a mouse model increased lifespan, improved synaptic and cognitive, but not motor, functions in mice, and decreased steady-state α-synuclein (α-syn) levels in the brains of male mice expressing wild-type human α-syn. Complementary in vitro studies showed that klotho rescued α-syn-induced deficits in NMDAR-dependent signaling through GluN2B and augmented α-syn microglial-related uptake, suggesting a potential mechanism by which klotho counters PD-related toxicity. Together, these findings indicate that klotho can counteract cognitive deficits related to PD, possibly by modulating α-syn levels, and these findings may be relevant to new therapeutic pathways for PD.