Report New Research Substantiates the Anti-Aging Properties of DHEA

Life Extension Magazine December 2010

New Research Substantiates the Anti-Aging Properties of DHEA

By Kirk Stokel

In 2007, Life Extension® led the battle against Congress’s ill-conceived campaign to re-classify DHEA (dehydroepiandrosterone) as an “anabolic steroid drug”—an act that would have made this life-sustaining compound unavailable to the American public without a prescription.

Thanks in no small part to the efforts of Life Extension® members, the battle was won.

Today, less than three years later, scientists have uncovered even more research substantiating DHEA’s remarkable health-promoting benefits.

Sometimes called the “youth hormone,” DHEA is the most abundant hormone precursor in the human body and a source of the sex hormones.

Its steady and precipitous decline is an inevitable consequence of aging, 1 and contributes to the onset of degenerative disease.

The latest scientific discoveries indicate that as little as 50 mg of DHEA per day may:

1. Inhibit multiple factors implicated in metabolic syndrome by favorably altering gene expression;
2. Boost bone strength and ward off osteoarthritis;
3. Enhance memory.2-5

Daily intake of 90 mg per day and higher has been shown to improve cognitive function and alleviate depression both in the elderly and among individuals suffering from debilitating mental illness.6,7

First introduced to Americans in 1981 by the Life Extension Foundation®, the anti-aging effects of DHEA have been described in medical textbooks starting in the early 1990s.

In this article, you will discover the most up-to-date evidence of DHEA’s profoundly beneficial impact across multiple systems of the body.

Potent Cognitive Support

DHEA deficiency is implicated in numerous age-related conditions, including declines in brain and nervous system function. The latest research suggests that DHEA supplementation may exert powerful neuroprotective effects.

In fact, 2009 witnessed extraordinary advances in our understanding of the cognitive and memory-enhancing benefits of DHEA.

Two large studies showed that levels of DHEA-S in elderly patients correlated significantly and positively with cognitive function. (Chemically similar to DHEA, DHEA-S is the sulfated form of DHEA.)8,9 Prior research had shown that higher DHEA-S levels were directly associated with improved concentration, working memory, and executive (decision-making) function.10

Israeli scientists found that the cognitive dysfunction that occurs in schizophrenia is also partly associated with levels of DHEA-S and other neurosteroids.11 Supplementation with 200 mg per day of DHEA in schizophrenic patients improved attention and motor skills compared with placebo.6 Although the direct symptoms of schizophrenia were unaffected, DHEA’s ability to provide relief from the cognitive deficits associated with this severe psychiatric condition may significantly improve quality of life in these individuals.

The last few years have also yielded new pre-clinical data on DHEA’s neuroprotective, memory-enhancing effects. In one noteworthy study, DHEA significantly improved memory retention and consolidation in mice—especially when the experimental equivalent of an emotional stimulus was involved.12 This may be related to DHEA’s ability to stimulate the proliferation of key brain cell receptors specifically associated with memory processing.13

When given to aging rats, DHEA was shown to enhance brain cell utilization of ATP—the body’s fundamental energy-storage molecule—thereby protecting the cell membranes from age-related damage.14 Impaired energy utilization and reduced production of ATP contribute to the “neuronal energy crises” that underlie Alzheimer’s and other neurodegenerative diseases.15

A landmark 2007 study showed that DHEA supplementation of 150 mg twice daily improved memory recall and mood in healthy young men, specifically increasing activity in the hippocampus, the region of the brain most closely associated with mnemonic function (memory).5

Enhance Your Mood—Naturally

Depression often accompanies aging, frequently emerging in older individuals.16,17 Fortunately, we now recognize depression as an essentially physiological condition—one that can be treated. Low DHEA levels are known to render aging humans more vulnerable to depression in the presence of triggers such as rejection or isolation.18 Negative emotional stimuli have been shown to lower DHEA levels even further.19

Supplementation with DHEA can powerfully mitigate depression and its effects. A National Institute of Mental Health study of depressive men and women aged 45-65 years showed significant improvement over 6 weeks among those who took 90 mg of DHEA per day for 3 weeks and then 450 mg per day for 3 weeks, compared with placebo.7 The study also showed significant improvements in sexual functioning scores in supplemented patients, but not among control patients. In a rare admission from the generally conservative National Institute of Mental Health, their conclusion was, “We find DHEA to be an effective treatment for midlife-onset major and minor depression.”

In a set of studies, DHEA was found to improve both mood and energy while alleviating depression.20-22 Israeli researchers also demonstrated minimal effects on other hormonal profiles, alleviating concerns about adverse events with DHEA.23

A remarkable 2006 study demonstrated reduction in depressive symptoms in an especially challenging population—patients with HIV/AIDS.24

Several 2009 studies revealed associations of low DHEA levels with a number of neuropsychiatric conditions and were able to show that DHEA influences gene expression in the brain.25 For example, DHEA modulates expression of genes directly involved in appetite regulation, energy utilization, and alertness.26 Another study demonstrated that DHEA acted in synergy with the antidepressant fluoxetine (Prozac®), leading researchers to suggest DHEA as “a useful adjunct therapy for depression.”27

Support for Aging Bones and Joints

A 2000 study demonstrated improved bone turnover—more marked in women than in men—during a year-long study of daily 50 mg supplementation with DHEA.28 (Bone turnover is the natural process by which the body replaces old bone from the skeleton and replaces it with new bone.) By 2003, laboratory evidence emerged suggesting that DHEA could potentially enhance joint function and ward off osteoarthritis (OA).2

DHEA treatment of cartilage tissue taken from patients with OA increased production of healthy, flexible type II collagen protein, while reducing production of the less flexible type I collagen associated with scar formation.2 DHEA also modified the imbalance between cartilage-destroying enzymes and those that protect cartilage from damage. These impressive effects were the direct result of DHEA’s capacity to favorably modulate gene expression.

DHEA’s effects on bone structure are no less significant. A double-blind, randomized, controlled trial of 50 mg per day of DHEA administered orally versus placebo for 12 months showed improved hip bone mineral density (BMD) in older men and women with low DHEA-S levels, with additional improvements in spine BMD in women.3,29 A larger study in 2008 showed that DHEA not only improved lumbar spine BMD in women (not men) taking 50 mg per day for a year, but it also reduced blood-borne markers of bone resorption,30 an important measure of overall bone health and bone aging. Not surprisingly, the addition of vitamin D and calcium supplements to a DHEA regimen may afford further benefit.31

What you need to know: DHEA

• DHEA, the most common hormone precursor in the body, is intimately associated with youthful and healthy functioning across a range of physiological systems.
• Levels of DHEA decline steadily with age, and low DHEA levels are associated with increased cardiovascular risk, diabetes, obesity, loss of vigor and sexual energy, depression, and even visible skin aging.
• The most up-to-date scientific research indicates that DHEA can protect brain cells involved in memory function, alleviate depression and enhance mood, strengthen bone health, bolster immunity, lower blood glucose, limit the complications of obesity and diabetes, support healthy cardiovascular function, and enhance sexuality at both the psychological and physical levels.
• As little as 50 mg of DHEA per day may favorably alter gene expression to inhibit multiple factors implicated in metabolic syndrome; boost bone strength; enhance cognitive function and memory; and ward off osteoarthritis.
• DHEA is also available in topical crèmes that has been shown to dramatically enhance the youthful appearance of skin.
• Individuals who have been diagnosed with any type of hormone-related cancer should not supplement with DHEA.

Optimal Immune Strength and Anti-Viral Protection

The precipitous age-related decline in DHEA/DHEA-S levels results in the immune deficiency we call immunosenescence.32 Supplementation with DHEA may beneficially modulate immunity33,34 to help combat debilitating age-related conditions through multiple, complementary pathways.

DHEA has boosted immune function in blood cells taken from patients after major abdominal surgery.35 This action may help to prevent serious infections and promote healing. In the setting of dangerous infections and trauma in laboratory animals, DHEA and its metabolites markedly upregulate host immune responses, modulate inflammation, and improve survival.36-38 In animal models, DHEA’s ability to raise sex hormone concentrations to youthful levels also promoted wound healing.39

DHEA also possesses significant antiviral properties. It has blocked replication of several different, potentially deadly virus families in the laboratory—more effectively and more selectively than the drug ribavirin!40,41

A 2008 study showed that DHEA also increases natural resistance to certain lethal parasites, including Trypanosma cruzi (the cause of Chagas disease),42 a microorganism that causes death from heart disease and brain damage, particularly in immunocompromised patients. Subsequent research conducted in 2009 found that DHEA supplementation reduced parasite levels, raised levels of defensive macrophage white blood cells, and increased levels of immune signalling interferons.43,44

Among individuals stricken with autoimmune disorders such as rheumatoid arthritis or lupus, treatment with conventional corticosteroids not only over-suppresses the immune system, it can also promote bone resorption and catastrophic fractures. DHEA has been shown to reduce expression of cytokines and other factors that lead to bone resorption in steroid-treated tissue, while still suppressing inflammation effectively.45

There’s good news for asthma and allergy patients who respond poorly to regular steroid usage as well. DHEA is now known to suppress allergy-induced inflammatory cytokines in reactive airway cells while increasing the ratio of beneficial interferon to inflammatory cytokines—highly significant advances in the management of this troubling condition.46

Combat Metabolic Disorders

We’ve known for over a decade that DHEA protects against obesity and its consequences in aging and diabetic animals.47,48 In 2009, scientists confirmed that low DHEA levels in men were linked to diabetes and coronary heart disease.49 DHEA powerfully modulates gene expression to shift the metabolic balance in favor of energy utilization and away from storage as fat.50

DHEA also activates gene expression of cellular machinery that affects a cell’s consumption of fats and sugars to remove them from circulation.51,52 These molecules help correct harmful lipid abnormalities and unhealthy body fat distribution—a possible mechanism by which DHEA decreases total body fat.53,54

In 2007, researchers demonstrated in aged rats fed a high-fat diet that DHEA increased body protein, while decreasing total caloric intake, body weight, body fat, and total size and number of fat cells.55 In a related experiment, researchers discovered that DHEA could change the composition of adipose tissue, boosting levels of beneficial omega-3 fatty acids while reducing harmful omega-6 fatty acids.56

A human study showed how powerfully these DHEA effects can modify body composition.4 When 52 elderly men and women took 50 mg per day of DHEA or placebo for 6 months, it reduced stubborn abdominal and subcutaneous body fat. Insulin levels dropped significantly in supplemented patients as well, indicating enhanced insulin sensitivity. The researchers concluded appropriately that “DHEA replacement could play a role in prevention and treatment of the metabolic syndrome associated with abdominal obesity.”

“DHEA replacement could play a role in prevention and treatment of the metabolic syndrome associated with abdominal obesity.”

DHEA is highly protective against diabetes and its complications. In diabetic rats, DHEA prevented increases in oxidant stress and oxidative damage related to the disease. It also significantly improved blood vessel relaxation, improving blood flow.57 DHEA induces genes in muscle tissue that increase uptake and utilization of blood glucose as energy, significantly lowering blood sugar in diabetic animals.58 In humans with type 2 diabetes, DHEA counteracts oxidative imbalance and the formation of deadly advanced glycation end products (AGEs), and downregulates the inflammatory TNF-alpha system—effects that may prevent the onset and slow the progression of deadly diabetes.59

Cardiovascular Disease Defense

The past several years have witnessed extraordinary advances in our understanding of DHEA’s cardioprotective power—and its relationship to cardiovascular disease.

A 2009 study of 153 diabetic men with stable coronary heart disease (CHD) found that 77% were DHEA-S deficient, significantly more than in healthy peers.60 Over the next 19 months of follow-up, 43 of those men died of CHD; the data showed that low DHEA-S and low testostosterone levels were two of the four most significant predictors of death.

Another 2009 study of 247 men with a mean age of 76 years revealed that those with low DHEA-S had a 96% increased risk of diabetes and a 48% increased risk of coronary heart disease.49

A 2009 study from the University of Pennsylvania discovered a surprisingly close relationship between mortality and the trajectory of DHEA-S decline in older adults.61 Specifically, a rapid or erratic decline in DHEA-S predicted earlier death, and both together increased the death rate by nearly threefold! Regular blood testing for healthy DHEA-S levels are the only way to detect these lethal changes in DHEA levels early. It is of paramount importance that you have your DHEA-S levels checked at least once a year.

A Mayo Clinic study found that DHEA supplementation (50 mg per day) in women with low DHEA levels and low adrenal function improved plasma DHEA content, significantly lowered total cholesterol, and tended to reduce triglyceride and low-density lipoprotein (LDL) levels.62 But supplemented patients also had reductions in their beneficial high-density lipoprotein (HDL) levels. This study suggests that long-term studies are needed to determine the impact of DHEA supplementation on cardiovascular risk in women with low adrenal function.

Additional support for DHEA’s benefits in patients suffering from vascular disease came in two remarkable 2009 studies.63,64 The first examined vascular remodeling, a dangerous process that occurs when vessels are injured by atherosclerosis.63 Vascular remodeling can impede blood flow and ultimately worsen cardiovascular disease.65

DHEA significantly inhibited vascular remodeling in a rabbit model of carotid artery injury and limited deadly buildup of smooth muscle in vessel walls.63 Another study of rabbits fed a high-fat diet showed that DHEA supplements restored oxidative balance, lowered lipid levels and inflammatory damage, and prevented heart muscle tissue death and dysfunction, delaying the onset of cardiac damage.64

Enhanced Well-Being and Libido Even in Challenged Populations

Studies as early as 2000 demonstrated how DHEA improved well-being and could help to manage menopause without deleterious effects.28,66 In 2006 it was revealed that 50 mg per day of DHEA could improve psychological well-being even in challenging populations such as those with decreased pituitary function.67

DHEA exerted a remarkably positive effect on health-related quality of life in women taking long-term steroids for lupus (chronic steroid therapy can produce powerful depression and reduction in quality of life measures).68 Of particular importance, the DHEA-supplemented groups also reported improvement in sexuality.

Additional research supports an excitatory effect for DHEA on sexuality—especially in women. In one study, sixteen sexually functional postmenopausal women were randomly given either placebo or a single DHEA supplement of 300 mg, 60 minutes before presentation of an erotic video.69 Women in the supplement group showed significantly greater mental and physical sexual arousal during the video than did the control women. The supplemented women also reported a greater increase in positive affect (generally feeling good) compared to placebo recipients.

A 2009 animal study may shed light on some of the physical causes behind these benefits: DHEA applied to the smooth muscle of rabbit clitoris resulted in significant relaxation,70 allowing the increased blood flow and engorgement that results in enhanced sensitivity during sexual arousal.

Favorable Gene Expression for Youthful, Glowing Skin

A growing body of scientific evidence suggests that DHEA has especially favorable effects on skin health and appearance. In a 2000 laboratory study, DHEA was shown to increase production of collagen—the protein that gives youthful skin its suppleness—while decreasing production of the collagenase enzymes that destroy it.71

It wasn’t until 2008, however, that Canadian scientists discovered more than 50 DHEA-responsive genes in the skin of women using a topical DHEA crème.72 DHEA “switched on” multiple collagen-producing genes and reduced expression of genes associated with production and cornification (hardening) of the tough keratinocytes that form calluses and rough skin. The researchers concluded, “DHEA could exert an anti-aging effect in the skin through stimulation of collagen biosynthesis, improved structural organization of the dermis while modulating keratinocyte metabolism.”

Other unexpected benefits of topical DHEA on aging skin are emerging. DHEA treatment increases production of sebum, or skin oil.73 Sebum not only contributes to smooth, supple skin; it also contains myriad antimicrobial components that prevent infection and irritation. Topical DHEA also improves skin “brightness” and counteracts the “papery” appearance of aging skin, combating the epidermal thinning that is a visible hallmark of aging.73 The study authors note that these are “beneficial effects on skin characteristics that are rarely provided by topical treatments.”

Summary

In the past few years alone, significant scientific substantiation of DHEA’s anti-aging effects has emerged. Its neuroprotective effects are now recognized as being vital in protecting memory and reducing depressive symptoms in older adults. DHEA enhances bone health by improving mineralization to reduce fracture risk. DHEA modulates immunity in a coordinated fashion, boosting resistance to infection while quelling dangerous inflammation. DHEA supports cardiovascular health and activates genes that prevent cardiovascular risk factors, including diabetes and obesity. DHEA is intimately involved in improving quality of life and bolstering sexual arousal, while dramatically improving the appearance of healthy, youthful skin. As little as 50 mg of DHEA per day may favorably alter gene expression to inhibit multiple factors implicated in metabolic syndrome; boost bone strength; enhance cognitive function and memory; and ward off osteoarthritis. DHEA topical crèmes allow ready application of DHEA to the site of action.

Note: Individuals who have been diagnosed with a hormone-dependent cancer should not supplement with DHEA until their cancer is cured.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

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62. Srinivasan M, Irving BA, Dhatariya K, et al. Effect of dehydroepiandrosterone replacement on lipoprotein profile in hypoadrenal women. J Clin Endocrinol Metab. 2009 Mar;94(3):761-4.

63. Ii M, Hoshiga M, Negoro N, et al. Adrenal androgen dehydroepiandrosterone sulfate inhibits vascular remodeling following arterial injury. Atherosclerosis. 2009 Sep;206(1):77-85.

64. Aragno M, Meineri G, Vercellinatto I, et al. Cardiac impairment in rabbits fed a high-fat diet is counteracted by dehydroepiandrosterone supplementation. Life Sci. 2009 Jul 3;85(1-2):77-84.

65. Mitchell GF. Effects of central arterial aging on the structure and function of the peripheral vasculature: implications for end-organ damage. J Appl Physiol. 2008 Nov;105(5):1652-60.

66. Stomati M, Monteleone P, Casarosa E, et al. Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause. Gynecol Endocrinol. 2000 Oct;14(5):342-63.

67. Brooke AM, Kalingag LA, Miraki-Moud F, et al. Dehydroepiandrosterone improves psychological well-being in male and female hypopituitary patients on maintenance growth hormone replacement. J Clin Endocrinol Metab. 2006 Oct;91(10):3773-9.

68. Nordmark G, Bengtsson C, Larsson A, Karlsson FA, Sturfelt G, Rönnblom L. Effects of dehydroepiandrosterone supplement on health-related quality of life in glucocorticoid treated female patients with systemic lupus erythematosus. Autoimmunity. 2005 Nov;38(7):531-40.

69. Hackbert L, Heiman JR. Acute dehydroepiandrosterone (DHEA) effects on sexual arousal in postmenopausal women. J Womens Health Gend Based Med. 2002 Mar;11(2):155-62.

70. Lee SY, Myung SC, Lee MY, et al. The effects of dehydroepiandrosterone (DHEA)/DHEA-sulfate (DHEAS) on the contraction responses of the clitoral cavernous smooth muscle from female rabbits. J Sex Med. 2009 Oct;6(10):2653-60.

71. Lee KS, Oh KY, Kim BC. Effects of dehydroepiandrosterone on collagen and collagenase gene expression by skin fibroblasts in culture. J Dermatol Sci. 2000 Jun;23(2):103-10.

72. Calvo E, Luu-The V, Morissette J, et al. Pangenomic changes induced by DHEA in the skin of postmenopausal women. J Steroid Biochem Mol Biol. 2008 Dec;112(4-5):186-93

New Human Study Confirms Potent Antidepressant Effects of SAMe

By David Hoffnung

Life Extension® introduced SAMe (S-adenosylmethinone) in 1997. Back then it was enormously popular in Europe, but unknown in the United States.

The National Institute of Mental Health decided to fund a double-blind, placebo-controlled trial that would evaluate SAMe as an additive therapy in those suffering major depression who were resistant to FDA-approved drugs.

Researchers at Harvard Medical School and Massachusetts General Hospital gave patients 800 mg of SAMe twice daily along with a selective serotonin reuptake inhibiting drug (SSRI).

Relative to placebo, patients who received the SAMe showed a 105% higher response rate and a 121% higher remission rate.1 Said differently, add-on therapy with SAMe in patients with drug-resistant depression produced double the response rate AND remission rate compared with placebo within a 6-week period.

This study was published in the August 2010 issue of the American Journal of Psychiatry.1 It was a follow-up to a 2004 pilot study that showed greater benefits when antidepressant drugs were combined with SAMe than when the same drugs were taken alone.2

For the past 13 years, SAMe has been on Life Extension’s TOP TEN list of the most important steps to take to ensure optimal longevity. SAMe has been recommended to aging individuals not to just feel better, but also to protect the brain, liver, joints, and other tissues of the body like no other substance.

This article reviews and updates the many studies documenting the anti-aging properties of SAMe.

A listing of all the drugs the FDA has approved to treat depression would fill several pages of this magazine. A major problem with these antidepressant drugs is that they fail a significant number of patients—up to 30%, by some accounts.3 In many cases, the drugs make depressed individuals feel worse, and FDA-mandated labeling now requires a warning that use of some antidepressants increases suicide risk—which is an incredible contradiction considering that suicide is a leading cause of death amongst depressives.

An equally disconcerting issue is the many side effects associated with antidepressant medications such as weight gain, constipation, dry mouth, and other symptoms that cause many depressives to stop using them.

There is thus an urgent need for a new approach to treating those who fail to respond to currently available antidepressant medications. Encouraging news from a recent study shows that the addition of S-adenosylmethinone (SAMe) to a serotonin reuptake inhibitor drug markedly improves the percentage of severe depressives who are relieved of their disorder.

Unlike synthetic prescription drugs that induce unintended side effects, SAMe is a naturally-occurring agent in the body that performs a multitude of beneficial functions, such as boosting glutathione levels in the brain and liver. The anti-aging properties of SAMe are so profound that non-depressives take it each day (in lower doses) just like they do their other dietary supplements.4,5

Antidepressants Don’t Work

As a team of Harvard researchers noted in a remarkable 2010 study published in the Journal of Clinical Psychiatry,6 “The majority of depressed patients will not experience remission when treated with a first-line antidepressant.”

In other words, antidepressants don’t really work for most patients. More is needed to help depression’s victims.

This is where SAMe comes in.

In modern high-tech imaging studies of healthy human brains, SAMe produces effects typical of several classes of antidepressant drugs7—but unlike those drugs, SAMe has remarkably few side effects and is well-tolerated even in elderly subjects.8

People with depression may exhibit a variety of biochemical imbalances, but the most common and best-known has to do with neurotransmitters like serotonin (involved in mood, sleep, appetite, and learning) and norepinephrine (involved in heart rate, blood pressure, and the fight-or-flight response). These chemical messengers belong to a class of molecules known as monoamines, and their synthesis in brain cells is largely controlled by the presence of folic acid, vitamin B12—and SAMe.9-12 When released into the space between brain cells (the synapse), monoamines exert stimulating or inhibiting effects on postsynaptic neurons.

With too little serotonin or norepinephrine available, the brain cannot sustain a positive mood—and depression results. Virtually all antidepressant drugs work to boost levels of these neurotransmitters within the synapse. And therein lie many of their limitations—and the causes of many of their side effects.13

SAMe operates through a completely different mechanism than these drugs. A molecule derived from the sulfur-containing amino acid methionine, SAMe is found in every living cell and plays a central role in cellular function.14,15 In addition to being required for monoamine synthesis, it also affects cell membrane fluidity, which may in turn influence how well a neuron transmits an electrical signal.16 Recent studies have shown that SAMe is also involved in the so-called “epigenetic” control of cellular function—the ability of cells to activate or suppress specific genes based on environmental influences—by its effects on proteins associated with chromosomes.17

These multi-targeted effects, coupled with an extraordinary safety profile, make SAMe a compelling treatment for a wide variety of brain disorders, from depression and cognitive decline to congenital metabolic dysfunction.18,19 SAMe crosses the blood-brain barrier, making it readily available to the brain and nervous system.10 This is vital: SAMe levels in the spinal fluid of depressed individuals have been shown to be significantly lower than those of healthy people.11

Animal models of depression shed additional light on how SAMe works in the brain. More than two decades ago Japanese scientists demonstrated a reduction in aggression in rats treated with SAMe as a result of its action in the central nervous system.20 By the turn of this century, researchers in Italy and Spain showed that SAMe reverses experimentally-induced depression in rats, at a rate faster than that of the prescription antidepressant imipramine, the first tricyclic antidepressant developed, and without apparent side effects.21,22 And in a remarkably detailed study, the Italian group showed that SAMe restored diminished brain levels of “polyamines,” essential brain molecules that are reduced in depressed patients.23

In 2007 a team of scientists at the University of Massachusetts launched a study using a combination of SAMe with N-acetyl cysteine (NAC) and acetyl-L-carnitine.24 Their subjects were aging mice with neurodegeneration similar to Alzheimer’s disease, in which depression is often a major manifestation. The combination rapidly enhanced cognitive function and prevented or reduced aggression in the animals, an effect that was rapidly reversed when the combination was withdrawn. The combination also prevented a decline in levels of the neurotransmitter acetylcholine, while contributing important antioxidant effects as well.

What You Need to Know: SAMe

• A landmark study funded by the National Institute of Mental Health revealed that the addition of S-adenosylmethionine or SAMe produces compelling results in people taking SSRIs, the majority of whom do not experience relief when taking the drug alone.
• SAMe is a naturally occurring molecule found in all living cells; it supports a host of chemical functions necessary for normal brain activity.
• SAMe acts by several distinct and independent mechanisms to target multiple sites of action in brain cells that are involved in producing depression.
• In clinical trials, SAMe has been shown to be at least as effective as prescription antidepressants, but with far fewer side effects.
• Because of its strong safety record, SAMe should be part of any regimen for brain health, particularly when depressive symptoms are present—and when prescription drugs alone don’t work.
• SAMe has also been shown to confer enormous benefits to the brain, liver, and joints, halting and even reversing various degenerative conditions, from osteoarthritis and neurodegeneration to nonalcoholic fatty liver disease.

Let’s turn now to the clinical realm and examine how well SAMe actually functions in humans suffering from depression.

SAMe Dramatically Improves Therapeutic Outcomes

Clinical trials have repeatedly demonstrated the benefits of SAMe in patients with major depression in a variety of populations: doses of 400-1,600 mg daily consistently resulted in rapid improvement in depressive symptoms and side effects that were mild and transient.25-27

SAMe is even effective in patients previously labeled “nonresponders” to conventional drug treatment.25 This led first to additional studies of SAMe compared with standard drugs rather than placebos, and later to studies in which SAMe was used in addition to such drugs.

SAMe consistently performs as well as or better than older-generation antidepressants such as imipramine and desipramine, drugs which are highly effective but have an unfavorable safety profile.28-30 In every case, the side effects of SAMe were trivial or mild. Interestingly, one such study found that regardless of whether patients received SAMe or the drug, their levels of SAMe in blood rose significantly as their depressive symptoms improved.28

Support for the Aging Brain

Experts have known for more than a decade that severely reduced brain levels of SAMe are directly linked to Alzheimer’s disease.1 More recent research reveals a direct correlation between levels of SAMe in the brain and Parkinson’s disease. In aging individuals stricken with Parkinson’s disease, parkinsonian symptoms (including increased levels of neurodegeneration) have been shown to be worse when SAMe levels are low, while cognitive function is markedly better when levels of SAMe are higher.2 At the core of SAMe’s ability to support brain function and neuronal health is its role in boosting levels of glutathione (GSH) and enhancing the antioxidant power of superoxide dismutase (SOD).3

Scientists have noted that these twin capabilities underscore SAMe’s importance as a neuroprotective compound, given the extraordinarily high metabolic activity and energy-intensive demands of both brain cells and neurons.3

References

1. Morrison LD, Smith DD, Kish SJ. Brain S-adenosylmethionine levels are severely decreased in Alzheimer’s disease. J Neurochem. 1996 Sep;67(3):1328-31.

2. Obeid R, Schadt A, Dillmann U, Kostopoulos P, Fassbender K, Herrmann W. Methylation status and neurodegenerative markers in Parkinson disease. Clin Chem. 2009 Oct;55(10):1852-60.

3. Cavallaro RA, Fuso A, Nicolia V, Scarpa S. S-adenosylmethionine prevents oxidative stress and modulates glutathione metabolism in TgCRND8 mice fed a B-vitamin deficient diet. J Alzheimers Dis. 2010;20(4):997-1002.

A study conducted in 1992 demonstrated the benefits of combining SAMe and imipramine for speeding the onset of the drug31—a critical benefit since almost all antidepressants take three or more weeks to manifest their effects, during which time patients often become discouraged and may discontinue treatment.

In 2004, a Harvard team of psychiatrists used SAMe in patients who were resistant to treatment with more modern drugs.2 In this open study design, the Harvard group provided 800-1,600 mg per day of SAMe orally to 30 patients who remained depressed despite adequate doses of their medications. Using even a highly conservative statistical analysis, they found that 50% of these previously resistant patients responded to treatment, with an impressive 43% experiencing complete remission of symptoms.2 These compelling results prompted the same Harvard group to design a larger study to more rigorously examine SAMe’s benefits in augmenting existing drug treatments.1,32

The outcome of this study was revelatory, creating a sensation within the scientific community. The group studied 73 patients who were “nonresponders” to standard treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants. Subjects stayed on their SSRI for the entire 6-week study period, and took 800 mg of SAMe, or a placebo, twice daily. Their depressive symptoms were monitored using the standard Hamilton Depression Rating Scale. Thirty-six percent of the supplemented patients responded to treatment, and 26% experienced complete remission of their depression—patients who had not felt any difference with standard medications. The placebo recipients had a much worse response rate; just 18% felt a difference and a dismal 12% experienced complete remission.1

Arthritis Defense

A comprehensive 2002 SAMe study conducted by the US Department of Health and Human Services confirmed SAMe’s power not only to sustain mood, but also to optimize joint function.1 Clinical trials have shown reduced pain and stiffness in aging individuals stricken with osteoarthritis, while in vitro and animal studies have shown SAMe can stimulate the production of cartilage—a crucial factor in halting and reversing arthritis’s progression.2 Scientists have even found SAMe to be as effective as ibuprofen at reducing morning stiffness, pain at rest, pain during motion, swelling, “cracking” or “popping” sounds, and limited range of motion in arthritic joints.3

References

1. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=erta64. Accessed September 22, 2010.

2. Hosea Blewett HJ. Exploring the mechanisms behind S-adenosylmethionine (SAMe) in the treatment of osteoarthritis. Crit Rev Food Sci Nutr. 2008 May;48(5):458-63.

3. Muller-Fassbender H. Double-blind clinical trial of S-adenosylmeth onine versus ibuprofen in the treatment of osteoarthritis. Am J Med. 1987 Nov 20;83(5A):81-3.

The lead author of the Harvard study, Dr. George Papakostas, noted “SAMe can be an effective, well-tolerated, and safe adjunctive treatment strategy for serotonin reuptake inhibitor nonresponders with major depressive disorder.”1

Summary

A landmark study funded by the National Institute of Mental Health revealed that the addition of S-adenosylmethionine or SAMe produces compelling results in major depression sufferers taking SSRIs, the majority of whom do not experience relief with prescription drugs alone. SAMe is a naturally occurring molecule found in all living cells, where it supports a host of chemical functions necessary for normal brain activity. It has been found to be safe at very high doses. Despite a wealth of data from the early 1990s, SAMe hadn’t found clinical acceptance until very recently, when new, rigorously controlled trials demonstrated its effectiveness in instances where drugs don’t work. Given SAMe’s impressive safety record, virtually anyone suffering from depressive symptoms should consider it, whether currently taking medication or not.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

Optimal Liver Protection

SAMe’s extraordinary capacity to protect and enhance liver function has been well-documented in a wealth of studies. To take one dramatic example, blood alcohol levels among binge drinkers who ingest SAMe at the point of consumption have been shown to be significantly lower than controls.1 In 2010, researchers were able to determine why: SAMe boosts the liver’s alcohol elimination rate by increasing expression of genes within liver cells that are specifically involved in alcohol metabolism.1 Insufficient levels of SAMe have also been linked to a variety of liver diseases, including nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, both increasingly common disorders characterized by fat deposits in liver tissue that may progress to cirrhosis and full-blown liver failure.2,3 Scientists believe SAMe supplementation can prevent the onset and progression of these potentially fatal conditions.

References

1. Bardag-Gorce F, Oliva J, Wong W, et al. S-adenosylmethionine decreases the peak blood alcohol levels 3h after an acute bolus of ethanol by inducing alcohol metabolizing enzymes in the liver. Exp Mol Pathol. 2010 Sep 7.

2. Wortham M, He L, Gyamfi M, Copple BL, Wan YJ. The transition from fatty liver to NASH associates with SAMe depletion in db/db mice fed a methionine choline-deficient diet. Dig Dis Sci. 2008 Oct;53(10):2761-74.

3. Caballero F, Fernandez A, Matias N, et al. Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-L-methionine and glutathione. J Biol Chem. 2010 Jun 11;285(24):18528-36.

Harvard Clinical Trials of SAMe

In a recent study published in the American Journal of Psychiatry, the results of a clinical trial conducted at Harvard Medical School and Massachusetts General Hospital were announced. The researchers found a significant benefit in male and female patients taking S-adenosylmethionine (SAMe) as an additive therapy to treat major depressive disorders.1

What made the findings of this study so remarkable is that this favorable response was observed in those who had already failed to respond to standard antidepressant drugs.1

This double-blind, randomized controlled trial to evaluate SAMe as an additive therapy against major depression in this drug-resistant population was funded by The National Institute of Mental Health.1

The trial is a follow-up to a smaller study in 2004 that found greater benefit when antidepressant drugs were combined with SAMe than when these drugs were used alone.2 In the current investigation, Harvard Medical School researchers assigned adult depressives taking serotonin reuptake inhibitor drugs (like Prozac®, Effexor®, Celexa®, Zoloft®, Paxil®, and Cymbalta®) to receive 800 mg SAMe or a placebo twice per day for six weeks. Those who received SAMe experienced a 36.1% response rate and a 25.8% remission rate, compared to a 17.6% and a 11.7% response and remission rate in the placebo group.1 This translates into a beneficial response and remission rate that was double for those receiving SAMe compared with placebo.

An accompanying editorial written by University of California-San Francisco professor of psychiatry J. Craig Nelson, MD stated that the Harvard findings are “persuasive” and that “SAMe offers a novel mechanism of treatment action and opens up a new area for future exploration.” 3

References

1. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry. 2010 Aug;167(8):942-8.

2. Alpert JE, Papakostas G, Mischoulon D, et al. S-adenosyl-L-methionine (SAMe) as an adjunct for resistant major depressive disorder: an open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine. J Clin Psychopharmacol. 2004 Dec;24(6):661-4.

3. Nelson JC. S-adenosyl methionine (SAMe) augmentation in major depressive disorder. Am J Psychiatry. 2010 Aug;167(8):889-91.

REFERENCES:

1. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry. 2010 Aug;167(8):942-8. 2. Alpert JE, Papakostas G, Mischoulon D, et al. S-adenosyl-L-methionine (SAMe) as an adjunct for resistant major depressive disorder: an open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine. J Clin Psychopharmacol. 2004 Dec;24(6):661-4. 3. Perovic B, Jovanovic M, Miljkovic B, Vezmar S. Getting the balance right: Established and emerging therapies for major depressive disorders. Neuropsychiatr Dis Treat. 2010 Sep 7;6:343-64. 4. Panza F, Frisardi V, Capurso C, et al. Polyunsaturated fatty acid and S-adenosylmethionine supplementation in predementia syndromes and Alzheimer’s disease: a review. ScientificWorldJournal. 2009 May 22;9:373-89. 5. Gregory PJ, Sperry M, Wilson AF. Dietary supplements for osteoarthritis. Am Fam Physician. 2008 Jan 15;77(2):177-84. 6. Fava M. Switching treatments for complicated depression. J Clin Psychiatry. 2010 Feb;71(2):e04. 7. Saletu B, Anderer P, Di Padova C, Assandri A, Saletu-Zyhlarz GM. Electrophysiological neuroimaging of the central effects of S-adenosyl-L-methionine by mapping of electroencephalograms and event-related potentials and low-resolution brain electromagnetic tomography. Am J Clin Nutr. 2002 Nov;76(5):1162S-71S. 8. Saletu B, Anderer P, Linzmayer L, et al. Pharmacodynamic studies on the central mode of action of S-adenosyl-L-methionine (SAMe) infusions in elderly subjects, utilizing EEG mapping and psychometry. J Neural Transm. 2002 Dec;109(12):1505-26. 9. Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev. 2008 Sep;13(3):216-26. 10. Carney MW, Toone BK, Reynolds EH. S-adenosylmethionine and affective disorder. Am J Med. 1987 Nov 20;83(5A):104-6. 11. Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000 Aug;69(2):228-32. 12. Herrmann W, Obeid R. Biomarkers of folate and vitamin B(12) status in cerebrospinal fluid. Clin Chem Lab Med. 2007;45(12):1614-20. 13. Racagni G, Popoli M. The pharmacological properties of antidepressants. Int Clin Psychopharmacol. 2010 May;25(3):117-31. 14. Bottiglieri T. S-Adenosyl-L-methionine (SAMe): from the bench to the bedside--molecular basis of a pleiotrophic molecule. Am J Clin Nutr. 2002 Nov;76(5):1151S-7S. 15. Scott JM, Molloy AM, Kennedy DG, Kennedy S, Weir DG. Effects of the disruption of transmethylation in the central nervous system: an animal model. Acta Neurol Scand Suppl. 1994;154:27-31. 16. Baldessarini RJ. Neuropharmacology of S-adenosyl-L-methionine. Am J Med. 1987 Nov 20;83(5A):95-103. 17. McGowan PO, Kato T. Epigenetics in mood disorders. Environ Health Prev Med. 2008 Jan;13(1):16-24. 18. Bottiglieri T, Hyland K, Reynolds EH. The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs. 1994 Aug;48(2):137-52. 19. Paul RT, McDonnell AP, Kelly CB. Folic acid: neurochemistry, metabolism and relationship to depression. Hum Psychopharmacol. 2004 Oct;19(7):477-88. 20. Yamamoto T, Yatsugi S, Ohno M, Ueki S. Inhibition of mouse-killing behavior by S-adenosyl-L-methionine in midbrain raphe-lesioned and olfactory-bulbectomized rats. Pharmacol Biochem Behav. 1989 Oct;34(2):395-8. 21. Benelli A, Filaferro M, Bertolini A, Genedani S. Influence of S-adenosyl-L-methionine on chronic mild stress-induced anhedonia in castrated rats. Br J Pharmacol. 1999 Jun;127(3):645-54. 22. Bellido I, Gomez-Luque A, Plaza A, Rius F, Ortiz P, Sanchez de la Cuesta F. S-adenosyl-L-methionine prevents 5-HT(1A) receptors up-regulation induced by acute imipramine in the frontal cortex of the rat. Neurosci Lett. 2002 Mar 15;321(1-2):110-4. 23. Genedani S, Saltini S, Benelli A, Filaferro M, Bertolini A. Influence of SAMe on the modifications of brain polyamine levels in an animal model of depression. Neuroreport. 2001 Dec 21;12(18):3939-42. 24. Chan A, Shea TB. Effects of dietary supplementation with N-acetyl cysteine, acetyl-L-carnitine and S-adenosyl methionine on cognitive performance and aggression in normal mice and mice expressing human ApoE4. Neuromolecular Med. 2007;9(3):264-9. 25. Rosenbaum JF, Fava M, Falk WE, et al. The antidepressant potential of oral S-adenosyl-l-methionine. Acta Psychiatr Scand. 1990 May;81(5):432-6. 26. Salmaggi P, Bressa GM, Nicchia G, Coniglio M, La Greca P, Le Grazie C. Double-blind, placebo-controlled study of S-adenosyl-L-methionine in depressed postmenopausal women. Psychother Psychosom. 1993;59(1):34-40. 27. Fava M, Giannelli A, Rapisarda V, Patralia A, Guaraldi GP. Rapidity of onset of the antidepressant effect of parenteral S-adenosyl-L-methionine. Psychiatry Res. 1995 Apr 28;56(3):295-7. 28. Bell KM, Potkin SG, Carreon D, Plon L. S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl. 1994;154:15-8. 29. Delle Chiaie R, Pancheri P, Scapicchio P. Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Am J Clin Nutr. 2002 Nov;76(5):1172S-6S. 30. Pancheri P, Scapicchio P, Chiaie RD. A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. Int J Neuropsychopharmacol. 2002 Dec;5(4):287-94. 31. Berlanga C, Ortega-Soto HA, Ontiveros M, Senties H. Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine. Psychiatry Res. 1992 Dec;44(3):257-62. 32. Papakostas GI. Evidence for S-adenosyl-L-methionine (SAM-e) for the treatment of major depressive disorder. J Clin Psychiatry. 2009;70 Suppl 5:18-22

Don’t worry too much about radiation from airport X-ray screening

Due to media headlines, we at Life Extension® have been inundated by calls from members who are worried about the risks of the radiation emitted from new airport X-ray screening devices.

No organization has been more vocal about avoiding unnecessary exposure to radiation than Life Extension. We have long warned members to say NO to unnecessary X-rays and especially certain types of CT or CAT scans that can poison the body with the equivalent radiation of more than 400 regular chest X-rays.

Radiation exposure not only increases the risk of certain cancers, but also damages endothelial DNA, thus accelerating pathological atherosclerotic processes. When it comes to radiation exposure, there is no safe dose.

As far as the amount of radiation emitted from the new airport screening devices, however, the amount is so trivial that you probably should not worry about it. As you will read below, we are exposed to far more radiation as part of ordinary living — which is why it is so important to protect our precious DNA with antioxidants such as resveratrol, N-acetyl cysteine, green tea and others each day.

Here is a brief summary on the radiation emitted by X-ray airport security screening systems:

1. Naturally occurring ionizing radiation is all around us. We are continuously exposed to this background radiation during ordinary living. In 42 minutes of ordinary living, a person receives more radiation from naturally occurring sources than from screening with any general-use X-ray security system.
   
   
2. A full-body X-ray security system delivers less than the dose (of ionizing radiation) a person receives during 4 minutes of airline flight. The TSA has set the dose limit to ensure a person receives less radiation from one scan with a TSA general-use X-ray security system than from 2 minutes of airline flight.
   
   
3. Compared with a conventional CT scan, the dose of radiation generated by the airport screening system is very low. "A passenger would need to be scanned using a backscatter scanner, from both the front and the back, about 200,000 times to receive the amount of radiation equal to one typical CT scan," said Dr. Andrew J. Einstein, director of cardiac CT research at Columbia University Medical Center in New York City. "Another way to look at this is that if you were scanned with a backscatter scanner every day of your life, you would still only receive a tenth of the dose of a typical CT scan," he said. By comparison, the amount of radiation from a backscatter scanner is equivalent to about 10 minutes of natural background radiation in the United States, Einstein said. "I believe that the general public has nothing to worry about in terms of the radiation from airline scanning," he added. For moms-to-be, no evidence supports an increased risk of miscarriage or fetal abnormalities from these scanners, Einstein added. "A pregnant woman will receive much more radiation from cosmic rays she is exposed to while flying than from passing through a scanner in the airport."

Having said all the above, when I travel this Thanksgiving weekend, I will insist on an intrusive physical pat down as opposed to the X-ray scanners. The public has been deceived so many times by the makers of radiation equipment that I simply don’t trust their numbers. It also gives me the opportunity to educate other human beings (in this case, perfect strangers) that there is no safe dose of radiation that one should intentionally expose oneself to.

For longer life,

William Faloon

References:
http://www.fda.gov/Radiation-EmittingProducts/RadiationEmittingProductsandProcedures/SecuritySystems/ucm227201.htm
http://www.businessweek.com/lifestyle/content/healthday/634724.html
http://www.lef.org/magazine/mag2010/aug2010_Lethal-Danger-of-CT-Scans_01.htm

Inflammation and the aging brain

Inflammation and the aging brain
By Dale Kiefer

Inflammation is now thought to play a role in pathological conditions ranging from anemia and allergy to coronary heart disease, psoriasis and even stroke. From inflamed gums that may contribute to cardiovascular disease, to playing a crucial role in fanning the flames of cancer cell growth, inflammation has been implicated in many more diseases than was previously believed.

Recently, inflammation has also been recognized as playing a central role in the debilitating cognitive decline that characterizes neurological disorders such as Alzheimer’s disease and vascular dementia. Although mental decline and memory loss have long been considered inevitable hallmarks of old age, new research suggests that such inflammation/age-associated decline is avoidable. Indeed, findings reported by some scientists suggest that early intervention in low-grade inflammation may offer some protection against these dreaded brain diseases.

The many guises of inflammation
Inflammation is as familiar as an overworked muscle, and as common as your latest sunburn. Parents who have agonized over a child’s escalating fever know that inflammation occasionally transcends the merely annoying to become something far more troubling: Fever that climbs too high for too long can inflict serious, even life-threatening, damage.

But inflammation, including fever, serves a useful purpose in the body. Even sunburn is a result of the body’s attempt to repair damage inflicted by ultraviolet radiation. In fact, inflammation is an ingenious adaptation that allows the body to defend against clear and present dangers.

For instance, when virulent bacteria invade, they thrive precisely at the body’s normal temperature of 98.6 ºF (37 ºC). Once established, they pour toxins into the bloodstream, while continuing to proliferate exponentially. The immune system mounts a defense, but cellular defenders may be thwarted or simply overwhelmed. In response, the body turns up the furnace. Sensitive to the slightest temperature increases, pathogens perish. The body wins the battle. Fever breaks and all is well.

This is just one example of inflammation’s beneficial nature. But some inflammation goes too far. Fever doesn’t always vanquish the invading horde and fade back to a state of disease-free normalcy. Occasionally the cost of battle is too dear and fever damages the very body it is defending. Autoimmune diseases provide another example of inflammation gone awry. The immune system targets the body’s own tissues by its inability to differentiate between some of the body’s proteins and foreign invaders. In essence, the immune system wages war, against itself. Diseases such as rheumatoid arthritis and lupus erythematosus are the result. Clearly, inflammation can be a double-edged sword.

News from the hot zone
The inflammation of most concern, however, generally goes unnoticed. It is this low-grade chronic inflammation (as opposed to the acute, intense inflammation associated with a healing wound, for instance) that is believed to underlie the most serious neurodegenerative diseases. Huntington’s disease, for example, is characterized by chronic brain inflammation caused by the immune system’s misguided attempts to eliminate a defective protein that results from a genetic defect. And although their inflammation triggers are different, diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (Lou Gehrig’s disease, or ALS) and even multiple sclerosis, are also characterized by chronic inflammation of neural tissues.

Regarding Alzheimer’s disease, one research team noted, “Inflammation is becoming increasingly substantiated as a contributor to Alzheimer’s disease pathogenesis”1 For this reason anti-inflammatory drugs, such as the non-steroidal anti-inflammatory drugs (NSAIDs, e.g. aspirin, ibuprofen and acetaminophen) and the newer COX-2-inhibitor class of prescription drugs, are under investigation as therapies for this and other inflammation-related diseases.

Inflammation and the brain
To better understand inflammation’s role in disease, it’s helpful to comprehend its more benevolent role in keeping the body healthy. Inflammation is the body’s response to a perceived threat. In the case of an invasion by bacteria, the immune system correctly identifies the unwelcome entity and attempts to neutralize it. This involves a complex chain of events and may require the cooperation of a variety of specialized cells. Their activity is generally beneficial, but the goal is always the same: to rid the body of intruders and to dispose of damaged tissue so healing may take place.

Throughout most of the body, cells known as macrophages act as living soldiers, searching for invaders, and then engulfing and neutralizing them. In the brain, supporting cells of the glial family, known as microglial cells, act as scavengers, in much the same fashion as macrophages. They engulf and eliminate dead neurons that have been damaged by injury or illness. Unfortunately, they also secrete harmful neurotoxins and toxic oxygen free radicals in an attempt to neutralize foreign or undesirable substances.2

Regrettably, the inflammatory response is occasionally worse than the stimulus that triggered it in thefirst place. Even when the original trigger is eliminated, inflammation may become self-perpetuating. Such, apparently, is the case in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, ALS and multiple sclerosis, which are characterized by a great deal of microglial activity. The presence of activated microglial cells is an indicator of chronic inflammation.3,4

Alzheimer’s and inflammation
Much remains to be elucidated regarding the onset and progression of Alzheimer’s disease, but it seems clear that an inflammation-provoking protein fragment, a peptide known as amyloid-B, triggers inflammation. Uninterrupted, the inflammation gradually accelerates, killing nerve cells and causing a drastic decline in levels of a vital brain chemical, the neurotransmitter acetylcholine. This downward spiral of neural degeneration commences with the induction of nearly undetectable inflammation, progresses to the erosion of memory, concentration and learning ability and ends with death. Upon demise, Alzheimer’s patients display abnormal spaghetti-like neuritic amyloid-B plaques and neurofibrillary tangles. Like a battleground littered with the remains of the combatants, these damaging plaques are associated with reactive microglial cells, and consist of amyloid-B protein fragments, immune system proteins such as interleukin-6 (IL-6)and other components indicating long-term, and ultimately counterproductive, inflammation.5

Microglial cells, which accompany the neuritic plaques of Alzheimer’s disease, are normally dormant. They are activated only in response to inflammation, thus their presence is a sure sign of brain inflammation. Although present in large numbers in the brains of patients with degenerative neurological diseases, such as Huntington’s6 and Alzheimer’s diseases, their numbers are also elevated in otherwise healthy elderly individuals. This implies that a certain degree of neuroinflammation is an ordinary result of nothing more than advanced age.2 Indeed, some scientists have suggested that cognitive decline begins early in the aging process and is an inevitable result of advancing age.7 Controlling inflammation, therefore, could presumably benefit anyone interested in preventing eventual memory loss and cognitive decline.

Dual pathways to inflammation
Just in the last decade, scientists discovered a key enzyme produced by the body in response to inflammatory provocations: cyclooxygenase-2 (better known as COX-2). COX-2 has been identified as an important link in the inflammation cascade. Unlike COX-1, COX-2 is only present in the body during inflammation Research has revealed that cells convert cell membrane phospholipids to arachidonic acid, which serves as a substrate that gives rise, in turn, to two powerful and potentially damaging classes of inflammation mediators, known as eicosanoids: the prostaglandins and leukotrienes. As one researcher noted, “Arachidonic acid release and production of eicosanoids are prerequisites for inflammation”1 The eicosanoids are synthesized from arachidonic acid by the action of two enzymes that form the crux of dual inflammatory pathways: cyclooxygenase (COX) and lipooxygenase (5-LOX).

The COX proteins take two forms: COX-1 and COX-2. The actions of COX-1 are generally beneficial. But the activity of COX-2 is generally harmful. COX-2 inserts an oxygen molecule into arachidonic acid to synthesize prostaglandins, which are powerful triggers of pain and inflammation. 5-LOX converts arachidonic acid into inflammatory leukotrienes.

NSAID medications treat inflammation by blocking the activity of both the COX-2 enzyme and its more benevolent sibling, COX-1. But COX-1 is necessary for stomach lining protection; so interfering with COX-1’s activity can cause gastric disturbances ranging from simple discomfort to dangerous bleeding ulcers. For this reason the new COX-2-inhibitor class of prescription drugs (e.g. Celebrex and Vioxx) has rocketed to popularity. Their more selective action effectively relieves inflammation while minimizing the distressing side effects that are possible with chronic use of NSAIDs.

Researchers are investigating the possibility that anti-inflammatory agents, such as the COX-2 inhibitors, may provide viable therapy not only for Huntington’s, but also for other neuro-degenerative diseases such as Alzheimer’s and Parkinson’s disease. It’s well documented that the COX pathway generates inflammatory prostaglandins. But medical research has largely ignored the potentially damaging effects of 5-LOX, the enzyme that forms the second branch of the dual arachidonic acid inflammation pathways. As a recent study reported, 5-LOX might play a significant role in the pathobiology of aging-associated neuro-degenerative diseases.8

5-LOX generates inflammatory leukotrienes, which are known to be potent inflammatory mediators that play a role in allergic reactions. They may also play a role in ischemia and atherosclerosis.9 Stroke, traumatic brain injury and Alzheimer’s disease have also been linked to the activity of 5-LOX and leukotrienes.2 The results of a recent study indicate that blocking COX-2 while ignoring the effects of 5-LOX may be counter-productive. In fact, using COX-2 inhibitors to block the activity of COX-2 may actually cause 5-LOX levels to increase further, making inflammation worse, rather than better.2 This “rebound” inflammation is evidently caused by shifting arachidonic acid toward synthesis of damaging leukotrienes through the 5-LOX pathway.

An obvious solution to this problem would be the addition of a drug to the anti-inflammatory regimen that can block 5-LOX. Fortunately, such substances exist, although they have only recently come under scrutiny as complements to far more heavily researched NSAIDs and COX-2 inhibitors.

In one 5-LOX inhibition study, researchers speculated, ‘Inhibitors of the two pathways might have additive, or even synergistic neuroprotective effects when used in combination.’ By study’s end, they had concluded that a 5-LOX inhibitor “significantly potentiated the effects of three different COX inhibitors.”2 Their findings suggest, quite simply, that while anti-inflammatory therapy with COX-inhibitors may be neuroprotective, therapy combining both COX and 5-LOX inhibitors should prove considerably more effective.

The promise of anti-inflammatory therapy
The feedback loops in the brain do not allow for simplistic approaches to the treatment of multi-factorial diseases. Not surprisingly, a recent study in the Journal of the American Medical Association found that COX-2 inhibition alone was ineffective in slowing the progression of clinically diagnosed Alzheimer’s disease. It is likely that these results reinforce a growing body of research that dual inflammatory pathway inhibition may be needed to fully realize the promise of anti-inflammatory therapy. While anti-inflammatory therapy may slow progression of some diseases, it may be necessary to begin taking anti-inflammatory agents long before symptoms appear, in order to prevent or reverse the ravages of neurodegenerative diseases.

REFERENCES:

1. Paris D, et al. AB vasoactivity: an inflammatory reaction. Ann N Y Acad Sci (no date provided) pp.97-108.

2. Klegeris A et al. Cyclooxygenase and 5 lipooxygenase inhibitors protect against mononuclear phagocyte neurotoxicity. Neurobiol of Aging 2002 (23) 787-794.

3. Teismann P, et al. Cyclooxygenase-2 is instrumental in Parkinson’s disease neurodegeneration. PNAS 2003; 100 (9):5473-5478.

4. Pompl PN, et al. A therapeutic role for cyclooxygenase-2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. FASEB J. 2003; 10.1096/fj.02- 0876fje

5. Scali C, et al. The selective cyclooxygenase-2 inhibitor rofecoxib suppresses brain inflammation and protects cholinergic neurons from excitotoxic degeneration in vivo. Neuroscience 2003; 117:909-919.

6. Sapp et al., Early and progressive accumulation of reactive microglial in the Huntington Disease Brain. Neuropathol Exp Neurol 2001; 60(2): 161-172.

7. Jorm AF, et al. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand 1987; 76: 465-479.

8. Uz T, et al. Aging-associated up-regulation of neuronal 5- lipoxygenase expression: putative role in neuronal vulnerability. FASEB 1998; 12: 439-449.

9. Spanbroek R et al. Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. PNAS 2003; 100:12381243.