Study on the anti-aging mechanism of Scutellaria baicalensis based on network pharmacology and molecular docking
Population aging is a difficult problem facing China and the world today. The aging population not only brings about a decrease in the age appropriate labor force and an increase in the burden of elderly care for the country and families, but also brings a series of health problems. Research has confirmed that aging is a risk factor for many complex diseases, such as cardiovascular and cerebrovascular diseases, diabetes, cancer, neurodegenerative diseases, etc. Although aging cannot be prevented, it can be delayed through methods such as calorie restriction, genetic manipulation, and drug intervention. More importantly, delaying aging not only prolongs the lifespan of the body, but also significantly improves its health status. For example, in most chronic diseases, limiting food intake can effectively reduce the severity of symptoms; Metformin and rapamycin have been shown to extend life span in many model organisms. Epidemiological studies show that taking metformin and rapamycin in an appropriate amount can prevent the occurrence of many cancers and reduce the incidence rate of neurodegenerative diseases. Therefore, delaying aging is one of the effective methods to reduce the incidence of age-related diseases.
Traditional Chinese Medicine (TCM) has always emphasized health and wellness, treating pre-existing illnesses before they occur. TCM anti-aging has received increasing attention. Erigeron breviscapus (Vant.) Hand Mazz. is a commonly used traditional Chinese medicine for treating age-related diseases such as cardiovascular and cerebrovascular diseases. Its active ingredients are mainly flavonoids and caffeoyl compounds. Research has found that the flavonoid component breviscapine can counteract D-galactose-induced aging, improve memory impairment and abnormal liver and kidney changes in mice, but its mechanism of action is still unclear. However, there is currently no report on whether the caffeic acid compounds in Scutellaria baicalensis have anti-aging effects. Network pharmacology is a research method based on receptor theory and biological network technology that comprehensively elucidates drug action and its mechanism of action. Traditional Chinese medicine is mainly taken orally, and only the components that enter the bloodstream can be effective ingredients for treating diseases and promoting health. In order to explore the anti-aging mechanism of Scutellaria baicalensis and provide ideas for subsequent experimental research, this study retrieved the orally administered blood components of Scutellaria baicalensis, applied network pharmacology methods to predict the anti-aging targets of the blood components, analyzed the biological functions and pathways of action of the targets, and verified the binding effect between the blood components and key targets using molecular docking methods.

Network pharmacology often screens research components based on oral bioavailability (OB) ≥ 30%, half-life (HL) ≥ 4, and drug like (DL) ≥ 0.18. The author found that if the ingredients of Scutellaria baicalensis were screened under these conditions, the main active components of flavonoids, baicalin and caffeic acid, were completely excluded. This is obviously inconsistent with the current understanding that these two types of components are the main active components of Scutellaria baicalensis. Traditional Chinese medicine is mainly taken orally, and the components absorbed into the bloodstream after oral administration may be the active ingredients of traditional Chinese medicine. Therefore, following the approach of serum pharmacochemistry, this study focused on the components present in Scutellaria baicalensis that have been reported to be orally absorbable into the bloodstream as the subject of network pharmacology research. This study retrieved 30 orally administered blood components of Scutellaria baicalensis, including 13 flavonoids, 11 caffeoyl compounds, and 6 other compounds, predicting their effects on 37 aging targets. These 37 targets mainly involve biological processes and pathways such as aging and tumor regulation, which is consistent with the understanding that “tumors and aging are closely related, and aging is the biggest risk factor for tumors”. Research has shown that with age, DNA damage and mutations increase, leading to an increased risk of cancer. In addition, changes in the circulatory system, endocrine system, and immune system caused by aging may also lead to an increase in cancer incidence. PPI network analysis shows that TP53, AKT1, RB1, RHAS, HDAC1, and STRT1 are potential key targets for the anti-aging of Scutellaria baicalensis. Tumor protein P53 (TP53) is a tumor suppressor protein that regulates tumorigenesis and aging processes. Overexpression of TP53 can induce cellular aging, and abnormal activation of P53 in mice reduces tumor incidence, but also leads to premature aging in mice. Further research has found that high expression and normal regulation of P53 can improve the body’s tolerance to tumors without leading to premature aging and shortened lifespan. AKT1 is a serine/threonine protein kinase. Inhibiting AKT1 activity can prolong lifespan, such as in AKT1 deficient mice (AKTG1+/-) where male lifespan is extended by 8% and female lifespan is extended by 15%. Retinoblastoma gene 1 (RB1) is a tumor suppressor gene. In terms of aging regulation, RB1 mainly induces cell aging through the P16 pathway of the tumor suppressor gene. Harvey mouse sarcoma virus oncogene (HRAS) is a member of the RAS oncogene family. Overexpression of HRAS can induce cellular aging, and it has been shown that the RAS pathway, together with insulin/insulin-like growth factor, affects the development and aging of nematodes. Histone deacetylase 1 (HDAC1) plays an important role in development, transcriptional regulation, and cell cycle progression. Overexpression of HDAC1 can induce cellular aging. Mutating the homolog Rpd3 of HDAC1 in fruit flies prolongs the lifespan of male fruit flies by 33% and female fruit flies by 52%. STRT1 is an NAD+- dependent deacetylase, whose activation can delay aging and promote longevity. Overexpression of STRT1 specifically in the mouse brain prolongs female lifespan by 16% and male lifespan by 9%. Therefore, Scutellaria baicalensis can regulate aging by acting on these targets.
Analysis of the blood components target network showed that flavonoids are important active ingredients in the anti-aging properties of Scutellaria baicalensis; Molecular docking showed that the binding scores of flavonoids to four potential key targets, TP53, AKT1, HDAC1, and SIRT1, were higher than the threshold, further suggesting that flavonoids are potential active ingredients in the anti-aging properties of Scutellaria baicalensis. Differently, network analysis showed that caffeoyl compounds were not key components in the anti-aging effect of Scutellaria baicalensis. However, molecular docking analysis showed that, except for caffeic acid and ferulic acid, 11 caffeoyl compounds had binding scores higher than the threshold for TP53, AKT1, HDAC1, and SIRT1, and overall were even higher than flavonoids. The reason for the analysis may be that there is not much research on caffeic acid compounds at present, and there are few compounds with similar structures to this type of component included in the target prediction database, or there is limited information about the validated targets of this type of component, resulting in a small number of predicted targets. Among the 777 predicted targets of Scutellaria baicalensis, the average number of predicted targets for each of the 13 flavonoid components was 102, while the average number of predicted targets for each of the 11 caffeic acid components was only 26. Through literature research, flavonoids and caffeic acid compounds may be the main active ingredients of Scutellaria baicalensis in anti-aging, and may exert anti-aging effects through targets such as TP53, AKT1, HDAC1, and SIRT1. In fact, some of these two types of ingredients have been proven to have anti-aging effects through life tests, and the anti-aging mechanisms of some ingredients are consistent with the predicted results of this study. The lifespan experiment of nematodes found that quercetin, baicalein, kaempferol, chlorogenic acid, 5-CQA, 4-CQA, 1,3-DCQA, and 1,5-DCQA extended the average lifespan of nematodes by 18.0%, 45.0%, 10%, 20.1%, 12.1%, 15.2%, 12.5%, and 8.0%, respectively. Among them, literature has confirmed that chlorogenic acid prolongs the lifespan of nematodes by inhibiting AKT1 activity, which is consistent with the results of this study that AKT1 is a key target of anti-aging in Scutellaria baicalensis and chlorogenic acid has a good binding effect with AKT1. The above reports corroborate the results of this study, indicating that the findings of this study have a certain level of reliability. Therefore, there is currently no clear experimental evidence in the research results to confirm the anti-aging effect of the ingredients, and corresponding experiments can be designed based on the predicted results for verification.
In summary, this study focuses on the oral absorption of blood components in Scutellaria baicalensis as the research object. The potential anti-aging targets and pathways of Scutellaria baicalensis were analyzed through network pharmacology methods, and the binding ability of these blood components to the main potential targets was verified by molecular docking. The research results showed that flavonoids and caffeic acid components are the potential active ingredients of Scutellaria baicalensis in anti-aging, which may exert anti-aging effects by acting on targets such as TP53, AKT1, HDAC1, SIRT1, and regulating related biological processes and pathways such as aging and tumors. The research results provide ideas for subsequent experimental verification.