Aging and Immunity by James South, MA We live in a world of entropy.

Entropy is the tendency of complex structures to gradually decay or break down with time. Entropy is one of the brute facts of existence. It is "codified" as one of the basic laws of physics: the second law of thermodynamics, which governs both living and inanimate matter. We humans normally call the process of entropy "ageing." The anti-ageing movement is literally an anti-entropy movement. Modern science has discovered that we can at least slow down entropy through various means such as exercise, proper diet, nutrient supplements and anti-ageing drugs. Unfortunately for us, there is a whole micro-universe of agents of entropy who are literally out to get us - to accelerate our entropic decay. We call them "germs" and "cancer cells." A host of viruses, bacteria, fungi, parasites, worms and cancer cells are ready to invade our bodily turf and wreak havoc with our cells, tissues and organs, leading to disease or even the ultimate entropy - death. Fortunately for us, we are endowed with a superb, multifaceted, synergistically interacting defence force - our immune system. This amazing defence force can, in principle, defeat any entropic germ science has yet discovered. There is virtually no germ known to be 100% lethal. Even the dreaded Ebola fever virus is usually only lethal to 70-90% of those it infects, before their immune system saves the unlucky 10-30%. Unfortunately, there are many minor and some major forces of entropy that can weaken, even destroy our immune system's ability to successfully defend us. One of the most common entropic immune weakeners is malnutrition: "malnutrition is the commonest cause of immunodeficiency worldwide" (1), and "Nutritional deficiencies are seen in at least one-third of the elderly in industrialized countries." (2) Overeating and obesity, now epidemic in the Western world, also decrease immune function. (2) Stress is also a major assault on immune health. (2) Indeed, the stress hormones cortisol/corticosterone are sometimes used in experiments to weaken the immune system (3) Perhaps the most inevitable entropic weakener of our immune vigor is ageing itself. Ageing is known to bring about adverse changes in almost every aspect of our immune power. "Aging is associated with a decline in immune function that leads to an increased incidence of infection, cancer, and autoimmune disease. Age-related changes in immunity primarily involve alterations in T cell function.... Altered B cell function also occurs with aging...." (4) Fortunately, modern science has discovered many nutrients, hormones and anti-aging drugs that we can use to combat the otherwise inevitable entropic destruction of our priceless immune health. Many different immune boosters are needed to optimize immune power throughout life, even into old age, because there are so many facets of immune function that decay with age. Immuno-suppressive PGE2 levels increase with age, even in healthy aged adults. (5) "One of the biological changes associated with aging is an increase in free radical formation with subsequent damage to [immune] processes." (5) Active thymulin, one of the most important thymus gland hormones for T cell activity, "disappears from blood circulation by the 5th - 6th decade in humans." (5) "... after primary immunization, antibody responses of aged individuals are characterized by lower, slower, and shorter responses than those observed in young subjects." (7)"Normal aging in human beings is associated with increased basal IL-6 [interleukin-6] production by lymphocytes .... Dysregulation of this cytokine with increased basal secretion has been proposed to contribute to ... age-associated diseases such as B cell lymphoma, osteoporosis, and Alzheimer's disease." (45) And these are just a few of the many immune parameters that weaken with age! A program consisting of various vitamins, minerals, hormones and anti-aging drugs will cover virtually all the areas - nutritional, stress and aging - that are known to weaken the immune system. Experimental results from invitro (test tube), animal and human studies have shown an amazing ability of these anti-entropic biochemicals to repair immune damage, often restoring the measured immune parameter to youthful, healthy levels. In order to better understand the power of a pro-immune supplement program to restore immune health, it is first necessary to have a basic overview of our immune system. Immunology 101 Immunity may be defined as resistance to our protection from disease. There are two primary divisions of our immune function: innate immunity and acquired immunity. Innate immunity results from general processes, rather than processes directed at specific disease organisms. (13) Human natural immunity makes us resistant to such diseases as animal paralytic viral infections, hog cholera, cattle plague and canine distemper. (13) Acquired immunity results from the response of T cells and B cells (T-and B-lymphocytes) to specific invaders: viruses, bacteria, toxins, animal hair, etc. T and B lymphocytes are both activated by foreign antigens. Antigens are proteins or large polysaccharide molecules that help immune cells recognize self and other - i.e. germs, toxins, foreign tissue, etc. T lymphocytes are the basis of "cell-mediated immunity" (CMI) and B lymphocytes are the basis for "humoral immunity." (13) When B cells are stimulated by a foreign antigen they react by transforming into a plasma cell, which then

manufactures specific antibodies - proteins specifically tailored to link up with the activating antigen. Antibodies can inactivate the invading organism in four different ways, including agglutination, precipitation, neutralization and lysis. However, these antibody powers are weak and rarely serve to completely repel a foreign invader. (13) The real power of antibodies comes through activating the complement system, which consists of about 20 interacting enzymes/proteins. When antibodies attach to antigens, they create antigen-antibody complexes, which activate the complement system. The complement proteins can inactivate germs in a multitude of ways. One of the most important occurs when complement protein C3a attaches to the antigen-antibody complex. This new immune complex causes neutrophils and macrophages to ingest the germ to which the antigen is attached. Neutrophils and macrophages (phagocytes) can ingest and digest germs even with antigen-antibody complexes to identify the germs, but the complement/antigen-antibody complex sends them into a "feeding frenzy." (13) CMI, or T lymphocyte immunity, is partly independent from, but also interacts with, humoral immunity. T cells have receptors (TCR) on their surface that can react with foreign antigen. TCRs cannot recognize antigens directly. Macrophages must first attack and digest a given pathogen into protein (antigen) fragments. The macrophage then presents the antigen to the TCR of a nearby T lymphocyte. Until the TCR of a T cell is activated by a specific antigen, the T cell can potentially react to thousands of different antigens. Once a T cell is antigen activated, it begins reproducing itself by cloning. This is called "proliferation." The cloned T cell copies can now react only to the specific antigen (e.g. a Candida membrane protein), their progenitor first reacted to. This allows rapid production of massive numbers of T cells focused on destroying the specific pathogen currently threatening the body. Some of the activated T cells will become memory cells, (so also will some of the activated B cells), put in storage as a "rapid reaction force" should the same antigen show up again in the future. (13) T cells occur in one of 3 forms: T helper cells (T4 or CD4+), T suppressor cells (T8 or CD8+), and cytotoxic T lymphocytes (CTL). T8 cells help reduce immune activity so that it doesn't go to excess. Ideally proper T8 activity prevents auto-immune disease. CTLs directly attack and destroy pathogens which have the antigen a CTL has been activated toward. (13) T4 helper cells come in 2 varieties. Helper cell type 1 (TH1) is the booster/activator of cell-mediated immunity. Helper cell type 2 (TH2) is the activator of B cell antibody production. Both TH1 and TH2 cells do their helper/activator work through secretion of immune proteins called "cytokines" or "lymphokines." There are at least 17 different cytokines. TH1 cells produce interleukin-2 (IL2), interferon gamma (IFN-G), and tumor necrosis factor alpha (TNF-A). IL2 activates CTL, T8 cells, and natural killer cells. TH2 cells produce IL4, 5, 6, and 10. IL4 activates plasma cell antibody production and inhibits TH1 cells. (14) "Immune senescence [aging] is characterized by specific cytokine changes that favor Th2 T-helper responses (antibody production, including auto [self] antibody production) while suppressing Th1 responses (cytotoxic T cell and macrophage activation, i.e. cell-mediated immunity." (15) TH1, cell-mediated immunity (CMI) is more effective (and youthful) immunity; TH2 antibody-dominated immunity is less effective and more troublesome, due to autoimmune disease (and typical of aged immunity). Unfortunately, the main stimulator of TH1 CMI is thymic hormones (16), yet thymic hormones decrease radically with ageing (6-9). Another key determinant of immune power is the T4:T8 cell ratio. (17) Too many T8 cells tends to suppress CMI; not enough T8 cells allows CMI to run rampant, with possible damage to the body itself. The ideal T4:T8 ratio is about 2:1; less than 1:1 represents serious immune weakness. (17) Thymic hormones tend to normalize T4:T8 ratios in a broad range of conditions, including HIV infection, atopic dermatitis, chronic bronchitis, recurrent respiratory infections, viral hepatitis and rheumatoid arthritis. (17) With this brief introduction to the immune system, we can now proceed to the exciting research which shows the way to immune rejuvenation. Immunoscience has shown that it's (usually) never too late to restore immune activity to more vigorous, balanced and youthful levels. Nutrient and the immune response As noted previously, malnutrition is the main worldwide cause of immunodeficiency, and nutrient deficiencies are common in industrialized countries. A 1993 Detroit study of healthy, ambulatory elderly people found a mean zinc intake of 9mg/day, 40% below the 1980 U.S. RDA (recommended dietary allowance) of 15mg. Zinc levels in neutrophils and lymphocytes were significantly lower than those of control subjects (15). A Belgian study of selenium status in institutionalized adults found the daily selenium intake averaged only 40 mcg, less than the U.S. "safe and adequate" intake range of 50-200 mcg/day (18). In a study of immune function in elderly patients receiving nursing care as a result of stroke, but who had no active medical problems at the time of study, 22% were vitamin A-deficient and 48% were vitamin C-deficient (19). These results are typical of modern dietary studies, showing many people, especially the elderly, to be nutrient-deficient even by (modest) RDA standards, and RDA levels are far below so-called "optimum dietary allowance" or "therapeutic" nutrient levels. Not surprisingly, therefore, even research studies using modest nutrient amounts have yielded positive immuneenhancing results. In a 1992 study Chandra gave elderly subjects a low-potency multivitamin/mineral supplement or placebo. The nutrient levels were set at 50-300% of the U.S. RDA. After 12 months, technical measures of immune response were enhanced in the supplement group. T-helper cell levels, natural killer cell activity, T cell proliferation in response to mitogens (artificial experimental antigens), and IL2 and IL2 receptor levels all increased significantly, with no change in the placebo group. And these technical measures of immune improvement were correlated with clinical benefits. The mean number of days of infectious illness was 23 for the supplement group vs. 48 for the placebo group. Antibiotics were used for a mean of 18 days in the supplement group vs. 32 days in the placebo group (20).

In another study 30 elderly patients were supplemented with vitamins A, C, and E or placebo. The supplement group got 8000 IU A, 100 mg C and 50 mg E. These levels are about 1 2/3 the 1980 U.S. RDA for each of these nutrients. " Following 28 days of supplementation with ... vitamins A, C and E there was a distinct improvement in cell-mediated immune function. In particular, the number of T cells, T4 cells and the T4:T8 ratio increased significantly. The responsiveness of lymphocytes to the mitogen PHA also increased significantly .... In contrast, no significant change was noted in the immune function of the placebo group." (19) What these two modest-dose multi-nutrient studies show is that even low-level nutrient supplementation can provide immune enhancement, based both on technical measures of immune function, as well as clinical benefit in the Chandra study. They also show that a combination of nutrients may be synergistic, even though most published studies focus only on a single nutrient, hormone or drug to boost immunity. We shall therefore review a range of immune studies with various nutrients, hormones and anti-aging drugs, with the aim of compiling a comprehensive program to promote "super-immunity." Vitamin A: The anti-infective vitamin Vitamin A, or retinol, is a fat-soluble vitamin that is essential for innate (non-specific) immunity. Vitamin A is necessary for the health of the epithelial (mucous-secreting) cells that line the mouth, nose, throat, stomach, intestines, lungs and urogenital tract, due to its role in mucopolysaccharide production (21). Without adequate Vitamin A, epithelial cells dry up and harden, then becoming more easily penetrated by bacteria and parasites. The epithelial cells provide one of the chief barrier functions of innate immunity. Also, Vitamin A-deficient epithelial cells don't secrete lysozyme, the enzyme that digests bacteria. (21) Vitamin A was dubbed the "anti-infective" vitamin in 1928 when two British researchers published a review of human and animal research linking Vitamin A deficiency to impaired resistance to infection. (22) In a 1979 study, surgery patients were treated with Vitamin A for 7 days before surgery. They were given 300 450,000 IU Vitamin A/day. (The 1980 U.S. RDA for Vitamin A is 5000 IU) T lymphocyte counts were taken at 1 and 7 days post-surgery. T lymphocyte counts rose by day 7 in the Vitamin A group, while surgery patient controls not given Vitamin A suffered the usual post-surgical severe T cell immunosuppression. No Vitamin A-toxicity symptoms were observed in the Vitamin A patients. (23) In 1973, Seifter and colleagues reported a thymotrophic action of Vitamin A in stressed mice. Animals were stressed for 3 or 7 days through partial-body cast. Control mice ate normal lab chow, while Vitamin A mice got extra Vitamin A one day in advance of stressing. "Non-stressed mice had thymus: body wt. ratios of 0.18; stressed mice values were 0.12, while stressed mice receiving vitamin A had values of 0.16. Vitamin A also speeded the rate of thymus weight recovery after the stress was removed. In non-stressed animals vitamin A elevated the thymus: body ratio to 0.22." Seifter thus concluded that Vitamin A had a thymus-protecting effect. (24) In a 1994 review article on Vitamin A and immunity, R.D. Semba concluded that Vitamin A deficiency is an immunodeficiency disorder which results in widespread changes in immunity, including pathological impairment of mucous membranes, impaired antibody responses to antigen challenges, alterations in lymphocyte subgroups (ratios of T4, T8 and CTL cells), and altered T and B cell functions. Semba noted that Vitamin A is an immune enhancer that has been shown to increase lymphocyte clonal proliferation responses to antigens and mitogens, increase antibody responses to T cell-dependent antigens, inhibit programmed cell death (apoptosis), and restore the health and function of damaged mucous membranes. (25) Mega-nutrient pioneer M.D., Robert Atkins considers Vitamin A to reinforce the immune system's resistance to any infectious disease, even AIDS. He reports that some scientists suggest that even a modest Vitamin A supplement of 13,000 to 20,000 IU/day may slow AIDS disease advance. People with AIDS are much more likely than healthy people to have low levels of Vitamin A, even when Vitamin A intake is adequate. Atkins notes that doctors can predict life expectancy of AIDS patients just by measuring Vitamin A blood levels. (26) High dose Vitamin A supplementation is controversial, as Vitamin A can build up in the liver to toxic levels. In a review of Vitamin A toxicity, Hathcock and colleagues report that in adults, Vitamin A toxicity at supplemental intakes of less than 50,000 IU daily for long periods is rare. They state that "...reports of vitamin A toxicity in adults with supplemental intakes <[less than] 50 000 IU/day mainly involve persons with unusually high dietary intakes or with confounding medical conditions, such as liver disease, malnutrition, or use of drugs or alcohol." (27) They also note birth defects have occurred in pregnant women taking 25,000 IU/day. (27) However, even more recent evidence has suggested that intakes over 10,000 IU Vitamin A/day in pregnant women increases the risk of birth defects, so it is now commonly recommended that women who are pregnant, or who are expecting or trying to get pregnant limit their supplemental preformed (i.e. not counting carotenoids) Vitamin A intake to 5,000 IU/day. (28) For most other reasonably healthy adults, a daily Vitamin A supplement of 10 - 20,000 IU will probably be safe and effective. ( I have used 20 - 50,000 IU Vitamin A daily for 31 years with no signs of toxicity.) Chronic toxicity signs and symptoms include hair loss, anemia, bone pain, brittle nails, dry mucous membranes, edema, fatigue, fever, headache, enlarged liver, insomnia, irritability, muscle pain and stiffness, skin rash or scaliness, vomiting and weight loss. (27) Vitamin C: More may be better Vitamin C (ascorbate or ascorbic acid) is the subject of a massive amount of experimental and clinical research. In a 1984 review article, long time Vitamin C researcher R. Anderson labeled Vitamin C an "immunostimulatory, anti-inflammatory, anti-allergic" vitamin. (29) Anderson stated that Vitamin C is essential to promote optimal

migration of neutrophils and macrophages to infection sites. He notes that high serum levels of Vitamin C increase neutrophil mobility and lymphocyte transformation. Neutrophils and macrophages secrete toxic oxidants - superoxide, hydrogen peroxide, hypochlorite and hydroxyl radicals - to kill germs. Unfortunately, these oxidants leak out of the neutrophils/macrophages, damaging them and surrounding tissue, promoting excessive inflammation, unless neutralized by adequate antioxidants such as Vitamin C. Anderson also reports that Vitamin C enhances neutrophil microbial killing action by multiple chemical pathways. Anderson also notes that many experiments show Vitamin C to enhance T lymphocyte reactivity to mitogens in humans and animals. Vitamin C also lessens allergic reactions at high doses through inactivating histamine. (29) A 1993 study with 20 healthy adults found that Vitamin C given at a dose of 60 mg/Kg (e.g. 4200 mg Vitamin C for a 70 Kg adult) increased natural killer (NK) cell activity against tumor cells by 129-231%. NK activity peaked 8 - 24 hours post-dose. (30) In a 1997 follow-up study, the same dose of Vitamin C was used in 55 patients suffering toxic chemical exposure, which often decreases NK activity. Vitamin C increased NK activity 300 to 1000 % in 43 (78%) of the test subjects. Lymphocyte proliferation responses to T and B cell mitogens were also restored to normal in the same 78% of subjects. (31) In 1997 Prinz and coworkers reported the effects of 75 days of 1 gm Vitamin C supplementation during the winter season on 25 healthy university students. 20 similar control subjects got no Vitamin C. Serum antibody (IgA, IgM, IgG type antibodies) and complement protein C3 (which reacts with antigen-antibody complexes to stimulate neutrophil/macrophage antimicrobial activity) levels were measured on day 1 and day 75. There was no change in IgA levels in the Vitamin C group, while control IgA levels dropped 15%. For IgG, there was no change for controls, but a 15% increase for the Vitamin C group. For IgM levels, controls dropped 8% while the Vitamin C group rose 20%. For C3, controls lost 10%, while the Vitamin C group increased 15%. This experiment showed Vitamin C's ability to enhance neutrophil/macrophage microbe-killing. (32) In a review of Vitamin C's effect on cold symptom alleviation, H. Hemila noted that there was a 19% decrease in symptom severity in cold studies that used 1 gm Vitamin C/day, with a 29% reduction in symptom severity in studies that used 2 - 4 gm Vitamin C/day. Hemila also commented that "...the diet of our ancestors contained 0.4 2g/day of vitamin C, which indicates that such amounts are not unfamiliar to human physiology, i.e. they are not pharmalogical.... Vitamin C is a cheap and safe nutrient; several of the suspected side effects of fairly large amounts are unfounded.... none of the intervention trials has revealed any significant side effects of the vitamin." (33) In a 1987 review of Vitamin C safety, J.Rivers reports that most of the alleged dangers of Vitamin C, such as B12 destruction, iron overload in healthy people, mutagenicity and oxalate formation, are simply not shown by the evidence. He does caution, however, that chronic stone-formers, patients with kidney impairment or on hemodialysis should not ingest large Vitamin C doses. He also points out that people who are genetically susceptible to iron overload (hemochromatosis and hemosiderosis) may be adversely affected by long-term high dose Vitamin C. (34) The available evidence suggests that for most reasonably healthy adults 2 - 10 gm Vitamin C/day, divided into at least 4 doses, should be a safe and effective immune enhancer. If diarrhea or severe gas develops, reduce dosage. Vitamin E: The antioxidant immunostimulant Vitamin E is the chief fat soluble antioxidant in human tissues - it is the "lipid soluble, chain-breaking free radical scavenger". (35) that protects cell membranes. When Vitamin E sacrifices itself to protect polyunsaturated fats in cell membranes, it becomes the tocopheroxyl free radical. This free radical Vitamin E is then reduced back to Vitamin E by Vitamin C. (35) Thus, Vitamin C and Vitamin E act synergistically to protect membranes from lipid auto-oxidation and play a key role in protecting phagocytes from damage by self-generated free radicals, since immune cells have a high percentage of easily oxidised fatty acids in their membranes (35). Phagocyte membrane auto-oxidation is a major immune problem - so much so that neutrophils typically die from oxidant auto-oxidation after killing just 3 - 20 bacteria. A 1998 study gave 30 women (average age 72) 1000 mg ASC and 200 mg Vitamin E daily for 16 weeks. 10 were healthy controls, 10 suffered from heart disease (CHD) and 10 had major depressive disorder (MDD). The study found a 60 - 70% drop in serum lipid peroxides in the MDD and CHD groups, and significant increases in neutrophil adherence, chemotaxis/migration and phagocytic activity in all 3 groups. The phagocytic index - how many germs a neutrophil can kill before dying itself - rose 260% in the controls, 225% in the MDD group, and 1000% in the CHD group. The vitamins also lowered superoxide production in all 3 groups - a good thing, as aging usually leads to a major increase in superoxide production in phagocytes. (37) Excessive neutrophil superoxide production shortens their germ-killing lives. The study also found a massive increase in lymphocyte proliferation in response to mitogen testing in all 3 groups. There was also a modest drop in serum cortisol in all 3 groups, especially large in the CHD group - cortisol being an immunotoxic stress hormone that often increases with aging. (37) In 1990 Meydani and coworkers gave 32 healthy older adults either placebo or 800 mg synthetic Vitamin E for 28 days. They found that in the Vitamin E group 1) Vitamin E content of plasma, macrophages and lymphocytes was significantly increased; 2) there was a significant increase in delayed type hypersensitivity - a skin test that measures cell-mediated immunity; 3) IL2 production and mitogen response to optimal doses of ConA were increased; and 4) PGE2 (an immunosuppressive prostaglandin) production and plasma lipid peroxides were reduced. The decreased PGE2 production was especially noteworthy, as PGE2 tends to increase in aged

individuals. Lymphocytes from elderly people are more sensitive to the immunosuppressive effects of PGE2. Macrophages from healthy elderly people make more PGE2 than those from healthy young people, and PGE2 suppresses production of IL2, the most critical cytokine for T lymphocyte activity. (38) In a 1998 study on mouse macrophages, Vitamin E was shown to increase macrophage adherence - the first step in macrophage migration to an infection site. Vitamin E also stimulated chemotaxis and random migration of macrophages - the two processes by which they get to infection sites. Vitamin E also significantly increased the macrophage phagocytic index - the ability of macrophages to ingest germs. Since macrophages are necessary to antigenically activate T lymphocytes, this Vitamin E increase in macrophage activity would presumably benefit cell-mediated immunity, as well. (35) A 1991 experiment found that 800 mg synthetic Vitamin E given to healthy people for 60 days before undergoing an "eccentric exercise" test prevented the exercise-induced rise in IL1, a major inflammatory cytokine involved in over-strenuous exercise muscle damage. Vitamin E also reduced IL6 production, a cytokine that suppresses cellmediated immunity. (12) In a 1988 review of Vitamin E safety, Bendich and Machlin looked at all the human double-blind and large population Vitamin E supplementation studies published since 1975. They stated that "... the toxicity of vitamin E is low and ... the vitamin is not mutagenic, carcinogenic, or teratogenic.... few side effects have been reported, even at doses as high as 3200 mg/day (3200 IU/day)". (39) Thus, a daily supplement of 200 - 800 IU natural Vitamin E (as Vitamin E succinate, mixed tocopherols, or d-alpha/gamma tocopherol) is a reasonable, safe, immunoenhancing dose for most people. Vitamin B6: RDA is too low A 1990 study of U.S. vitamin B6 intake found that 71% of men and 90% of women consumed less than the 1980 RDA for B6. (40) Yet even if most people got the RDA for B6 (2 mg), this would not necessarily be enough for optimum immune health, Karl Folkers, M.D., Ph.D., has published a biochemically-based methodology to establish a more realistic RDA for B6. Folkers noted that B6, in its active form of pyridoxal-5-phosphate, is required to activate a blood enzyme known as EGOT. The specific activity (SA) of EGOT could be correlated with varying B6-intake levels. Folkers discovered that a maximally B6-saturated EGOT enzyme SA is approximately 0.7. Folkers tested 17 people who had no overt B6 deficiency symptoms and determined their EGOT SA levels before and after B6 doses of 2, 25 and 50 mg. The initial mean EGOT SA level was 0.35. After 12 weeks of 2 mg B6, the SA level increased only slightly to 0.45. With a dose of 25 mg B6, EGOT SA rose to 0.64, but 6 of 13 subjects at that dose still had SA of only 0.5 - 0.6. At a dose of 50 mg for 7 subjects, every one showed a SA very close to 0.7, the "ideal" level. Folkers' research showed that even for "well" patients a more realistic B6 RDA is 25 - 50 mg. In line with Folkers' ideas, Talbott and colleagues gave 11 elderly people 41 mg B6 daily for 4 months. 4 subjects got placebo. Immune measurements were made in all subjects before and after supplementation. After one and two months, plasma levels of active B6 increased about 500% in the B6 group, with no change in the placebo group. Lymphocyte proliferation in response to three different mitogens increased significantly. T4 helper cells increased in number in the B6 group, but not T8 suppressor cells. "These results suggest that improving B6 status is important in stimulating immunocompetence in the elderly." (42) Folkers and colleagues conducted a study on the effects of CoQ10 and B6 on immune response. 200 mg CoQ10 and 300 mg B6 were given separately or together to 3 groups, ages 30 to 75. The B6-only group had significant increases in T4 helper cells, no change in T8 levels, and a significant increase in the T4:T8 ratio. This represented an increase in cell-mediated immunity. (43) B6 has widespread effects on immune function in animal studies. B6 deficiency leads to thymus atrophy and lymphocyte depletion in lymph nodes and spleen in monkeys, dogs, rats and chickens. (44) In animals B6 deficiency leads to reduced antibody production, delayed type hypersensitivity reaction, T cell cytotoxicity (germkilling), and reduced response of lymphocytes to T cell mitogens (42). Depletion of B6 in humans decreases antibody production and reduces blood lymphocyte levels. (42) B6 is necessary for the production of cysteine, the rate-limiting amino acid for production of glutathione, a critical cell and immune biochemical. Glutathione prevents the activation of nuclear factor kappa B (NFKB) by reducing intracellular oxidant load. NFKB activates inflammatory cytokine production, especially immunosuppressive IL6. (44) A vegetarian diet, typically low in both cysteine and B6, can be expected to be anti-immune health at least through this pathway. B6 dosages of 100 mg or less are generally considered safe. A 50 - 100 mg B6 supplement is thus a reasonable way to increase immunocompetence. B6 is best taken with other B vitamins. CoQ10 or idebenone? Coenzyme Q10 (CoQ10) is absolutely critical to life. No mitochondrial production of ATP bioenergy can be produced without it. (45) And without ATP there is no life. (45) CoQ10 is also an important antioxidant. Lester Packer, a leading antioxidant researcher, believes CoQ10 is one of the 5 main cellular antioxidants that mutually reinforce and regenerate each other. (46) Immune cells generate massive levels of oxidants which often poison themselves and surrounding cells. Also, high oxidant levels lead to increased inflammatory cytokine activity, and excessive inflammatory activity suppresses immunity. (44)

CoQ10 is an effective antioxidant only in its reduced, i.e. non-oxidised form. Weiland and colleagues report that "(idebenone), a synthetic [Co] Q10 derivative, is known to have greater antioxidative capacity than [Co] Q10, which is not restricted to the reduced form of the molecule. In our experiments, idebenone was far more effective than Q10 in preventing oxygen radical-mediated damage to microsome lipid and proteins.... idebenone is nontoxic to humans and has been used successfully in the therapy of patients suffering from a variety of neurological disorders." (47) Mouse macrophage activity was measured in a 1983 study that compared CoQ10 and idebenone. Macrophages taken from control mice, CoQ10-treated mice, and idebenone treated mice were tested for cytolytic (killing), cytostatic (germ-growth inhibiting) and hydrogen peroxide activity. The cytolysis score was 0.9% for the control group, 6% for the CoQ10 group, and 24% for the idebenone group. The cytostasis score was 0 for the controls, 53% for the CoQ10 mice, and 92% for the idebenone mice. Hydrogen peroxide release was 37 for the controls, 360 for the CoQ10 mice, and 211 for the idebenone mice. Note that the higher hydrogen peroxide levels of the CoQ10 mice, lead to less germ killing/inhibition than the lower hydrogen peroxide levels of the idebenone mouse macrophages. This demonstrates the point made earlier that excessive phagocyte oxidant release often impairs germ killing/inhibiting activity. The researchers also reported that idebenone increased antibody-dependent cell cytotoxicity compared to controls, but CoQ10 did not. (48) As mentioned in the B6 section, Folkers tested immune responses to CoQ10 with and without B6. The experimental results showed increased T4 helper cells, no change in T8 cells, and increased T4:T8 ratio in both CoQ10 and CoQ10/B6 subjects. (A seriously decreased T4:T8 ration is one of the main immunologic aberrations in AIDS). In addition, blood levels of the antibody IgG increased in the CoQ10 and CoQ10/B6 subjects. Folkers concluded that: "These increased in IgG and T-4 lymphocytes with CoQ10 and vitamin B6 are clinically important for trials on AIDS, other infectious diseases, and on cancer." (43) A supplement of at least 100 mg CoQ10 and and/or 90 mg idebenone is a safe and useful immune booster. My own immune program includes both CoQ10 and idebenone. Zinc: Thymic rejuvenator Zinc is a trace mineral often in short supply in the diet. As mentioned previously, a 1993 study of elderly adults found their zinc intake 40% below the 1980 U.S. RDA. (15) Bogden and colleagues reported that greater than 90% of healthy elderly subjects had zinc intake below the RDA. (9) Zinc deficiency is hardly a rare phenomenon. Zinc is essential for the integrity of the thymus gland and for cell-mediated immunity. (3) The thymus incorporates zinc into the inactive form of thymulin, a thymic hormone, creating active thymulin (ZnFTS). (3) ZnFTS is necessary for the maturation and differentiation of stem cells into mature T cells. (6) T lymphocyte responsiveness to mitogens is increased by zinc. (6) Mocchegiani and coworkers reported that 90 days of zinc supplementation in mice caused a regrowth of atrophied thymus, with renewal of both hormone-secreting cells and T cell-processing cortex cells. (6) An increase in natural killer cell activity also occurred. Saha and colleagues reported that zinc supplementation of hydrocortisone-treated aged mice augmented T lymphocyte response to interleukins 1 and 2 and several different mitogens an average of 100%. (3) In this experiment zinc did better than injected ZnFTS in aiding T cell activation. Hadden lists the following effects of dietary zinc deficiency on immune function: (Zinc may be properly considered one of the most critical immunonutrients): Boukaiba and co-workers performed a 16 week crossover study with 44 institutionalized elderly adults, using 20 mg zinc/day. The subjects were divided into a lean and average weight group. The zinc supplementation led to a significant increase of active (zinc-bound) thymulin in the lean group, with a smaller increase in the active thymulin level in the average weight group. (9) This was a biologically important result as inactive thymulin increases with age, and inactive thymulin inhibits the activity of zinc-active thymulin. (6) Extremely high zinc doses (300 mg/day) can be immunosuppressive (49), but 50 mg or less daily doses are generally considered safe. A 20 - 50 mg daily zinc supplement as zinc orotate, zinc monomethionine, or zinc ascorbate is a generally safe and useful immune booster. (Ed. - Remember that our T1-Melatomin contains 50 mg zinc per tablet, as well as Melatonin and Selenium). Selenium: IL2 enhancer The trace mineral selenium (Se) is best known for its role in activating the crucial antioxidant enzyme glutathione peroxidase (GSHPx) (50). Se-GSHPx uses glutathione (GSH) to break down hydrogen peroxide into water and oxygen, protecting cells from oxidant molecules that are produced from immune activation. (50) GSHPx activity in liver and plasma and serum is very sensitive to body selenium levels. (50) GSHPx/GSH are key antioxidant factors necessary to minimize the activation of NFKB, the nuclear factor that activates excessive production of oxidants and inflammatory cytokines, which are immunosuppressive at excessive levels. (44) Diminished Sestatus and excessive NFKB activation is a major factor in moving HIV-infected people into full-blown AIDS. (50) In experiments with mice and humans, M. Roy and colleagues found identical results when Selenium (90 mcg/day as sodium selenite for humans) was given. There was a major increase of IL2 receptors on T cells, enhanced nuclear DNA synthesis with "enhanced proliferation and .... the generation of a greater number of cytotoxic lymphocytes within a given cell population after stimulation with antigen" (51) There was a resultant 118% increase in tumor cell destruction by cytotoxic lymphocytes and an 83% increase in natural killer cell - mediated

cytotoxic activity (52). Selenium also up-regulates production of IL2. (50) IL2 is the chief activator of cell-mediated immunity, which declines with aging (15). Thus selenium may play a major role in normalizing the age-associated decline in TH1 immunity. IL8 can be an immunosuppressive cytokine, especially in people with AIDS or chronic lung infections (bacterial infections, pneumonia, tuberculosis). (50) Selenium as Se-GSHPx is inversely correlated with IL8 in serum in both HIV-infected and non-infected persons. (50) SeGSHPx can inhibit IL8 release by endothelial cells. (50) High levels of IL8 were found in tuberculosis patients who died in contrast to those who survived. (50) A 1991 study by Peretz and coworkers with institutionalized elderly subjects found that 100mcg Se/day as Seyeast increased plasma Selenium levels by 85% after two months. By six months, Selenium had increased T cell proliferation in response to PWM mitogen by 138%, to the upper limit for normal healthy adults. (53) Se is a potentially toxic mineral. Selenium expert R. Passwater notes that "organic forms of selenium are toxic at levels in the vicinity of 3,500 micrograms (3.5 milligrams) daily. Inorganic forms of selenium may be toxic at onethird that level." (54) However, intakes up to 200 mcg/day are generally considered safe, and Passwater notes many Japanese average 600mcg daily, and Greenlanders may ingest 1300mcg/day. A supplement of 100-200 mcg Selenium/day, as selenium yeast, selenomethione, or sodium selenite/selenate, should be an excellent booster of cell-mediated immunity which declines with age. Acetyl-L-Carnitine: Not just a nootropic Acetyl L-Carnitine is a nootropic nutrient familiar to life extension enthusiasts. It is used to regenerated agerelated deficits in mitochondrial function, as well as to enhance brain levels of the key neurotransmitter acetylcholine. (55) Yet three recent reports suggest Acetyl L-Carnitine to be an enhancer of cell-mediated immunity as well. Jirillo and colleagues gave either placebo or 2gm Acetyl L-Carnitine/day for 30 days to 20 active pulmonary tuberculosis patients. T cell-mediated antibacterial activity and serum levels of the lymphokine tumor necrosis factor alpha (TNF-A) were evaluated before and after treatment. T cells from the patients were added to tubes containing S. typhi bacteria at 3 different ratios: 1:20, 1:10, 1:5 (T cells: bacteria). Antibacterial activities of placebo and Acetyl L-Carnitine groups were almost identical at day zero. By day 30, the antibacterial activity of the Acetyl L-Carnitine group had increased from 10 (day 0) to 21 at the 1:20 ratio, from 4 to 12 at the 1:10 ratio, and remained the same at the 1:5 ratio. In the placebo group at day 30, activities dropped from 12 to 4 at the 1:20 ratio, from 4 to 0 at the 1:10 ratio, at 4 to 0 at the 1:5 ratio. The authors remark that "The lymphocyte antibacterial activity is a CD4+ [Thelper] and CD8+ [T suppressor and T cytotoxic] T cell function that represents a good index of the host's resistance against invading microorganisms, M. tuberculosis included." (56) There was no increase in serum TNF-A in the Acetyl L-Carnitine group, a positive result as high TNF-A in chronic disease states promotes tissue-wasting and death, and increased antibacterial activity by neutrophils/macrophages can raise TNF-A. The lack of increase of TNF-A in the Acetyl L-Carnitine group showed that it activated cell-mediated immunity and not chronic overactivation of inflammatory neutrophil/macrophage activity. In a 1989 book on stress, immunity and aging, two studies with Acetyl L-Carnitine were included. One study found a reduced decline of macrophage phagocytic and cytotoxic capabilities in aged rats treated long-term with Acetyl L-Carnitine (57) The other study reported an increase in PHA mitogen induced T lymphocyte proliferation in elderly people treated with Acetyl L-Carnitine (58). Immune rejuvenation can now be added to Acetyl L-Carnitine's potential for mitochondrial and neuroendocrine regeneration. 1 gm Acetyl L-Carnitine twice daily is a safe and useful dose for all three. Resveratrol: PGE2 inhibitor Resveratrol is a phenolic compound that contributes to the antioxidant potential of red wine, where transResveratrol concentrations may reach 15 mg/L (59). According to Fremont, major biological activities of Resveratrol include inhibition of membrane lipid peroxidation (important for optimal phagocyte activity), free radical scavenging, alteration of eicosanoid (prostaglandin) synthesis, anti-inflammatory and anticancer activity (59). Trans- Resveratrol in combination with vitamin C and/or E was more effective in protecting cells from oxidant stress than was any of the three antioxidants alone. The results of the experiment showed Resveratrol was not only antioxidant and antimutagen, but could also reduce oxidant-caused cell death (59). Resveratrol was shown to inhibit production of nitric oxide and tumor necrosis factor alpha (TNF-A) by lipopolysaccharide-stimulated Kuppfer cells. Kuppfer cells are macrophages fixed in place in the liver. Their chronic overproduction of No and TNF-A due to chronic infection can cause severe liver damage (59). Perhaps Resveratrol's most important property is its ability to inhibit cyclooxygenase-2 (CoX-2) (59). Prostaglandin E2 (PGE2) is the chief inflammatory prostaglandin. PGE2 is produced from arachidonic acid (a polyunsaturated fatty acid) via the CoX-2 pathway. "Macrophage- and splenocyte-derived PGE2 levels are greatly increased with age. Furthermore, PGE2 favors production of Th2-associated cytokines (IL-4 and IL-5) while suppressing Th1-associated cytokines (IL-2 and IFN-G), a pattern analogous to immune senescence. Inhibition of cyclooxygenase can restore PGE2 levels to normal." (15) In addition, trans- Resveratrol has been shown to modulate the activity of polymorthonuclear leukocytes (PMN) mainly neutrophils. Trans- Resveratrol "interfered with the release of inflammatory mediators by activated PMN...." (59). Excessive release of inflammatory mediators by germ-stimulated neutrophils inhibits cell-mediated immunity

(5,29). In a study using commercial grape juice with trans- Resveratrol added at a level of 4 mg/litre consumption of the beverage by healthy subjects for 4 weeks led to positive effects on platelet aggregation and thromboxane production, compared to no such effect in those drinking the same commercial grape juice without added Resveratrol (59). This experiment proved 1) that trans- Resveratrol is absorbed in biologically active quantities; and 2) the dose of trans- Resveratrol provided by the "spiked" grape juice was only 2 mg - therefore even modest quantities of trans- Resveratrol have significant biological activity. As an immune synergist with C and E, 5 - 40 mg/day of trans- Resveratrol may be a useful part of any immune program. Pyritinol: Pro-immune nootropic Pyritinol, also known as pyrithioxine or dipyridoxine disulphide, is almost identical to vitamin B6, but it has no B6 activity. (60) Pyritinol consists of two pyridoxine sulphide molecules linked by their sulphur atoms. Pyritinol has been used to treat dyslexia, post-stroke states, cerebral trauma, attention deficit disorder, etc. since 1961. (60) Pyritinol has been shown to be a powerful antioxidant, quenching the most toxic free radical, the hydroxl radical, formed through interaction of superoxide and hydrogen peroxide (11): All three of these oxidants are secreted by activated neutrophils and macrophages to kill germs (36). As Pavlik and Pilar remark in their report on Pyritinol's antioxidant activity: "The most dangerous [kind] of oxygen radicals is the hydroxyl radical that can attack proteins, lipids, nucleic acids and actually, almost any molecule of a living cell." (11): Unfortunately, the human body has no enzymatic defense against hydroxyl radicals, as it does for superoxide and hydrogen peroxide. Vitamin C and cholesterol are the two main hydroxyl quenchers for humans. (60) A 1991 report cites oxygen radicals as the main cause of damage in viral influenza in mice, and points out that in viral disease such as viral hepatitis, AIDS, dengue fever, measles and herpes diseases, the virus damage to cells was minimal. The main damage to cells is actually caused by the oxygen radicals released by activated neutrophils and macrophages. (61) The researchers examined neutrophils/macrophages in influenza-infected mouse lungs and found an 800% increase in superoxide production compared to non-infected control mice. The researchers noted that superoxide is not particularly toxic to many cells and pathogens, and that it was more likely the hydroxyl radicals generated from superoxide/hydrogen peroxide release by the lung neutrophils/macrophages that was causing the lung damage. (61) Thus, Pyritinol, along with vitamin C, may have a useful role in fighting viral disease by quenching hydroxyl radicals. A 1993 Pyritinol study found that Pyritinol enhanced neutrophil mobility (62). Not only is the neutrophil ability important for getting them to infection sites, it's important to help them survive and leave infection sites. Anderson remarks that "... antioxidants [that quench hydroxyls] such as ascorbate [and Pyritinol] may prevent immobilization of inflammatory cells [neutrophils/macrophages]... by inhibiting auto-oxidation of the cell membrane. These cells, especially neutrophils, therefore may enter the inflammatory zone, phagocytose [eat germs] and depart without contributing to the development of chronic inflammation." (29) Normally, neutrophils are quickly immobilized at infection sites in massive numbers (they comprise 60% of white blood cells), where they die from self-poisoning by their own secreted oxidants, then becoming (collectively) the pus that forms in wounds (36). Thus vitamin C and Pyritinol have the potential to increase the useful germ killing power of neutrophils, while reducing the inflammatory damage they inflict on wound sites or inflamed tissue (as in rheumatoid arthritis, which Pyritinol is used to treat. (60) Pyritinol is a very well tolerated drug, with only occasional skin rash or gastric upset noted as side effects. (60) Pyritinol should only be used with physician monitoring by rheumatoid arthritis sufferers, as there are occasionally side effects from Pyritinol in rheumatoid arthritis patients. (60) A daily dose of 100-300 mg Pyritinol should serve as a generally safe and effective antioxidant, nootropic immune booster. Thymus extract: Tonic for the aging thymus gland The thymus gland is the master gland for cell mediated immunity. T lymphocytes are processed in the thymus cortex to mature them into the various T cell types, and to destroy T cells that might attack the body (13). The thymus gland also secretes various hormones, including zinc-thymulin, thymosin, thymopoietin, and thymus humoral factor (63). Unfortunately, the thymus tends to atrophy early in life, usually by age 20, and "with advancing age, the thymus turns from a well-structured organ to a few sparse lymphoid lobules within a fat tissue." (6). As noted earlier, vitamin A can help regrow thymus structure, and zinc can re-activate zinc-thymulin secretion. Thymic extracts may serve to regenerate thymic structure and replace the variety of thymic hormones, since properly prepared thymus extracts contain the whole range of the polypeptide hormones. Thymus gland extracts (TGE) have shown a broad range of immune-modulating activity. TGE has increased IL2 receptors on mitogen-stimulated T cells, a necessary step in rapid lymphocyte proliferation and activation to fight invading germs (16). TGE has reduced autoimmune reactions, clinically and experimentally, such as occur in rheumatoid arthritis. (17) TGE has prevented the bone marrow injury and subsequent reduction in white and red blood cell production frequently produced by x-ray or chemotherapy cancer treatment. (17) TGE has reduced the "allergy antibody" IgE in patients suffering allergic rhinitis, asthma and atopic dermatitis. (17) TGE has normalized T4:T8 ratios in subjects suffering various diseases, bringing low ratios up toward normal (2:1), and high ratios down toward normal. (64) Pharmaceutical-grade oral TGE supplements are normally standardized to contain polypeptides with molecular weights under 10,000. The various major thymic hormones range in molecular weight from 860 (thymulin) to 5600 (thymopoietin). Although one might expect that TGE polypeptides would be destroyed during digestion, the large number and broad range of double-blind experimental and clinical studies using TGE has shown they are effectively absorbed (see ref. 17 for a detailed list of references). It has been known since the 1970s that significant quantities of various proteins, such as wheat gliadin, milk casein, ferritin, hemoglobin, and milk

immunoglobins routinely survive digestion and enter the body - and even the brain-intact, due in part to the pioneering research of Hemmings (65) and Zioudrou and colleagues. (66) Thym-Uvocal is a pharmaceutical-grade TGE. The active polypeptides found in Thym-Uvocal are obtained by a selective, multi-stage biotechnology process. The starting material is thymus glands from strictly selected and healthy calves. (Ed.-of Australian origin). Tissue from any given animal is used only after a veterinary physician has examined the live animal and issued a certificate of good health. Before the tissue is processed, histological and bacteriological tests are performed. During the multi-safe processing, proteins and prohormones in the tissue are enzymatically cleaved to short-chain pharmacologically active oligopeptides. Filtration and special heat treatment ensure the inactivation and removal of any micro-organisms. The controlled and reproducible manufacturing process produces and activation and concentration of the desired low molecular weight peptides. Injectable Thym-Uvocal is standardized to be under 2000 molecular weight, thus minimizing the risk of allergic reaction, while oral Thym-Uvocal has a molecular weight under 10,000. Since animal experiments and human research have found no single thymic hormone to be capable of performing all the immune-optimizing functions induced by the whole family of thymic hormones, a pharmacologically balanced thymus peptide mixture is both more natural, and more likely to be safe and effective, than any one thymic hormone. Thym-Uvocal has been in clinical use in Europe since 1976. The German company Mulli which produces Thym-Uvocal has published research, as well as in-house and physician anecdotal evidence to support the safety and efficacy of Thym-Uvocal (67). Two to four capsules taken once or twice daily on empty stomach, is a typical dose. DHEA: Cell mediated immune booster DHEA (dehydroepiandrosterone) is an adrenal steroid hormone that decreases radically with age. DHEA levels peak around age 25, decrease 60% by age 50-60, and drop to 20% of maximum by age 70 (68). DHEA is antiglucorticoid (anti-cortisol), due to its down-regulation of glucocorticoid (GC) receptors (69). Since GCs are immunosuppressive (4,70,71), DHEA's immunostimulant role is due at least in part to its counter-regulatory action opposing GC action. Thus Khorram and colleagues note: "The 4-fold increase in DHEAS/cortisol ratio in response to a 50 mg dose of DHEA as seen in our age-advanced male cohort may thus be viewed as favorable adrenal hormone milieu for up-regulating immune function ...." (4) Both human and animal studies show similar effect of DHEA in boosting immune function. Perhaps the most important benefit of DHEA is increasing IL2 output in aging individuals. Khorram and co-workers reported a 50% increase in IL2 output in mitogen-stimulated T cells in DHEA-treated aged men (4). IL2 is the basis for the cellmediated TH1 type immunity that declines with age (69). Suzuki and colleagues also noted the DHEA-stimulated increase in IL2 production, with increased cytotoxic effect, in human T cells treated with typical youthful blood of DHEA (72). They also point out that "...DHEA represents the only naturally occurring hormone to up-regulate IL2 secretion." (72) DHEA has also prevented thymus gland involution in mice treated with the synthetic GC dexamethasone. (70) DHEA has increased both numbers and cytotoxic activity of natural killer cells in humans. (4,73) Administration of 200 mg/day of DHEA for 3-6 months significantly reduced corticosteroid requirements in patients with lupus erythematosus. (69) Another major DHEA immune effect involves decreasing IL6. IL6 tends to promote inflammatory, degenerative or autoimmune diseases such as Alzheimer's disease, atherosclerosis, Parkinson's disease, leukemias, osteoporosis and lupus. (69, 74) IL6 levels tend to increase dramatically with age, inversely to falling DHEA levels. (69,74) IL6 is a type TH2 helper cell interleukin which tends to suppress the age-decreased TH1 helper cell-mediated immunity. (69) Straub and colleagues found that youthful DHEA levels suppressed IL6 secretion by human T cells. (74) 7-keto DHEA may be a more effective form of DHEA for immune benefit, especially for women. When Casson and co-workers gave postmenopausal women 50 mg DHEA for three weeks, they observed a dramatic increase in natural killer cell cytotoxicity, but a slight decrease in CD4+ TH1 helper cells (73), contrary to the effect observed in aged men (4). DHEA can be converted to androgens, such as testosterone and dihydrotestosterone, and androgens decrease the important CD4+(T helper): CD8+ (T suppressor) ratio (4). Yen and co-workers noted a 200-400% increase in circulating androgens in women given 50-100 mg DHEA/day (75). 7-keto DHEA is naturally formed from DHEA in human skin, and cannot be converted to androgens. (76) 7-keto DHEA has been shown in pilot studies at the University of Wisconsin to more effectively augment human T cell IL2 production than DHEA, to increase antibody production in mice given trivalent influenza vaccine better than DHEA, and to increase CD4+T helper cells, CD8+ T suppressor cells, and total white cell counts in primates infected with simian immunodeficiency virus. (77) A reasonable DHEA dose for women would be 5-25 mg/day, with 25-50 mg/day being a more suitable male dose. 7-keto DHEA doses of 12.5-50 mg for women, or 25-100 mg for men, would also be a reasonable immuneboosting doses. Melatonin: More than a sleeping pill Melatonin is a hormone produced by the pineal gland (a small gland inside the brain) that decreases with aging. Melatonin's most widely known role is in regulating the sleep-wake cycle, and has been widely used as a sleeping pill since the 1990s. Melatonin secretion peaks around age 10, drops to half its peak level by age 25, one-fourth

peak level by 35, and drops to 10% peak level by age 50. (78) Melatonin is a powerful hydroxyl radical scavenger, and is more than twice as effective as vitamin E at scavenging peroxyl radicals. (79) Various studies in humans and animals have shown a powerful pro-immune effect, especially in stressed, aging or diseased animals. Lissoni and colleagues gave 3,000,000 IU IL2 by subcutaneous injection for 4 weeks to 130 advanced cancer patients. 90/130 got 40 mg melatonin as well. "The mean increase in T lymphocytes, natural killer cells, and eosinophils was significantly higher in patients treated with IL-2 plus melatonin than in those who received IL2 alone." (80) In cancer patients with metastatic solid tumors, melatonin administration increased the T4:T8 cell ratio. (82) In a study with human T helper cells, Garcia-Maurino and co-workers showed that "...melatonin is able to activate human Th1 lymphocytes by increasing the production of IL2 and IFN-G [interferon] in vitro. Th2 cells appear not to be affected by melatonin.... The results suggest that melatonin may be involved in the regulation of human immune function by modulating the activity of Th1 cells and monocytes ...." (81) When Caroleo and colleagues injected melatonin into mice immunodepressed by ageing or cyclophosphamide treatment, they found it enhanced antibody response, as well as increased IL2 production and T helper activity (82) Mocchegiani and co-workers gave melatonin to aging mice. They noted that "chronic melatonin treatment ... of old mice restores a number of age-associated immune alterations. In particular, at thymic level, regrowth of the organ is observed .... Recovery of the reduced thymic endocrine activity, as demonstrated by the restoration to normal values of both thymulin plasma [levels] and number of thymulin-secreting cells is also observed. At peripheral level, corrections of the low number of peripheral blood lymphocytes ... and, at least, partial reconstitution of responsiveness to T-cell mitogens are observed."(83). Zhang and colleagues reported two studies in 1998 and 1999 combining DHEA and melatonin. In their 1998 study they reported that either melatonin alone, or DHEA plus melatonin, significantly increased B cell proliferation in old female mice. They also observed that DHEA and melatonin, alone or in combination, significantly increased the TH1 cytokines IL2 and interferon, while simultaneously decreasing the TH2 cytokines IL6 and IL10. "This shift in cytokines results in a regulation of immune function typically seen in the young, thereby normalizing humoral and cellular immunity." (79) In their 1999 study, Zhang and colleagues worked with female mice infected with a leukemia retrovirus that induced mouse AIDS. They observed that the retrovirus infection reduced the release of TH1 cytokines, stimulated the release of TH2 cytokines, increased liver lipid peroxidation, and caused a vitamin E deficiency. Treatment with DHEA or melatonin, alone or in combination, "...largely prevented the reduction of B-and T-cell proliferation as well as of Th1 cytokine secretion caused by retrovirus infection. Supplementation also suppressed the elevated production of Th2 cytokines stimulated by retrovirus infection. DHEA and melatonin simultaneously reduced hepatic lipid peroxidation and prevented vitamin E loss." (84) Zhang reported that DHEA plus melatonin was more effective in preventing the retrovirus-induced immune dysfunction than either DHEA or melatonin alone. Given the steep age decline of melatonin, as well as its powerful antioxidant and immune-enhancing effects, melatonin combined with DHEA or 7-keto DHEA represents a core immune supplement. 11/2-6 mg at bedtime is a typical reasonable dose. Melatonin expert P. Rozencwaig believes that although melatonin is generally non-toxic, certain people should not use melatonin. His list includes pregnant women, women trying to get pregnant; manic depressives or schizophrenics; normal children; severe autoimmune disorder cases (rheumatoid arthritis, lupus, etc.); and those with immune cancers such as leukemia or lymphoma. (85) Conclusion Either we must negate entropy, or entropy will negate us! A weak immune system is typical of "normal' old age, and leads to the sickness, debility and death that is typical of "normal" old age. The 14 supplements discussed in this article provide us with the ammunition needed to vanquish the microbial and cancerous agents of entropy, as much as it's in our power, and to maintain a youthful (powerful and effective) immune system well into old age. You don't have to be a victim - the choice is yours! And since each of the supplements has many pro-immune effects, even a small subset of the 14, such as DHEA, melatonin, and zinc, may provide significant immune benefits. Take as many of the 14 supplements as you see fit - they all provide general health and anti-ageing benefits, beyond their immune enhancing effects. The Immune Program at a glance Vitamin A 5000-20,000mg IU Breakfast or lunch 5000 IU (Women pregnant or attempting pregnancy) Vitamin C 500-2000mg 4-6 times daily Vitamin E 200-800 IU Daily with fat-containing meal Vitamin B6 25-50mg Breakfast and lunch (take with 10-100mg B1, B2, B3, B5)

CoQ10 100-200mg With fat-containing breakfast or lunch Idebenone 30-60mg Breakfast and lunch Zinc 20-50mg Breakfast or lunch Selenium 100-200mcg Breakfast or lunch Acetyl-L-carnitine 1000mg AM and PM empty stomach Resveratrol 5-20mg Breakfast and lunch Pyritinol 100mg 1-3 times daily Thym-Uvocal 2-4 caps Once or twice daily - empty stomach 7-Keto DHEA 12.5-50mg (women) Upon arising 25-100mg (men) Upon arising Melatonin 11/2-6mg Bedtime References 1. Chandra, R.K (1996) "Nutrition, immunity and infection" Proc Natl Acad Sci USA 93: 14304-07. 2. Chandra, R.K. (1997) "Nutrition and the immune system" Am J Clin Nutri 66: 460s - 3s. 3. Saha, A. et al (1995) "Zinc induces thymulin secretion from human thymic epithelial cells in vitro and augments splenocyte and thymocyte responses in vivo" Int J Immunopharmac 17: 729-33. 4. Khorram, O. et al (1997) "Activation of immune function by dehydroepiandrosterone (DHEA) in age-advanced men" J Geront 52A: M1-M7. 5. Maydani, S.N. et al (1990) "Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects" Am J Clin Nutr 52: 557-63. 6. Mocchegiani, E. et al (1995) "Reversibility of the thymic involution and of age-related peripheral immune dysfunctions by zinc supplementation in old mice" Int J Immunophermac 17: 703-18. 7. Lesourd, B.M. (1997) "Nutrition and immunity in the elderly: modification of immune responses with nutritional treatments" Am J Clin Nutr 66: 478s-84s. 8. Hadden, J.W. (1995) "Editorial: The treatment of zinc deficiency is an immuntherapy" Int J Immunopharmac 17: 697-701. 9. Boukaiba, N. et al (1993) "A physiological amount of zinc supplementation: effects on nutritional, lipid, and thymic status in an elderly population" Am J Clin Nutr 57: 566-72. 10. Elferenk, J. and deKoster, B. (1993) "Differential stimulation of neutrophil functions by pyrithioxine" Int J Immunopharmac 15: 641-46. 11. Pavlik, A. and Pilar, J. (1989) "Protection of cell proteins against free-radical attack by nootropic drugs" Neuropharmacol 28: 557-61. 12. Meydani, S.N. et al (1992) "Influence of vitamins E and B6 on immune response" Ann NY Acad Sci 669: 12540. 13. Guyton, A. and Hall, J. Textbook of Medical Physiology. Philadelphia: W.B. Saunders, 2000. Ch. 34. 14. Keith, M. and Jeejeebhoy, K. (1997) "Immunonutrition" Bailliere's Clin Endocrin Metab 11: 709-38. 15. High, K.P. (1999) "Micronutrient supplementation and immune function in the elderly" Clin Infec Dis 28: 71722. 16. Stein, M.B. et al (1986) "Modulation of interleukin 2 receptor expression on normal human lymphocytes by thymic hormones" Proc Natl Acad Sci USA 83: 6107-11. 17. Kouttab, N.M. et al (1989) "Thymomodulin: biological: properties and clinical applications" Med Oncol & Tumor Pharmacother 6: 5-9.

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