Triiodothyronine (T3) enhances lifespan and protects against oxidative stress via activation of Klotho in Caenorhabditis elegans

Age predisposes individuals to significant diseases, and the biological processes contributing to aging are currently under intense investigation. Klotho is an anti-aging protein with multifaceted roles and is an essential component of the endocrine fibroblast growth factor. In Caenorhabditis elegans (C. elegans), there are two prospective orthologs of α-Klotho, C50F7.10, and E02H9.5, identified. The two orthologs' products are homologous to the highly conserved KL1 domain of human and mouse Klotho protein. Considering the endocrine system's major involvement in an organism's homeostasis and that thyroid disorders increase with advancing age, the molecular mechanisms underlying its impact on different endocrine components during the aging process remain poorly characterized. In this study, we sought to determine the regulatory role of Triiodothyronine (T3) on homologs genes of klotho and its impact on different parameters of aging in the C. elegans model organism. We showed that T3 could increase the mRNA expressions of the klotho homologous genes in C. elegans. Moreover, T3 could also extend a worm lifespan and modulate oxidative stress resistance and aging biomarkers significantly and positively. Further investigations employing different mutant and transgenic strains reveal that these observed effects are mediated through the EGL-17/EGL-15 pathway via Klotho activation along with the involvement of transcription factor DAF-16. In conclusion, these findings have revealed an unexpected link between T3 and Klotho and how this link can modulate the aging process in C. elegans via activation of klotho. This study will help understand the crosstalk and regulations of different endocrine components and their consequences on the aging process in multiple species.