The gene klotho encodes a secreted soluble protein that has been implicated in regulation of lifespan. In rodents, mutation in the gene results in a premature aging syndrome; in humans, specific alleles of the gene appear to improve one’s chances of living an unusually long life.

Klotho is expressed primarily in the kidney. In PNAS this week, Haruna et al. explore the role of the protein in a model of kidney disease. The results indicate that increase klotho gene dosage significantly protects the kidney against degenerative damage:

Klotho, an antiaging gene with restricted organ distribution, is mainly expressed in the kidney tubules; the mutant mice have shortened life span, arteriosclerosis, anemia, and osteoporesis, features common to patients with chronic renal failure. Conceivably, the reduction of the Klotho gene expression may contribute to the development of kidney failure; alternatively, its overexpression may lead to the amelioration of renal injury in an ICR-derived glomerulonephritis (ICGN) mouse model with subtle immune complex-mediated disease. To address this issue, four different strains of mice were generated by cross-breeding: ICGN mice without the Klotho transgene (ICGN), ICGN mice with the Klotho transgene (ICGN/klTG), wild-type mice with the Klotho transgene (klTG), and wild-type mice without the Klotho transgene (control). At 40 weeks old, the survival rate was approximately 30% in ICGN mice, and approximately 70% in the ICGN/klTG group. This improvement was associated with dramatic improvement in renal functions, morphological lesions, and cytochrome c oxidase activity but a reduction in beta-galactosidase activity (a senescence-associated protein), mitochondrial DNA fragmentation, superoxide anion generation, lipid peroxidation, and Bax protein expression and apoptosis. Interestingly, improvement was seen in both the tubular and glomerular compartments of the kidney, although Klotho is exclusively confined to the tubules, suggesting that its gene product has a remarkable renoprotective effect by potentially serving as a circulating hormone while mitigating the mitochondrial oxidative stress.

The results raise the possibility that the otherwise healthy klotho mutant mice (in which the lifespan phenotype was first detected) are dying young because of kidney problems. Is this the case? If so, is it the loss of kidney function per se or problems arising from degenerative cell loss that shorten lifespan? It’s a tough question to answer, because Klotho is a circulating factor. Hence the ideal experiment (transplanting klotho+/+ kidneys into klotho-/- mutant mice to restore normal kidney function) would be complicated by the fact that Klotho secreted by the wildtype kidney could act upon the mutant’s kidneys (and other organs). One would like to have a way of restoring kidney function without introducing more Klotho into the bloodstream, and then asking whether the mutant mice still display a premature aging phenotype.

Mouse dialysis, anyone?