The Review Of Anti-aging Mechanism Of Polyphenols On Caenorhabditis Elegans Part 2
Jul 26, 2023
TANNINS
Tannic acid (TA) belongs to the hydrolyzable tannins, containing five gallic acid residues covalently linked to a central glucose molecule, and it can precipitate protein. As a strong anti-oxidant, the observed increase in heat stress resistance and oxidative stress resistance is not due to its ability to directly remove oxygen free radicals but its ability to act as a stimulus to activate the anti-oxidant system of the body (Saul et al., 2010, 2011). Studies have shown that a low concentration of TA might simulate mild pathogenic stress, strengthen the SEK-1-based pathogen defense system, inhibit the potentially harmful effects of TA, and induce nematodes to prolong their life effectively (Saul et al., 2010). In addition, TA itself does not reduce the food intake of nematodes, but exerts molecular regulation through eat-2 in the DR pathway or precipitates and combines nutritional proteins and digestive enzymes (eat-2 mutant suffered from insufficient food intake due to decreased pharyngeal pumping). It is worth noting that the concentration range of health effects of TA is relatively narrow, so it is also very important to find a suitable concentration to treat C. elegans. Unlike TA, ellagic acid (EA) can be used as a chemical repellent to reduce the feeding behavior of nematodes and prolong the lifespan of nematodes by its strong antibacterial ability (Saul et al., 2011). Oenothein B (Chen et al., 2020) and pentagalloyl glucose (Chen et al., 2014) extracted from eucalyptus leaves can prolong healthy life by regulating multiple targets. They can regulate the IIS pathway via age-1 and daf- 16, the DR pathway via eat-2 and sir-2.1, and the mitochondrial electron transfer chain via isp-1 to promote healthy life, including reducing age pigment and ROS accumulation and improve exercise flexibility, heat stress tolerance, and lifespan. isp-1 is one of the genes encoding mitochondrial electron transport chain components, and the deletion of isp-1 exists in the respiratory chain complex III. Their mechanism of action might be the same because of their similar structure.
Glycoside of cistanche can also increase the activity of SOD in heart and liver tissues, and significantly reduce the content of lipofuscin and MDA in each tissue, effectively scavenging various reactive oxygen radicals (OH-, H₂O₂, etc.) and protecting against DNA damage caused by OH-radicals. Cistanche phenylethanoid glycosides have a strong scavenging ability of free radicals, a higher reducing ability than vitamin C, improve the activity of SOD in sperm suspension, reduce the content of MDA, and have a certain protective effect on sperm membrane function. Cistanche polysaccharides can enhance the activity of SOD and GSH-Px in erythrocytes and lung tissues of experimentally senescent mice caused by D-galactose, as well as reduce the content of MDA and collagen in lung and plasma, and increase the content of elastin, have a good scavenging effect on DPPH, prolong the time of hypoxia in senescent mice, improve the activity of SOD in serum, and delay the physiological degeneration of lung in experimentally senescent mice With cellular morphological degeneration, experiments have shown that Cistanche has the good antioxidant ability and has the potential to be a drug to prevent and treat skin aging diseases. At the same time, echinacoside in Cistanche has a significant ability to scavenge DPPH free radicals and has the ability to scavenge reactive oxygen species and prevent free radical-induced collagen degradation, and also has a good repair effect on thymine free radical anion damage.
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CONCLUSIONS
Before studying the signaling pathway implicated in a certain disease in a model organism, some researchers first test this pathway in suitable cell lines. For example, resveratrol was found in the generation of different effects, such as promoting proliferation in mesenchymal stem cells, with possible involvement of the ERK/GSK-3β pathway (Yoon et al., 2015). Nematodes were further utilized to test the MPK-1 (an ERK homolog) signaling (Yoon et al., 2019). When we treat nematodes with plant extracts, we can first analyze each extract component using mass spectrometry, high-performance liquid chromatography, or similar methods; this analysis might help to identify the key components responsible for the biological effects.
At present, researchers rarely treat C. elegans with polyphenols, such as flavanones and isoflavones; therefore, it is unknown whether or not these polyphenols have direct effects on C. elegans. However, many studies demonstrated that the abovementioned polyphenols can act on homologous genes of C. elegans in other species and that these genes are involved in aging and regulation of lifespan. Flavanones, of which the representative molecule is hesperidin, are mainly found in citrus plants and have been demonstrated to be able to reduce oxidative stress caused by a high-fat diet in mice and to slow down the aging process in old-aged rats. Some studies found that one of the targets of flavanones in animals is Nrf2, whereas C. elegans has an Nrf2-homolog gene, SKN-1 (Ferreira et al., 2016; Barreca et al., 2017; Habtemariam, 2019; Miler et al., 2020). Isoflavones, such as genistein and daidzein, are generally regarded as phytoestrogens; there is evidence that Nrf2 is also one of the downstream targets of isoflavones and that it can also regulate fat metabolism in rats with diet-induced obesity, acting through the AMPK pathway (Li and Zhang, 2017; Krizova et al., 2019). In conclusion, further studies should be conducted to test whether these polyphenols have beneficial effects on C. elegans.
PROSPECTS
To the best of our knowledge, in the study of total polyphenols in plants, especially medicinal plants, their functions, the bioactive substances, and molecular mechanisms for prolonging lifespan and delaying senescence have not received enough attention. For example, mulberry leaves have been widely used in traditional Chinese medicine and folk dietary therapy for their outstanding effects of detoxifying the liver, improving eyesight, and prolonging life. It is believed that mulberry leaf extracts used in traditional Chinese medicine have anti-oxidant and hepatoprotective effects, and those two activities are related to mitochondria function (Meng et al., 2020). Liver tissue contains a large number of mitochondria, and the fatty acids are activated into ester-acyl-coenzyme A, which is metabolized by β oxidation in mitochondria. Acetyl-coenzyme A and fat synthetases required for fatty acid synthesis come from mitochondria. At present, mulberry leaf extract has been confirmed to have beneficial effects on several diseases, such as cancer, type 2 diabetes, and obesity. In addition, modern medicine experiments have proved that mulberry leaf extract can delay aging in mice (Lim et al., 2013; Turgut et al., 2016). Mulberry leaf extract is an effective and natural free-radical scavenger and anti-oxidant, but the research on mulberry leaf extract and mulberry leaf polyphenol is limited to its anti-oxidant activity in vitro, and its specific mechanisms of action have not been elaborated. Moreover, the activities of mulberry leaf polyphenols have not yet been associated with any specific physiological functions. Besides, nematodes being treated by the combination of two extracts from different plants revealed stronger effects than the treatment with only either of the single extract. A recent study shows that nematodes treated with mixtures of blueberry and apple peel extracts have a longer lifespan than those treated with only one substance (Song et al., 2020a,b). Could mulberry leaf extract exert the effects observed in traditional Chinese medicine by regulating fat metabolism? What are the specific anti-aging mechanisms of mulberry leaves in C. elegans? Could the combinations of mulberry leaves, polyphenols, and other polyphenols, or other bioactive substances play their beneficial roles more significantly, and what are their mechanisms? We would like to answer these questions by conducting further research.
AUTHOR CONTRIBUTIONS
ZQ and NL conceived the idea and wrote the manuscript with input from LL, PG, and SZ. PG and PW prepared the figures. LL, PW, and SZ prepared the tables. All authors edited and approved the final manuscript.
FUNDING
This review was supported by the National Natural Science Foundation of China (Nos. 81872584 and 81472941), the National 863 Young Scientist Program (No. 2015AA020940), the Natural Science Foundation of Guangdong Province (No. 2016A030313138), Key R & D and Promotion Project of Henan Province (No. 192102310259), Key Scientific Research Project of Henan Province (No. 21A330001), the Key Projects of Guangzhou Science and Technology Program (No. 201704020056), Interdisciplinary Research for First-Class Discipline Construction Project of Henan University (No. 2019YLXKJC04), the Scientific Research Project for University of Education Bureau of Guangzhou (No. 201831841), and the Yellow River Scholar Foundation of Henan University.
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