As people's lives become longer, particularly in the more civilised societies which have adequate medical and preventative services, ageing presents many problems. As we age we become less physically fit, we show obvious changes such as whitening or loss of hair, wrinkled skin which recovers more slowly from the pinch test, weakened hearing and vision, general slowing down of physical activities and we become more liable to suffer from various illnesses. Less obvious is the deterioration of the body organs prompting glandular disorders, reduction of hormone output leading to sexual impotency, gradual mental deterioration and breakdown of the immune system. Any life style, drug or medicine that can delay or slow this inevitable decline and improve the quality of life is therefore important. The ancient Chinese were convinced that ginseng was the tonic that fulfilled this role. After all, it is an adaptogen coping with stress, it is a metabolism regulator for proteins, carbohydrates and lipids including cholesterol, a regulator that also stimulates production of bone marrow DNA, protein and blood cells, and it is a controller that ensures the harmony of visceral action and stimulates immune function.
Interest was focused on ginseng and the elderly when reports of trials in Eastern Europe and Italy were published in the 1970's. One German group conducted a trial involving 540 patients divided into groups, one group receiving ginseng extract, the second group ginseng extract with added vitamins and the final group a placebo. The results of a wide range of tests indicated improvements in psychological performance, mental and psychological coordination and mood as well as better control of blood pressure and blood sugar. Similar results were obtained by the Italian team who, in 1972, stressed the value of ginseng in improving the lives of old people suffering incoordination, reduced mobility, fatigue, failing concentration and memory and disturbed psychological behaviour (Fulder, 1993).
In 1979 Quiroga and Imbriano reported that cerebrovascular deficits in 36 per cent of a group of 134 aged patients were corrected very favourably and in 54 per cent favourably by treatment with ginseng extract G115 at 100-200 mg per day for 90 days. Improvement of the circulatory insufficiency was assessed as 60 per cent. In a subsequent report of a double-blind trial involving 45 patients (Quiroga, 1982) the effect of the ginseng treatment was compared with use of 1.5 mg/day of the ergot alkaloid-derived vasodilator co-dergocrine (Hydergine). For ginseng an improvement quotient of 34 per cent was stated and for hydergine 58 per cent with the placebo shewing only 1 per cent. Ginseng was, however, less likely to cause adverse reactions. Confirming such beneficial use of ginseng, Ragusin et al. in 1980, in a clinical trial, administered 40-80 mg/day of ginseng extract G115 or a similar placebo to 98 geriatric patients. Parameters recorded included effects on tension, depression, sleep, memory deficit, muscle fatigue, work capacity and appetite. The test group of patients shewed significant improvement when compared with the placebo group (Owen, 1994).
Neuronal energy requirements remain high throughout life, the most efficient source of brain energy being aerobic glycolysis during which adenosine triphosphate (ATP) is continuously synthesised. The ageing process alters cerebral metabolism with lowered glucose and oxygen consumption producing reduced ATP synthesis in persons demonstrating senile cerebral insufficiency (Sebban, 1982). Studying the effect of ginseng extract G115 on rabbit brain both in vitro and in vivo, Samira et al. (1985) concluded that there was a significant increase of glucose uptake with a corresponding decrease of lactate, pyruvate and lactate/ pyruvate ratio, indicating aerobic rather than the less economical anaerobic pathway. Thus G115 can be considered as a metabolic stimulant for brain tissue at doses equivalent to the recommended single human therapeutic dose, suggesting that altered neuronal metabolism rather than impaired cerebral blood flow is the problem in old age. Li et al. (1997), using fluorescence spectrometry and the dye 1,6-diphenyl-1,3,5-hexatriene, noted that the neuronal membrane fluidity decreased with age and was marked in old age. Ginsenoside Rg1 (10-40 mg/kg-1) significantly increased the fluidity of ageing cortical cells and this may, in part, account for the anti-ageing effect of ginseng. There was thus general agreement with the observations of Zhang et al. (1995) that ginsenoside Re also enhanced the membrane fluidity of both juvenile and mature human red blood cells and thus promoted protective and anti-ageing effects on cell membranes.
Today gerontologists believe that malondialdehyde binds nonspecifically with enzyme biomacromolecules to yield lipofuscin, a pigment accumulated in living cells as part of the ageing process. Diseases of old age may be related to the membrane damage caused by free radical chain reactions and the protein binding of malondialdehyde. Therefore naturally occurring antioxidants able to reduce the lipid peroxide content of the cells are regarded as anti-ageing compounds It is also suggested that internally in the nervous system ginseng acts in the presence of tocopherol against the free radicals by interruption of their formation.
Choi and Oh (1984) noted that the diol- and triol-type ginsenosides inhibited lipoperoxide formation in both in vitro and in vivo experiments and that the anti-oxidation effects of the triol-saponins were greater than the diol-saponin effects in vitro. However in in vivo experiments diol-type, triol-type and total saponins behaved similarly. Irrespective of the route of administration (oral or intraperitoneal) the greatest activity was in the liver with less in the kidneys and blood stream and the enzymes superoxide dismutase and peroxidase were inhibited. Oral rather than interperitoneal red ginseng extract was found to be more effective as a lipid peroxidation inhibitor than white ginseng extract; in in vitro experiments it was shewn to be more effective in the enhancement of liver superoxide dismutase, in electron donation and in the prevention of pyrogallol auto-oxidation. White ginseng extract was reported as more effective in preventing liver peroxide formation; liver peroxidase was enhanced 5.4-9.4 per cent for both red and white ginseng extracts. The butanol fraction of the ginseng extract contains the saponins and is the most effective as an anti-ageing medication. Further work confirmed that in rats the saponin hydrolysates prosapogenin, panaxatriol and panaxadiol inhibited lipid peroxide formation and superoxide dismutase and peroxidase activities in vivo and in vitro and contributed to the anti-ageing effect. The hydrolysates inhibited superoxide dismutase and peroxidase activities more efficiently than red ginseng extract (Choi and Oh, 1985). It was also reported that ginseng leaf saponins administered orally at 100 mg/kg daily to young rats (3-6 months old) for 3 months stimulated growth but for older rats (ca 18 months) there was a tonic effect.
Study of the ultrastructure of the myocardium for degenerative signs such as accumulation of lipofuscin and indistinct appearance of the crustae and outer membrane of the mitochondria and collagenous fibres and fibroblasts revealed that ginseng treatment produced decreased degeneration (Wang et al., 1986). Aerobic cells are usually protected from free radical damage by enzymic antioxidants such as catalase, glutathione peroxidase, glutathione S-transferase, glutathione reductase and superoxide dismutases, enzymes that scavenge available free radicals. Non-protein antioxidants also present include albumin, ceruloplasmin and non-protein-bound sulphydryls including glutathione. Superoxide generation increases with age whilst copper and zinc superoxide dismutase and catalase enzymes decrease with advancing age. Ginsenoside Rb2 treatment was shewn in senescence-accelerated mice to significantly increase the antioxidative enzymes copper and zinc superoxide dismutase and also manganese superoxide dismutase in the liver. In addition ginsenoside Rb2 stimulated increase of antioxidative catalase activity as well as marked elevation of the antioxidant serum albumin and non-protein bound SH levels in the liver. A further benefit of ginsenoside Rb2 treatment was the significant decrease in hepatic malonyldialdehyde levels. Thus the anti-ageing effect can be related to an increase in antioxidants giving protection against reactive oxygen species (Chung et al., 1994). The anti-superoxidation activities of several ginsenosides have been investigated in vitro using rat liver homogenates with added hydrogen peroxide or Fe2+ ions to generate the superoxide anions and hydroxyl radicals. Dong et al. (1996) concluded that total ginseng saponins and ginsenoside Rc offered considerable antioxidant protection although the total saponins and ginsenosides Rb1, Rc and Rd but not Rb2 suppressed the peroxidation induced by hydrogen peroxide. Discussing the probable mechanism these workers noted that ginseng and its glycosides did not react directly with oxygen-containing radicals or with their inducers (hydrogen peroxide and Fe2+ ions). Therefore the anti-superoxidation action is by activation of the endogenous free radical scavenging system. They also observed that the saccharides linked at C-20 in the protopanaxadiol nucleus played an important role in protection against lipid peroxidation. Recent work by Boulianne's team in Toronto (1998) has demonstrated that the life-span of fruit flies can be increased by about 40 per cent by inducing the development of the human enzyme superoxide dismutase (SOD) in their motor neurones. SOD inactivates and therefore scavenges the highly reactive oxygen radicals which are regarded as the cause of the cellular damage related to ageing effects. In fruit flies it is suggested that the weak link in the defences against free radicals occurs in the motor neurons and this may be also true for humans. As ginseng has a stimulating effect on SOD production in man, this may in part explain the anti-ageing properties of ginseng. Recently Kim et al. (1998c), studying glutamate-induced neurodegeneration in cultured rat cortical cells, confirmed that pretreatment with ginsenosides Rb1 and Rg3 inhibited the overproduction of nitric oxide characteristic of glutamate neurotoxicity as well as inhibiting the formation of malondialdehyde resulting from lipid peroxidation. Such neuroprotective activity would in part account for the potential value of ginseng in the treatment of senile dementia.
An alternative study by Zhang et al. (1992) investigated the rate of unscheduled DNA synthesis in cultured human lung fibroblasts through many generations. DNA-damage was induced with mitomycin-C and studied using a 14C- and 3H-thymidine double labelling technique. Unscheduled DNA synthesis was found to decrease during ageing, being significantly greater in the 28th generation than at the 40th generation. It was noted that mitomycin-C (1-10 ng/mL) induced both DNA-damage and repair in the 27th generation but damage only in the 40th generation. Ginseng saponins from root, stem and leaf, and fruit were found to antagonise the increase in unscheduled DNA repair induced by mitomycin-C in young cells but such saponins increased the unscheduled DNA synthesis in aged cells. Therefore it was concluded that ginseng saponins prompted antimutagenic and antiageing effects through the regulation of DNA repair.
Ginsenoside Rg1 reputedly possesses both antiageing and nootropic functions, that is, the ability to retard ageing and to improve the cognitive state of the mind and particularly the memory. Liu and Zhang (1996) used Northern and Western blot analyses to estimate the levels of c-fos rnRNA and fos protein in the hippocampus of both young and aged rats with or without ginsenoside Rg1
treatment. The expression of the c-fos gene and protein was found to be reduced in aged rats. Treatment with ginsenoside Rg1 however caused a dose-dependent increase in both aged and young rats and there was also an increase in hippocampal cAMP. It was concluded that changes at the genomic and protein levels caused by the increase in cAMP offered a possible explanation of the mechanism of action of ginsenoside Rg1 on the ageing process and memory deterioration.
Immunoregulatory function in all animals, including man, declines with increasing age. In aged cells blood cell membrane permeability increases, membrane fluidity decreases and lymphocyte production in response to mitogenic stimulation falls with a decrease of glycoprotein interleukin IL-2 production. Ginsenoside Rg1 was shewn to be capable of enhancing the proliferation of lymphocytes and the generation of interleukin IL-2 in old rats, with resultant increase of interleukin IL-2 ribonucleic acid and IL-2 protein contents. However, this phenomenon was not observed in young rats, suggesting that ginsenoside Rg1 is an immunoregulator rather than an immunopotentiator (Liu and Zhang, 1995). Further studies involving incubation of lymphocytes isolated from healthy aged humans (Liu et al., 1996) confirmed that ginsenoside Rg1 significantly increased lymphocyte subtypes, lymphocyte phenotype expression and protein tyrosine kinase activity in the elderly.
There is little doubt that the anti-ageing effect of ginseng is related to the free-radical scavenging activity of the saponins. However, in addition to the inhibition of lipid peroxide formation in the tissues and the elevation of blood and brain superoxide dismutase activity, there is also evidence of the reduction of lipofuscin in brain neurons and in liver as a result of treatment with ginseng stem and leaf saponins (Wu et al., 1992) and also improvement of DNA repair in the ageing cells. Not surprisingly a number of patents have been registered for geriatric tonics, for ageing, for cerebral vascular disease in the aged, for senile dementia and for Alzheimer's disease (see Chapter 9).
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