Aging is inevitable; however, the molecular mechanism of aging has not been fully elucidated. Investigations into aging are facing difficulties because aging is influenced by complex factors such as circumstances, living habits and genetic background. Recently, a variety of animals, such as Caenorhabditis elegans, Drosophila and mice, that have aberrations in their lifespan, have been investigated and a large number of genes related to aging have been found, one of which is alpha-klotho. The alpha-Klotho mouse (alpha-kl(-/-) mouse), which has a defect of the alpha-klotho gene expression, was established a decade ago. It is of great interest because the alpha-kl(-/-) mouse shows various phenotypes resembling human aging. The relationship between aging and alpha-klotho protein function is gradually becoming clear. This review covers the recent advance in alpha-klotho protein research.