Antioxidants form the body's primary defence against reactive oxygen species (ROS), also known as free radicals, which are generated during aerobic metabolism. This process is increased by both physiological and pathological processes, such as exercise and inflammation, as well as from exogenous sources such as environmental pollutants, UV light radiation, and drugs. Although ROS do play physiological roles, notably the bacteriocidal function of ROS generated by activated phagocytes, excessive production of ROS is injurious resulting in oxidative stress and damage to cellular lipids, nucleic acids and proteins.
Mammals have evolved sophisticated antioxidant strategies to guard against damage from free radicals, and these primarily comprise enzymes that prevent the formation of ROS or facilitate the repair of injured DNA. Several nutrients also act as secondary antioxidants by trapping ROS. These include vitamins C and E, taurine, and carotenoids. Other nutrients, specifically zinc, manganese, iron, selenium, and copper, form integral parts of the antioxidant enzyme systems.
Sustained oxidative damage has been implicated in the pathogenesis of ageing and certain chronic diseases, as well as defective immune function, in humans. There is increasing interest in the role of oxidative stress in diseases of dogs and cats and the potential for dietary antioxidant supplements to intervene in disease processes in these species. The role of antioxidants in the maintenance of immunocompetence is discussed in this paper, with particular regard to data from recent studies in cats.
Immunostimulatory effects of antioxidants
The immune system is particularly sensitive to oxidative stress, primarily because the coordination of an effective immune response relies heavily on cell-to-cell communication. Peroxidation of cell membranes compromises membrane structure and function, thereby disrupting the processes of signal transduction by which cells communicate. Immune cells typically have higher levels of antioxidant nutrients than other cells in order to combat the heightened risk of oxidative damage. Consequently, deficient intake of dietary antioxidants, specifically vitamins C and E, taurine, and carotenoids can lead to suppression of immune functions. This may explain the associations that exist in humans between malnutrition, poor immune status, and increased incidence of infection, cardiovascular disease, cancer, and arthritis.
There is also the potential to boost immune function through increased consumption of antioxidants, for which there is increasing support from experiments in humans and laboratory animals. These studies indicate that dietary intakes in excess of those required to prevent nutritional deficiency are associated with improved immune responses in otherwise healthy individuals. The ability of dietary antioxidants to enhance immune function appears due to increased lymphocyte proliferation and numbers of T-helper cells, up-regulation of interleukin-2 (IL-2) expression, which in turn has a positive effect on the growth of T and B lymphocytes and natural killer cells, and heightening of the humoral response. Antioxidants also appear capable of decreasing the production of prostaglandin (PG) E2, which normally acts to reduce cell-mediated and humoral responses, decrease IL-2 expression, and slow lymphocyte proliferation.
Vitamin E is a potent chain-breaking antioxidant that is present in cell membranes; its effects on immunocompetence are likely due to the maintenance of function integrity of immune cells. In human and rodent studies, dietary supplementation to levels of 10 to 50-times the minimum daily requirement are reported to enhance immunological function.(3) Like vitamin E, taurine also appears to promote cellular integrity and is known to modulate neutrophil activity through interaction with the respiratory burst enzyme myeolperoxidase,(4) as well as attenuating an age-related decline in T-lymphocyte proliferation.(5)
Dietary antioxidants appear particularly effective in countering the progressive decline in immune function that is associated with ageing. In one prospective epidemiological study, 66% of elderly (> 60 years old) humans with plasma vitamin E concentrations of < 1.35 mg/dl typically experienced more than three infectious episodes over a three-year period. In contrast, in similarly aged people with plasma vitamin E levels in excess of 1.35 mg/dl, only 37% of subjects experienced three or more infections over the same period.(6) Dogs and cats may experience a similar age-related decline in immune function, as suggested by recent research.(7,8) Furthermore, studies at the WALTHAM Centre for Pet Nutrition have established that the total plasma antioxidant capacity of older cats is significantly lower than that of younger animals, with a transitional period of antioxidant status at approximately six years of age.(9)
Studies of dietary antioxidant supplementation in cats
Feeding studies at the WALTHAM Centre for Pet Nutrition have clearly established that it is feasible to achieve sustained increases in circulating levels of antioxidants through dietary supplementation in cats. This is true of vitamins C and E, taurine, and the carotenoids, ß-carotene and lycopene.(10,11) Dietary supplementation with antioxidants that are collectively active in the lipid and aqueous phases, appear to offer the best opportunity to boost antioxidant defences.
Specific effects of antioxidant supplementation on immune function were recently studied at the WALTHAM Centre for Pet Nutrition in adult cats. Two groups of cats were fed antioxidant-supplemented diets (diets A and B) for 12 months and their immune responses to administration of an anticalicivirus vaccine compared with a third group of cats fed a basal diet (diet C) containing no additional antioxidants. Diet A contained lycopene and enhanced levels of vitamin E, b-carotene, taurine, and lutein, whereas diet B contained red palm oil and enhanced levels of vitamins C and E, ß-carotene, taurine, and lutein. Serum samples were obtained from all cats immediately prior to vaccination and then seven and 14 days later for measurement of antibody titres to feline calicivirus. Cats that received diet B had a substantially higher mean antibody titre by day seven compared with those fed diets A and C (Fig 1). By day 14, cats fed diet A had also achieved substantially higher titres than cats fed the basal diet. These data clearly demonstrate the ability of dietary antioxidant supplements to enhance the humoral immune response to antigen challenge.
FIGURE 1: Antibody titres to feline calicivirus following annual vaccination in cats fed 3 different diets.
We have also investigated the role that dietary antioxidants might play in maintaining cellular integrity, particularly of immune cells, in cats. Using the ability of erythrocytes to withstand osmotic haemolysis, we compared the fragility of cells from cats fed diet A in the study described above with cells from cats fed a commercially available cat food. Osmotic haemolysis was induced by incubating isolated erythrocytes with decreasing concentrations of sodium chloride and assaying the concentration at which 50% of cells were lysed. This was significantly lower for cats fed the antioxidant-supplemented diet, compared with cats fed a standard product (Fig 2).
FIGURE 2: Concentrations of sodium chloride at which 50% of erythrocytes lysed for cats fed either an antioxidant-supplement or standard diet.
Other workers have recently reported that dietary vitamin E supplementation resulted in a dose-dependent increase in serum vitamin levels in both young and old cats.(8) In this study, lymphocyte proliferation in response to stimulation by the mitogen concanavalin A was significantly higher in older cats receiving vitamin E-supplemented diets compared with counterparts fed the basal diet. This effect was not apparent in younger cats. Cats of both age groups fed the supplemented diets also demonstrated significantly lower PGE2 production. These data suggest that dietary supplementation with vitamin E may enhance immune function, particularly in older cats where there was evidence of weakened T cell proliferation to mitogenic challenge and reduced cell-mediated immunity, although vitamin E supplementation had no effect on the latter.
Results of recent studies suggest that dietary supplementation with antioxidants have beneficial effects on the immune system and promote immunocompetence in cats. Work is required to more fully elucidate the mechanisms underlying these effects and to understand their impacts on ageing and chronic disease as well as immune function in this species.
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