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ABSTRACT: Owing to a dramatic increase in average life expectancy and the Family Planning program of the 1970s - 1990s, China is rapidly becoming an aging society. Therefore, the investigation of healthspan-extending drugs becomes more urgent. Astragalus membranaceus (Huangqi) is a major medicinal herb that has been commonly used in many herbal formulations in the practice of traditional Chinese medicine (TCM) to treat a wide variety of diseases and body disorders, or marketed as life-prolonging extracts for human use in China, for more than 2000 years. The major components of Astragalus membranaceus are polysaccharides, flavonoids, and saponins. Pharmacological research indicates that the extract component of Astragalus membranaceus can increase telomerase activity, and has antioxidant, anti-inflammatory, immunoregulatory, anticancer, hypolipidemic, antihyperglycemic, hepatoprotective, expectorant, and diuretic effects. A proprietary extract of the dried root of Astragalus membranaceus, called TA-65, was associated with a significant age-reversal effect in the immune system. Our review focuses on the function and the underlying mechanisms of Astragalus membranaceus in lifespan extension, anti-vascular aging, anti-brain aging, and anti-cancer effects, based on experimental and clinical studies.
Owing to a dramatic increase in average life expectancy and the Family Planning program of the 1970s-1990s, China is rapidly becoming an aging society. Thus, aging and aging-associated diseases, such as neurodegeneration, cardiovascular disease, and cancer, are becoming some of the most important global problems. Aging is defined as a progressive decline in intrinsic physiological function, leading to an increase in age-specific mortality rate and a decrease in age-specific reproductive rate . The major theories of aging include telomere shortening theory , epigenetic and genetic regulation theory [3,4], stem cell theory , mitochondrial dysfunction , metabolic and immune deregulation [7,8], proteostasis loss , and gut microbiota regulating theory . Hence, targeting these pathological changes could reverse aging and treat age-associated diseases. In traditional Chinese medicine, some herbals have been used for anti-aging since ancient times.
Astragalus membranaceus (Huangqi), as one of the most important Qi tonifying adaptogenic herbs in Trational Chinese Medicine, has a long history of medicinal use. Astragalus membranaceus was originally described in the Shennong's Classic of Materia Medica, the earliest complete Pharmacopoeia of China written from the Warring States Period to Han Dynasty [11,12]. It is valued for its ability to strengthen the primary energy of the body which we know as the immune system, as well as the metabolic, respiratory and eliminative functions. This fact is being increasingly substantiated by pharmacological studies showing that it can increase telomerase activity, and has antioxidant, anti-inflammatory, immune-regulatory, anticancer, hypolipidemic, antihyperglycemic, hepatoprotective, expectorant, and diuretic effects [13-18]. Specifically, constituents of the dried roots of Astragalus spp. Radix Astragali provide significant protection against heart, brain, kidney, intestine, liver and lung injury in various models of oxidative stress-related disease [19,20]. In order to clarify the potential application of Astragalus membranaceus in anti-aging, we summarize the effect and mechanism of its extracts and effective component monomer against aging and age-related disease. This information could help clinicians and scientists develop novel target-specific and effective therapeutic agents that are deprived of major systemic side effects, so as to establish a better treatment regimen in the battle against aging.
Astragalus membranaceus includes over 2000 species, among them, Astragalus membranaceus (Fisch.) Bge. (Fam Leguminosae) and Astragalus membranaceus (Fisch.) Bge. Var. mongholicus (Bge.) Hsiao are the most commonly used. In traditional Chinese medicine, Astragali Radix, the root of Astragalus membranaceus, was used in patients with chronic diseases and healthy persons who want to improve their body vital functions.
At present, more than 200 compounds have been isolated and identified from Astragalus membranaceus. Its total polysaccharides, saponins and flavonoids fractions and several isolated compounds have been the most studied, and these bear the biological activities of Astragalus membranaceus [21,22].
There are more than 161 saponins including about 142 kinds of cycloartane-type saponins and about 19 kinds of oleanane-type saponins. Among them, 5 major saponins, including astragalosides I, II, and IV, and isoastragaloside I and II, all being cycloartanetype triterpenoids, make up more than 80% of the total saponins. And Astragaloside IV is the qualitative control biomarker .
There are more than 63 flavonoids mainly including isoflavones, isoflavans, pterocarpans, flavonols, flavones, and flavonones. Among them, isoflavones are the major constituents, and calycosin-7-O-β-D-glucoside, as one of the isoflavones, is the dominant component, and used as a chemical marker in quality analyses of Astragalus membranaceus . In addition, there are 3 special flavonoids including sulfuretin, isoliquiritigenin, and pendulone.
Knowledge about the precise chemistry of Astragalus polysaccharides is quite limited. Since polysaccharides are macromolecules with complicated chemical structures, it is relatively difficult to isolate and characterize their individual components. There are 14 polysaccharides in Astragalus membranaceus, and 13 kinds of them have β-D-(1→3)-galactan moieties branched with β-D-(1→6)-galactooligosaccharide side-chains[25,26].
Astragalus membranaceus can inhibit the oxidant stress by up-regulating the antioxidant factors. Aqueous extract of Astragali radix decreased the myocardial infarction size and improved the cardiac function in a myocardial ischemic rat model, which is related to the antioxidant effects via maintaining the activity of superoxide dismutase (SOD), decreasing the production of malondialdehyde (MDA) and free radical levels, and reducing cell apoptosis . Besides, Astragalus injection can decrease the reactive oxygen species (ROS) and MDA levels in a rat model of cerebral ischemia through up-regulating the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), SOD, catalase and glutathione peroxidase (GSH-Px) .
Astragalus membranaceus was used to promote immune function and as a tonic to build the stamina . The aqueous extract of Astragali radix also has significant immunological adjuvant activity when compounded with human vaccines .
Astragalus membranaceus could affect the innate immune response. The aqueous extract of Astragali radix induced the activation and migration, and monocytematuration of peripheral blood mononuclear cells .In the macrophage cell line RAW 264.7, aqueous extract of Astragali radix reversed the increasing iNOS expression and NO production by lipopolysaccharide (LPS), and reduced the suppression of macrophage cell proliferation by methotrexate . Another research found that in the macrophage cell line ANA-1, aqueous extract of Astragali radix inhibited cytokine production via depressing p38 MAPK and NF-κB signaling pathways induced by advanced glycation endproduct . Astragalus membranaceus could also affect the acquired immune response. The aqueous extract of Astragali radix exhibits mitogenic activities on T-cell depleted populations, augments the antibody response, and restores the lymphocyte blastogenic response in aging mice . And aqueous extract of Astragali radix activated CD4+ and CD8+ T cells of humans without influencing proliferation [35,36]. In addition, the ethanol extracts of Astragali Radix selectively alter Th1/Th2 cytokine secretion patterns of CD4+ T cells through enhancing the IL-4 and IL-10 levels in Th2 cells and reducing the levels of IL-2 and IFN-γ in Th1 cells [37,38]. Similarly, hydroalcoholic extract of Astragalus gypsicolus also modulated the balance of Th1/Th2 cytokines in allergic mice model .
Beyond that, aqueous extracts of Astragali radix promote myelopoiesis in myelosuppressed mice by improving the hematopoietic microenviroment, including enhancing the survival of bone-marrow-derived mesenchymal stem cells (BMSCs), proliferation of colony-forming unit-fibroblast through upregulation of granulocyte-macrophage colony stimulating factor and of bcl-2 expression in BMSCs .