Association of Klotho polymorphisms with healthy aging: a systematic review and meta-analysis.

Today it is clearly evident that genetic background constitutes an integral part of aging and longevity. Many studies on long-lived people have been conducted emphasizing the role of certain genes in long life. Classic case-control studies, genome-wide association studies, and high-throughput sequencing have permitted identification of a variety of genetic variants seemingly associated with longevity. Over the years, aging research has focused on the insulin/insulin-like growth factor-1 (IGF-1) signaling pathway because of its evolutionarily conserved correlation with life-span extension in model animals. Indeed, many single-nucleotide polymorphisms (SNPs) associated with longevity were identified in genes encoding proteins that take part in this metabolic pathway. Closely related to this pathway is the Klotho gene. It encodes a type-I membrane protein expressed in two forms, membrane and secreted. The latter form suppresses oxidative stress and growth factor signaling and regulates ion channels and transporters. In particular, its over-expression seems to be able to suppress insulin/IGF-1 signaling extending life span. Thus, our aim was to assemble the results in the literature concerning the association between the functional variant of the Klotho "KL-VS" stretch, which contains six polymorphisms in linkage disequilibrium, and successful aging to quantify the possible effect of the variants. The results of our systematic review indicate that the Klotho KL-VS variant is associated with healthy aging.