Cognition impairment in the klotho gene mutant mice and oxidative stress

Klotho is a recently identified gene that is a very different type from those involved in previously described premature-aging syndromes and cell senescence. Although a high level of expression of the klotho gene was detected in the kidney and brain, little is known about the function of the klotho gene in the brain. Here we investigated the changes in mnemonic function accompanying aging in klotho mutant mice. Cognitive function measured by novel-object recognition and conditioned-fear tests in klotho mutant mice was normal at the age of 6 weeks, but markedly impaired at the age of 7 weeks. Lipid peroxide (malondialdehyde) and DNA peroxide (8-hydroxy-2′ -deoxyguanosine) levels in the hippocampus of klotho mutant mice increased at the age of 5 weeks, 2 weeks prior to the development of cognition deficits. Pro-death Bax increased, while anti-death Bcl-2 and Bcl-X_L decreased, and apoptotic TUNEL-positive cells were detected in the hippocampus of klotho mutant mice at the age of 7 weeks. A potent antioxidant α-tocopherol prevented the cognition impairment and lipid peroxide accumulation, and decreased the number of apoptotic cells in klotho mutant mice. These results suggest that oxidative stress has a crucial role in the aging-associated cognition impairment in klotho mutant mice. Klotho protein may be involved in the regulation of antioxidative defense.