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08-15-2006, 02:57 PM
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Melatonin May Help Prevent Alzheimer’s Disease
Melatonin Is Full of Surprises
Melatonin May Help Prevent Alzheimer’s Disease The “sleep hormone” demonstrates versatile, powerful antioxidant and other neuroprotective properties By Hyla Cass, M.D. favorite of newspaper editors is the kind of story in which a 108-year-old man is asked the secret of his longevity, and he answers, “A good cigar and a pint of whisky every day since I was sixteen.” We laugh, and wonder if he’s putting us on or if it’s really true. True that he did that—not true that it caused his longevity. We know it couldn’t have caused his longevity … right? Epidemiology, the study of the determinants and distribution of health-related states (including longevity) in specified populations, is a tricky business. It’s all about evaluating correlations and trying to determine whether or not they mean something in a causal sense. Does A cause B, or is their association just a coincidence? For example, we comb our hair every day, and eventually it turns gray. Does combing cause graying? Of course not—that’s absurd. OK, what about the fact that we eat and drink all kinds of stuff every day, and we show signs of aging as the years go by? Do eating and drinking cause aging? Certainly not! Well, wait a minute—maybe it depends, to some degree, on what kinds of things we eat and drink. Some things are, after all, better for us than others. Perhaps some foods—French fries and sugary colas, say—do cause aging, in a sense. Well, then, what about the really good foods—broccoli and green tea, say? Do they cause antiaging? In either case, how could you prove it? Better Health = Antiaging = Life Enhancement You see, it’s getting confusing already, and we’re just talking about ordinary food. What happens when we talk about less common things, such as nutritional supplements? And what if, as is usually the case, the nutrients in question are endogenous compounds (those made naturally within ourselves), and we alter their normal levels and the delicate chemical balance between them and their cellular surroundings? Does that cause aging (we hope not!) or antiaging (perhaps), or neither? But what is “normal,” anyway? Doesn’t that usually depend on our age to begin with? Such questions plague scientists, who seek knowledge and understanding. Most consumers, however, simply seek better health, whether they understand the reasons or not. (You, dear reader, are obviously seeking better health and understanding, or you wouldn’t be reading this magazine.) And if better health means a lower risk for chronic degenerative diseases that make life miserable or shorter, or both … well, that’s a pretty good operational definition of antiaging. Another term for it is life enhancement. Melatonin Can Be Helpful Many nutrients—including exogenous ones (those obtained only from outside sources)—are believed to have antiaging potential. Take the hormone melatonin, for example, which is made primarily in the pineal gland, a pea-sized bit of tissue deep within the brain. Melatonin is synthesized from the nutritional amino acid tryptophan, via its derivative 5-hydroxytryptophan (5-HTP) and the neurotransmitter serotonin. It is the body’s chief regulator of sleep. Sleep and wakefulness follow a natural daily cycle called a circadian rhythm. During the day, light entering our eyes sends neural signals to our pineal gland, causing it to suppress melatonin output, and we stay awake while the hormone levels remain low. When darkness falls, the absence of light sends signals that cause melatonin output to rise sharply (about 2 hours later), making us feel sleepy. Melatonin levels peak during the night and fall off by daybreak, when we awake to start a new day. At least, that’s the way it used to be, before Thomas Edison came along and changed everything. With artificial illumination available 24/7, darkness has become almost a luxury in our fast-paced, highly artificial lifestyle, which tends to override the natural circadian rhythms that evolution designed us for. That can be seriously detrimental to our health in many ways—but supplementation with melatonin can be helpful.* -------------------------------------------------------------------------------- *It’s important to realize that melatonin, although it has some sedating properties, does not act as a sleeping pill, but rather as a chronobiotic, a regulator of circadian rhythms. Scientific studies on the use of supplemental melatonin for improving sleep have generally used doses in the range of 0.3 to 5.0 mg/day. For more on melatonin and sleep, see “Melatonin Is Good … for … Zzzz” (July 2002), “Better Sleep May Mean Longer Life” (June 2003), “Melatonin Can Reset Your Biological Clock” (March 2005), “Had Any Good Sleep Lately?” (June 2005), and “Let There Be Dark—and Melatonin” (March 2006). -------------------------------------------------------------------------------- Melatonin Is Exceptionally Versatile If melatonin supplementation were helpful only with sleep disorders, it would still be a fine thing. But there’s more to melatonin than that. Human clinical trials with this versatile hormone have also provided evidence for its beneficial effects in treating a variety of cancers, as well as cluster headaches, anxiety, and tinnitus (ringing in the ears).1 (For dramatic evidence of melatonin’s anticancer activity, see the sidebar “Melatonin Suppresses Breast Cancer” in the March 2006 article cited in the footnote.) But it doesn’t stop there. A large body of evidence, obtained mostly in animal experiments, indicates that melatonin may protect against Alzheimer’s disease, with virtually no downside. Evidence also suggests a potentially beneficial role in other neurodegenerative diseases, notably Parkinson’s and Huntington’s, but in those cases, melatonin’s benefits must be weighed against liabilities that do not occur with Alzheimer’s. A Melatonin “Laundry List” Let’s outline some documented scientific facts and expert opinions regarding melatonin and Alzheimer’s disease (AD) and then see what they add up to. Most of the information that follows is from two recent review papers, one by scientists in China2 and the other by a team from Malaysia, the United States, Argentina, and Germany.3 In our forties or fifties, typically, our nightly melatonin output begins a steep decline from its youthful levels—a decline that correlates with physical deterioration of the pineal gland itself. By our late seventies, melatonin output has dropped to very low levels. Accounting for age, abnormally low levels of melatonin in the blood and cerebrospinal fluid are observed even in the early, preclinical stages of AD, suggesting that this hormone may be a useful early marker for the disease. As AD progresses, the levels decline further—dramatically—in correlation with the severity of the patients’ cognitive impairment. Sundown(ing) Melatonin output in AD can also be highly irregular, resulting in severe disruptions of normal circadian rhythms, including the sleep/wake cycle. This often manifests as sundowning, a decrease in cognitive functions and an increase in bizarre behaviors during the evening and nighttime hours. Melatonin has been successful in treating AD-related sleep disorders, the severity of which correlates with the severity of the patients’ cognitive impairment. Oxidative stress—the damage done to molecular and cellular entities by reactive oxygen species, including free radicals—is very strongly implicated in AD, as both a causative factor and an exacerbating factor. The brain is exceptionally vulnerable to oxidative stress, owing to its high rate of chemical energy generation (through cellular respiration, the primary source of free radicals) and its high content of polyunsaturated fatty acids, which are easily damaged by free radicals. Melatonin is a powerful antioxidant. Its actions occur not only through the scavenging of free radicals but also through a variety of other, less direct chemical mechanisms that reduce oxidative stress, including the upregulation of antioxidant enzymes and the downregulation of prooxidant enzymes. This makes melatonin more versatile and potent than conventional antioxidants. It also makes it extremely difficult for researchers to distinguish, where melatonin is concerned, between causal connections and mere correlations that may or may not mean anything. Melatonin’s antioxidative protection may also be related to its chronobiological role as a regulator of circadian rhythms, the disruption of which promotes abnormal levels of oxidative stress. This suggests the value of melatonin supplementation in the elderly, in whom the normal daily fluctuations in melatonin levels are greatly reduced, and especially in AD patients, in whom the daily fluctuations may, in addition, be highly irregular, as noted above. A significant advantage of melatonin over most other antioxidants is that its molecular structure allows it to cross the blood-brain barrier and to enter any component of the neurons (brain cells), including the mitochondria. These organelles, where the brain’s chemical energy is generated, are the chief source of free radicals—and they are its chief victims. Oxidative damage to the mitochondria is thought to be a centrally important factor in aging and dementia. Melatonin is neuroprotective, i.e., it helps protect brain neurons from damage or death caused by a variety of factors, notably oxidative stress. This protective effect is most pronounced in the mitochondria and is believed to be melatonin’s most important benefit. Melatonin is protective against neuritic plaques and neurofibrillary tangles, the two dominant neuropathological features of Alzheimer’s brains. Specifically, melatonin protects against the destructive effects of two dangerous proteins: amyloid-beta (the principal constituent of neuritic plaques) and hyperphosphorylated tau (of which neurofibrillary tangles are composed). Amyloid-beta attacks and destroys neurons, resulting in the substantial loss of brain matter seen in Alzheimer’s victims at autopsy. Hyperphosphorylated tau (rhymes with wow) is also destructive; it’s the result of a chemical modification of a benign (and vital) protein called simply tau. Melatonin is believed to promote neurogenesis (the formation of new neurons) by playing a role in the construction of the cytoskeleton, the neuron’s structural framework. One of the key constituents of the cytoskeleton is tau, which, when it becomes damaged through hyperphosphorylation, forms neurofibrillary tangles. Melatonin inhibits that process. Rats in which melatonin biosynthesis was inhibited (by means of the antipsychotic drug haloperidol) suffered impaired spatial memory. Administration of melatonin before and during the haloperidol treatment, however, significantly prevented memory loss. It also inhibited the hyperphosphorylation of tau, and it reduced oxidative stress. Those two benefits are probably related, because the former phenomenon is influenced by the latter. Typical fluctuations of core body temperature over a 24-hour period. This circadian rhythm is regulated by melatonin. Oxidative stress is also implicated in the formation of amyloid-beta from its precursor, amyloid precursor protein (APP), and amyloid-beta itself promotes further oxidative stress, playing a role in the promotion of tau hyperphosphorylation and the death of brain neurons. Melatonin regulates APP metabolism and prevents amyloid-beta pathology and neuronal death—but only, apparently, if given before the deposition of neuritic plaques (which are also called senile plaques) begins; after that, it’s too late. Amyloid-beta also has proinflammatory effects on brain tissue, mainly through its stimulation of molecules called cytokines and chemokines. Melatonin inhibits this activity and thus has an anti-inflammatory effect. Melatonin has some protective effect on the brain’s cholinergic nervous system, i.e., those parts of the neural circuitry that depend on acetylcholine as the neurotransmitter. A marked decline in cholinergic activity is primarily responsible for the memory loss and other cognitive deficits seen in Alzheimer’s patients. Melatonin is known to enhance immune-system function by promoting the production of T lymphocytes, a type of white blood cell that enhances the production of antibodies. Melatonin promotes regular, healthy sleep, which is considered to be neuroprotective through its fostering of improved neuronal metabolism. That’s especially important in preventing age-related neurodegenerative diseases or attenuating their progression. Melatonin has very low toxicity and can be taken by most people in large amounts (many milligrams daily) with no serious side effects. (As with many supplements, however, one must beware of possible interactions with prescription drugs; consult your doctor.) In the elderly, a common side effect of relatively large doses (3 mg or more) is reduced body temperature, the result of sudden alterations in melatonin’s circadian thermoregulatory function. International Opinion Is Hopeful So, what picture emerges from all this? Chances are, you’ve formed a positive opinion regarding melatonin’s potential for preventing and perhaps treating Alzheimer’s disease—it would be hard not to. Bear in mind, though, that the subject is very complex, and it’s still impossible for frustrated scientists to determine whether or not melatonin deficiency is a causative factor of AD or only a secondary process associated with AD pathology. Let’s see what their opinions are. The Chinese researchers stated,2 Melatonin has been proposed as a treatment for AD based on the fact that the level of melatonin reduces during aging and in AD patients, as well as for its antioxidant and anti-amyloid effects. Recent studies from APP transgenic mice have indicated that early, long-term melatonin supplementation produces anti-amyloid and antioxidant effects, but no such effect is produced when melatonin treatment is initiated after the age of amyloid formation. … If melatonin has no effect at the late stage of AD, studies on melatonin should be limited to the prevention of AD, rather than treatment. … Early, long-term application of melatonin may at least slow down the development of AD. Taking a somewhat broader view, the Malaysian/ American/Argentinean/German team stated,3 Whether melatonin exerts a preventive effect is a hope, but can be judged only after extensive epidemiological studies. … The question whether melatonin has a causal value in preventing or treating AD, affecting disease initiation or progression of the neuropathology and the driving mechanisms, remains to be answered in future studies. … With all due reserve, one can, however, state that the application of melatonin is still a source of hopes for possibilities of intervention, also because melatonin is usually remarkably well tolerated by the treated individual, contrary to many other medications. … With regard to prevention, melatonin should also be seen in the general context of aging. … Life extension with melatonin is possible in model animals, but melatonin’s value is not only a matter of lifespan, but also of health during aging, and pertinent observations have, in fact, been made in mammals. There you have it. As they say on Fox News, “We report. You decide.” References PDR for Herbal Medicines, 3rd ed. Thomson PDR, Montvale, NJ, 2004. Wang J, Wang Z. Role of melatonin in Alzheimer-like neurodegeneration. Acta Pharmacol Sin 2006;27(1):41-9. Srinivasan V, Pandi-Perumal SR, Cardinali DP, Poeggeler B, Hardeland R. Melatonin in Alzheimer’s disease and other neurodegenerative disorders. Behav Brain Funct 2006, 2:15 (published online: doi:10.1186/1744-9081-2-15). 
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