Klotho KL-VS variant

The KL-VS haplotype of the klotho gene (comprising variants F352V and C370S in exon 2) increases serum klotho protein levels and is associated with longevity in heterozygous but not homozygous carriers — a pattern consistent with heterozygote advantage. Heterozygous KL-VS carriers show elevated circulating klotho and, in several studies, improved cognitive function and reduced dementia risk, with functional MRI data suggesting enhanced prefrontal connectivity (Dubal et al., 2014; Yokoyama et al., 2015). The variant also associates with favorable cardiovascular and bone mineral density profiles in some cohorts. Mechanistically, higher serum klotho is thought to enhance FGF23 co-receptor signaling, modulate Wnt and IGF-1 pathways, and exert neuroprotective effects independently of its endocrine roles.