The anti-aging gene Klotho was named after the Greek Goddess who spins the thread of life. Klotho was discovered in a mouse that showed many manifestations of human aging, including cognitive decline. In contrast, mice that are genetically engineered to express high levels of Klotho live 30% longer. In the brain Klotho's role is entirely unknown. We found that the Klotho protein is significantly reduced in the brain white matter of aged mammals. The long-term project was to identify what causes cognitive decline in 50% of, otherwise healthy, individuals as they age. Our findings indicate that the Klotho protein induces the maturation of brain cells responsible for the production and maintenance of myelin. Myelin, the fatty layer that insulates nerve extensions allowing nerve cells to communicate with each other efficiently, is produced in the brain only by specialized cells called oligodendrocytes, and only by mature oligodendrocytes. The mature cells are derived from oligodendrocyte precursor cells in the presence of specific growth factors. We hypothesized that the precursor cells need Klotho as a growth factor to become mature, myelin-producing oligodendrocytes. This discovery is of particular relevance to understanding what causes white matter abnormalities in Alzheimer's disease and failed repair of myelin in multiple sclerosis. We then screened 150,000 small compounds and identified a number of lead compounds able to elevate Klotho protein expression.Next step is to test whether optimized Klotho-enhancing compounds have the potential to induce the maturation of oligodendrocyte precursor cells, first in the petri dish. The results will directly lead to in vivo testing of optimized compounds in animal models of Alzheimer's disease and multiple sclerosis. These studies are expected to provide a better understanding of the functions of Klotho in myelin biology, and lead to ways to protect brain myelin against age-dependent and pathological changes.