A recent study published in Molecules has tested multiple thiazole-based derivatives that appear to activate the sirtuin SIRT1 more than resveratrol .
Resveratrol, commonly found in grape skins and red wine, generated some of the initial interest in sirtuin activators after initial studies showing many therapeutic benefits, such as cancer prevention . Combined with the discovery of the seven human homologs of the yeast Sir2 protein , researchers delved into ways to stimulate sirtuin genes.
These sirtuins (Sir2-like proteins) have great relevance to the mechanisms of aging. The seven sirtuin proteins (SIRT1-7) are NAD-dependent enzymes that consume NAD+ to perform their two functions of regulating mono-ADP-ribosylation and performing deacetylation. The NAD+ acts as a cofactor for these functions and has created a whole branch of research around NAD+ precursors, such as NMN and NR, that lead to the stimulation of sirtuin activity.
Sirtuin activators work by increasing the binding affinity to acetylated substrates; for example, MDL-800 increases SIRT6’s binding affinity, and hence activity, 22-fold . Resveratrol greatly activates SIRT1, a cancer-suppressing protein with many other health benefits , but it is limited in its bioavailability, leading to impressive results in vitro but subpar in vivo results .
These specific compounds had not been previously tested regarding sirtuin activation, but they were similar to other molecules that the research group had tested. The researchers made slight changes to these synthetic molecules, which are based on natural polyphenol activators such as resveratrol, and measured their ability to activate the gene.
These molecular alterations involved the movement of hydroxide groups, and placing these groups at specific places on the ends of the molecule proved useful. Different concentrations of each of the new compounds were tested against a reference treatment of resveratrol (100 µM) in vitro. At least two compounds performed similarly, and one had 116% ± 25.9% SIRT1 activation compared to resveratrol. With lower concentrations of 10 and 30 µM, compounds 8 and 9 showed 140% ± 8% and 155% ± 3%, respectively.
This compound showed higher activation of SIRT1 genes without causing any toxic events in vitro at 10 µM. In vivo tests were performed in a rat model of ischemic heart disease and demonstrated significant positive effects, protecting them against injury.
This new molecule has been shown to activate SIRT1 to a greater extent than resveratrol. In vivo tests of bioavailability have yet to be done, but this is a promising start for a new and potentially superior SIRT1-activating compound. While sirtuins are still not fully understood and overexpression may lead to increased tumor cell migration and lung metastasis , this is still a critical discovery of a new class of thiazole-based SIRT1-activating compounds.
We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. We are committed to responsible journalism, free from commercial or political influence, that allows you to make informed decisions about your future health.
All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future. You can support us by making a donation or in other ways at no cost to you.
GIVE PER MONTH
Vitalik Buterin Exclusive Interview: Longevity, AI and More
Centenarians Have Slightly Different Gut Ecologies
Hypoxia Extends Median Lifespan in Fast-Aging Mice by 50%
Discovering Why Adrenal Cancer Is More Dangerous for Women
 Bononi, G., Citi, V., Lapillo, M., Martelli, A., Poli, G., Tuccinardi, T., Granchi, C., Testai, L., Calderone, V., & Minutolo, F. (2022). Sirtuin 1-Activating Compounds: Discovery of a Class of Thiazole-Based Derivatives. Molecules, 27(19). https://doi.org/10.3390/molecules27196535
 Jang, M., Cai, L., Udeani, G. O., Slowing, K. v., Thomas, C. F., Beecher, C. W. W., Fong, H. H. S., Farnsworth, N. R., Kinghorn, A. D., Mehta, R. G., Moon, R. C., & Pezzuto, J. M. (1997). Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science, 275(5297), 218–220. https://doi.org/10.1126/science.275.5297.218
 Frye, R. A. (2000). Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochemical and Biophysical Research Communications, 273(2), 793–798. https://doi.org/10.1006/bbrc.2000.3000
 Huang, Z., Zhao, J., Deng, W., Chen, Y., Shang, J., Song, K., Zhang, L., Wang, C., Lu, S., Yang, X., He, B., Min, J., Hu, H., Tan, M., Xu, J., Zhang, Q., Zhong, J., Sun, X., Mao, Z., … Zhang, J. (2018). Identification of a cellularly active SIRT6 allosteric activator. Nature Chemical Biology, 14(12), 1118–1126. https://doi.org/10.1038/s41589-018-0150-0
 Chen, C., Zhou, M., Ge, Y., & Wang, X. (2020). SIRT1 and aging related signaling pathways. In Mechanisms of Ageing and Development (Vol. 187). Elsevier Ireland Ltd. https://doi.org/10.1016/j.mad.2020.111215
 Yu, C., Shin, Y. G., Chow, A., Li, Y., Kosmeder, J. W., Lee, Y. S., Hirschelman, W. H., Pezzuto, J. M., Mehta, R. G., & van Breemen, R. B. (2002). Human, Rat, and Mouse Metabolism of Resveratrol.
 Suzuki, K., Hayashi, R., Ichikawa, T., Imanishi, S., Yamada, T., Inomata, M., Miwa, T., Matsui, S., Usui, I., Urakaze, M., Matsuya, Y., Ogawa, H., Sakurai, H., Saiki, I., & Tobe, K. (2012). SRT1720, a SIRT1 activator, promotes tumor cell migration, and lung metastasis of breast cancer in mice. Oncology Reports, 27(6), 1726–1732. https://doi.org/10.3892/or.2012.1750
Write a comment: