Study on Ginseng Extract Ginsenoside Anti-Aging

Aging is a complex biological phenomenon in which various bodily functions gradually decline after the body has matured. There are currently different theories about its mechanism, which can be broadly classified into two categories: traditional Chinese medicine theories on prolonging life and modern theories on aging. Ginseng saponins are the main active ingredients in the medicinal herbs of the Araliaceae family, such as ginseng and American ginseng, and have a wide range of pharmacological effects and medical uses. Studies have shown that ginsenosides have a significant effect on the nervous system, endocrine system, immune system, signal transduction, anti-aging, anti-tumor synergy, etc. [1-3].

With the accelerating pace of social aging and the improvement of modern living standards, research on aging and anti-aging has become one of the hotspots in the field of medical biology, and research on ginsenosides' anti-aging effects has also received increasing attention from scholars. With the development of modern science and technology, especially the application of molecular biology techniques, research on the anti-aging mechanism of ginsenosides has gradually penetrated to the cellular, molecular and genetic levels. This paper reviews recent advances in the research on the mechanism of aging and the anti-aging effects of ginsenosides by scholars at home and abroad. It will provide theoretical guidance for the development and utilization of ginseng drugs, health care and beauty products.

1 Mechanism of aging

1.1 Traditional Chinese medicine theory of prolonging life

The Chinese medical theory of prolonging life has a long history of understanding human aging or premature aging, and its content is extremely rich, which is recognized by most scholars. Among them, the theory of organ weakness and decline is considered to have better practical results, and the theory of kidney deficiency causing decline is considered to be the most important [4]. Kidney deficiency causing decline refers to the depletion and deficiency of the yang energy of the kidney essence and the essence of the kidney, which leads to many aging pathologies and processes caused by the lack of energy for the biochemical reactions of the blood, body fluids, and tissues of the five zang organs. The kidney stores essence and is the source of life. It is the master that presides over and maintains all the physiological functions of the human body, enabling it to maintain a unified balance and to maintain normal activities with self-regulation and stability, thereby protecting against disease. A deficiency of kidney essence means that the five internal organs lack the source of qi, blood, and body fluids for biochemical processes, and various aging symptoms become increasingly apparent.

1.2 Modern aging theory

Modern research suggests that aging is a comprehensive manifestation of various biochemical reactions in the body, and is the result of the combined effects of many factors inside and outside the body (environmental pollution, mental stress, genetics, etc.). There are many modern theories of aging (the free radical theory, the brain aging center theory, the decline in immune function theory, etc.). The free radical theory was proposed by Harman in 1956 [5] and is currently one of the more widely accepted theories. This theory states that free radicals are constantly produced in the body, but at the same time there is an effective free radical scavenging system (such as superoxide dismutase) to maintain the free radicals in the body at a normal level. As we age, this balance gradually breaks down, resulting in an excess of free radicals. Excess free radicals can attack membrane structures such as cell membranes and mitochondrial membranes, as well as biological macromolecules such as nucleic acids, proteins and enzymes, through peroxidation, causing lipid peroxidation of unsaturated fatty acids on cell membranes and mitochondrial membranes and the production of lipid peroxides. These lipid peroxides and their decomposition products cause nucleic acids and protein molecules to cross-link and polymerize, which further causes DNA gene mutations or replication abnormalities and a decrease in the activity of biological enzymes, ultimately leading to serious damage to cell function, aging, and death.

At present, with the development of modern biotechnology, especially the rapid development of molecular biology research techniques, the genetic program theory of aging has gradually been confirmed. Since the 1990s, it has been reported that there are genes related to aging on chromosomes 1, 4, 7 and X, respectively [6]. Recent studies have found that the two family genes of CDI, NK4 (including P15, P16NK4A, P18, and P19) and CIP/KIP (including P21, P27, and P57), are all genes related to inducing cell senescence [7]. These studies show that aging is also determined by genetic factors [1]. In recent years, the discovery of telomeres and telomerase has led to new developments in the genetic aging theory. Telomeres are a special structure at the end of eukaryotic chromosomes. They are composed of 2 to 20 kb tandem repeats of the short sequence (TTAGGG)n and some binding proteins. They play an important role in chromosome positioning, replication, protection and control of cell growth and life, etc., plays an important role [8]. Each time DNA is replicated, telomeres lose 50 to 200 bp. When they shorten to a certain extent, the cell stops dividing, ages, and dies [9]. Telomerase is a special DNA polymerase that is dependent on the replication of telomere sequences. It can use its own RNA molecule as a template to synthesize and extend the length of telomeres from the 3′ end [10], thereby delaying cell aging.

2 Ginseng saponins and their anti-aging effects

Ginseng saponins are the main active ingredients of the medicinal herbs Panax ginseng and American ginseng. So far, at least 40 ginsenoside monomers have been isolated from the ginseng plant. According to the Rf value of ginsenosides in thin-layer chromatography, they are named from small to large as R0, Ra1, Ra2, Rb1, Rb2, Rb3, Rc, Rd, Re, Rf, Rg1, Rg2, Rh1, etc. [11]. Ginseng saponins can be divided into two types according to the aglycone: the dammarane type and the oleanane type (R0, Rh3) [12]. Among them, the dammarane type saponins are further divided into protoginsenolide and prototriginsenolide types according to the position of the sugar group attached to the aglycone. The representatives are Rb1 and Rg1 [13]. Ginsenosides of the diol and triol types account for the majority of ginsenosides and are considered to be the main active ingredients of ginseng. With the accelerating pace of an ageing society and the improvement of modern living standards, while people are desperately looking for ways to develop natural anti-ageing drugs, the anti-ageing effects of ginsenosides have also attracted the attention of more and more scholars, and research into the mechanism of ginsenosides' anti-ageing effects is also deepening.

2.1 Antioxidant effects

Free radicals produced during normal metabolic processes will not cause harm if they can be quickly removed by the body's defense system. If they cannot be completely removed, they will damage biological macromolecules and lead to aging of the body. Existing results have shown that ginsenosides can not only inhibit the production of free radicals, but also directly fight the damaging effects of free radicals on tissues and cells, or directly remove free radicals, and also enhance the function of the body's own antioxidant system, blocking the damaging effects of free radicals from multiple links. Zhang Jialin [14] and others studied the effects of ginseng saponins Rb1 and Rg1 on the activity of antioxidant enzymes in the blood of old mice. They found that ginseng saponins Rb1 and Rg1 can significantly increase the activity of superoxide dismutase (SOD) and catalase (CAT), enhance the body's ability to defend against damage caused by toxic oxygen free radicals, and have an anti-aging effect.

Wang Hongli et al. [15] found in an experiment on the anti-skin aging effect of ginsenosides that oral administration of 100 mg/kg·d-1 ginsenosides significantly increased SOD activity and hydroxyproline content and significantly decreased malondialdehyde (MDA) content in the skin of mice with an aging model induced by D-galactose. The activities of CAT and glutathione peroxidase (GSH2Px) activity was significantly increased. The mechanism may be the hydrolysis of ginsenosides to produce saponins, including ginsenol, ginsenoside Rb1 and Rg1, which are the main active compounds in ginseng. These substances can promote cell metabolism, accelerate the synthesis of nucleic acids and proteins in senescent skin cells, and increase the content and activity of SOD in the skin. They can also exert their powerful antioxidant and free radical scavenging effects, reduce the deposition of lipid peroxidation products such as MDA, restore the normal physiological functions of cells, and stimulate the activity of skin fibroblasts. Ginseng saponins can also promote collagen synthesis rejuvenating the skin and thereby delaying the skin aging process. Chang [16] and others found that ginsenoside diol induces SOD and CAT gene expression 2 to 3 times that of total saponins, with ginsenoside Rb2 being the most effective, thus demonstrating the key role of ginsenosides in regulating antioxidant enzymes at the genetic level.

Zhang Xinmu [17] and others found in their study of the effect of ginsenoside Rb on blood lipid metabolism and its antioxidant effect in rats with hyperlipidemia that ginsenoside Rb can significantly increase SOD activity, reduce lipid peroxide (LPO) and its metabolite MDA levels, and delay the aging process. Cheng Junlin et al. [18] observed the anti-aging effect of ginseng stem and leaf total saponins on the skin. They found that 100 mg/kg·d-1 ginseng stem and leaf total saponins can significantly increase the activity of CAT and GSH2Px in the whole blood of aging mice, significantly increase the activity of SOD in skin tissue homogenates, and reduce the content of MDA. 50 mg/kg·d-1 and 100 mg/kg·d-1 ginseng stem and leaf total saponins can both increase the hydroxyproline content in the skin tissue of aging mice, and there is a significant difference compared with the aging model group. It is believed that oral administration of ginseng stem and leaf total saponins has an anti-aging effect on D-galactose-induced mouse skin.

2.2 Regulating the nervous system

The decline in brain memory is one of the early symptoms of aging. Experiments have confirmed that changes in neurotransmitters and their receptors are closely related to the aging of brain function, and the specific manifestation is learning and memory dysfunction [19]. Early studies found that ginsenoside Rb1 can promote the release of neurotransmitters. Xue Jianfei et al. [20] first proved that the mechanism of ginsenoside Rb1 promoting the release of neurotransmitters is related to its upregulation of the phosphorylation level of synaptic proteins, and confirmed that the mechanism of action of Rb1 is through the PKA cell signaling pathway. Cheng et al. [21] believe that acetylcholine (Ach) is an important neurotransmitter in the human brain, and a lack of Ach can lead to damage to learning and memory abilities. Early experiments found that ginsenosides Rg1 and Rb1 can increase the content of Ach in the central nervous system, and it is inferred that this is related to the fact that Rg1 and Rb1 can increase the activity of acetylcholine transferase (ChAT) and inhibit the activity of acetylcholine esterase (AchE).

Wang et al. [22] further confirmed this inference. Zhao [23] and others recently found that ginsenosides prevent the decline in memory in older rats by reducing oxidative stress in the hippocampus of senescent rats and upregulating plasticity-related proteins in the hippocampus. Chen Huiliang [24] believes that a mixture of ginsenosides Rb1 and Rg3 delays aging by preventing neurons from producing excess nitric acid. Zhao Haihua [25] investigated the effect of ginsenosides on the expression of tyrosine kinase (TrkB) mRNA in NBM neurons of aging rats. The results showed that the expression of TrkB mRNA in NBM neurons of aging rats was significantly lower than that of young rats, while the administration group had increased expression compared to the aged group, indicating that ginsenosides promote the expression of TrkB mRNA in NBM neurons. The results provide a morphological basis for ginsenosides' anti-brain aging effects. Jia Jimin et al. [19] believe that ginsenosides Rg1 and Rb1 can increase neuronal plasticity, promote the proliferation and differentiation of neural stem cells in the dentate gyrus of the hippocampus in model animals, and increase the production of Bcl-2 and antioxidant enzymes, thereby delaying aging.

2.3 Regulating immune function

As we age, the immune organs gradually atrophy, the immune function gradually declines, and the resistance to external pathogens is significantly weakened. This is one of the causes of aging [26]. Moderate regulation of the immune system at the cellular and molecular levels can delay aging. Jiang Biwu [27] and others reported that ginsenosides have a stimulating effect on both humoral and cellular immunity in mice, can enhance the phagocytic function of the reticuloendothelial system, promote antibody formation, increase the content of immunoglobulins in the blood, and can stimulate the transformation function of lymphocytes in the elderly, and increase the synthesis of DNA, RNA and proteins in bone marrow cells.

Chang Yaping et al. [28] demonstrated that American ginseng total saponins and ginsenosides have a variety of immunomodulatory effects, which are related to their ability to induce various cells to produce a variety of cytokines. Among these, IFN is an important component of the body's immune regulatory network. An increase in the concentration of cGMP in lymphocytes has a significant effect on the proliferation of cells. cAMP, on the other hand, has a regulatory effect on genetic activity, as it promotes the phosphorylation of histones and non-histones and relieves gene repression. Changes in intracellular cyclic nucleotide levels are a mechanism for regulating immune function at the cellular level [29].

2.4 Affects the expression of cell cycle regulatory factors and senescence genes

The cell cycle is a fundamental process of cellular life activity. Cells operate in the order of G1 phase – S phase – G2 phase – M phase during the change of the cell cycle phase. The G1 phase is the key to starting the cell cycle. Cell senescence is a complex physiological and pathological process involving multiple factors under the regulation of the cell cycle. It is the basis of organism senescence, and its key feature is cell cycle arrest. A prominent feature is that the cell maintains metabolic activity for a long period of time, but is blocked in the G1 phase, losing its ability to respond to mitosis and synthesize DNA, and unable to enter the S phase. Cyclin is a cyclin protein that is expressed periodically. At the junction of the G1 and S phases, it exerts its protein kinase activity together with cyclin-dependent kinase 2 (CDK2), and is a key cyclin protein that allows cells to enter the S phase from the G1 phase [30].

Senescence genes are genes that exist in organisms and have the effect of causing or delaying aging. The existence of senescence genes in vivo has been found and confirmed in a large number of studies [31], such as P15, P16NK4A, P18, P19, P21, P27, P57, etc. Song Shuxia et al. found that ginsenosides have a bidirectional regulatory effect on human embryonic lung fibroblasts, and promote cell proliferation and regulate Cyclin D1 gene expression in cells of high age [32].

Zhao Zhaohui et al. [33, 34] further studied the effect of ginsenoside Rg1 on the anti-aging effect of t-butyl hydroperoxide (t-BHP)-induced cells, and found that it may be related to its ability to change the expression levels of P21, Cyclin E and CDK2, and may also be related to telomeres and telomerase. Zhao Zhaohui et al. [33] observed senescent cells using cell ultrastructure, flow cytometry, and β2-galactosidase cytochemical staining. The protein expression of P21, Cyclin E, and CDK2 was detected by western blot. It was found that compared with the t-BHP treatment group alone, the Cyclin E and CDK2 protein expression levels in the Rg1 pretreatment group increased, while the proportion of G1 phase cells decreased significantly, suggesting that at the junction of the G1 phase and S phase, ginsenoside Rg1 may exert its anti-cell aging effect by upregulating the expression of Cyclin E and CDK2, causing the cell to enter the S phase. Jin Jiansheng et al. [35] used immunoblotting to detect the expression of CDK4, Cyclin D1, and P16 to explore the anti-aging effect of ginsenoside Rg1 on WI-38 cells induced by t-BHP and its possible cell cycle regulatory mechanism. The results showed that Rg1 may exert its anti-aging effect on WI-38 cells induced by t-BHP by changing the expression of cell cycle regulatory factors. effect.

3 Outlook

Aging is a normal physiological process in the human body that involves the whole body's multi-functional systems. Delaying aging is currently one of the focuses and difficulties of life science research. Ginseng saponins have obvious anti-aging effects, and research on their anti-aging mechanisms has greatly promoted the understanding of the mechanisms of human aging. At present, research into the anti-aging mechanism of ginsenosides has made great progress, but there are still limitations. For example, research on the relationship between ginsenosides and NO-related signal transduction pathways, DNA damage repair pathways, and the mechanism of ginsenosides delaying aging by extending telomere length and telomerase activity is still not very clear. Therefore, it is necessary to conduct a multi-faceted study on the anti-aging mechanism of ginsenosides at the cellular, molecular, and genetic levels, using appropriate experimental methods, with the help of aging theories, modern scientific research techniques, and literature, experimental, and clinical research. This will provide some theoretical guidance for the development and utilization of ginseng drugs, health care products, and beauty products.

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