PART Ⅱ： Anti-ageing Active Ingredients From Herbs And Nutraceuticals Used in Traditional Chinese Medicine: Pharmacological Mechanisms And Implications For Drug Discovery

Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com

Chun-Yan Shen1, Jian-Guo Jiang1, Li Yang1, Da-Wei Wang2 and Wei Zhu2

Ageing, an unanswered question in the medical field, is a multifactorial process that results in a progressive functional decline in cells, tissues and organisms. Although it is impossible to prevent ageing, slowing down the rate of ageing is entirely possible to achieve. Traditional Chinese medicine (TCM) is characterized by the nourishing of life and its role in anti-ageing is getting more and more attention. This article summarizes the work done on the natural products from TCM that are reported to have anti-ageing effects, in the past two decades. The effective anti-ageing ingredients identified can be generally divided into flavonoids, saponins, polysaccharides, alkaloids and others. Astragaloside, Cistanche tubulosa acteoside, icariin, tetrahydrocurcumin, quer- cetin, butein, berberine, catechin, curcumin, epigallocatechin gallate, gastrodin, 6-Gingerol, glaucarubinone, ginsenoside Rg1, luteolin, icarisid II, naringenin, resveratrol, theaflavin, carnosic acid, catalpol, chrysophanol, cycloastragenol, emodin, galangin, echinacoside, ferulic acid, huperzine, honokiol, isoliensinine, phycocyanin, proanthocyanidins, rosmarinic acid, oxymatrine, piceid, puerarin and salvianolic acid B are specified in this review. Simultaneously, chemical structures of the monomers with anti-ageing activities are listed, and their source, model, efficacy and mechanism are also described. The TCMs with anti-ageing function are classified according to their action pathways, including the telomere and telomerase, the sirtuins, the mammalian target of rapamycin, AMP-activated kinase and insulin/insulin-like growth factor-1 signalling pathway, free radicals scavenging and the resistance to DNA damage. Finally, Chinese compound prescriptions and extracts related to anti-ageing are introduced, which provides the basis and the direction for the further development of novel and potential drugs.

anti-ageing cistanche

Anti-damage of DNA

DNA damage, the primary programme of ageing in the body, can be roughly divided into four types: base damage, glycosyl damage, bond rupture and DNA chain cross-linking. Many studies have shown that DNA damage and self-repair ability are closely related to ageing. Damage of DNA is the main reason leading to mutations, cancer, ageing and death because it can directly affect DNA replication, transcription and protein synthesis, thereby affecting cells’ growth, development, genetics, metabolism, reproduction and other vital biological activities (Jiang 2005).

TCM and its active ingredients could protect the integrity of DNA duplex and prevent gene mutation by resisting DNA damage (Jiang 2005). An experiment was carried out to study whether Radix puerariae (R. puerariae) and puerarin (Figure 5) have effects on delaying naturally senile mice of 18 months old and discovered that the rate of missing mtRNA in the elderly control group, the middle R. puerariae dose group and the middle puerarin dose group in all are 0.13, 0.11 and 0.11, respectively, indicating that puerarin could retard mitochondrial DNA damage (Wu et al. 2011). Furthermore, a metabolomics approach has been already used in a pharmacological study of Salvia miltiorrhiza (S. miltiorrhiza). For example, Jiang et al. identified 26 primary and secondary metabolites in S. miltiorrhiza from different regions and demonstrated that malonate and succinate possibly were the key markers for discriminating the geographical origin (Jiang et al. 2014). The application of metabolomics in S. miltiorrhiza provided novel insights into its essence. It was found that salvia acid B (Sal B) extracted from S. miltiorrhiza, exerted anti-ageing effects on D-galactose-induced senile mice models presumably by promoting anti-oxidation and affecting mitochondrial DNA levels, based on the findings that there was a better performance in Morris water maze test and stand-jumping test, an increase of cerebral SOD activity, a reduction of MDA content and mitochondrial DNA level in Sal B treatment group (Gao et al. 2009). Additionally, Chen et al. showed that tea polyphenols have anti-ageing effects and could significantly increase DNA methylating enzyme activity (Chen et al. 2001). Many other studies involved in the mechanism of anti-damage of DNA by TCM active ingredients are shown in Table 5.

Effects of TCM on DNA repair are being constantly revealed with an in-depth understanding of the procedure of DNA damage and repair (Jiang 2004). However, the targets of drugs are rarely involved in current studies. Therefore, more researches are needed to explore the mechanisms of DNA repair by TCMs.

cistanche benefit: anti-ageing

Chinese compound prescription and its extracts

Chinese compound prescription (CCP) is usually composed of several kinds of single herbs, each of which contains multiple effective constituents (Peng et al. 2015). In fact, the safety and effectiveness of CCP have been confirmed by the clinical practice for thousands of years. In the past decades, more and more attention in TCM has been focused on the effects of active ingredients from formulae (Yin et al. 2015). Of note, synergism, when the effects of the combination are greater than that of the individual drug, is a core principle of TCM and has played an essential role in improving its clinical efficacy (Zhang et al., 2014b).

Although the mechanisms of CCP are unclear owing to its complex composition, a large number of experimental studies have shown that several anti-ageing mechanisms mentioned above are also applicable to CCP. Specifically, a traditional Chinese herbal formula, Zuoguiwan pill, composed of seven herbal constituents, was found to exert anti-ageing effects by improving blood anti-oxidative ability and decreasing DNA damage of lymphocytes (Xia et al. 2012). Similarly, it could significantly decrease the levels of 8-hydroxy-2’-deoxyguanosine in the cerebral genome of 24-month-old rats, suggesting that the underlying mechanism relies on the protection and repair of DNA in cerebral genome (Zhao et al. 2002). Furthermore, there was a dose-dependent increase in the expression of FOX, SIRT1 and c-Myc in ovary cells of sub-acutely ageing rats induced by D-galactose after treatment with a decoction of Fallopia multiflora (F.- multiflora), suggesting that this decoction could block ovary apoptosis probably by regulating the expression of FOX, SIRT1 and c-Myc (Zhang et al., 2013a). Additionally, Zhang et al. applied ultra-high-performance liquid chromatography coupled with the quadrupole time-of-flight MS metabolomics to evaluate the therapeutic effect of Liuwei Dihuang (LWDH) pills, Jinkui Shenqi (JKSQ) pills and their combinations (administration of JKSQ pills in the morning and LWDH pills at night) on kidney deficiency in Sprague–Dawley rats induced by dexamethasone and D-galactose (Zhang e al., 2014b). The results showed that the group treated with JKSQ pills in the morning and LWDH pills at night displayed the strongest rehabilitation for metabolic disorder, and it concluded that lipid metabolism and energy metabolism might be closely related to kidney deficiency and ageing as most of the potential biomarkers identified of the kidney deficiency and ageing are related to fatty acids. Similarly, extracts of TCM are the other active ingredients possessing anti-ageing functions under investigation. In support, aqueous extracts of Portulaca oleracea possibly exert anti-ageing effects on senile mice by inhibiting expression of the p53 gene and activating telomerase, so as to protect against telomere shortening in the brain(Huang et al. 2007). Moreover, Guo et al. found that alcoholic ex- tracts of C. officinalis can fight against senility by inhibiting the non-enzymic glycosylation of proteins in vivo and reducing DNA damage of peripheral blood lymphocyte (Guo et al. 2005)

anti-ageing cistanche

A systematic review of the clinical and non-clinical efficacy of anti-ageing herbs was published based on six human and 61 animal studies, most of which showed significantly improved brain function, sexual disorder and skin wrinkling (Hasani-Ranjbar et al. 2012). For example, Lee et al. investigated the clinical efficacy of P. ginseng in the cognitive performance of Alzheimer’s disease patients and found that the mini-mental state examination scores and Alzheimer’s disease assessment scale scores both were significantly decreased after treatment with P. ginseng (Lee et al. 2008). Additionally, several other clinical trials were also performed with CPP or TCM extracts and demonstrated beneficial effects (Zhang et al. 1992; Zhang 1993; Wang 1994; Tian et al. 1997; Xu

and Zhi 1998; Sugiyama 2006; Amagase and Nance 2008; Yonei et al. 2008; Gim et al. 2009). More related researches are listed in Table 6 as below.

In summary, there is much evidence, as mentioned above, for the anti-ageing effect of combinatorial intervention in TCM to achieve synergistic interactions that could produce sufficient effects at low doses. However, the regulation of compatibility, principles of composition and effective sub- stance basis of CPP or TCM extracts are poorly understood, thus hampering the development and modernization of TCM (Sheridan et al. 2012). Therefore, chemical fingerprint- ing coupled with systems biology should be applied to TCM to scientifically and accurately explore the pharmacokinetics of multi-ingredients in TCM (Zhang et al., 2014b).

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