Klotho KL-VS variant
DEKlotho-KL-VS-Variante
Reviewed by Maurice Lichtenberg
The KL-VS haplotype of the klotho gene (six linked variants in complete linkage disequilibrium, two of which produce the amino-acid substitutions 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.
Sources
- Yokoyama JS, Sturm VE, Bonham LW, et al.. (2015). Variation in longevity gene KLOTHO is associated with greater cortical volumes. *Annals of Clinical and Translational Neurology*doi:10.1002/acn3.161
- Liu H, Fergusson MM, Castilho RM, et al.. (2007). Augmented Wnt signaling in a mammalian model of accelerated aging. *Science*doi:10.1126/science.1143578
- Dubal DB, Yokoyama JS, Zhu L, Broestl L, Worden K, Wang D, Sturm VE, Kim D, Klein E, Yu GQ, Ho K, Eilertson KE, Yu L, Kuro-o M, De Jager PL, Coppola G, Small GW, Bennett DA, Kramer JH, Abraham CR, Miller BL, Mucke L. (2014). Life extension factor klotho enhances cognition. *Cell Reports*doi:10.1016/j.celrep.2014.03.076