The Anti-Aging Effect of Metformin on C. elegans Through Idha-1, an Isocitrate Dehydrogenase in the TCA Cycle

Songting Zhu

doi:10.54254/2753-8818/2025.AU25075

Theoretical and Natural ScienceOpen access

The Anti-Aging Effect of Metformin on C. elegans Through Idha-1, an Isocitrate Dehydrogenase in the TCA Cycle

Research Article

Open Access

The Anti-Aging Effect of Metformin on C. elegans Through Idha-1, an Isocitrate Dehydrogenase in the TCA Cycle

Songting Zhu ^1*

¹ Asheville School, Asheville, United States

^*Corresponding author: ammmyzhu515@gmail.com

Published on 20 July 2025

TNS Vol.126

ISSN (Print): 2753-8826

ISSN (Online): 2753-8818

ISBN (Print): 978-1-80590-265-2

ISBN (Online): 978-1-80590-266-9

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Abstract

Global population aging is a hot topic in the 21stcentury, and it drives demand for anti-aging interventions. However, there are no proven anti-aging drugs available, and there are also ethical and practical challenges in testing anti-aging compounds in humans. In this case, Caenorhabditis elegans (C.elegans) serves as a powerful model to study aging due to genetic similarities with humans and short lifespans. In this study, we tested the effect of four compounds (metformin, rapamycin, royal jelly, and rilmenidine) on C. elegans aging. Metformin and rapamycin significantly extended lifespan by 30% and 23%, respectively. Meanwhile, metformin uniquely enhanced the pumping rate, indicating slowed aging. Among the aging-related pathways in C. elegans, the metabolic genes play a vital function. To test the mechanism of metformin in slowing aging, we analyzed the aging-related metabolic genes with RT-qPCR. Metformin was demonstrated to upregulate the expression of the metabolic gene, isocitrate dehydrogenase alpha-1 (idha-1), potentially by elevating the tolerance to oxidative stress. Results highlight idha-1 as a key target for anti-aging interventions.

Keywords:

Caenorhabditis elegans, aging, metformin, rapamycin, royal jelly, rilmenidine

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References

[1]. Kaeberlein, M. (2018). "How healthy is the healthspan concept?" Geroscience 40(4): 361-364.

[2]. Le Couteur, D. G. and J. Thillainadesan (2022). "What Is an Aging-Related Disease? An Epidemiological Perspective." J Gerontol A Biol Sci Med Sci 77(11): 2168-2174.

[3]. Murphy, C. T. and P. J. Hu (2013). "Insulin/insulin-like growth factor signaling in C. elegans." WormBook: 1-43.

[4]. Vagero, D., et al. (2018). "Why is parental lifespan linked to children's chances of reaching a high age? A transgenerational hypothesis." SSM Popul Health 4: 45-54.

[5]. Zhang, Y. P., et al. (2022). "Intestine-specific removal of DAF-2 nearly doubles lifespan in Caenorhabditis elegans with little fitness cost." Nat Commun 13(1): 6339.

[6]. Martel, J., et al. (2020). "Plant and fungal products that extend lifespan in Caenorhabditis elegans." Microb Cell 7(10): 255-269.

[7]. Pan, H. and T. Finkel (2017). "Key proteins and pathways that regulate lifespan." J Biol Chem 292(16): 6452-6460.

[8]. Navabpour, S., et al. (2020). "A neuroscientist's guide to transgenic mice and other genetic tools." Neurosci Biobehav Rev 108: 732-748.

[9]. Mitani, S. (2017). "Comprehensive functional genomics using Caenorhabditis elegans as a model organism." Proc Jpn Acad Ser B Phys Biol Sci 93(8): 561-577.

[10]. Brenner, S., & Gratzer, W. (1997). Loose ends. Nature, 390(6655), 35-35.

[11]. Lin, Z., et al. (2023). "Transcriptome analysis of the adenoma-carcinoma sequences identifies novel biomarkers associated with development of canine colorectal cancer." Front Vet Sci 10: 1192525.

[12]. Steven, R., et al. (2005). "The UNC-73/Trio RhoGEF-2 domain is required in separate isoforms for the regulation of pharynx pumping and normal neurotransmission in C. elegans." Genes Dev 19(17): 2016-2029.

[13]. Papadopoli, D., et al. (2019). "mTOR as a central regulator of lifespan and aging." F1000Res 8.

[14]. Fabrizio, P., et al. (2001). "Regulation of longevity and stress resistance by Sch9 in yeast." Science 292(5515): 288-290.

[15]. Vellai, T., et al. (2003). "Genetics: influence of TOR kinase on lifespan in C. elegans." Nature 426(6967): 620.

[16]. Barzilai, N., et al. (2016). "Metformin as a Tool to Target Aging." Cell Metab 23(6): 1060-1065.

[17]. Orsolic, N. and M. Jazvinscak Jembrek (2024). "Royal Jelly: Biological Action and Health Benefits." Int J Mol Sci 25(11).

[18]. Bennett, D. F., et al. (2023). "Rilmenidine extends lifespan and healthspan in Caenorhabditis elegans via a nischarin I1-imidazoline receptor." Aging Cell 22(2): e13774.

[19]. Parkhitko, A. A., et al. (2020). "Targeting metabolic pathways for extension of lifespan and healthspan across multiple species." Ageing Res Rev 64: 101188.

[20]. Katewa, S. D., et al. (2014). "Mitobolites: the elixir of life." Cell Metab 20(1): 8-9.

[21]. Lin, Z. H., et al. (2022). "Isocitrate Dehydrogenase Alpha-1 Modulates Lifespan and Oxidative Stress Tolerance in Caenorhabditis elegans." Int J Mol Sci 24(1).

[22]. Gabriel, J. L., et al. (1986). "Activity of purified NAD-specific isocitrate dehydrogenase at modulator and substrate concentrations approximating conditions in mitochondria." Metabolism 35(7): 661-667.

[23]. Kishore, R., et al. (2020). "Automated generation of gene summaries at the Alliance of Genome Resources." Database (Oxford) 2020.

[24]. Barros, S., et al. (2022). "Metformin disrupts Danio rerio metabolism at environmentally relevant concentrations: A full life-cycle study." Sci Total Environ 846: 157361.