Fig. 1.

Existent methods to increase circulating Klotho levels. Recombinant Klotho protein can be given parentally to achieve adequate circulating levels. Klotho cDNA can be delivered. either as naked cDNA (full-length plasmid or minicircles) or encapsulated by adeno-associated virus. The majority of these reside in the liver and Klotho is released. The Klotho gene can be inserted into the genotype as a transgene with a strong promoter driving Klotho protein production. Finally, there are pharmacologic means to increase endogenous Klotho production. Statin: 3-hydroxy-3-methylglutaryl CoA reductase inhibitors. TZD or peroxisome proliferator-activated receptor-gamma agonists. The minicircle technology represents another version of Klotho cDNA. AAV, adeno-associated; PPAR-γ, peroxisome proliferator-activated receptor-gamma; ACEI, angiotensin-converting enzyme inhibitors; TZD, thiazolidinediones.