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

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Abstract

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.

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Abbreviations

T3:

Triiodothyronine

tBOOH:

Tert-Butyl hydroperoxide

FGFR:

Fibroblast growth factor receptor

µM:

Micro molar

mM:

Milli molar

SEM:

Standard error of mean

FUDR:

5-Fluoro-2′-deoxyuridine

Hours:

Hrs

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Acknowledgements

The authors acknowledge the Department of Biochemistry and Molecular Biology, Pondicherry University, India and Department of Science & Technology (DST), Science and Engineering Research Board (SERB), Government of India, for financial and overall support.

Funding

This work was supported by the Department of Biochemistry and Molecular Biology, Pondicherry University, India. KS is a recipient of funding from SERB (File No EEQ/2016/000343). SKM was supported by a fellowship from the Council of Scientific and Industrial Research (CSIR) (File No 09/559(0128)/2019-EMR-I), Ministry of Science and Technology, Government of India.

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  1. Department of Biochemistry and Molecular Biology, Pondicherry University, Pondicherry, 605 014, India

    Saswat Kumar Mohanty & Kitlangki Suchiang

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  1. Saswat Kumar Mohanty
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SKM: Conceptualization, methodology, investigation, formal analysis, writing—original draft, project administration. KS: Supervision, conceptualization, validation, analysis, review and editing, funding acquisition.

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Correspondence to Kitlangki Suchiang.

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Mohanty, S.K., Suchiang, K. Triiodothyronine (T3) enhances lifespan and protects against oxidative stress via activation of Klotho in Caenorhabditis elegans. Biogerontology 22, 397–413 (2021). https://doi.org/10.1007/s10522-021-09923-0

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