Life Extension Magazine June 2002
One participant asked whether environmental enrichment (and hence dramatically enhanced neurogenesis) influences life span. Kempermann replied that enrichment probably does prolong life span. Mark Mattson joined in with an unqualified yes. Human epidemiological studies also indicate that social and mental stimulation is associated with better health and longer survival. According to some experts, social stimulation and overall mental stimulation may in fact be more important for longevity than exercise and diet (excluding the calorie-restricted diet).
Understanding factors that enhance neurogenesis will provide another extremely important tool in the struggle to prevent the ravages of aging. Alzheimer's disease continues to be a growing nightmare. For a long time, the treatment was focused mainly on trying to raise the levels of acetylcholine. But the main pathology in Alzheimer's disease is not so much shortage of neurotransmitters as the massive neuronal loss in the cortex and the hippocampus. The brain literally atrophies. Increasing the levels of neurotransmitters is not the answer in the advanced stages, since "there is no one home to answer"-the neurons are no longer there.
The good news is that ibuprofen has been shown to reduce the deposition of amyloid plaque. Celebrex also had some positive effect, but the results did not reach statistical significance. Expensive new anti-Alzheimer's drugs are in the process of development, but effective protection can be bought for pennies a day (by the way, aspirin is also protective, but to a lesser degree).
Polyphenol power: less inflammation, more dopamine release
Polyphenols have also attracted the attention of researchers. Polyphenols such as those found in green tea extract have an anti-inflammatory action, and are also potent iron chelators. Iron plays a pivotal role in Alzheimer's and Parkinson's disease. Epigallocatechin gallate (EGCG), the main active ingredient in green tea extract and one of the most powerful iron chelators we have, was used by Moussa Youdim, a pharmacologist in a center on Parkinson's in Haifa, Israel, in his studies of Parkinson's disease in an animal model of the disease.
Besides chelating iron, EGCG and green tea extract in general also induce antioxidant enzymes (SOD and catalase) and have an anti-inflammatory action by inhibiting the activation of NFkB, a transcription protein that translocates to the nucleus and initiates a destructive inflammatory cascade. Youdim tested the protective properties of various doses of EGCG in prevention of neuronal death when the animals' brains are injected with 6-hydroxydopamine or MTPT. It turned out that pre-treatment with EGCG protected the cells, as long as the dose was not excessive (extremely high doses of catechins are toxic and lead to cell death through apoptosis). EGCG could prevent mitochondrial collapse and thus save neurons and prevent dopamine depletion.
EGCG may also turn out to be a good preventer of Alzheimer's disease. It has been shown to increase soluble amyloid (the "good amyloid"). Interestingly, EGCG-fed animals were also leaner. Youdim thinks this may confirm the recent findings that green tea has an anti-obesity effect.
Youdim thinks that the most effective treatment of brain diseases necessitates the use of many agents. One of these is likely to be rasagiline, a MAO-B inhibitor related to deprenyl. Cholinesterase inhibitors also show promise, but only when combined with other drugs.
Youdim stressed that the best approach to reducing the ravages of brain diseases is preventive. "By the time you see the symptoms, it's too late," he said. "It's like falling down the Grand Canyon-how are you going to stop the fall?" It makes vastly more sense to use neuroprotective measures, including anti-inflammatories, exercise, mental and social stimulation, and phenolics such as green tea extract (the caffeinated kind is more effective than decaf; it has been established that caffeine helps lower the risk of Parkinson's disease. Chocolate is also neuroprotective, Youdim said).
A participant observed that Chinese Americans have much lower incidence of Alzheimer's disease and other neurodegerative diseases; this may be related to the custom of drinking tea.
Ginkgo biloba (in a standardized extract) has also been shown to be amazingly effective in protecting against neuronal death, even when administered after the neurotoxin was injected. In the case of amyloid beta, ginkgo protected against its toxicity if administered up to eight hours after the amyloid injection. For other toxins, ginkgo was able to achieve hippocampal cell rescue for up to two hours post-treatment.
The whole ginkgo extract has been shown to be more effective than any of the individual flavonoids. The ginkgo terpenes by themselves are not effective.
Other phytonutrients known to be neuroprotective include resveratrol and quercetin, the powerful phytoestrogens found in red wine. Resveratrol (a phytoestrogen similar in chemical structure to DES) has been shown to rescue nerve cells after exposure to toxins. The neuroprotective mechanism may depend chiefly on anti-inflammatory properties of phytonutrients. Epidemiological studies show that those people who drink moderate amounts of red wine later have a lower incidence of Alzheimer's disease and macular degeneration.
One cannot discuss the neuroprotective properties of polyphenols without mentioning the amazingly powerful anthocyanins found in blueberries and bilberries. Even when added to an already adequate diet, blueberry extract has been shown to increase dopamine release and improve various cognitive markers in aged rats. For instance, middle-aged rats fed blueberries show more exploratory behavior. Learning and motor skills are enhanced. The most powerful active ingredients appear to be anthocyanins, found mainly in the skin of blueberries. While proanthocyanidins are also very effective antioxidants, anthocyanins are more powerful anti-inflammatories, according to the studies at Tuft University. Hydroxycinnamic acid, found inside the blueberry (anthocyanins are mainly in the skin), is also an excellent antioxidant and anti-inflammatory, as measured by its
ability to reduce the pathology induced by amyloid beta and tumor necrosis factor alpha (TNF alpha).
The research update on blueberries included information on increased neurogenesis, increased membrane fluidity, increased levels of signaling molecules, increased protease activity, and direct antioxidant and anti-inflammatory effect in muscles. While serum levels of anthocyanins are highest within an hour or so of consumption, the "downstream effects" may manifest themselves much later. James Joseph, the head of neuroscience at the Human Nutrition Research Center at Tufts University in Boston, stated that while dopamine release can be brought back to youthful levels with blueberry extract, only partial cognitive improvement is achieved.
There is no clear answer as to whether wild or cultivated blueberries confer the most benefits. Cultivated blueberries produced greater improvements in some areas of cognitive function, wild blueberries in other areas. It has also been found that anthocyanins are absorbed better when they are heated. Thus, you may want to consider having a slice of freshly baked blueberry pie-preferably made with a calorie restriction mimetic, of course.
Currently, Joseph is also studying black currants. He recommends eating "fruits and vegetables of color"-the more intense the color, the better. Deep-colored berries, plums and grapes are the richest in phytonutrients such as polyphenolics (including anthocyanins, also available in bilberry extract). If compounds such as those found in blueberries turn out to be effective in the prevention of brain dysfunction, then we are lucky indeed.
At last, we have the first human study using blueberries-in this case, 50 pounds of flash-frozen blueberries per subject. Joseph briefly described the Dansbury MS Blueberry Study, also presented by Rolf Martin during the post session. MS patients were chosen partly due to folk medicine's use of blueberries to ameliorate MS. Eighteen MS patients were recruited; 13 provided useful data. After a practice period, choice reaction time improved by almost 8% when one to two cups of blueberries were consumed every day for six weeks. Most subjects also reported an improvement in mood, energy and overall health. A more extensive study seems warranted.
It's exciting to see that the focus in chemoprevention of brain diseases is widening to include the prevention of inflammation. At a previous conference, one participant stated, "If we can prevent inflammation, we can prevent Alzheimer's disease." Thus, the anti-inflammatory properties of flavonoids are of enormous practical significance. Lipoic acid is another potent anti-inflammatory, shown to be highly neuroprotective in animal studies (a study on the aging-retarding effects of lipoic acid on brain function in rats was presented at the 1999 AGE conference in Seattle). Fish oil and ibuprofen are two other anti-inflammatory agents proven to reduce the risk of Alzheimer's disease.
It is also important to remind the reader that estrogens or estrogens plus natural progesterone have been shown to help prevent neural loss. In men's brains, a portion of testosterone is converted to estradiol. Correct (physiological) hormone replacement is likely to become part of the neuroprotective regimen.
Finally, stem cell research represents yet another promising venue in the search for an effective treatment of degenerative brain diseases. We now know, for instance, that mobilized bone marrow stem cells can enter the circulation and can, through their plasticity, support other organ systems by replacing damaged cells in the liver, muscle or brain. If we learn to manipulate the activity of stem cells, we might even achieve life span extension.
If no preventive measures are taken, there may be as many as 12 million Alzheimer's patients by the year 2040, Dr. Joseph and other speakers warned. If a person lives to the age of 90, his or her chances of developing Alzheimer's disease rise to 50%. The current annual cost of Alzheimer's care is estimated at between $80 and $100 billion in the U.S. alone, and may eventually equal the budget of the Defense Department.
We would be wise to remember Dr. Youdim's warning about the "Grand Canyon effect." The main focus should be on prevention. We can't afford to wait until symptoms become obvious and disabling.
Hormone research update
Growth hormone continues to be both the most promising and the most controversial anti-aging hormone therapy. Dr. Mitchell Harman reviewed the results of his study, which achieved spectacular results such as 21% loss of body fat in men when growth hormone was combined with testosterone. Because of the serious side effects, however, Harman is opposed to growth hormone replacement as it is currently administered, and is waiting for more developments in the field of growth hormone releasers before continuing his research. One of these releasers, ghrelin, has already been found to be quite effective; unfortunately, ghrelin has been shelved because Merck executives decided that HMOs would be unwilling to pay for ghrelin, and thus there would not be enough profit.
The development of effective growth hormone releasers, which could maintain growth hormone at youthful physiological levels, appears to be of great importance. We now know that growth hormone receptors exist in the brain, and that growth hormone stimulates neurogenesis (the production of new nerve cells). It is possible that growth hormone helps prevent Parkinson's disease. In addition, growth hormone has a tremendous impact on sleep, the maintenance of lean body mass and prevention of obesity, and on sexual function.
Recent studies on testosterone confirmed its impact on muscle growth. Part of testosterone's mechanism of action could be anti-glucocorticoid. Glucocorticoids upregulate myostatin, a protein that acts as a muscle-growth inhibitor. Testosterone reverses this effect.
Another benefit of testosterone is its ability to lower serum beta amyloid, and thus probably help prevent Alzheimer's disease.
There are still very few studies of the benefits of testosterone replacement for postmenopausal women. The existing studies agree that testosterone produces an increased sense of well-being in women, including greater sexual satisfaction. As for raloxifene, it does have positive effects on bone mass, but its inability to raise HDLs and its lack of effects on cognitive function are a disappointment.
Mary Lou Voytko of Wake Forest University School of Medicine, North Carolina, presented findings on the neurotrophic and neuroprotective effects of estradiol in ovariectomized rhesus monkeys. Estrogen withdrawal has been found to have a negative impact on learning, memory, attention (the ability to screen out distracting stimuli) and motor skills. It is also associated with more neuron loss in the hippocampus. Overall, estrogen deficiency appears to accelerate brain aging. Estrogen replacement, on the other hand, has many neuroprotective benefits, including "a significant enhancement of the dopaminergic system," according to Voytko. Interestingly, this study found greater benefit of estrogen replacement on the memory of older rather than ovariectomized monkeys. It is possible that higher levels of adrenal hormones in younger animals play a role.
Another speaker, Samuel Gandy of New York University, presented findings that showed estradiol diminishes the generation of amyloid beta by 50%. Testosterone is probably just as beneficial. A study done in Perth, Australia, found a twofold rise in plasma amyloid in men undergoing androgen depletion therapy due to prostate cancer.
While the field of hormone replacement remains riddled with controversy, current knowledge points to a prevalence of benefits, especially in terms of quality of life and the extension of health span.
In the famous words of Jonathan Swift, "Every man desires to live long, but no man would be old." The quest is not only for more quantity of life, but for more quality as well; for extended health span as well as extended life span. Journalists who seek to be provocative sometimes ask researchers in the field of aging, Do we really need more old people in wheelchairs? Fortunately, extending life span seems to go hand in hand with extending health span. As the lectures at this conference documented again and again, when animals or people live longer, they also stay healthy and active almost up to the very end.
Fortunately, the means to a longer, healthier life are within our reach, even before more aggressive interventions such as gene therapy or stem-cell implants become available. Anyone can take ibuprofen, green tea extract and bilberry extract to lower the risk of brain diseases. Anyone can adopt a program of regular exercise, and choose a diet rich in phytonutrients, fiber, fish oil or other omega-3 fatty acids, but relatively low in calories. A conference like this helps clarify such points, teaching us that high-intensity strength training works best for building muscle, for instance, or that a continuous hormone replacement regimen appears safer than sequential (cyclic) replacement for menopausal women.
A very important addition to our anti-aging knowledge this year came from the lectures on neurogenesis. Physical, mental and social stimulation are all important for the enhancement of neurogenesis. Early childhood stimulation (enriched environment) may be of special importance, with consequences that last a lifetime. Certain hormones and drugs also induce more neurogenesis, as does calorie restriction. This area of research is extremely important, since neurogenesis is critical to the prevention and treatment of degenerative brain diseases and depression.
Depression is a huge public health problem, and is in many ways connected with obesity, heart disease, diabetes and cancer. As Dr. Moussa Youdim pointed out, depression precedes neurological symptoms in brain diseases. Thus, the discovery that the healing of depression involves increased neurogenesis is of monumental importance.