Ginseng: An Nonnegligible Natural Remedy for Healthy Aging

Aging is an irreversible physiological process that affects all humans. Numerous theories have been proposed to regarding the process from a Western medicine perspective; however, ancient Chinese medicine practices and theories have increasingly gained attention, particularly ginseng, a grass that has been studied for the anti-aging properties of its active constituents. This review seeks to analyze current data on ginseng and its anti-aging properties. The plant species, characteristics, and active ingredients will be introduced. The main part of this review is focused on ginseng and its active components with regards to their effects on prolonging lifespan, the regulation of multiple organ systems including cardiovascular, nervous, immune, and skin, as well as the anti-oxidant and anti-inflammatory properties. The molecular mechanisms of these properties elucidated via various studies are summarized as further evidence of the anti-aging effects of ginseng.

Aging is an inevitable biological process that leads to progressive structure modification and physiological dysfunction. According to Zhores Medvedev, there are more than 300 hypotheses of aging [1]. Many theories attempt to explain the process of aging, but none seem to be comprehensive [2]. The theory of aging can essentially be categorized into two main schools of thought as to the underlying factors: programmed factors vs. damagerelated factors. Programmed factors follow a biological timetable, perhaps a continuation of the one that regulates childhood growth and development. Changes in gene expression subsequently affect the systems responsible for the responses involved in maintenance, repair and defense. Damage-related factors, on the other hand, include internal and environmental assaults to the living organism that induce cumulative damage at various levels [3]. Both theories conclude that the aging body is unable to maintain its normal function and constitution, ultimately leading death. While humans are now living longer, we are not necessarily living healthier. Recent evidence has shown the promise of herbal medicine in protecting against aging and aging related pathologies. LW-AFC, prepared from Liuwei Dihuang decoction, a well-known Chinese herbal medicine believed to delay senescence, has been proven to be beneficial against the deterioration of memory and learning, and play a role in regulating N-glycan in Senescence-Accelerated Mouse Prone 8 Strain, a Mouse Model of Alzheimer's Disease [4]. Another Chinese herbal medicine, Danggui-Shaoyao-San (DSS), has been shown to have anti-inflammatory and anti-oxidant properties, and reduce cell apoptosis in the hippocampus of free radical-mediated neurological

Species of ginseng
The English word "ginseng" stem from the Chinese word rénshēn. Rén means person, while shēn means plant root. Ginseng's pronunciation comes from Cantonese "yun sum" or the Hokkien pronunciation "jîn-sim". Ginseng is a slow-growing perennial plant with fleshy roots, and belongs to the genus Panax of the family Araliaceae. The genus Panax derives its name from the Greek words pan (all) and akos (healing). Ginseng is commonly used as a health supplement, and in many herbal formularies to treat all kinds of illnesses in East Asian countries [7]. There are a total of 13 species that grow widely in Asia, North America and Europe [8]. Commonly, ginseng is referred to the dry root and rhizome of Panax ginseng C.A.Meyer (Araliaceae), which is originally grow typically in cooler climates like Northeast China, Korea peninsula and Russia and North America [9,10]. Panax ginseng include three different species of Korean, Chinese, and American ginseng, which have been globally cultivated and traded [10].

Plant characteristics
Ginseng is a perennial umbel plant, often with a branched， rootstock and a stalk bearing 2-5 whorls and long-stalked leaves with jagged edges. It is a self-pollination plant that bloom at its third-year growth phase. Once the flowers bloom in May, then they develop into red berries, with each fruit containing two seeds. At the time of collecting, seeds are immature without a clear embryo shape, and need a quiescent stage to mature to germination. During cultivation in the latter half of July, the harvest seeds are set in moist, shaded soil for approximately 100 days, and sown during the first half of November and transplanted during the next spring. Ginseng roots are usually harvested at 4 to 6 years of age during autumn. The roots consist of three parts, namely the rhizomes (neck), primary roots and rootlets. A matured 6-year-old ginseng on average would have a total root length of about 34 cm, with the primary root being about 7-10 cm long and 3 cm wide, with several stout rootlets. Average weight ranges from 70-100 g. New buds grow from its rhizome each spring, and the stalk withers away each autumn but traces of it remain in the rhizome each year. The annual stalk growth from ginseng's rhizome is an important identifier in distinguishing ginseng from other ginseng-related products [11,12].

Processing of ginseng
Ginseng's medical products are classified into three categories -fresh, white, and red ginseng depending on the processing [9]. Almost all medical products are derived from ginseng after 4 to 6 years of cultivation. Fresh ginseng is defined as less than 4-year-old and required minimal processing. White ginseng is 4-6-yearold, and is peeled and dried. Red ginseng is 6 years old that is first steamed and then dried. Each type of ginseng can be further processed into different formulations, including powder, extract (tinctured or boiled), juice, tea, capsules, tablets, and more [8]. Red ginseng is considered to be more effective since heating inactivate its catabolic enzymes, thereby restraining its overall deterioration while increasing antioxidant-like substances that suppress lipid peroxide formation, and improve gastrointestinal absorption. Heating red ginseng has been proven to degrade the thermally unstable malonyl-ginsenoside into proportionable neutral ginsenosides, causing degradation or transformation of neutral ginsenosides and reducing acidic malonyl-ginsenosides. The hydrolyzed ginsenosides in red ginseng is responsible for its multiple regulatory effects including inhibition of cancer cell growth via apoptosis, antimetastatic activities, vasorelaxation properties, and anti-platelet aggregation activity [13]. Data from experiments on the standardization and optimization of red ginseng preparation allow for guaranteed quality [14]. Newer methods that improve product efficacy include fermentation [15,16] or organic acid pretreatment [17,18]. A new study has shown that pectinase-treated Panax ginseng improves hydrogen peroxide-induced oxidative stress in GC-2 sperm cells and regulates testicular gene Aging and Disease • Volume 8, Number 6, December 2017 expression in aged rats [19].

Active part and ingredients
Traditionally, the root of ginseng is considered to be the only effective part used to treat various conditions, but through phytochemical studies and pharmacological research, its other parts including the flowers, leaves and fruits have also been discovered to be effective against fatigue, hyperglycemia, obesity, cancer, and possess antioxidant, anti-inflammation and anti-aging properties [20,21]. Approximately 200 substances have been isolated from Korean ginseng [22], and 100 substances from American ginseng thus far [21]. Recent phytochemistry and pharmacological studies have discovered a variety of potent components in all parts of the ginseng plant including ginsenosides, alkaloids, phenolics, phytosterol, carbohydrates, polypeptides, ginseng oils， amino acids, nitrogenous substances, vitamins, minerals, and certain enzymes. Ginsenosides are the major bioactive metabolites [23,24]. There are a total of 38 ginsenosides in Panax ginseng C A Meyer (Korean ginseng) and 19 ginsenosides in Panax quinquefolius L (American ginseng) [11]. Ginsenosides are triterpene saponins. Most consist of a dammarane skeleton (17 carbons in a four-ring structure) with different sugar groups (e.g. glucose, rhamnose, xylose and arabinose) connected to the C-3 and C-20 positions [25,26]. Ginsenosides are nominated as 'Rx', where the 'R' represents the root and the 'x' describes the chromatographic polarity in an alphabetical order [27]. For instance, Ra is the least polar compound, and Rb is more polar than Ra. Ginsenosides can be classified as dammarane-type, ocotillol-type and oleanane-type oligoglycosides [28]. Dammarane-type saponins can be further classified into protopanaxadiol (PPD like Rb1, Rb2, Rb3, Rc, Rd, Rg3, Rh2, Rs1) and protopanaxatriol (PPT like Re, Rf, Rg1, Rg2, Rh1) types [21,26,29,30].
The chiral carbon C-20 position in PPD and PPT type can be substituted for isobutyl, and is further divided into 20 (S) and 20 (R). So far, more than 70 ginsenosides have been separated from the three main kinds of ginseng. Among them, ginsenosides Rbl, Rb2, Rc, Rd, Rgl, Rg2, and Re are the major constituents of white and red ginseng, while ginsenosides Rg3, Rg5, and Rg6 are unique to red ginseng [31]. Some rare ginsenosides, like the ocotillol saponin F11 (24-R-pseudoginsenoside) [32] and the pentacyclic oleanane saponin Ro (3,28-O-bisdesmoside) [33] have also been isolated and identified. The quality and composition of ginsenosides in the ginseng plants are influenced by a number of factors including the species, age, part of the plant, cultivation method, harvesting season and storage method [34,35]. Using ginsenoside Rf as example, Rf is exclusive to Asian ginseng whereas F11 is unique to American ginseng. Thus the Rf/F11 ratio is applied as a phytochemical label to differentiate American from Asian ginseng [36,37]. Many reports indicate that ginsenoside metabolites show better biological effects than ginsenosides. For example, Rh2 and PD, metabolites of Rg3, have more potent anti-tumor activities than ginsenoside Rg3. Unlike Ginsenosides Rb1, Rb2, Rg1 and Re, compound K, PT and PD, the intestinal metabolites of PPTs and PPDs, , have inhibitory effects similar to that of the human liver enzyme cytochrome P450 inhibitory effects [38,39].

Anti-aging properties of ginseng
As aging is a multisystem and multifactorial process, the different theories of aging are actually contradictory. In this review, we present evidence of the anti-aging properties of ginseng discovered through research, and how the evidence largely supports the damage or error theory as aforementioned.

Prolonging lifespan
Historically, ginseng has been thought to prolong lifespan. Recently, several studies have shown that the components of ginseng can prolong the life span of experimental models such as Drosophila and C.elegans [40,41]. While ginseng does not significantly prolong the lifespan of aging mice, but it stabilize mice's behavior by antagonizing stress [42]. In one study, CVT-E002, a proprietary extract from North American ginseng, extends the life span of infant and juvenile mice with leukemia in a dose-dependent manner, with a limit of 20 mg/day [43].

Anti-oxidation effects of ginseng
Increase in oxygen-derived free radicals is closely related to the aging process. Reactive oxygen species are produced by intracellular molecular pathways located mainly in the cytoplasm and mitochondria [44]. Korean red ginseng decreases lipid peroxidation and restores antioxidant potential by reducing oxidative stress in rats. Aged rats fed with a Korean red ginseng water extract diet exhibited much less oxidative damage [45,46].Ginseng's anti-oxidant effects have also been clinically proven. In a double-blind randomized controlled clinical trial, administration of Korean ginseng led to a significant decrease in the levels of serum reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA), while potentiating the total glutathione content and glutathione reductase (GSH-Rd) activity [47]. Other studies have focused on oxidation induced organ injury. Fermented Panax ginseng extract administration to aged rats resulted in enhanced activities of superoxide dismutase e(SOD), glutathione peroxidase (GPx), glutathione reductase (GR), Aging and Disease • Volume 8, Number 6, December 2017 catalase (CAT) and glutathione-S-transferase (GST) while increasing glutathione (GSH), ascorbic acid and αtocopherol levels in the liver, kidneys, heart and lungs [46]. In an experimental mouse model of chronic cyclosporine (CsA) nephropathy, Korean ginseng reduced serum creatinine and blood urea nitrogen and increased creatinine clearance. Proinflammatory and profibrotic molecules such as cytokines, induced nitric oxide synthase, transforming growth factor (TGF)-β1 and TGF-β1-inducible gene h3 and apoptotic cell death were reduced [48]. Another study showed that in an ethanolinduced liver damage rat model, pretreatment with Korean ginseng extract maintained the activity of serum Glutamic Pyruvic Transaminase (GPT), and decrease MDA concentrations [49]. Free radicals play a major role in mediating skeletal muscle damage and inflammation after strenuous exercise and in muscle diseases [50]. Ginseng extract is believed to protect muscle from oxidative stress caused by acute exercise by decreasing MDA level in rats [51]. What components of ginseng play a role in these anti-oxidation effects? Studies of the components in ginseng has been productive and new compounds is continuously being isolated. The chemical constituents isolated from ginseng including polysaccharides, ginsenosides, peptides, polyacetylenic alcohols, fatty acids, etc [9]. IH901 or compound K, is considered to be the final intestinal bacterial metabolite of ginseng in humans. IH901 administration has beneficial effects on moderating exercise-induced oxidative stress and restores antioxidant defense capabilities in rat skeletal muscles and lung tissue [52]. Polysaccharides, another major bioactive constituents of P. ginseng, also is a strong antioxidant [53]. A recent study showed phenolic compounds in white ginseng can effectively trigger antioxidant enzyme activity [54]. The essential oils from ginseng leaves possess weak DPPH (1,1-Diphenyl-2picrylhydrazyl radical 2,2-Diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl) and 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid(ABTS) radical scavenging activities [55]. Ginseng's antioxidant effects hold exciting clinical potential. Red ginseng has the ability to protect cells from AA + iron-induced ROS production and mitochondrial impairment through AMPactivated protein kinase (AMPK) activation. At the molecular level, ginseng triggers LKB1-dependent AMPK, which in turn leads to increased cell survival [56]. Using old rat fatigue model of major small intestinal resection (MSIR), ginsenoside Rb1 counteracts fatigue, the mechanism of which likely involves activation of the PI3K/Akt pathway with subsequent Nrf2 nuclear translocation and induction of antioxidant enzymes [57].

Cardiovascular effects of ginseng
Aging is associated with various, complicated and changes in cardiovascular structure and function. The heart becomes slightly hypertrophic and has a dampened response to sympathetic stimuli, including increase in heart rate and myocardial contractility. The aorta and central elastic arteries become dilated and stiff, exhibiting enhanced pulse wave velocity, endothelial dysfunction and biochemical transformation that resembles early atherosclerosis [58]. To compensate for the decrease in arterial compliance and increase in peripheral resistance, the heart must pump with greater force. The myocardium responds in much the same way as other muscles do after exposure to increased load -enlargement and hypertrophy that result in a gradual increase in cardiac weight [59]. There is a gradual decrease in cardiac myocytes, while remaining myocytes become hypertrophic and the myocardium shows increased levels of collagen [58]. Ginseng has been shown to be cardioprotective through its anti-oxidative, antiarrhythmic, calcium channel-antagonistic, antiinflammatory and anti-apoptotic properties [60]. Acute administration of ginseng resulted in depressed cardiac contractile function, as evidenced by reductions in HR and blood pressure that persisted up to 24 h. This acute reduction in cardiac contractility appears to be intrinsic to the myocardium, as spontaneously beating perfused hearts exposed to different concentrations of North American ginseng also demonstrated inhibitory response [61]. On the contrary, Panax ginseng dramatically increases cardiac contractility in normal rats [62]. The different in response in contractility may due to the differences in components in ginseng of different origin. For instance, in North American ginseng, ginsenosides Rb1 and Re appear to be most abundant, whereas Asian ginseng is enriched more in Rg1 and Rg2 ginsenosides [61]. In intermediate-aged rats, long term consumption of ginseng extract decreased the sensibility of hearts to acute ischemia reperfusion injury. These effects might be regulated through the activation of Akt/eNOS, inhibition of Erk/caspase7, and upregulation of Sirt1 and Sirt3. A study on American ginseng also showed its protection of myocardium from ischemia and reperfusion injury via the upregulation of endothelial nitric oxide synthase [63]. In addition to the effects on myocardium, a clinical investigation revealed that Korean red ginseng may improve arterial stiffness determined by augmentation index (AI). It appears that ginsenosides, rather than polysaccharides, may be the major pharmacologically active constituent of the root of Korean red ginseng [64]. Another major cardiovascular effect of ginseng is endothelial regulation, which plays an important in role in the alteration of blood vessels with age. The endothelium is the innermost layer of blood vessels that comes into direct contact with the blood. It is composed of a single Aging and Disease • Volume 8, Number 6, December 2017 layer of squamous epithelial cells, which are regular and smooth in children and young adults, offering minimal resistance to blood flow. With age, the endothelial layer starts to have atypically shaped cells and becomes thickened due to smooth muscle fibers that migrate from the tunica media. This thickening not only contributes to a reduction in arterial elasticity and compliance, but also the lumen size, further increasing resistance to blood flow [65]. A clinical trial demonstrates that Korean red ginseng (KRG) and its ginsenosides significantly improved flow mediated vasodilatation post treatment [66]. A recent study showed that KRG inhibited arginase activity, maintained nitric oxide (NO) generation, reduced ROS production, and increased eNOS coupling in aged mice. KRG also improved blood vessel tension, as indicated by increased acetylcholine-induced vasorelaxation and decreased phenylephrine-stimulated vasoconstriction. In addition, KRG reduced plasma peroxynitrite production in aged mice, indicating decreased lipid peroxidation. These results suggest KRG exerts its vasoprotective effects by suppressing arginase activity and enhancing NO signaling [67]. However, cardiovascular remodeling due to age is by no means a uniform and generalized structural degeneration; rather, different components of the cardiovascular system may be affected heterogeneously [58]. More multi-level analyses are needed to evaluate the long-term benefits of ginseng.

Anti-aging effect of ginseng on nervous system and motor function.
There is a progressive loss of neural tissue with age, usually reflected by a gradual decline in cognitive function. With age, cerebral blood flow decreases by around 20% [68].There is an age-related decline in the synthesis of many neurotransmitters and their receptors. These include the catecholamines (adrenaline and noradrenalin), dopamine and serotonin. These reductions can slow reaction time, impair information processing and, sometimes, increase the risk of depression [65]. Neurodegenerative disorders occur when cells fail to react to age-related increases in oxidative, metabolic and ionic stress, consequently resulting in the accumulation of damaged proteins, deoxyribonucleic acid (DNA) and cell membranes [69]. Ginseng has been commonly applied and studied for its enhancement of cognition enhancing and stress reduction. The underlying molecular mechanisms of ginseng's effects on the brain have been widely studied, and found to involve monoamine transmission, glutamatergic transmission, estrogen signaling, nitric oxide production, the Keap1/Nrf2 adaptive cellular stress pathway, neuronal survival, apoptosis, neural stem cells and neuroregeneration, microglia, astrocytes, oligodendrocytes and cerebral microvessels [70].
Cognition is a fundamental action of the brain that becomes disrupted with aging, and the capabilities of maintaining and processing information decline with age [71]. Memory impairment is considered one of the most predominant downfalls of aging, and thereby has been a major point of research focus [72,73]. A recent study demonstrated that prolonged Red ginseng administration inhibited the production of age-processed inducible nitric oxide synthase, cyclooxygenase-2, interleukin-1b and tumor necrosis factor-a expressions. Furthermore, the antioxidative properties of red ginseng in aged mice restored glutathione level, and increased antioxidativerelated enzymes nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). These results indicate that age-related decline of learning and memory can be halted through anti-inflammatory mechanisms [74]. A double-blind clinical trial from Korea revealed that Korean ginseng can improve certain psychomotor functions such as as mental arithmetic in healthy subjects, as assessed by different tests of psychomotor performance [75]. Early animal experiments demonstrated that red ginseng improves learning and memory in aged animals. Red ginseng had a more prominent effect on memory than on learning in rats of all ages. In 22-month old rats, red ginseng not only improved memory, but also promote the rapid acquisition of responses [76]. The underlying mechanism of memory improvement has been explored by several studies. Ginseng extracts and ginsenoside Rg1, Rb1 improved acquisition and retention of memory in aged rats, ovariectomized rats, and cerebral ischemiareperfusion rats [77]. Ginsenoside Rg1 and Rb1 were found to increase cholinergic activity through two signaling pathways. First, both types of ginsenosides increase the density of central M-cholinergic receptors without specifically binding to the receptors. Second, Rg1 and Rb1 increased the level of acetylcholine (Ach) in the central nervous system (CNS), which might be the result of ginsenoside-induced choline acetyl transferase activity and inhibition of acetylcholine esterase activity [78,79]. As the same time, both ginsenosides also promote cholinergic neurotransmission by increasing cholinergic metabolism in the CNS [80]. Further investigation prompt that Ginseng extract in a dose-dependent manner can improve memory defect through the restored homeostasis via increasing neurotransmitter levels and reducing acetylcholinesterase (AChE) activities in rat brain areas in cortex, hippocampus and striatum [81]. Korean scientists found that gintonin, an isolated novel lysophosphatidic acids (LPAs)-ginseng protein complex derived from ginseng, activating LPA receptor via N-methyl-D-aspartic acid (NMDA) receptor channel activity in Xenopus oocytes, and elevated long term potentiation (LTP) in cultured hippocampal neurons in concentration-dependent manners, which might be responsible for ginseng-mediated improvement of memory-related brain functions [82]. Neural progenitor cells (NPCs) proliferation and differentiation is essential for brain development. They are thereby believed to be a potential focus in the treatment of age-related neurodegenerative diseases. Ginsenoside Rg1 significantly increases the number of proliferating progenitor cells in animal hippocampus, enhances the activity of the antioxidant enzymes glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), decreases the levels of proinflammatory cytokines such as IL-1b, IL-6 and TNFa. These positive results suggest that the regulation of proinflammatory cytokines levels, and enhancement of antioxidant activities could be the anti-aging mechanism of ginsenoside Rg1 [83,84]. In the brain aging animal model, administration of Rg1 also protected neural stem cells (NSCs) as demonstrated by an increased level of SOX-2 expression, reduced astrocytes activation shown by reduced level of Aeg-1 expression, increase in telomere lengths and telomerase activity, and downregulation of mRNA expression of cellular senescence associated genes p53, p21Cip1/Waf1 and p19Arf in the hippocampus. These results imply that ginsenoside Rg1 plays a beneficial role in the regulation of proliferation of hippocampal progenitor cells proliferation, which may be the crux of its anti-aging properties [83]. Further investigation indicate that Rg1 significantly increases the expression of synaptic plasticity-associated proteins in hippocampus in normal old aged mice, including synaptophysin, N-methyl-daspartate receptor subunit 1, postsynaptic density-95, and calcium/calmodulin-dependent protein kinase II alpha, by targeting rapamycin pathway activation. This data has provided powerful evidence for Rg1 regulation of cognitive decline during aging [85].
Ginseng and its components, especially ginsenosides, is not only effective in anti-aging, but also beneficial in aging-related neurological disorders, including Alzheimer's disease (AD). In senescence-accelerated mouse prone 8 (SAMP8) mice model, 3 months administration with ginsenoside Rg1 significantly reduced the contents of soluble Aβ1-40 in the hippocampus, and decreased hippocampal PKA RIIα (isoform IIα of the regulatory subunit of PKA) levels. Consequently, learning and memory improvement was evident, suggesting long-term application of ginsenoside Rg1 may postpone cognitive decline via increasing Aβ generation, PKA/CREB activity, as well as brain derived neurotrophic factor (BDNF) content in the brain [86]. In addition to ginsenoside Rg1, ginsenoside Rb and Rd also have potent neurological protective and regulatory effects. For instance, Rb fraction protected both astrocytes and neurons, especially GABAergic inter neurons, and preserved microglial homeostasis against kainate-induced excitotoxicity. Rb1 shows its anti-oxidative effects as it can increase embryonic cortex-derived neural progenitor cells (NPCs) and suppress the cell apoptosis int-BHPinduced oxidative injury via Nrf2 pathway activation [87]. In old rats following acute lead (Pb) exposure, ginsenoside Rd reduces of microglial activation and maintains of neural stem cells proliferation [61,[88][89][90]. PPD, the main intestinal metabolite of ginsenosides, is one of the active ingredients in ginseng, exert neuroprotective effect by triggering antioxidant activation and promoting mitochondrial function that in turn suppress apoptosis to maintain regular neurological activity [91].
Ginseng is also considered to have stress-relieving properties. Its active component, ginsenoside, is similar in structure to estrogen. In immobilization (IMO) stressed mice, red ginseng administration prior to IMO stress down regulated peptidyl arginine deiminase type 4 (PADI4) through up regulation of the estrogen receptor (ER)β expression in the brain, which was in itself up-regulated by various stresses factors such as H2O2, acrylamide, and tunicamycin [92]. Ginseng also significantly enhanced the memory of AD rats, and prolonged platform crossing times and the percentage of residence time in the original platform quadrant of spatial probe test. Ginseng also decreases the content of Aβ1-42 and p-tau and promotes the expression of PI3K, p-Akt/Akt, and Bcl-2/Bax mRNA and protein in the hippocampus [93]. American Ginseng, very similar to Asian Ginseng, has similar neuroprotective properties. Daily consumption of American ginseng improved neurocognitive function in senescenceaccelerated mice, which could be related to the upregulation of insulin and ChAT gene expression in the brain [94]. Long-term stress causes massive loss of neurons and cognitive deficits. Mounting evidence argue that accumulation of nitric oxide (NO), a intercellular messenger, plays a vital role in the pathogenesis of memory impairment. Chronic unpredictable stress (CUS) model showed induction of remarkable impairment in both acquisition and retention memory associated with alterations in oxidative stress markers, mitochondrial enzyme complex activities, proinflammatory cytokine (TNF-α), and acetylcholinesterase levels in the hippocampus. Furthermore, a significant increase in serum corticosterone levels was seen. American Ginseng administration decreased TNF-α, acetylcholinesterase and corticosterone levels, and reduced oxidative-nitrergic tension. These results demonstrate that regulation of nitrergic signaling cascade associate with the protective effects of American Ginseng by antagonizing CUSinduced oxidative stress, cognitive dysfunction, and neuroinflammation [95]. In an A1-42-induced AD mice model, cognitive function was recovered by oral Aging and Disease • Volume 8, Number 6, December 2017 administration of Cereboost™, the main ingredients being ginsenoside Rb1 derived from American Ginseng. Moreover, Cereboost™ recovered brain microtubuleassociated protein 2 and synaptophysin as well as acetylcholine concentration. The data suggest that ginsenoside Rb1 restored the cognitive function of AD model mice by increasing acetylcholine levels via ChAT gene expression [96]. These results suggest that Na+ channel block by American ginseng extract and Rb1 was primarily due to interaction with the inactive state of the channel. Inhibition of the Na+ channel activity by American ginseng extract may contribute to its neuroprotective effect during ischemia [97].
Motor function disorder is another important manifestation of aging. Ginseng has been proved experimentally to also affect motor function [98,99]. Research on the spontaneous motor activity and central dopaminergic systems in old rats with ginseng interference showed that oral intake of a water extract of Panax ginseng for a certain period of time induced an increase in spontaneous motor activity during the dark and a remarkable reduction of spontaneous motor activity during the daytime. These results indicate that ginseng extract intake may affect the activity of nigro-striatal dopamine neurons via inhibition during the daytime and activation during the dark in old rats [99]. Ginseng and its extracts have been demonstrated to protect experimentally demonstrate skeleton muscle protection from damage due to excess exercise, likely by reducing the release of myocellular proteins, lipid peroxidation and inflammation [51,100,101].

Skin effects of ginseng
The aging process is often visible in the skin. Several factors are involved in the aging of skin, including genetics, environmental stress, hormonal alterations and metabolism, all of which lead to accumulative transformations in skin constitution, function and appearance [102]. With age, skin becomes thin, dry, and loses its elasticity and structural regularity. A reduction in the number of fibroblasts in the extracellular matrix result in general atrophy. Decreased levels of collagen and elastin are mainly the results of suppressed protein synthesis affecting types I and III collagen in the dermis, associated with a loss of extracellular matrix proteins and wrinkle formation Oxidative stress is also considered to be a primary driver in the aging process [102]. Panax ginseng and ginsenosides have shown to prevent aging of skin. Two separate clinical trials indicated that ginseng extract improved facial wrinkling [103,104]. Fermented red ginseng is believed to be more effective in reducing wrinkles and enhance whitening compared to unfermented red ginseng [105]. The reduction in wrinkles may be due to an increase in type I procollagen synthesis [104]. Ginseng and can protect against UV radiationinduced skin damage The skin of the UV-irradiated mice manifested characteristic signs of photoaging, such as deep wrinkles across the back, increased epidermal thickness, cell infiltration, and many enlarged keratinizing cysts, which remarkably improved with red ginseng administration [106]. ginsenoside Rb1 (100 fg, 10 pg, or 1 ng/mouse, topical application) reduced the increase in skin wrinkling, thickness, and epidermis in UVBirradiated skin aging in hairless mice [107]. The mechanism of wrinkle inhibition in chronic UVB irradiation in hairless mice with red ginseng extract may be due to an increase in the protein level of procollagen type I, unlike observations obtained through clinical trials [105]. MMP-1mRNA and protein levels were significantly downregulated. This data indicates that the anti-wrinkle effect of Korean red ginseng involved the suppression of collagen degradation, rather than increased collagen synthesis [108]. Further investigation showed that one of the stereoisomeric forms of Ginsenoside Rh2, 20(S)-ginsenoside Rh2 [20(S)-Rh2], was able to suppress UV-B-induced ROS production with inhibition of MMP-2 activity and expression in HaCat cells [109]. Hyaluronan is considered to play a major role in the organization of the extracellular matrix structure, as well as the defense responses in human skin cells. Ginseng can also the upregulate hyaluronic acid generation [110,111]. 20-O-β-D-glucopyranosyl-20 (S)-protopanaxadiol (compound K), one of the major metabolites of ginsenosides, triggered a two-fold increase in hyaluronan synthase2 (HAS2) gene expression in HaCaT cells and induced significant hyaluronan synthesis in human skin cells and hairless mouse skin [110]. 20GPPD is the primary bioactive metabolite of Rb1. In human keratinocytes, 20GPPD increased HA production by elevating hyaluronan synthase 2 (HAS2) expression as an upstream regulator of ERK and Akt activity [111]. The ingredients of ginseng leaves inhibit ROS generation, GHS depletion, and expression of MMP-2 and MMP-9 induced by UVA irradiation in human keratinocyte cells (HaCaT) [112]. The anti-melanogenic activity of ginseng berry extract in skin was strongly associated with the activation of the longevity gene foxo3a [113].

Immuno-regulatory and anti-inflammatory effects of ginseng
As the adaptability of the immune system declines accordingly with age, it is less able to respond properly to invasion of foreign agent. Such changes in defenses result in immune vulnerability [114]. Both Korean and American ginseng have been reported to have immuneregulatory properties [115][116][117][118]. In a clinical trial, Y-75 (Ginsan), an acidic polysaccharide extracted from Korean Panax ginseng, was shown to be an immunomodulator that significantly increased NK cell cytotoxic activity, and enhanced phagocytic activity of peripheral blood cells as well as serum TNF-α levels [115]. American ginseng root polysaccharides (AGRPS) stimulates immune function while simultaneously inhibiting the response to lipopolysaccharide (LPS)-induced proinflammatory response [116]. Ginsenoside Rg1 stimulates lymphocyte proliferation drawn from 10 young and 19 elderly patients, and increased the lymphocyte membranes fluidity [117]. In mice forced to undergo a swimming test, P. ginseng was shown to boost immunity via cytokine production of T cells in mouse peritoneal macrophages [118]. Another study with Ginseng polysaccharide，an isolated bioactive constituent from the root of North American ginseng or Panax ginseng C.A. Meyer，was found to induce the proliferation of T cells and B cells, activate macrophages to produce reactive nitrogen intermediates and release some anti-tumor cytokins as TNF-α and IL-6 [119]. Another investigation showed that ginseng can initiate a transcriptional profile of immunoregulation featuring a net T(h)1 immune response, by up-regulating multiple pro-inflammatory cytokines while down-regulating TGFβ, IL-13 and the lipopolysaccharide (LPS) co-receptor CD14, the pivotal signaling pathways might involve the MAPK (ERK-1/2), PI3K, p38 and NF-κB cascades [120]. Ginsenoside Rg1 treatment was also proved significantly up regulate tumor necrosis factor (TNF)-α, but down regulate interleukin-6 (IL-6) protein expression in both lipopolysaccharide (LPS)-activated RAW 264.7 cells and mouse peritoneal macrophages, which support a novel mechanism for Rg1 immune-regulation in macrophages via the NF-κB and PI3K/Akt/mTOR pathways [121]. Korean red ginseng extract (RGE) is considered one of the most common herbs that regulate the immune system. RGE inhibited IL-1β maturation modulated with the nucleotide-binding domain leucine-rich repeat containing (NLR) family, as well as that of pyrin domain-containing 3 (NLRP3) inflammasome activation, and reduced IL-1β secretion and pathogen clearance through pyroptotic cell death by macrophages via inhibition of AIM2 inflammasome activation [122]. Shenzao Cha (SZC), a herbal combination of American ginseng and Chinese jujube, notably enhances spleen and thymus indices and T-lymphocyte proliferation, increase NK cell activity, demonstrating its potent immune-regulatory effects on both innate and adaptive immunity in healthy ICR mice [123]. The extracts from Ginseng Radix et Rhizoma can also improve immune function in rats [124]．Dammarane triterpenes compounds from leaves of panax ginseng significantly upregulated interleukin-12 expression in LPS-activated mouse peritoneal macrophage, enhanced the Th1 response-mediated cytokine IL-2, and decreased Th2 response-mediated cytokines IL-4 and IL-6 expression on ConA-activated splenocytes, suggesting a stronger effect on cellular immunity [125]. Red ginseng acidic polysaccharide (RGAP), apharmacological ingredient of Korean red ginseng, shows immunestimulatory and anti-tumor activity through activating macrophage function by stimulating transcriptional factors including NF-κB and AP-1 and their upstream signaling enzymes, such as ERK and JNK [126]. American ginseng root polysaccharides (AGRPS) stimulate innate immune function while inhibiting lipopolysaccharide (LPS)-induced pro-inflammatory response [116]. Recent research has proposed the concept of chronic inflammation as a major risk factor for aging and age-related diseases, especially low-grade, unresolved, molecular inflammation which may be the deciding factor in development of age-related pathologies [127]. There has been much recent interesting in the antiinflammatory effects of ginseng. In inflammatory skin diseases such as atopic dermatitis, ginseng extracts inhibit cytokines such as TNF-α and IL-8 in LPS-stimulated human keratinocytes in human dermal fibroblasts [128]. Panax ginseng extract suppresses exercise-induced muscle injury and inflammation by reducing plasma creatine kinase activity (CK) and interlukin-6 (IL-6) levels [101]. American ginseng extract not only prevents but also treats colitis, likely due to a mechanism involving the down-regulation of inducible nitric oxide synthase and cyclooxygenase-2 (markers of inflammation), as well as induction of apoptosis of inflammatory cells via the p53 pathway [129,130]. Ginseng of different origin have been proven to also inhibit cardiac hypertrophy and atherosclerosis, both of which are closely related aging and aging related disease [131][132][133].

Conclusion
Aging is a complicated process with multiple modulations occurring at many levels, from the molecular to the cells. Ginseng, an ancient Chinese herb widely used in Eastern medicine, has been studied for its anti-aging properties., and has been shown to have beneficial effects with regards to anti-inflammation, anti-oxidation, cardiovascular regulation, neurological improvement, anti-tumor, skin protection and immune modulation. The evidence on the life-prolonging effects of ginseng remains inadequate, and further studies are recommended. Investigations integrating science and technology will be needed to further explore the effects of ginseng on the human body to fully understand its potential.