Background: The mechanism by which polymorphisms in the anti-aging protein klotho lead to increased disease risk is unknown. Results: In vitro, klotho-VS decreases homodimerization and increases heterodimerization with and activation of FGFR1c. Conclusion: Altered dimerization explains klotho-VS association with increased disease risk. Significance: Understanding how the VS variant leads to changes in klotho function will elucidate the role klotho plays in disease and lifespan.© 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.