The Optimum Level of Antioxidants

The epidemiological evidence and the guidelines of the National Cancer Institute and the National Research Council/National Academy of Sciences suggest that at least two fruits and three vegetables per day is a desirable intake.

Since ascorbate, tocopherol, and ß-carotene supplements are inexpensive and high doses are remarkably non-toxic, there is a school that believes that supplements, in addition to a diet containing recommended levels of fruits and vegetables, are desirable.

There is suggestive, but inadequate epidemiological and biochemical evidence bearing on the question. What is clear is that fruits and vegetables contain many necessary micronutrients in addition to antioxidants, some of which also can prevent mutations. Folic acid, for example, is required for the synthesis of the nucleotides in DNA.

Inadequate intake has been shown to cause chromosome breaks and increased cancer and birth defects. Folate deficiency may be a risk factor for myocardial infarction as well. Niacin is required for making poly (ADP-ribose), a component of DNA repair. Other micronutrients are also likely to be part of our defense systems.

The U.S. Recommended Daily Allowances (RDAs) for ascorbate and tocopherol intake--there is no guideline for [[beta]]-carotene independent of its provitamin A activity--are not adequate for several reasons:

1) The amount recommended, e.g., 60 mg/day for ascorbate, is primarily for avoiding an observable deficiency syndrome, e.g., scurvy, and is not necessarily the amount for optimum lifetime health, which is usually not known.

2) A recommended blood level of each antioxidant, e.g., 60 uM ascorbate, would be a more desirable standard. People vary considerably in the intake required to keep their blood level adequate. A smoker, for example, needs to take in several times as much ascorbate as a non-smoker to keep the blood level the same.

Infections may also cause an oxidative stress that leads to antioxidant depletion by activating phagocytic cells. The observation that antioxidant inadequacy is associated with oxidative damage to DNA of the germ line as well as somatic cells, emphasizes the urgency of defining adequate blood levels.

Since only 9% of Americans, and fewer in most other countries, are eating five fruits and vegetables per day, there is a great opportunity to improve health by increasing consumption.

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Antioxidants and Brain Dysfunction

Biochemical studies suggest that oxidation may be important in a number of brain pathologies. The few epidemiological studies are consistent with a protective effect of fruits and vegetables or antioxidants in a number of neurological pathologies, including brain ischemia, Parkinsons disease (PD), and familial amyotrophic lateral sclerosis (FALS), a degenerative disorder of motor neurons .

Ischemic episodes liberate iron, an important catalyst in oxygen radical forming reactions; iron chelators reduce neuron loss following this trauma. In individuals suffering from Parkinson's disease, oxidative DNA damaged is elevated within brain regions rich in dopaminergic neurons (E. Övervik, J. Sanchez-Ramos and B. Ames, unpublished). The most convincing evidence so far for a link between neurological disorders and oxygen radical formation is the strong association found between FALS and mutations in the Cu/Zn superoxide dismutase gene, suggesting that oxygen radicals might be responsible for the selective degeneration of motor neurons occurring in this fatal disease.

The protective role of superoxide dismutase against brain injury due to ischemia is supported by the finding that its overproduction is protective in a transgenic mouse model. Based on the similar protective effects against ischemia induced brain injury by inhibition of nitric oxide formation, and the recent evidence implicating these two radical species in cytotoxicity of neuronal cells, it would appear that peroxynitrite, a powerful oxidant formed from the combination of superoxide anion radical and nitric oxide, plays an important role in neuronal injury following ischemia and reperfusion.

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Antioxidants Protect Against Disease

Many defense mechanisms within the organism have evolved to limit the levels of reactive oxidants and the damage they inflict. Among the defenses are enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. The glutathione S-transferases inactivate reactive electrophilic mutagens, including the aldehyde products of lipid peroxidation.

There are also many structural defenses such as sequestering H202 generating enzymes in peroxisomes and chelating any free iron or copper salts in transferrin and ferritin or ceruloplasmin to avoid Fenton chemistry. Superoxide, however, can release iron from ferritin.

Oxidized DNA is repaired by a series of glycosylases that are specific for particular oxidized bases and possibly by non-specific excision repair enzymes. In the absence of cell division these oxidative lesions are removed from DNA quite effectively and the mutation rate is kept to a minimum. Oxidized proteins are degraded by proteases. Lipid hydroperoxides are destroyed by glutathione peroxidase.

Almost all of these defenses appear to be inducible, as are most other types of defenses, i.e., the amounts increase in response to damage. There is a large literature showing that cells respond to low levels of radiation, an oxidative mutagen, by inducing antioxidant defenses that help to protect them against mutation by high levels of radiation.

There is a tradeoff however, since the induction of these defenses makes the cell more sensitive to alkylating mutagens.

In addition to the protective effects of endogenous enzymatic antioxidant defenses, consumption of dietary antioxidants appears to be of great importance. Fruits and vegetables, the main source of antioxidants in the diet, are associated with a lowered risk of degenerative diseases. Block and her colleagues have recently reviewed 172 studies in the epidemiological literature that relate, with great consistency, the lack of adequate consumption of fruits and vegetables to cancer incidence.

The quarter of the population with low dietary intake of fruits and vegetables compared to the quarter with high intake has double the cancer rate for most types of cancer (lung, larynx, oral cavity, esophagus, stomach, colon and rectum, bladder, pancreas, cervix, and ovary). Data on the types of cancer known to be associated with hormone levels are not as consistent and show less protection by fruits and vegetables: for breast cancer the protective effect was about 30%. There is also literature on the protective effect of fruit and vegetable consumption on heart disease and stroke. Only 9% of Americans eat five servings of fruits and vegetables per day, the intake recommended by the National Cancer Insitute and the National Research Council. European countries with low fruit and vegetable intake (e.g., Scotland) are generally in poorer health and have higher rates of heart disease and cancer than countries with high intake (e.g., Greece).

The cost of fruits and vegetables is an important factor in discouraging consumption. Poorer people spend a higher percentage of their income on food, eat less fruits and vegetables, and have shorter life expectancy than wealthier people. A major contributor to health in this century was synthetic pesticides which markedly decreased the cost of food production and ensured that most of the crops planted would be eaten by humans rather than insects. Synthetic pesticide residues do not appear to be a significant cause of cancer.

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