The frequency of Klotho KL-VS polymorphism in a large Italian population, from young subjects to centenarians, suggests the presence of specific time windows for its effect

Abstract

In mice a defect of Klotho gene expression results in multiple aging-like phenotypes including short lifespan, osteoporosis and atherosclerosis, while its over-expression suppresses aging and extends lifespan. Contrasting data have been reported as far as the importance of the functional variant of Klotho termed "KL-VS" on human longevity, depending on the average age of the old subjects that were compared with young controls. We therefore performed a study on a large Italian population sample including people from very young to very old age (centenarians). A total of 1,089 (669 women and 420 men) unrelated individuals from 19 to 109 years, born and residing in northern and central Italy, were subdivided into three age classes defined on the basis of the survival curve constructed using Italian demographic mortality data, and genotyped for the KL-VS allele. We found a significant increase of the heterozygous Klotho genotype in the class of elderly people compared to young controls. On the contrary, no difference was present between centenarians and young controls. Such a non monotonic trajectory is evident only when a large, comprehensive age range is investigated, and is compatible with the hypothesis that this KL-VS heterozygous genotype is favorable for survival in old people, its beneficial effect decreasing thereafter, and becoming no more evident at the extreme ages. Such unusual age-related changes in the Klotho KL-VS genotype frequency is compatible with the hypothesis that alleles and genotypes involved in aging and longevity may exert their biological effect at specific time windows.

Bone mineral density, carotid artery intima-media thickness, and Klotho gene polymorphism in postmenopausal women

“…The authors concluded that, "large differences in allele frequencies were not observed between ethnically and or geographically diverse populations for a given age group," However, our patients were younger than in the aforementioned study. In a study performed on a large Italian population sample, Invidia et al [28] reported a higher frequency of carrier of VV genotype (2.6%) in an age group similar to that of our patients group. We believe that the lack of evidence of F352 polymorphism effect on BMD and IMT measurements observed in our study is much more likely a result of the small sample size, rather than from differences in the allele frequency.…”

Demographic characteristics of Sardinian centenarian genealogies: Preliminary results of the AKeA2 study

“…We regard this result as very important, particularly in relation to the many results recently obtained in genetics. All the data collected in this and other studies suggest that, as well as a variety of nuclear DNA polymorphisms (Di Bona et al 2009;Gravina et al 2009;Invidia et al 2010;Lescai, Marchegiani, and Franceschi 2009;Salvioli et al 2006;Testa et al 2009), maternally inherited mitochondrial DNA variants (Capri et al 2008;Raule et al 2007;Rose et al 2007;Rose et al 2010;Santoro et al 2006) contribute substantially to human longevity too.…”

Promoter methylation and age-related downregulation of Klotho in rhesus monkey

“…Changes in KL gene expression would, over time, impact normal function of all downstream pathways. Evidence of such an effect is observed in the KL polymorphism KL VS (Arking et al 2002) where slight changes in KL function increases risk of disease (Arking et al 2002(Arking et al , 2003(Arking et al , 2005Invidia et al 2010;Wolf et al 2010). Of course, the overall contribution of a small change in one gene would not induce a dramatic phenotype in humans as it does in the KL knockout mouse; however, small changes in KL and numerous other genes would add up over time.…”