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Today, we want to highlight a new study that used in silico analysis to look at the interaction between metformin and SIRT1 [1].

SIRT1 and metabolism

Silent mating type information regulation 2 homolog (SIRT1) is a member of the sirtuin protein family, and studies suggest that human sirtuins act as intracellular regulatory proteins.

Sirtuin 1 is downregulated in cells with high insulin resistance, and inducing its expression in those cells increases insulin sensitivity [2]. This and other research suggests that SIRT1 is an important molecule involved in regulating metabolism and insulin sensitivity.

SIRT1 is known to stimulate autophagy, linking sirtuin expression with the cellular response to limited nutrients experienced during caloric restriction [3]. SIRT1 is also known to influence both members of the PGC1-alpha/ERR-alpha complex, which are key regulatory transcription factors in metabolism [4-6]

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is the master regulator of proinflammatory genes [7], and SIRT1 is shown to inhibit NF-κB-mediated gene expression [8]. This means that SIRT1 plays a key role in the chronic age-related inflammation known as inflammaging.

In normal metabolism, SIRT1 expression relies on the presence of NAD+; however, with age, NAD+ decreases significantly, meaning that SIRT1 activation becomes deregulated. The findings of the new study strongly suggest that the diabetic drug metformin is able to activate SIRT1 directly, even in a low-NAD+ environment.

Abstract

Metformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an in silico analysis focusing on the molecular docking and dynamic simulation of the putative interactions between metformin and SIRT1. Using eight different crystal structures of human SIRT1 protein, our computational approach was able to delineate the putative binding modes of metformin to several pockets inside and outside the central deacetylase catalytic domain. First, metformin was predicted to interact with the very same allosteric site occupied by resveratrol and other sirtuin-activating compounds (STATCs) at the amino-terminal activation domain of SIRT1. Second, metformin was predicted to interact with the NAD+ binding site in a manner slightly different to that of SIRT1 inhibitors containing an indole ring. Third, metformin was predicted to interact with the C-terminal regulatory segment of SIRT1 bound to the NAD+ hydrolysis product ADP-ribose, a “C-pocket”-related mechanism that appears to be essential for mechanism-based activation of SIRT1. Enzymatic assays confirmed that the net biochemical effect of metformin and other biguanides such as a phenformin was to improve the catalytic efficiency of SIRT1 operating in conditions of low NAD+ in vitro. Forthcoming studies should confirm the mechanistic relevance of our computational insights into how the putative binding modes of metformin to SIRT1 could explain its ability to operate as a direct SIRT1-activating compound. These findings might have important implications for understanding how metformin might confer health benefits via maintenance of SIRT1 activity during the aging process when NAD+ levels decline.

Conclusion

This is further support for the importance of NAD+ in maintaining metabolism and the role of SIRT1 in that process. It is interesting that metformin may be compensating for the loss of NAD+ in age via the direct activation of SIRT1.

Literature

[1] CUYÀS, E., VERDURA, S., LLORACH-PARÉS, L. A. U. R. A., FERNÁNDEZ-ARROYO, S. A. L. V. A. D. O. R., JOVEN, J., MARTIN-CASTILLO, B. E. G. O. Ñ. A., … & MENENDEZ, J. A. (2018). Metformin is a direct SIRT1-activating compound: Computational modeling and experimental validation. Frontiers in Endocrinology, 9, 657.

[2] Sun, C., Zhang, F., Ge, X., Yan, T., Chen, X., Shi, X., & Zhai, Q. (2007). SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell metabolism, 6(4), 307-319.

[3] Lee, I. H., Cao, L., Mostoslavsky, R., Lombard, D. B., Liu, J., Bruns, N. E., … & Finkel, T. (2008). A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proceedings of the National Academy of Sciences, 105(9), 3374-3379.

[4] Rodgers, J. T., Lerin, C., Haas, W., Gygi, S. P., Spiegelman, B. M., & Puigserver, P. (2005). Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature, 434(7029), 113.

[5] Nemoto, S., Fergusson, M. M., & Finkel, T. (2005). SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. Journal of Biological Chemistry, 280(16), 16456-16460.

[6] Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., … & Geny, B. (2006). Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell, 127(6), 1109-1122.

[7] Lawrence, T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009; 1: a001651. External Resources CrossRef (DOI) ISI Web of Science.

[8] Yeung, F., Hoberg, J. E., Ramsey, C. S., Keller, M. D., Jones, D. R., Frye, R. A., & Mayo, M. W. (2004). Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase. The EMBO journal, 23(12), 2369-2380.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.
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