Turmeric—Helping the Body Protect Itself

Turmeric’s Curcuminoids
Help Prevent Brain Plaque

They appear to stimulate the body’s innate immune system,
which may be crucial for averting Alzheimer’s disease
By Will Block

ne of life’s humble but cherished amenities is the self-cleaning oven, an appliance that saves untold amounts of caustic chemicals, steel wool, and elbow grease. Just turn the heat up high, wait awhile, and presto—a clean oven, ready for the next casserole or pizza. If only our bodies had a similar system for automatically cleaning out the biochemical gunk that tends to accumulate in various places, through no fault of our own.

Actually, our bodies do have such a system, and we’re all born with it (well, part of it, anyway—the rest must be acquired). It’s extremely versatile and efficient—usually. It is our immune system, a variegated collection of white blood cells, proteins, and biochemical processes that attack and neutralize things that could do us harm. Were it not for our immune system, we would all die in infancy or early childhood. (For an overview of the immune system, see the sidebar, which explains some of the basic concepts discussed below.)

How Your Immune System Protects You

The immune system is a mystery to most people. For one thing, it’s not easy to visualize, like the cardiovascular system, which has a structure with interconnected components whose basic functions can be readily understood. By contrast, the immune system is a subtle and complex phantom, operating invisibly throughout the body at the cellular and molecular levels.

The function of the immune system is to defend us against foreign or dangerous substances, such as microorganisms, toxins, and cancer cells. It does this by marshaling armies of specialized white blood cells or protein molecules to attack and destroy the enemies in one way or another. It must first, of course, be able to distinguish friend from foe, i.e., to discriminate reliably between cells or molecules that are part of the self and those that are alien and do not belong. This is no mean feat—it requires sophisticated molecular recognition systems that are unique to each individual.

Any substance whose molecular “signature” stimulates an immune response is called an antigen. There are two basic kinds of immune responses to antigens: one that we’re born with and one that we must acquire through actual exposure to antigens that come our way on life’s perilous road.

Innate immunity, or natural immunity, is inborn. It’s also called nonspecific immunity because the immune system components in question (mainly a variety of different types of white blood cells) treat all foreign substances in much the same way—a kind of indiscriminate, shotgun approach to anything that appears alien. What it lacks in finesse, it makes up for in comprehensiveness.

Acquired immunity, or adaptive immunity, on the other hand, develops during childhood. It’s also called specific immunity because here the immune response is directed at specific antigens in targeted ways, akin to the use of a rifle instead of a shotgun. The “bullets” in question are highly adaptive white blood cells called lymphocytes and various types of proteins, including antibodies; the latter are designed to recognize and bind to specific antigens via precisely tailored molecular interactions.* These abilities must be “learned” and “remembered” at the molecular level through real-life exposure to antigens.


*The mechanism by which this is accomplished was elucidated in the 1930s by Linus Pauling. His discoveries revolutionized the field of immunology, putting it on a solid physicochemical foundation for the first time. This was one of several epochal achievements in medicine for which Pauling deserved (but did not receive) the Nobel Prize.


Lymphocytes circulate in the lymphatic system and the bloodstream. They enable the body to distinguish self from nonself and to remember the molecular signatures of antigens; the latter trick enables our immune system to respond more rapidly and efficiently to antigens encountered previously. Most of our antibodies (which are also called immunoglobulins) develop in response to our exposure to antigens, as from vaccinations or attacks of infectious diseases. Some are inborn, however, having been transmitted from mother to fetus via the placenta. And babies acquire others through breast milk.

Innate immunity is the kind that’s particularly relevant to the accompanying article because of its apparently important role in preventing the formation of amyloid-beta deposits in our brains. Innate immunity is mediated primarily by various types of white blood cells: monocytes, neutrophils, eosinophils, basophils, and “natural killer cells” (which for some unfathomable reason escaped getting a fancy scientific name). All of them, actually, are killers, either directly or indirectly.

When monocytes leave the blood circulation and enter the tissues in response to an infection, they become macrophages, a type of large scavenger cell that devours bacteria, foreign cells, and damaged or dead cells. This vital function is called phagocytosis (“cell-eating”); the term is also used to denote the eating of noncellular material, such as amyloid-beta.

Finally, it’s worth noting that various organs and tissues are functioning parts of our immune system. They are the bone marrow and the thymus gland, where white blood cells are produced, as well as the lymphatic system, spleen, liver, tonsils, appendix, and groups of cells in the small intestine called Peyer’s patches.

Antigens Come from Without and Within

The most obvious examples of antigens (harmful agents) that threaten our health and mobilize our immune system against them are microorganisms invading us from the outside, such as bacteria, viruses, fungi, and parasites. Also potentially harmful are foreign blood cells from transfusions and foreign tissues from transplant operations. Other examples are environmental toxins, such as air pollutants and contaminants in our food or water, and self-inflicted toxins, such as cigarette smoke.

But what about toxic agents that develop naturally within our bodies? Although the processes in question are natural in the technical sense, they’re usually associated with disease—cancer, e.g.—and from the perspective of good health, disease is an unnatural state that we seek to avoid. So it’s natural to defy Mother Nature when she attempts to inflict harm on us from within. And by and large, our immune system does a good job of that throughout most of our lives.

The Hazards of a Declining Immune System

As we get older, however, our immune system tends to become less efficient, especially if we don’t exercise regularly and maintain good nutrition—including the use of supplements to make up for increasing deficiencies of some nutrients that our bodies no longer absorb and utilize as well as they did in our youth.

A declining immune system is less able to distinguish reliably between self and nonself; this increases the risk for autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, in which our own tissues come under attack by our immune system. The age-related decline in immune function also means that macrophages become less efficient killers of bacteria, cancer cells, and other antigens; this may help explain why cancer is more common in the elderly than in younger people.

Also more common—and more deadly—in the elderly are diseases such as pneumonia, influenza, infectious endocarditis, and tetanus; this is probably due, in part, to declining levels and declining efficacy of the white blood cells and the various immune-system proteins upon whose actions our continued health depends. As a final insult to the elderly, vaccinations are less likely to work in people with declining immune systems.

Amyloidosis of Aging Can Lead to Alzheimer’s

A particularly insidious aspect of aging is amyloidosis, a slow process in which harmful proteinaceous material is deposited in various parts of the body, especially the nervous system, the heart, and the pancreas. In the heart, amyloidosis can lead to intractable congestive heart failure. And in the brain, where the deposits are of a particular type called amyloid-beta (or beta-amyloid), it can lead to dementia, most notably Alzheimer’s disease.

Amyloid-beta is the principal constituent, along with some polysaccharides, of the neuritic plaques that clog the brains of Alzheimer’s victims. These plaques contribute greatly to the steady loss of cognitive functions that herald the disease and eventually rob its victims of their personalities—and their lives. A characteristic finding at autopsy is a major loss of brain matter owing to the death of countless neurons (brain cells) in certain regions of the brain.

Thus it’s a “no-brainer” to want to prevent, as best we can, the formation of neurotoxic amyloid-beta deposits in our brains. Here our immune system is obligingly helpful and efficient. Until it isn’t—that’s when the trouble begins.

Curcuminoids Are the Source of Turmeric’s Benefits

In normal, healthy people, macrophages attack and destroy amyloid-beta molecules before they can self-aggregate into neuritic plaques in the brain. In Alzheimer’s patients, however, this vital immune-system response is blunted, and the destructive process of plaque formation can proceed. That conclusion is supported by a series of immunological experiments performed recently by a team of researchers at UCLA.1 Their study also showed that a chemical compound found in turmeric can significantly improve the immune system’s response to amyloid-beta, thereby improving the chances of its clearance (removal) before it can do significant harm.

Turmeric (Curcuma longa) is the Indian spice that gives some mustards their bright yellow color, and it’s one of the principal ingredients in curry powders. In India and Southeast Asia, turmeric has long been known as “the spice of life.” In addition to tasting good, it has strong anti-inflammatory, antioxidant, and antitumor effects, which are attributed to a compound called curcumin and its naturally occurring chemical derivatives, called curcuminoids (the latter term is generally understood to include curcumin as well).

How Does the Immune System Deal with Amyloidosis?

The UCLA researchers, led by Dr. Milan Fiala, built not only upon their own previous work regarding the role of the innate immune system in Alzheimer’s disease but also on the previous work of another group of researchers, also at UCLA. That group, led by Dr. Sally Frautschy, had shown that curcumin is a potent inhibitor of amyloid-beta in the brains of mice and rats and that it suppresses the inflammation and oxidative stress associated with brain amyloidosis.2,3*


*For descriptions of these studies, see “Turmeric May Help Prevent Alzheimer’s and Parkinson’s Diseases” (February 2002) and “Turmeric Protects Your Brain Cells” (July 2004). And for further information on turmeric’s beneficial actions, see “Turmeric Is ‘The Spice of Life” (November 2004), the sidebar “Turmeric Fights Dementia” in the article “Galantamine Works Well in Real Life” (February 2007), and “Antioxidants Combat Age-Related Macular Degeneration” (April 2007).


The Fiala research team sought, first of all, to clarify the role of the innate immune system in brain amyloidosis and, secondarily, to identify and test the turmeric curcuminoid with the greatest potency as a stimulator of the innate immune system. For their experiments, they took monocytes from the blood of 73 Alzheimer’s patients and 42 healthy controls (average ages 74 and 69, respectively) and incubated them, under various conditions, with amyloid-beta. The purpose was to see how the activities of the monocytes from the two groups of individuals would differ when confronted with this immunological challenge.

In addition, some samples of the monocytes were cultured to produce macrophages so that the researchers could evaluate the ability of these scavenger cells of the innate immune system to ingest amyloid-beta through phagocytosis (which is explained in the sidebar above). And in one experiment, the researchers used frozen sections of the frontal lobes from the brains of three deceased Alzheimer’s victims, incubating them with monocytes from living Alzheimer’s patients and controls, again to see how the monocytes would respond to this challenge.

Alzheimer’s Immune System Is Severely Compromised

The experimental procedures were too complex to describe here, so let’s just summarize the results. There were dramatic differences between the healthy controls and the Alzheimer’s patients in terms of the immunoprotective function of their monocytes and macrophages. The cells taken from the controls showed strong phagocytic activity against amyloid-beta, and they upregulated (stimulated) the expression of certain genes that play important roles in this immune-system function.

By contrast, the cells taken from the Alzheimer’s patients were largely ineffective against amyloid-beta, and they downregulated (suppressed) the expression of the genes in question. This suggests that the Alzheimer’s patients’ innate immune systems were severely compromised, at least in terms of their ability to combat amyloid-beta and, therefore, the disease itself.

Which Curcuminoid Is Best for Immune Function?

These findings have great potential importance in terms of prevention and therapy for Alzheimer’s disease (AD). Agents that can improve innate immune function, particularly with respect to the phagocytosis of amyloid-beta, could be very useful. Knowing of the existing evidence that curcuminoids are effective against amyloid-beta, the researchers sought to determine which of them was the most potent in terms of its ability to stimulate the innate immune system.

Curcumin
The answer was bis(demethoxy)curcumin, a minor constituent (0.15% or less) of turmeric that constitutes 2–3% of a typical curcuminoid extract.* This compound actively stimulated the phagocytosis of amyloid-beta at levels that, according to the researchers, could be achieved in humans by direct infusion into the blood. Their experiments showed that this effect was due, at least in part, to an upregulation of the immune-system genes mentioned above. They concluded, “Thus, bisdemethoxycurcumin may correct immune defects of AD patients and provide a previously uncharacterized approach to AD immunotherapy.” The same could be said in reference to curcuminoids in general, and the authors did, in fact, make that claim elsewhere.


*In chemical parlance, bis means “two of,” de means “removed,” and methoxy means the organic chemical group –OCH3. So bis(demethoxy)curcumin is just curcumin with its two methoxy groups removed. If only one methoxy group is removed, the result is demethoxycurcumin, which is the third principal curcuminoid in turmeric. Even minor alterations in molecular structure can have profound effects on biological activity, and predicting such effects is very difficult. Experimental evidence is required.


A Fly in the Ointment

The scientific excitement inherent in these findings was dampened by a stinging critique of the paper from Drs. Sally Frautschy and Bruce Teter of UCLA, published online by the Alzheimer Research Forum.4 (Recall that Frautschy, who is a distinguished authority on Alzheimer’s disease, was the leader of the other UCLA research team mentioned earlier.) While acknowledging the potential importance of the findings—assuming that they can be confirmed by others—the critique detailed many serious methodological shortcomings and outright errors in the paper by Fiala et al. and called into question the validity of the authors’ conclusions. Dr. Fiala refuted some of the criticisms in a rebuttal posted 5 days later on the same site.

It’s clear that the study was seriously flawed and that its exposition was shoddy. That, alas, is not unusual in the medical literature, but here it’s surprising because the paper was published in the prestigious Proceedings of the National Academy of Sciences of the USA and was scientifically edited by Dr. Louis J. Ignarro (also of UCLA), who is a member of the Academy and a Nobel laureate in medicine. Go figure.

Curcuminoids Have Multiple Modes of Action

More and better research will have to be done before we know how valid these results are. Meanwhile, however, we can be confident from prior research that turmeric curcuminoids have beneficial effects against amyloidosis and deserve to be investigated further in this regard, to determine both what they do and how they do it. In that regard, Drs. Frautschy and Teter gave turmeric a strong endorsement by acknowledging that curcumin (and, by extension, the curcuminoids) has multiple modes of action:4

The structural characteristics of curcumin, . . . enabling it to inhibit multiple aspects of AD pathogenesis, are not fully elucidated. . . . Understanding mechanisms of Aβ [amyloid-beta] uptake in human cells is likely important . . . However, factors other than an influence on phagocytic Aβ uptake (e.g., anti-oligomer aggregation, anti-inflammatory, antioxidant, etc.) appear to be crucial for curcumin’s full impact in AD models.

So if you want to spice your life up a little and help protect your brain at the same time, consider turmeric—it’s good, and good for you.

References

  1. Fiala M, Liu PT, Espinosa-Jeffrey A, Rosenthal MJ, Bernard G, Ringman JM, Sayre J, Zhang L, Zaghi J, Dejbakhsh S, Chiang B, Hui J, Mahanian M, Baghaee A, Hong P, Cashman J. Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer’s disease patients are improved by bisdemethoxycurcumin. Proc Natl Acad Sci USA 2007;104(31): 12849-54.
  2. Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 2001;21:8370-7.
  3. Frautschy SA, Hu W, Kim P, Miller SA, Chu T, Harris-White ME, Cole GM. Phenolic anti-inflammatory antioxidant reversal of Aβ-induced cognitive deficits and neuropathology. Neurobiol Aging 2001;22:993-1005.
  4. Frautschy SA, Teter B. Comment on paper by Fiala M et al. Alzheimer Research Forum, posted Aug. 1, 2007. See www.alzforum.org/pap/annotation.asp?powID=68759.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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