Van der Merwe L.L. BVSc Hons MMed(Vet) Small Animal Medicine, Department of Companion
Animal Clinical Studies (Outpatients), Faculty of Veterinary Science, Lieselvdmvet@gmail.com
This short article attempts to summarise the most salient and practical aspects of the oxidative stress in the body and what mechanisms the body employs to minimise manage it.
Oxidative stress is a by-product of daily metabolic functions which enable living. The majority of complex life on earth requires oxygen for its existence but oxygen is also a highly reactive molecule that damages living organisms by producing reactive oxygen species. Inflammatory disease, ageing, congestive heart failure CHF, liver disease, stress, cancer, exercise can all increase oxidative stress. It is often unclear if oxidants trigger the disease, or if they are produced as a secondary consequence of the disease.
Changes associated with ageing may be physiological (changes in body composition, metabolic rates and special senses) or pathological. Several recommendations for alterations in nutrient intake in older dogs have been made.
|Several recommendation for alterations in nutrient intake in older dogs (and cats)|
|Energy||Increase / decrease||Senior dogs have overall decreased energy requirements but older dogs are also more likely to be underweight.|
|Protein||Increased – unless there is evidence of disease requiring protein reduction||Protein requirements of older dogs increase with age because of increased protein turnover. In cats protein absorption is decreased.|
|Fat||Increased or decreased||Senior dogs should have no alteration in fat digestibility with age.|
|Long chain W3 fatty acids||No alterations/ increase||Inconclusive evidence but long chain fatty acids may be beneficial in delaying the onset and progression of several physiological ageing processes|
|Anti-oxidants||No alterations or increase||Inconclusive evidence but studies indicate that dietary enrichment wih a variety of anti-oxidant combinations improves cognitive function.|
Organisms contain a complex network of antioxidant metabolites and enzymes that work together to prevent oxidative damage to cellular components such as DNA, proteins and lipids. In general, antioxidant systems either prevent these reactive species from being formed, or remove them before they can damage vital components of the cell. These oxidants can damage cells by starting chemical chain reactions such as lipid peroxidation, or by oxidizing DNA or proteins. Damage to DNA can cause mutations and possibly cancer, if not reversed by DNA repair mechanisms, while damage to proteins causes enzyme inhibition, denaturation and protein degradation.
Antioxidants are substances which have the ability to scavenge (ROS) and reduce the overall number of oxidants in a system. It is now accepted that the various antioxidant mechanisms in a system act synergistically. The major anti-oxidant systems in the body in include the enzymatic anti-oxidants superoxide dismutase (SAD), catalase and glutathione peroxidase, and the oxidant consumers which include Vitamin C, Vitamin E, glutathione and beta-carotene. The function of anti-oxidant systems is not to remove oxidants entirely, but instead to keep them at an optimum level as radical oxygen species (ROS) do have some positive functions.
Antioxidants are classified into two broad divisions, depending on whether they are soluble in water (hydrophilic) or in lipids (lipophilic). In general, water-soluble antioxidants react with oxidants in the cell cytosol and the blood plasma, while lipid-soluble antioxidants protect cell membranes from lipid peroxidation. See table 1
|Ascorbic acid (vitamin C)||Water|
|α-Tocopherol (vitamin E)||Lipid|
|Ubiquinol (coenzyme Q)||Lipid|
Some compounds contribute to antioxidant defence by chelating metals and preventing them from catalysing the production of free radicals in the cell. Of special importance is the ability to sequester iron, which is the function of iron-binding proteins such as transferrin and ferritin. The trace elements selenium and zinc are commonly referred to as antioxidant nutrients, but these chemical elements have no anti-oxidant action themselves and are instead required for the activity of some antioxidant enzymes.
Although certain levels of antioxidant vitamins in the diet are required for good health, there is considerable debate on whether anti-oxidant rich foods or supplements have anti-disease activity. Moreover, if they are actually beneficial, it is unknown which antioxidant(s) / combinations thereof are needed from the diet and in what amounts beyond typical dietary intake.
In order to critically evaluate the therapeutic potential for antioxidants (and other nutraceuticals) for the aging process is to consider the outcome measures used to determine efficacy. A variety of new laboratory methods have been developed to try to measure the effects of ROS in biologic systems the potential results of an intervention. Markers are specific for different biomolecules such as DNA (8-oxodeoxyguanosine), lipids (alkenals, MDA, TBARS), prostaglandins (isoprostanes) protein (nitrotyrosine, protein carbonyls), and advanced glycation endproducts (AGE). Some associations have been made between reduction of these markers of oxidative damage and improved health outcomes.
Supplementation and efficacy cannot be extrapolated from human studies. The selection of compounds, dosage range, length of administration, and route of administration may vary considerably across species. The selection of specific compounds may depend on bioavailability and supplementation with antioxidants may, or may not, increase absorption into tissues. Many have species or meal variation differences in absorption.
Vitamin C, a redox catalyst, is maintained in its reduced form by reaction with glutathione and can reduce, and thereby neutralize, reactive oxygen species such as hydrogen peroxide. Vitamin C is found in high concentrations in fruits. It can be synthesized in the canine liver but cannot be stored. Its production is decreased in chronic liver disease. Most commercial pet foods contain sufficient amounts of vitamin C and supplementation should only be required for malabsorption syndromes (EPI) and where extra anti-oxidant activity is required (cognitive dysfunction).
Vitamin E is a fat soluble vitamin found in high concentrations in nuts and oils. Vitamin E is the collective name for a set of eight related tocopherols and tocotrienols, which are fat soluble vitamins.
Alpha-tocopherol is the most widespread form of Vitamin E in animal foods and organisms. It is the form with the greatest bioavailability and biological anti-oxidant activity, with the body preferentially absorbing and metabolising this form. It protects membranes from oxidation by reacting with lipid radicals produced in the lipid peroxidation chain reaction which removes the free radical intermediates and prevents the propagation reaction. The oxidised α-tocopheroxyl radicals produced that can be recycled back to the active reduced form through reduction by other antioxidants, such as ascorbate, retinol or ubiquinol (Co-enzyme Q10).
Flavonols are anti-oxidants found in plants and are the most important plant pigments for flower colouration, producing yellow or red/blue pigmentation. Animals significant quantities in their diet. Foods with a high flavonoid content include parsley, onions, blueberries and other berries, black tea, green tea and oolong tea, bananas, all citrus fruits, Ginkgo biloba, red wine, sea-buckthorns, buckwheat, and dark chocolate (with a cocoa content of 70% or greater).
Sstudies indicate that flavonoids may affect anti-inflammatory mechanisms due to their ability to inhibit reactive oxygen or nitrogen compounds. Flavonoids have also been proposed to inhibit the pro-inflammatory activity of enzymes involved in free radical production, such as cyclo-oxygenase, lipo-oxygenase or inducible nitric oxide synthase.
Carotenoids are organic pigments which are produced by plants and algae, as well as several bacteria and fungi. Compounds are deeply coloured yellow, orange, or red. Carotenoids from the diet are stored in the fatty tissues of animals, and exclusively carnivorous animals obtain the compounds from animal fat. There are over 600 known carotenoids; they are split into two classes, xanthophylls (which contain oxygen) and carotenes (which are purely hydrocarbons, and contain no oxygen). Humans and animals are mostly incapable of synthesizing carotenoids, and must obtain them through their diet. Dogs absorb beta carotene differently from humans, cleaving it and leaving very little intact b-carotene. In part, the beneficial effects of carotenoids are thought to be due to their role as antioxidants. b-carotene may have added benefits due its ability to be converted to vitamin A.
S-adenosylmethionine (SAMe) is a precursor of glutathione, a major antioxidant molecule in the body. Oral supplementation can assist to replenish glutathione stores. In addition SAMe also has anti-inflammatory properties.
Glutathione is an important antioxidant in animals and is capable of preventing damage to important cellular components caused by reactive oxygen species such as free radicals, peroxides, lipid peroxides and heavy metals.
Glutathione reduces disulfide bonds formed within cytoplasmic proteins to cysteines by serving as an electron donor. In the process, glutathione is converted to its oxidized form, glutathione disulfide (GSSG). Once oxidized, glutathione can be reduced back by glutathione reductase, using NADPH as an electron donor. (Note: a very important antioxidant in haemoglobin – especially feline haemoglobin , due to the increased number of sulphide bonds in this species.)
Glutathione exists in both reduced (GSH) and oxidized (GSSG) states. In the reduced state, the thiol group of cysteine is able to donate a reducing equivalent (H++ e−) to other molecules, such as reactive oxygen species to neutralize them. After donating an electron, glutathione itself becomes reactive and readily reacts with another reactive glutathione to form glutathione disulfide (GSSG). Such a reaction is probable due to the relatively high concentration of glutathione in cells. GSH can be regenerated from GSSG by the enzyme glutathione reductase. In healthy cells and tissue, more than 90% of the total glutathione pool is in the reduced form (GSH) and less than 10% exists in the disulfide form (GSSG).
The ratio of reduced glutathione to oxidized glutathione within cells is often used as a measure of cellular oxidative stress.
Melatonin is a strong antioxidant which easily crosses cell membranes and the blood–brain barrier. Unlike other antioxidants, melatonin does not undergo redox cycling, which is the ability of a molecule to undergo repeated reduction and oxidation. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants and promote free radical formation. Melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.
Recent research has shown that some molecules classified as mitochondrial co-factors (lipoic acid, L-carnitine) may also act to enhance function of aged mitochondrion such that there are less ROS produced during aerobic respiration. Supplementation of foods with these co-factors increases their concentration within cells restores mitochondrial efficiency and reduces oxidative damage to RNA.
L-carnitine is an amino acid synthesised in the liver and kidney from lysine and methionine in the presence of ascorbate. L-carnitine facilitates the transportation of long chain fatty acids into the mitochondria where they undergo b–oxidation which produces a large amount of energy (ATP).The main dietary sources of carnitine are red meat, fish and dairy products. White meat is less rich in L-carnitine and vegetables contain none. Because L-carnitine can be synthesised de novo – it is not considered an essential nutrient.
Co-enzyme Q10 is a co-factor required for energy production and has anti-oxidant properties. It is a fat-soluble substance, which resembles a vitamin, and is present primarily in the mitochondria. It is a component of the electron transport chain and participates in aerobic cellular respiration, which generates energy in the form of ATP. Ninety-five percent of the human body‘s energy is generated this way. Therefore, those organs with the highest energy requirements—such as the heart, liver, and kidney—have the highest CoQ10 concentrations.
The take home message here is that nutraceutical supplementation of anti-oxidants is a very INEXACT science. One cannot just buy a single supplement from a health shop and start supplementing. There seems to be an important interaction between the different types of anti-oxidants for maximum effect . More publications assessing the oxidative stress of various disease processes in animals and the results of interventions are coming out in the literature in recent years.
References: Available online: www.vet360.vetlink.co.za