~ Strengthening the Body's Natural Weapons Against Oxidative Stress

Aging is part of life. But nurture the body with a diet and lifestyle that promote health and prevent cell damage and you can delay aging and extend a healthy life.

The Free Radical Theory of Aging is Alive and Well

A study published online on May 5 2005 in the journal Science (www.sciencemag.org) reports the finding of researchers at the University of Washington and other centers of a way to significantly extend the lifespan of laboratory animals while reducing the effects of aging.

University of Washington School of Medicine professor of pathology Dr. Peter Rabinovitch and colleagues studied mice bred to produce human catalase, the enzyme that converts hydrogen peroxide into water and oxygen.

Hydrogen peroxide is produced during metabolism and is a precursor of free radicals that lead to cell damage, which causes the generation of even more free radicals. The team targeted delivery of the catalase to the cytoplasm of the cell where catalase normally decomposes hydrogen peroxide, the nucleus, which is the center of the cell, and the mitochondrion, which are the cell's energy producing organelles.

While mice with elevated catalase levels in the nucleus and cytoplasm experienced small increases in lifespan, animals that produced catalase in their mitochondria were found to experience a 20 percent increase in average and maximum lifespan and had healthier heart tissue.

This adds credence to the theory that the mitochondria are a major source of free radicals generated as a byproduct of energy production. Dr Rabinovitch stated, "This study is very supportive of the free-radical theory of aging. It shows the significance of free-radicals, and of reactive oxygen species in particular, in the aging process."

He added, "People used to only focus on specific age-related diseases, because it was believed that the aging process itself could not be affected. What we're realizing now is that by intervening in the underlying aging process, we may be able to produce very significant increases in 'healthspan,' or healthy lifespan."

Antioxidants and Aging - A Review of Free Radicals

Free radicals are produced in normal metabolism when oxygen is used to burn food for energy. Free radicals are also produced in certain disease states and in response to toxins and trauma. A free radical is a molecule with an unpaired electron. This feature makes a free radical unstable and highly reactive, trying to capture an electron that will stabilize it.

By capturing electrons from molecules nearby, the free radical converts other molecules to free radicals, thereby initiating a destructive chain reaction. By producing oxidative damage in DNA, free radicals can produce mutations that, over time, can lead to cancer.

Oxidative Stress

Oxidative changes in fats (lipids) and proteins injure cell membranes, weaken blood vessels, affect immune cells, modify protective enzymes - among others - and damage many other molecules. These injuries alter cell functions and increase the risk of heart disease, stroke, cancer and brain disease.

Oxidation of Low Density Lipoprotein (LDL), the "bad" cholesterol, causes it to stick more easily to blood vessel walls, facilitating the formation of plaques in arteries, leading to atherosclerosis. If plaques detach as clots and travel in the circulation they can block vessels in the heart, causing a heart attack, or in the brain, causing stroke. Vascular damage and other forms of oxidant damage to brain cells are associated with Alzheimer's disease.

Free radical injury also increases the risk of wrinkles, cataracts, blindness and arthritis.

The most important free radicals made in cells are superoxide, hydroxyl radical and nitric oxide. Other reactive oxygen species that are not free radicals are singlet oxygen - from ultraviolet light - hydrogen and lipid peroxides, and the air pollutant ozone that is high in smog.

Free radical levels rise in the body during rigorous exercise and from exposure to pollutants, radiation, UV light and smoking. During infection and chronic inflammation, massive amounts of nitric oxide and superoxide radicals form in immune cells to fight off invading bacteria and viruses. Made in excess, these oxidants can harm and combine to form another toxic chemical that produces further damage in DNA and brain cells.

The Antioxidant Defense Force

Antioxidants are chemical substances that donate an electron to the free radical and convert it to a harmless molecule. In this way, antioxidants intercept free radicals and protect cells from the oxidative damage that leads to aging and disease. Antioxidants prevent injury to blood vessel membranes, helping to optimize blood flow to the heart and brain, defend against cancer-causing DNA damage, and help lower the risk of cardiovascular disease and dementia, including Alzheimer's disease.

Some antioxidants are made in our cells and include enzymes and the small molecules glutathione, uric acid, coenzyme Q10 and lipoic acid. Other essential antioxidants such as vitamin C, E and selenium must be obtained from our diet.

The enzyme superoxide dismutases (SOD) converts superoxide radicals into hydrogen peroxide, which is converted into water by the enzymes catalase or glutathione peroxidase. Defense mechanisms against oxidative changes in lipid peroxidation that severely damage membranes depend heavily on glutathione, an efficient free radical scavenger, and on glutathione peroxidase and other peroxidases that destroy peroxides.

Reducing Oxidative Damage Requires a 2-Pronged Strategy

The strategy for obtaining essential antioxidants not made in the body is to maintain a diet high in fruits, vegetables and grains that are rich sources of antioxidant vitamins, minerals and phytochemicals (botanicals), combined with high quality supplementation.

The strategy for maximizing the body's existing defense mechanism consists in strengthening the body's ability to respond to stress and reducing the triggers that cause these antioxidant enzymes to be depleted, especially lipid peroxidation (fat molecules are easily oxidized), the sequential breakdown of fatty substances in cells by chemical oxidation that leads to the destruction of membranes within and surrounding the cell.

This second strategy is behind the design of some antioxidant formulas, such as Antioxidant Optimizer and Protandim®. The strategy is to free up the body's supply of antioxidant enzymes by addressing the root causes of antioxidant enzyme depletion.

The Usual Suspects

Not surprisingly, Curcumin (turmeric), Milk Thistle (silymarin), and Green Tea concentrates play leading roles in formulas designed to boost the body's own antioxidant capability.

Curcumin. Curcumin, the extract found in a common household spice, has been drawing more and more attention among medical experts the last several years for its antioxidant and anti-inflammatory qualities.

As we mentioned above, when the body responds to a physical injury, a series of changes occurs through which free radicals are released. These free radicals, or "oxidants," protect the body from foreign invasion, such as infection. However, in the process of killing invading bacteria, oxidants can also harm our cells. Such oxidants can include superoxide, hydrogen peroxide, hydroxyl radicals and lipid peroxides. Over time, as our cells continue to be affected by these free radicals, or oxidants, organs begin to degenerate. The result can be such diseases and conditions as chronic inflammation, heart disease, aging acceleration and chaotic cell growth leading to cancer.

The body does have built-in defense mechanisms to protect itself from free radical damage, but eventually, aging and disease deplete the body's ability to keep oxidants at bay. Studies show that curcumin can inhibit, or possibly even reverse this process by scavenging or neutralizing free radicals and breaking their subsequent oxidative chain reaction.

Research as early as 1995 has shown that a diet that includes curcumin can restrict this oxidative stress. Scientists in India found curcumin inhibited lipid peroxidation, superoxides and hydroxyl radical.

Two more recent studies were published last year. In the first analysis, scientists found that prolonged exposure by curcumin to endothelial cells of the bovine aorta resulted in "enhanced cellular resistance to oxidative damage."

Doctors in a separate investigation discovered that curcumin suppressed oxidative stress induced by trichloroethylene in mouse liver. The researchers concluded that curcumin's benefit seems to be derived from its ability to inhibit increases in cellular levels of peroxisome, a component associated with oxygen utilization in cells.

The oxidation of LDL, the "bad" cholesterol, plays an important role in the development of atherosclerosis. Based on that knowledge, medical researchers have also examined the effect of curcumin on LDL oxidation and plasma lipid levels. In one investigation, doctors in Spain fed 18 rabbits a high cholesterol diet to induce atherosclerosis. The rabbits were divided into three groups; one group was given 1.66 milligrams of curcumin per kilogram of body weight, the second group was given 3.2 mg, and a third group was designated as a control. After seven weeks, the investigators found that the group fed the lower curcumin dosage decreased LDL's susceptibility to lipid peroxidation, and both dosage groups had lower cholesterol levels.

Milk Thistle (Silymarin). Milk thistle is an edible plant, and its leaves can be eaten like artichokes. The seeds can be roasted and brewed like coffee. Silybum marianum, a constituent of milk thistle, has been used for over 2,000 years as a traditional medicine specifically for liver ailments.

Milk thistle protects liver tissue; aids in the regeneration of damaged liver tissue; decreases liver and bile cholesterol; alleviates inflammation; and limits liver damage resulting from a disrupted oxygen supply.

Extracts of the milk thistle seed contains silymarin flavonoids (silybin, silydianin, and silychristin). Like Curcumin, Milk thistle is quite safe as a supplement. Neither toxicity nor drug interactions have been reported following high doses of milk thistle or its components.

Scientifically, researchers have found that silymarin, as well as an isolated form of flavonolignan called silybin, can prevent or counteract damage to the liver caused by toxins such as alcohol, acetaminophen (Tylenol) and other drugs, as well as environmental (heavy metals) and bacterial toxins, and even poisons such as those found in the lethal Deathcap mushroom.

Silymarin combats lipid peroxidation in the liver of rats; may hasten the restoration of liver cells in damaged liver tissue. The mechanism of liver damage may be depletion of glutathione and silymarin and silybin actually elevated glutathione levels in rats given alcohol. Human subjects with liver damage caused by chronic alcoholism, cirrhosis, hepatitis, or other toxicities were significantly benefited by treatment with silymarin.

Research on milk thistle as a liver cholesterol-lowering agent shows that rats given silybin had significantly lower cholesterol levels in their bile relative to rats given placebo. Even topical silymarin, applied to the ears of mice with dermatitis, caused a decrease in inflammation. Silymarin has also decreases histamine release from cells. And, giving silybin to rats following oxygen supply depletion to the liver decreased the severity of cell death.

Green Tea. Green tea is second only to water as the most consumed beverage in the world. It has been used medicinally for centuries in India and China. Green tea is prepared by picking, lightly steaming and allowing the leaves to dry whereas black tea is fermented before drying. Fermentation can destroy some of the active components of black tea.

The active constituents in green tea are powerful antioxidants called polyphenols (catechins) and flavonols. Tannins in tea are large polyphenol molecules and form the bulk of the active compounds in green tea, while catechins make up nearly 90% of the tannins.

Several catechins are present in significant quantities and account for the bulk of research: epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG) and epigallocatechin gallate EGCG. EGCG accounts for 10%-50% of the total catechin content and appears to be the most powerful of the catechins; its antioxidant activity about 25-100 times more potent than vitamins C and E. One cup of green tea may provide 10-40mg of polyphenols and has antioxidant activity greater than a serving of broccoli, spinach, carrots or strawberries.

Research shows that green tea may have be anti-atherogenic by reducing cholesterol & triglycerides; reduce blood clotting; enhance immune function; enhance weight loss; and be anti-cancenogenic.

In the laboratory, green tea is an effective antioxidant. It can protect against experimentally induced DNA damage; and slow or halt the initiation and progression of cancerous tumor growth. There is also evidence from some studies that green tea provides significant immunoprotective qualities, particularly in the case of cancer patients undergoing radiation or chemotherapy. White blood cell count appears to be maintained more effectively in cancer patients consuming green tea compared to non-supplemented patients

We recommend extracts standardized to at least 60% polyphenols and/or EGCG as a marker compound (this should be equivalent to 4-10 cups of brewed green tea). Green tea consumption of as much as 20 cups per day has not been associated with any significant side effects, though in high doses, teas that contain caffeine may lead to restlessness, insomnia, and tachycardia. Decaffeinated versions of green tea and green tea extracts are available – but the amounts of phenolic/catechin compounds can vary between extracts.

Antioxidant Optimizer . . .

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The Unusual Suspects - A New Look at Some Ancient Remedies

Ashwagandha and Bacopa are not new, but are gaining attention in the scientific community for their anti-aging benefits.

Ashwagandha. The word Ashwagandha comes from Sanskrit words, Ashv meaning horse and gandha meaning odor (from peculiar equine odor this plant has). Commonly known as winter cherry, this herb is regarded as a general tonic and is considered a Rasayana in Ayurvedic medicine.

Ashwagandha contains steroidal alkaloids and steroidal lactones. Currently, thirty-five withanolides have been isolated from the plant. These withanolides serve as important hormone precursors that convert into human physiologic hormones as needed by the body. Ashwagandha exerts amphoteric properties, which means it can help regulate important physiologic processes.

The effectiveness of Ashwagandha in a variety of rheumatologic conditions may be, in part, due to its anti-inflammatory properties which have been studied by several authors.  In animal studies, comparing the effectiveness of Ashwagandha and the prescription drug phenylbutazone in controlling inflammation, Ashwagandha was shown to be more effective. The Ashwagandha treated group completely reduced the inflammatory proteins, whereas animals treated with phenylbutazone as well as the control groups had increased inflammatory proteins.

Similar results were achieved in carrageenan induced inflammation. In another study, Ashwagandha extract showed far superior (almost double) results when compared to the drug hydrocortisone to reduce inflammation. In another study on paw swelling with adjuvant induced arthritis, Ashwagandha caused significant reduction in the swelling and showed degeneration as observed by radiological studies. The reduction in swelling and degeneration was better than the drug hydrocortisone. The mechanism of action is thought to be cox-2 inhibition similar to drugs: Celebrex or Vioxx. 

In another study, Ashwagandha root powder was given to 46 patients of rheumatoid arthritis with doses of 4, 6, or 9 grams for a period of 3-4 weeks. Pain and swelling disappeared completely in 14 patients, considerable improvement was noticed in 10 patients and 11 patients showed mild improvement. In one double blind, placebo control study, the combination of Ashwagandha with turmeric and zinc showed positive effects in osteoarthritis cases. Patients showed significant improvement in pain severity and disability score. In another animal study the dogs showed improvement in intermittent lameness, local pain and stiff gait, and external factors that aggravate lameness, such as "lameness when moving" and "lameness after a long rest" diminished gradually.

The free radical mechanism is one of the mechanisms considered to contribute to many inflammatory diseases. Ashwagandha has demonstrated its powerful antioxidant action on the nervous system. Oral administration of Ashwagandha in animals has prevented lipid peroxidation.

A typical dose of the Ashwagandha root powder is 3-6 grams per day and 300-500 mg of standardized extract. Ashwagandha is generally considered safe even in higher doses; its negligible toxicity, along with its antioxidant, anti-stress, anti-inflammatory, immunomodulatory and rejuvenative properties, make it an attractive addition to the antioxidant arsenal.

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Bacopa. As an Ayurvedic member of the materia medica (substances used in the preparation of medicinal drugs), Bacopa is classified as a medhyarasayana (an herb used to improve memory and intellect, or medhya). The Ayurvedic texts accentuate the crucial role of the mind in maintaining well-being and balance in life, and medhya herbal formulas help unlock full mental potential and ability.

The most active ingredient in Bacopa, called bacoside A, increases antioxidant activity in specific areas of the brain. Rats were studied to determine the effect of nearly chronic administration of Bacopa for 7, 14, and 21 days. The antiparkinsonian drug deprenyl (selegiline) was administered to another group of rats over the same time periods, and the effects of the two treatment regimens were compared.

Bacopa was found to increase, in proportion to the dose, the activity of the endogenous antioxidants SOD (superoxide dismutase), CAT (catalase), and GPX (glutathione peroxidase) in all the brain regions investigated, but only after the longer periods (14 and 21 days). Deprenyl, which has been shown in some studies to increase lifespan and in others to protect the brain, was also found to increase the activity of the endogenous antioxidants, but it did not perform as well as Bacopa in all areas of the brain, including the hippocampus, a structure normally rich in the memory neurotransmitter acetylcholine. In a previous study, Bacopa had been found to reverse the drug-caused depletion of acetylcholine in the hippocampus.

Research has shown that memory deficits caused by neurotoxins (an idea proposed as an animal model for Alzheimer's disease) can be alleviated through the use of antioxidants. Other research indicates that neurodegeneration caused by oxidative stress injury also affects memory. Indeed, the neurodegeneration caused by the accumulation of neurotoxic free radicals has been proposed as the causal factor in Alzheimer's disease, Parkinson's disease, and aging itself. What allows for the oxidative degradation that results in neurodegeneration and memory loss is a defect in the body's defense system that normally wards off damage. As alluded to earlier, these problems result from decreased function of the free-radical-scavenging enzymes, primarily SOD, CAT, and GPX. Thus, the potential therapies in these neurodegenerative conditions entail finding compounds that are capable of augmenting the body's natural defense systems.

Of all the free radicals in living organisms, the most abundant are the superoxide radical and the highly destructive hydroxyl radical. These radicals appear to work together to induce degeneration by oxidizing membrane lipids, breaking DNA strands, and damaging cellular proteins. The enzymatic defense system operates as a chain, starting with SOD and followed by the actions of CAT and GPX. In fact, SOD is effective only if followed by the actions of CAT and GPX, because when SOD removes superoxide radicals, it generates hydrogen peroxide and oxygen radicals. These, in turn, require the "defusing" actions of CAT and GPX.

This brings us back to the aforementioned study, in which an extract of Bacopa was found to increase SOD, CAT, and GPX activities significantly throughout all the brain regions examined. After only seven days of treatment, there were no significant increases in the measured antioxidants, suggesting that the memory benefits associated with oxidative stress relief are delayed. These results are consistent with some other Bacopa studies in which it took several weeks or more to reverse memory deficits. The fact that deprenyl has never been shown clearly to cause memory enhancement is thought to follow from its apparent inactivity in the hippocampus of the brain, unlike Bacopa. However, Bacopa has been shown in at least one study to possess possible antiaging benefits, just as has deprenyl, perhaps owing to their common ability to alleviate oxidative stress in the striatal area of the brain.

Antioxidants / Oxidative Stress . . .

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