The mediating influence of serum Klotho levels and the KL-VS heterozygosity on telomere shortening in schizophrenia

Abstract

Schizophrenia (SZ) has a considerable contribution of accelerated aging, and exploration of the mechanistic underpinnings of telomere attrition, one of the core pathophysiological hallmarks of accelerated aging could boost the development of new avenues for intervention in SZ. The longevity protein Klotho (KL) is reported to regulate the expression of key factors like telomeric repeat-binding factor. We tested the cross-sectional association between KL levels, its longevity genetic variant KL-VS and telomere length in schizophrenia, including 240 patients and 243 healthy controls (HCs). Relative telomere length (rTL) was measured through real-time polymerase chain reaction, and the KL-VS variant was genotyped using TaqMan® allelic discrimination assay. The associations between study variables were tested using linear regression, and mediation analysis was conducted using the SPSS Macro PROCESS. There was a significant association between rTL with serum KL levels in chronic patients, indicating their coregulation in the disease. KL levels partly mediated the indirect negative influence of telomere length on the risk of schizophrenia, with a 27.26 % contribution to the total association between telomere length and schizophrenia, substantiating the role of deficiency of circulating Klotho in partly contributing to the process of accelerated aging in schizophrenia. Furthermore, serum KL levels and heterozygosity of the KL-VS variant (Het^+ve) were significantly and positively associated with rTL in patients with SZ, but not in HCs, indicating a disease-specific influence of the KL on telomere length, which supports the hypothesis of a contextual advantage.