Scientists Find That Protein Controls Aging By Controlling Insulin

Theprotein, Klotho, is found in several species. In mice, the researchersdiscovered, it acts as a hormone, circulating through the blood andbinding to cells.

Therapies based on this hormone could prove tobe a way to extend life or slow its effects, said Dr. Makoto Kuro-o,assistant professor of pathology and senior author of the studypublished in today's online issue of Science Express and appearing inan upcoming issue of Science. "It could be one of the significant stepsfor developing anti-aging therapy."

Dr. Kuro-o and his colleaguesoriginally discovered the Klotho gene in 1997, naming it after one ofthe mythical Greek fates who controlled the length of human life. Theirprevious studies have shown that mutant mice lacking the Klotho geneappear normal until about 3 to 4 weeks old, and then begin showingsigns of age, such as skin atrophy, osteoporosis, arteriosclerosis andemphysema. The mice died prematurely at about two months.

For thecurrent study, they created a second strain of mutant mice in which theKlotho gene generated more of the protein than in normal mice. Thosemice lived between 19 percent to 31 percent longer than normal mice.

Theresearchers were especially interested in how the hormone affectedinsulin, because making an animal resistant to insulin increases itslifespan - a phenomenon found in animals ranging from worms to fruitflies to mice.

The mice with higher levels of Klotho had moreinsulin in their system than the normal mice, suggesting that theKlotho mice were resistant to insulin; they had to make more of it tomake up for the resistance. The opposite was true with the micedeficient in Klotho. They were more sensitive to insulin and hadreduced levels of it.

The influence on insulin creates a problemfor Klotho should it be used as a therapy against aging: It may extendlife, but it could also make an animal diabetic.

Mice with theexcessive Klotho also had fewer offspring than normal mice, said Dr.Kuro-o, a Southwestern Medical Foundation Scholar in BiomedicalResearch.

Other UT Southwestern researchers involved in the studywere Dr. Hiroshi Kurosu, senior research associate in pathology andlead author; Dr. Masaya Yamamoto, postdoctoral researcher in pathology;Jeremy Clark, research technician in pathology; Johanne Pastor, seniorresearch associate in pathology; Dr. Animesh Nandi, research scientistin pathology; Prem Gurnani, research associate in pathology; Dr.Yoshiharu Takayama, postdoctoral researcher in molecular genetics; Dr.Joachim Herz, professor of molecular genetics and in the Center forBasic Neuroscience, and Dr. Kevin Rosenblatt, assistant professor inpathology. Researchers from Vanderbilt University School of Medicine,the University of Tokyo, Osaka University and Joslin Diabetes Centeralso participated.

The work was supported by the Endowed ScholarsProgram in Medical Science at UT Southwestern, The Pew Scholars Programin the Biomedical Sciences, the Eisai Research Fund, the HighImpact/High Risk Research Program at UT Southwestern and the NationalInstitutes of Health.