Life Extension Magazine®
Although the exact causes of Parkinson’s disease (PD) continue to elude scientific understanding, the single most important risk factor for its development and progression is well known: aging.1 The first subtle signs can manifest in victims as early as age 50. The risk of onset then follows a steady rise, with incidence increasing dramatically at age 60.2,3 Slowed movement, tremors, mild cognitive impairment, and difficulty standing up or maintaining balance are PD’s harbingers, as the central nervous system commences a profound, irreversible decline. Over time, these early symptoms may progress to near-total immobility, accompanied by mood and personality disorders, loss of sensory function, dementia, and death.4 To date there is no known cure. Fortunately, great strides have been made in research into the prevention and improvement of parkinsonian symptoms without drugs. Natural interventions have been shown to counter aspects of the pathological aging process that accelerate the senescence and death of neurons under attack from PD.5,6 In this article, we detail the underlying physiological mechanisms implicated in Parkinson’s disease, along with a range of safe, low-cost, readily available compounds most Life Extension® members already take that may halt the threat of Parkinson’s before it takes hold. What you need to know
Progressive DegenerationParkinson’s victims undergo a progressive, deadly degeneration of the basal ganglia, a compact cluster of neurons in the brain associated with motor control and memory.7 Housed within this structure are the substantia nigra, whose cells release the neurotransmitter dopamine.
The incremental but relentless destruction of these dopaminergic neurons drives the devastation seen in Parkinson’s victims.8 Dopamine plays a central role in a constellation of mental and physical functions, including:
Every one of these functions comes under attack as Parkinson’s disease (PD) kills off successive layers of cortical brain tissue. Conventional medical treatment understandably aims to elevate and restore optimal dopamine levels. The most common approach is to use a drug such as levodopa, which is converted into dopamine in tissue. Unfortunately, only a small fraction of this conversion actually takes place in the brain, resulting in excessive dopamine levels elsewhere in the body and accounting for troubling side effects, including uncontrolled movements, nausea and vomiting, and depression.5,9 The good news is that the pressing need for a broader array of effective preventive measures, along with additional options to improve quality of life in PD sufferers, has given rise to a steadily growing body of sound research.10,11 Energy Management, Inflammation, and Nerve DamageThe human brain requires enormous blood flow to support its intensive metabolic and neurological activity. Fully one-fifth of the blood pumped with each cardiac contraction goes to the brain. Accordingly, the brain must manage the resulting flow of energy and oxygen with high efficiency or sustain potentially severe oxidative damage generated by excess free radical activity.
As it happens, neuronal tissue is highly vulnerable to free radical damage over time. This is now known to be one of the underlying causes of death for the dopaminergic cells that control movement.7,12,13 A primary contributor to this oxidative stress is mitochondrial insufficiency, the inability of the intra-cellular “furnaces” known as mitochondria to effectively manage energy flow, resulting in an excessive production of oxygen free radicals.8,14 Oxidative damage in turn leads to adverse inflammatory alterations in brain tissue.15,16 The resulting domino effect (oxidative stress = inflammation = additional oxidative stress = more inflammation, and so on) is especially destructive to the vulnerable dopamine-producing cells in the substantia nigra.17 While the inflammatory cascade characteristic of PD appears to be both progressive and inexorable, it is its very complexity that makes it a paradoxically attractive target for prevention. A comprehensive set of interventions has been identified that effectively neutralizes oxidative stress and disrupts inflammatory processes before they spiral out of control. This multi-faceted, multi-factorial approach has generated significant interest in the world of neuroscience today—and a growing body of exciting new research.6,18 CreatineCreatine, a nitrogen-bearing organic acid that helps shuttle energy into muscle tissue, is also crucial to overall cellular energy management. Its deficiency in the brain has been associated with nerve damage, leading researchers to explore its neuroprotective effects.19 Several animal models have shown creatine to be effective in preventing or slowing the progression of PD owing to its potent “pro-mitochondrial” biochemical activity.20-22 As a team of influential Harvard neurologists noted in 2007, “Creatine is a critical component in maintaining cellular energy homeostasis, and its administration has been reported to be neuroprotective in a wide number of both acute and chronic experimental models of neurological disease.”23 Results from the first clinical study of creatine in humans were published in 2006 by the Neuroprotective Exploratory Trials in Parkinson’s Disease (NET-PD) team at the prestigious National Institute of Neurological Disorders and Stroke (NINDS).24
They studied 200 subjects who had had a diagnosis of Parkinson’s disease within 5 years, but who did not require medication for symptom management. Subjects were randomly assigned to receive creatine 10 grams per day, the drug minocycline 200 mg per day, or placebo for 12 months, while their scores on a standard PD rating scale were monitored. Both performed well, though creatine showed a substantial edge in performance compared with minocycline. Tolerability of the treatment was 91% in the creatine group and only 77% in the minocycline group. This promising work was followed up in a 2008 study which provided further supportive data on creatine’s exceptional safety and tolerability.25 These findings are especially heartening given that they were derived from studies in aging individuals who already had PD, when much of the progressive damage to dopamine-producing (dopaminergic) cells had already been inflicted. It seems likely that creatine may offer superior benefits when used as a preventive and truly neuroprotective supplement. In the words of British neuroscientist Anthony H. Schapira, “Early dopaminergic support for the degenerating dopaminergic system per se provides significant long-term clinical benefit for PD patients,”22 leading to “a novel concept for neuroprotection, and that is simply to treat early rather than delay.”26 Omega-3 Fatty AcidsGiven the inflammatory cascade’s intrinsic role in PD, it is natural that scientists would turn to explore the anti-inflammatory effects of omega-3 fatty acids. Among their many beneficial characteristics, omega-3s happen to be the molecular precursors of inflammation-fighting substances the body uses in maintaining equilibrium between infection and inflammation. Further, their concentration in nerve cell membranes is known to decrease with age, oxidative stress—and in neurodegenerative disorders such as PD.27,28
Researchers in Norway have presented convincing evidence of systematic omega-3 deficits in PD, Alzheimer’s disease, and autism, indicating a potential therapeutic role.29,30 Supplementation with the omega-3 docosahexaenoic acid (DHA) can favorably modify brain functions and has been proposed as a natural intervention for PD and Alzheimer’s management.31 Japanese scientists have shown that omega-3 treatment of nerve cells in culture prevents neuronal apoptosis, the programmed cell death that occurs in part as the result of inflammatory stimuli in the brain.32 Their work produced dramatically better results when treatment was introduced before the chemical stresses that induced apoptosis were imposed, leading them to conclude that “dietary supplementation with [omega-3s] may be beneficial as a potential means to delay the onset of the diseases and/or their rate of progression.” Canadian researchers took this work to the next level in a study of mice given omega-3 supplementation before injection with a chemical that produces PD.33 The mice were fed either a control or a high omega-3 diet for 10 months prior to injection. Controls exhibited rapid loss of the dopaminergic cells in the substantia nigra and dramatic decrease of dopamine levels in brain tissue. These effects were prevented entirely in the omega-3 supplemented animals! Researchers also demonstrated actual changes in PD symptomatology in a study of monkeys.34 In this study, one group of animals was first treated with the PD drug levodopa for several months before being given the omega-3 DHA, while a second group was pre-treated with DHA before being started on levodopa. The researchers’conclusion? “DHA may represent a new approach to improve the quality of life of Parkinson’s disease patients.”34 Summarizing progress in omega-3 prevention of PD in late 2008, a leading nutritional scientist at the University of Tennessee, Knoxville concluded, “The literature reveals growing mechanistic evidence that cognitive function of the aging brain can be preserved, or loss of function can be diminished with docosahexaenoic acid, a long-chain omega-3.”35 CoQ10The strong connection between defects in mitochondrial energy management and its related oxidative stress have led neuroscientists to explore a number of supplemental compounds with energy-enhancing, antioxidant capabilities.36-40 Excellent laboratory and clinical evidence suggests that coenzyme Q10 (CoQ10), also known as ubiquinone because of its omnipresence in living cells, is an outstanding contender in this field.41-43 Deficiencies in this vital coenzyme produce disruptions in these processes that can have catastrophic consequences, contributing to many age-related neurodegenerative conditions.10,42,44,45 CoQ10 levels are known to be low in plasma and platelets drawn from patients with PD. A late 2008 study from England demonstrated for the first time that CoQ10 levels are low in vital regions of the brain itself in PD sufferers.39
In 2002, neuroscientists at the University of California-San Diego launched a clinical trial of CoQ10 intervention in early-stage PD sufferers.46 In this multicenter controlled study, 80 patients with early PD, not requiring treatment, were randomly assigned to placebo or to CoQ10 at dosages of 300, 600, or 1,200 mg per day for 16 months or until disability required drug treatment. All subjects were scored on the standard Unified Parkinson Disease Rating Scale (UPDRS), on which higher scores indicate progressively worsening disease. The results were compelling: placebo patients ended the trial with a mean change (worsening) of 11.99 on the UPDRS score. Low-dose CoQ10 supplemented patients increased by only 8.81, middle-dose patients by 10.82, and high-dose subjects by just 6.69—a significant difference. All doses were well-tolerated. The authors concluded that “Coenzyme Q10 appears to slow the progressive deterioration of function in PD.”46 Two years later the same researchers showed that doses of up to 3,000 mg per day were safe and well-tolerated, though plasma levels reached a plateau at the 2,400 mg per day level.47 With the introduction of the superior ubiquinol form of coenzyme Q10 in 2006, far lower doses may very well provide these same benefits. Ubiquinol CoQ10 absorbs far better into the bloodstream than conventional ubiquinone.48,49 Strong laboratory evidence for high-dose CoQ10 alone or in addition to levodopa therapy came in mid-2008 from a group exploring mitochondrial dysfunction and its role in PD.50 They induced PD in rats by injection of a toxin known to create an accurate model of the disease. Remarkably, after so much damage was already established, treatment with CoQ10 prevented cell death, restored ATP levels, and improved motor function in treated animals! The most dramatic effects were seen in rats given both levodopa and CoQ10 supplements—the researchers concluded that the “addition of coenzyme Q10 in a high dose in early Parkinson’s disease could be recommended based on its proved disease-modifying role on several levels of the proposed mechanisms, including improvement of respiratory chain activity.”50 Similarly encouraging results were recently reported from neuroscience labs at Cornell University, where researchers tested the effects of various doses of CoQ10 in food, finding significant protection against loss of dopamine.51 The researchers noted that their results “provide further evidence that administration of CoQ10 is a promising therapeutic strategy for the treatment of PD.” Coenzyme Q10 appears to slow the progressive deterioration of function in
Parkinson’s disease.
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The B ComplexVitamin B6 in physiologically active form is the prerequisite for the production of dopamine. Deficiencies and disorders in B vitamin and folate metabolism have thus been implicated in many neurological disorders, including PD, and studies as early as the 1970’s were directed at demonstrating the effects of supplementation—initially with discouraging results.52-54 As our understanding of the role of the toxic amino acid homocysteine grew, however, more targeted and mechanism-based studies became possible. Homocysteine levels are closely related to folate, vitamin B6, and vitamin B12 status, and elevated homocysteine is found in cardiovascular disease and a variety of neurological and psychiatric disturbances, including PD.55-57 Paradoxically, levodopa treatment of PD can itself lead to elevations in homocysteine, potentially worsening the condition. This has prompted researchers to recommend B complex supplements in those taking the drug.58 Definitive demonstration of the value of this approach came from Singapore in 2005, where neurologists supplemented PD patients who were stable and on their best doses of levodopa with pyridoxine, a common form of vitamin B6. Mean motor and activities of daily living scores improved significantly following supplementation, and deteriorated again when the supplements were stopped.59 Low serum folate is also found in PD patients, especially those taking levodopa;57 Canadian researchers have demonstrated that a folate/B12 supplement could decrease plasma homocysteine levels in patients taking levodopa.60 A review paper in 2007 points to recent work with the active form of vitamin B6, pyridoxal-5’ phosphate (P5P), noting that a number of neurological disorders including PD offer attractive therapeutic targets for this substance.61 Because of the association of elevated homocysteine and its deleterious effects with both PD itself and levodopa therapy, supplementation with folate, B6, and B12 is warranted.62-65 One note of caution regarding B6 supplements is if a PD patient is being treated with levodopa alone without the decarboxylase inhibitor carbidopa. Vitamin B6 may cause levadopa to convert to dopamine in the bloodstream before it crosses the blood-brain barrier (where it beneficially converts to dopamine in the brain). For safety’s sake, it is best to take vitamin B6 supplements at a time of the day furthest from the last dose of a levadopa (L-dopa)-containing medication and to have one’s blood tested periodically to make sure that excess dopamine does not accumulate in the bloodstream. CarnitineCarnitine serves as a co-factor in fatty acid metabolism—it helps to “shuttle” large fat molecules into the cellular powerhouses known as the mitochondria, where they are metabolized for energy. This makes carnitine a valuable weapon against PD.5,66 A small but burgeoning body of data indicates carnitine as a promising preventive for PD through its support of brain energy management.
Researchers at Mount Sinai Medical Center have successfully prevented experimentally-induced PD in monkeys by pre-treating them with acetyl-L-carnitine (ALC), a readily-absorbed form of the nutrient.67 Italian researchers have led the way in studies of carnitine as a neuroprotective agent in the brains of methamphetamine users, who develop an acute form of brain injury resulting from the same basic mitochondrial destruction and free radical damage observed in PD.66,68 This work has been extended in similar studies by researchers at the US National Center for Toxicological Research.69 In the most exciting recent development in this area of research, Chinese nutritional scientists in Shanghai explored the combination of ALC with another energy-related nutrient, lipoic acid, in preventing PD-like changes in human neural cells in culture.70 They found that either nutrient, or the combination, applied for 4 weeks prior to a PD-inducing chemical, protected the cells from mitochondrial dysfunction, oxidative damage, and accumulation of the dangerous alpha-synuclein protein characteristic of PD. Most notably, the combination of supplements was effective at 100- to 1,000-fold lower concentrations than were required for either acting alone—powerful evidence for a synergy that led the researchers to conclude, “This study provides important evidence that combining mitochondrial antioxidant/nutrients at optimal doses might be an effective and safe prevention strategy for PD.”70 Green TeaAccording to internationally-noted Israeli neuroscientist Sylvia Mandel, “Tea consumption is inversely correlated with the incidence of dementia and Al zheimer’s and Parkinson’s diseases.”71 Green tea contains valuable antioxidant polyphenols known to be protective against a host of chronic and age-related conditions. This has given rise to a tremendous scientific interest in green tea and its active compound epigallocatechin gallate or EGCG as a neuroprotectant in PD, especially because these compounds penetrate into brain tissue extremely well compared to many drugs.72-74 Israeli researchers showed in 2001, for example, that they could prevent the cellular changes associated with PD in mice by pre-treating them with either green tea extracts or EGCG ahead of inducing the condition by chemical injection,73 work that has subsequently been repeated and extended in laboratories around the world.75-80 The Israeli team also demonstrated that green tea extracts can prevent activation of the inflammation-producing nuclear factor-kappaB (NF-kB) system in brain cell cultures triggered to develop PD-like changes.81 EGCG’s specific anti-inflammatory properties have been further shown to protect cultured brain tissue from the loss of dopaminergic cells as well.16 An entirely distinct component of green and black teas, L-theanine, is a unique amino acid that can cross the blood-brain barrier.82 Korean scientists have recently shown it may prevent the dopaminergic cell death characteristic of PD.83 Another potential benefit of green tea extracts is their ability to sustain dopamine levels in ailing brain tissue, reducing the severity of symptoms.84 The multiple beneficial compounds found in green tea form a combination therapy all their own, maximize their neuroprotective effects in PD and other neurodegenerative conditions.71,80,85-89 ResveratrolSince dopamine itself is an oxidant compound which can contribute to the early demise of its own neurons, scientists have studied the antioxidant potential of resveratrol to prevent this paradoxical destruction. They found that human neural tissue treated with dopamine underwent rapid cell death as a result of loss of mitochondrial function, but that exposing the cells to resveratrol for just one hour prior to dopamine treatment prevented cell loss and preserved mitochondrial function.90 Canadian scientists showed in 2008 that they could prevent neuronal cell death caused by inflammation through the use of resveratrol.91 That anti-inflammatory action was further dramatically explored by Chinese researchers, who first administered a PD-inducing chemical to rats, and then gave them resveratrol orally each day for 10 weeks.92 They found that even as early as 2 weeks into supplementation, the diseased rats demonstrated significant improvement in their movement disorders, and examination of their brains showed marked reduction in mitochondrial and dopaminergic cell damage. Remarkably, they also found a reduction in expression of the inflammatory markers cyclooxygenase-2 (COX-2) and tumor necrosis factor-alpha (TNF-alpha). They were led to conclude that “resveratrol exerts a neuroprotective effect on [a chemically]-induced Parkinson’s disease rat model, and this protection is related to the reduced inflammatory reaction.” As with green tea extracts, it appears that resveratrol’s promise for PD prevention may reside in its multi-modal mechanisms of action, targeting oxidative stress, inflammation, and other cellular processes fundamental in regulating brain function.93 Additional InterventionsThe explosion of knowledge about the many interrelated probable causes of Parkinson’s disease in the past decade has led to a number of other nutrient molecules’ being explored for their neuroprotective, anti-parkinsonian potential. Vitamin D, for example, a known neurohormone with neuroprotective effects throughout the life span, has been shown to prevent many of the changes associated with PD in laboratory and animal studies; it is also known to be deficient in a large proportion of PD sufferers.94-99 Curcumin, a derivative of the spices turmeric and cumin, is a natural inhibitor of inflammation through its potent modulation of the inflammatory NF-kappaB system; it prevents chemically-induced changes in lab models of PD, and exerts significant neuroprotection.100-107 And the pineal hormone melatonin, an antioxidant in its own right, may help to preserve cells’ ability to make dopamine and to reduce accumulation of destructive alpha-synuclein proteins. It is also invaluable as a sleep aid for PD victims, who often suffer from distressing sleep disturbances.108-114 SummaryWhile its precise cause remains unknown—and there is no cure—aging is the single most important risk factor for Parkinson’s disease (PD). Symptoms manifest in PD victims as early as age 50 (earlier in rare instances). The risk of onset continues to rise with advancing age. Incidence increases dramatically at age 60. Slowed movement, tremors, mild cognitive impairment, and difficulty standing up are the early warning signs. End-stage PD is marked by dementia, near-total immobility, personality and mood disorders, and death. These are the result of multiple, interacting destructive processes triggered by oxidant stress, mitochondrial dysfunction, and inflammation. Together these processes selectively and irreversibly destroy vital movement-controlling cells deep in the brain, resulting in loss of control and gradual decline in movement and activity. Nutritional interventions acting through multiple mechanisms can slow or prevent the accumulation of brain cell damage that produces Parkinson’s disease. In particular, nutrients that enhance brain energy utilization, prevent mitochondrial dysfunction, protect against oxidant damage, and tame inflammation are among the leading contenders for anti-Parkinson’s therapies. The most promising among these include creatine, omega-3 fatty acids, coenzyme Q10, B vitamins (particularly B6 and pyridoxal-5’phosphate), carnitine, lipoic acid, green tea extract, and resveratrol. If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027. | ||
| References | ||
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