Life Extension Magazine February 2003
ACAM Convention 2002
Stress and brain aging
David Perlmutter, M.D., the medical director of Perlmutter Health Center, is currently involved in research at the National Parkinson's Disease Foundation, studying the effectiveness of glutathione treatment in Parkinson's disease. He is also widely known as an author and lecturer on the broader subject of brain aging and regeneration. At this conference, he presented a lecture on the effects of chronically elevated cortisol on the hippocampus, an area of the brain important in the formation of memory, as well as in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis.
In a dramatic slide, the audience saw the neuroprotective effects of cortisol reduction. Aged rats whose cortisol was kept down through adrenalectomy showed no more damage in their hippocampus than young rats, in sharp contrast to intact aged rats. Perlmutter also pointed out that dominant monkeys do not suffer the kind of hippocampal atrophy that is seen in subordinate monkeys. Humans with pathologically elevated cortisol, such as the victims of Cushing's syndrome, have overactive adrenals, and show much more cognitive decline than individuals with lower cortisol levels. Likewise, Alzheimer's disease patients show elevated levels of cortisol in their cerebrospinal fluid; in these patients, the degree of hippocampal atrophy accurately reflects cognitive decline.
How does cortisol damage the hippocampus? Perlmutter explained that glucocorticoids (cortisol is our main glucocorticoid hormone) increase levels of glutamate, an excitatory neurotransmitter. Excess glutamate causes neural mitochondria to produce defective ATP (ATP, adenosine triphosphate, is our energy molecule). This defective ATP eliminates the "magnesium block" guarding the neuron against excess influx of calcium ions, followed by generation of free radicals and cell damage or cell death.
Elevated evening cortisol indicates damage to the HPA axis. Evening cortisol elevation is related to sleep fragmentation (frequent awakenings) and less REM sleep. Even modest elevation in cortisol has been found to correlate with memory deficit. Unfortunately, our cortisol levels increase with aging, a problem that definitely needs to be addressed by anti-aging medicine.
Women who have been raped show higher cortisol, Perlmutter said. Likewise, stress in childhood may set the HPA axis at an over-reactive level, so that the individual reacts to even minor stressors with an exaggerated cortisol response.
Is there a remedy? Stress reduction has been much talked about, but Perlmutter thinks that we need to go beyond that, into positive feelings, including love. Supplements that have been shown to reduce cortisol levels are 4000 mg a day of vitamin C and DHEA.
We also need to stimulate neurogenesis in order to regenerate the brain. Dr. Perlmutter mentioned that lithium is both neuroprotective and neurotrophic. It inhibits neuronal death induced by beta amyloid. Lithium users were also found to have significant increases in gray matter. Stimulation of the vagus nerve also increases neurogenesis. On a practical level, physical exercise, which improves circulation and tends to lower emotional stress, also promotes neurogenesis.
Meditation, positive emotions and physical exercise are all effective tools in protecting the brain, and especially the hippocampus, against the deadly effects of chronic stress.
Magnesium, lipoic acid and flavonoids help protect against exitotoxicity
Russell Blaylock, M.D. assistant professor at the University of Mississippi Medical Center and a retired neurosurgeon, spoke about ways to protect the aging brain with diet and supplements. Because of its high (60%) content of polyunsaturated fat and high metabolism, the brain is especially vulnerable to damage. One mechanism of damage is called excitotoxicity. This term describes a process during which excessive extracellular glutamate promotes excessive influx of calcium ions into nerve cell, inducing a generation of free radicals, lipid peroxidation, and inflammation. This so-called excitotoxic cascade leads to damage and even cell death.
Fortunately, we know that magnesium is a natural calcium antagonist, and helps protect the neurons against excitotoxicity. Low levels of magnesium have been found in the hippocampus of Alzheimer's disease patients. Magnesium deficiency is extremely common.
Magnesium protects the brain in other ways as well: it lowers blood pressure and helps prevent atherosclerosis, and thus the risk of stroke. Magnesium also helps increase glutathione levels; magnesium deficiency has been found to cause a drastic decrease in glutathione. Glutathione, our key cellular antioxidant, is enormously important in defending neurons against free-radical damage. Besides magnesium, lipoic acid, acetyl-cysteine, vitamin C, and various flavonoids increase glutathione levels.
A diet high in antioxidants is also highly recommended. The catechins found in green tea are highly neuroprotective, as are the flavonoids found in blackberries, blueberries, cranberries and berries in general, in prunes and raisins, as well as deep green vegetables such as kale and spinach. Quercetin, found in tea, onion and apples, has been found to inhibit the initiation of the inflammatory cascade. Quercetin also powerfully inhibits the production of peroxynitrite.
Ginkgo has also been found to be very neuroprotective, improving circulation and increasing glucose uptake.
Other vitamins and nutrients that protect the brain include CoQ10, acetyl-l-carnitine, vitamin C (which helps control brain glutamate), vitamin E, and the anti-inflammatory omega-3 fats, especially DHA, found in fish oil. Phosphatidylserine also helps block glutamate excitotoxicity.
Dr. Blaylock is the author of Excitotoxins: the Taste that Kills, a book warning the public about MSG and aspartate.
Flavonoids synergize with antioxidants to fight cancer and heart disease
Jeffrey Blumberg, Ph.D., Associate Director and Chief of the Antioxidant Research Laboratory at the USDA Nutrition Research Center on Aging at Tufts University in Boston, presented a fascinating lecture that explained the puzzling contradiction in many studies on phenolic compounds found in fruits, vegetables, tea, coffee, chocolate, red wine and other plant-derived food products.
Over 4,000 flavonoids have been identified, including anthocyanins found in fruits and flowers; flavans, also known as catechins and found in tea; flavones such as apigenin, luteolin and tangeretin; flavonols such as quercetin, myricetin, and kaempherol; and isoflavones, including soy isoflavones, genistein and daidzein, and equol, a metabolite of daidzein produced by the intestinal flora.
Certain flavonoids have been shown to have anti-viral as well as an anti-cancer activity. They can also suppress the growth of new blood vessels by tumor tissue (anti-angiogenetic activity) and inhibit adhesion molecules. Many flavonoids chelate iron, help prevent blood clots, and show anti-inflammatory and antioxidant activity. In addition, certain flavonoids, such as those found in purple grape juice, can improve blood flow; pycnogenol has been shown to lower blood pressure in mild hypertension.
Epidemiological research has found that high consumption of phenolics is associated with lower cardiovascular disease, cancer, osteoporosis and Alzheimer's disease. Most notably, a well-known Dutch study found a 50% reduction in cardiovascular disease in subjects who consumed the most flavonoids, mainly those found in apples, onions and black tea. Likewise, Japanese studies found a 50% reduction in coronary stenosis (narrowing of coronary arteries) in patients who drank four or more cups of green tea a day. Some in-vitro studies on isolated flavonoids, however, have found no effect. The main reason for this, Blumberg argued, is that phenolic compounds act in synergy with other antioxidants such as vitamins E and C. The resulting synergy can provide powerful protection against disease.
To support his thesis, Blumberg presented the findings of studies done at Tufts University, investigating the protection of LDL cholesterol against oxidation. Oxidized LDL cholesterol plays a huge role in atherogenesis, Blumberg stated. It promotes inflammation and stimulates the proliferation of smooth muscle cells. Of the flavonoids tested, quercetin, luteolin, and epigallocatechin gallate (found in green tea) showed the highest ability to protect LDL cholesterol, especially when combined with vitamins C and E.
Blumberg also tested oat extract. It turned out that oat extract provided no antioxidant protection when used by itself. However, when vitamin E was added, its action was 20% to 36% more effective; there was even more synergy with vitamin C. Similarly, almond-skin extract, a rich source of quercetin and other polyphenols, was found to be an excellent LDL protector when combined with a small amount of vitamin E.
Actually, it has been known since the 1930s that flavonoids enhance the action of vitamin C. Yet, it is only now that we are beginning to grasp the essence of this synergy. In the body, antioxidants operate within networks rather than by themselves. The reason is that in the process of donating electrons to the harmful free radicals, antioxidant compounds themselves become oxidized, and need another antioxidant to restore them to the reduced state. Thus, the synergy of an antioxidant network comes from its ability to maintain its components in an antioxidant state much longer.
The idea of synergy in general has been gaining ground. More and more studies show that two or more compounds tend to be more potent than a single compound. This applies even to combinations of chemotherapy drugs and with natural anti-cancer compounds. Thinking in terms of a single "magic bullet" is rapidly becoming obsolete.
On the practical level, Blumberg warned that iced tea is less potent than strong hot tea. The research at Tufts discovered that iced tea that has been left in the refrigerator for more than one day, and bottled tea that has been sitting on the shelf, have no health benefits. The flavonoids in these beverages have become oxidized and no longer have any antioxidant activity.
Blumberg was honored with an ACAM award for his work on flavonoids.
Arthritis update: Glucosamine doesn't cause insulin resistance
Jason Theodosakis, M.D., Assistant Professor at the University of Arizona College of Medicine, presented an update on holistic treatment of arthritis. One important point was the effectiveness of anti-inflammatory enzymes such as bromelain and papain. Another was the speaker's rebuttal of the unfounded belief that glucosamine causes insulin resistance. An indirect proof that it does not was provided by a three-year study published in Lancet. Patients taking glucosamine actually had lower serum glucose than controls. Furthermore, rats given glucosamine showed no increase in insulin resistance, and had lower blood pressure than controls.
Glucosamine has a wide range of benefits, including suppression of interleukin-1 and interleukin-6. Glucosamine also suppresses the TNF alpha-induced production of nitric oxide in chondrocytes (cartilage-producing cells). It inhibits matrix metalloproteinases, enzymes that dissolve cartilage.
The popular COX-2 inhibiting drug Vioxx, according to Theodosakis, has been shown to lead to further joint deterioration. X-ray studies reveal dose-dependent cartilage loss with long-term use. A 25 mg dose produced greater damage than a 12.5 mg dose.
Theodosakis also mentioned the benefits of niacinamide, a form of niacin, in the treatment of arthritis. Niacinamide appears to inhibit pro-inflammatory interleukin-1.
The speaker also recommended exercise. "People who have good leg muscles have less knee arthritis; the muscles act as shock absorbers," Theodosakis explained. Also, the right exercise, such as working out on a stationary bicycle, stimulates chondrocytes to produce more cartilage.
As Dr. Gonzalez stated, "There is change in the air." Mainstream medicine can no longer afford to dismiss the ever-growing research on the effectiveness of natural therapies. Much more needs to be done; but at least the research has begun, as seen, for instance, in the excellent presentations of the speakers from Tufts University. Other outstanding presentations included Dr. Gonzalez's own lecture on the use of enzymes, nutrition, autonomic balancing and supportive supplements in the treatment of cancer. Dr. Perlmutter likewise excelled as usual, explaining how chronic stress and elevated cortisol levels lead to hippocampal atrophy and cognitive decline.
It is not easy to summarize a conference as rich in information as this Spring's ACAM convention. For one thing, the information tends to get more complex the more is discovered about human physiology, the aging processes and diseases such as cancer. It is important that both physicians and the public keep up with this growing body of knowledge. ACAM is a leader in providing this kind of education to physicians.
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