stephen holt md-a4m immunesenesense and anti-aging aug07
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8/8/2019 Stephen Holt MD-A4M ImmuneSenesense and Anti-Aging AUG07
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Immune SenescenceandAnti-Aging Initiatives
Stephen Holt MD, LLD (Hon.) ChB., PhD, DNM,FRCP (C), MRCP (UK), FACP, FACG, FACN,
FACAM, OSJDistinguished Professor of Medicine, NYCPM,
Scientific Advisor, Natural Clinician LLC
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THE IMMUNE SYSTEM: CONCEPTS 1
Immune function is a complex harmony of events
involving the interaction of immune competent cells withmost body structures.
Simplistic views of immunity, involving the concepts of depressed or exaggerated immune functions, hasdominated medical thought.
Research has underscored the importance of changes inthe direction or quality of immune responses e.g.autoimmunity.
Alternative medicine has obsessed about the role of NKcell function in disease management, used as a key
platform to promote the sale of dietary supplements andimmune-stimulating nutraceuticals.
It is relevant to discuss immune modulation rather than just quantitative changes in certain immune functions.
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THE IMMUNE SYSTEM: CONCEPTS 2
The immune system is cognitive.
The immune system can see both whatis right and what is wrong in the body.
The immune system interprets events,
evaluates results and makes decisionsabout how to act.
The immune system decides how to geta job done.
Maintenance of immune functionsupports its housekeeping programs of Recognition, Cognition and Action.
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Make cells grow and replicate
Make cells die
Make cells move Influence cell differentiation,
turning genes ³on and off´
Modify tissue support andsupply systems e.g. scaffoldsand blood vessel growth.
FUNCTIONS OF IMMUNE AGENTS
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Cells of the Immune System, Reproduced from Vanderhaeghe et al
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Immune Cells, Reproduced from Cohen, I.R. Tending Adam¶s Garden
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Immune Molecules, Cohen, I.R., Tending Adam¶s Garden
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Immune Cell, Functional Directions, Cohen, I.R., Tending Adam¶s Garden
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End Organ Distribution: Cohen, I.R., Tending Adam¶s Garden
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SUMMARY OF CONCEPTS: HARMONY OF LIFE
Immune Function has complex cascades of
events involving massive highways of intercommunication The communicators are immune cells thatspeak to each other and the body, using chemical
messengers Qualitative changes in immune operationsmust be considered within the cognitive immunesystem Complex immune functions require multi-pronged approaches to change overall functions Using a unitary approach to change immunefunction may be quite naïve e.g. a single drug.
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CONCEPTS OF IMMUNE DEFICIENCY
Primary: variable deficiencies of Tor B cell function, phagocytosis or
complement pathways,
congenital.
Secondary: mainly affecting
phagocytic and lymphocyte
function resulting from HIV,malnutrition, aging, drugs etc
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IMMUNESENESCENCE
Striking changes in immune status with age
Reduced response to vaccination andincreased infections
Involution of the thymus with loss of T cell
education. Decreased NK cell function. Memory T cells (CD45R0+) increase
Limited number of naïve T cells
A restricted repertoire with lack of clonalexpansion of T cells, diminishing cell-mediated immunity
Reductions in humoral immunity
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IMMUNESENESCENCE: HUMORAL IMMUNIT Y
Antibody specificities change fromforeign to autoantigens
Antibody isotypes change from IgG toIgM
Antibody affinities change from high tolow
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NATURAL THERAPEUTICS FORIMMUNE FUNCTION
The use of drugs or vaccines to stimulate
immunity possess disadvantages and limitations.
Humankind is constantly challenged by
infectious disease and environmental insults to
immunity.
The mainstay of natural approaches for the
modulation of immune function must involve
increasing an individuals immune capabilities and
avoiding damage to immune function.
Rational use of evidence-based nutrients, herbs
or botanicals that modulate immune function.
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KEY PROMOTERS OF IMMUNEFUNCTION
Nutritional status: antioxidants, vitamins,minerals, fat ratios in the diet,nutraceuticals.
Exercise: ³A Double-edged Sword´
Stress reduction, healing attitudes,interpersonal relationships etc.
Avoidance of environmentalcircumstances that damage immunity,
including prevention of microbial infection. Correction of common ³states´ associated
with impaired immunity e.g. MetabolicSyndrome X and Type 2 Diabetes.
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IMMUNESENESCENCE Impaired immunity with age promotes disease e.g.
infection, cancer and overall debilitation.
Micro or macronutrient deficiencies impair immune
function and their correction can promote balanced
immunity.
Interrelationships among nutrition, immunology and aging
are strong, but cross-over among these disciplines hasbeen slow to evolve.
Immune deficiency and dysregulation both occur in
Immunesenescence.
Age associated increase in the presence of
autoantibodies are well recognized and they depressantibody response to nominal antigens e.g. microorganisms
65% of individuals >65y have antibodies to one or more
autoantigens e.g. anti-DNA, anti-thyroglobulin, anti-IgG
(rheumatoid factor) etc.
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Inextricable linkage between malnutrition and aging on immunefunction, Lesourd, B., 1995
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Infection-related morbidity is decreased by supplementationwith vitamins and minerals, Chandra, R.K., Lancet, 1992
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NUTRITIONAL AND NUTRACEUTICAL APPROACHESFOR IMMUNE FUNCTION
Low fat diets link with calorie reduction and longevity and the role
of fat in the inhibition of CD4 cells and NK cells
Antioxidants
Minerals: ³A Double-edged Sword´ e.g. zinc deficiency weakens
immune responses and promotes atrophy of the thymus gland, but
excess zinc intake decreases cell-mediated immunity in the elderly.Vitamins: multiple benefits
Antioxidants: multiple benefits
Nutraceuticals, many variable benefits on different aspects of
immune function e.g. mushrooms and their fermentation products,
garlic, echinacea, ginseng, astragalus, teas, turmeric, ginger.
Popular nutraceuticals: MGN-3, BRM-4, ImmPower, Peak Immune
4, Epicor, AHCC, BioDefense, Clinical Immune Modulator etc.
(trademarks of different companies who produce nutraceutical
products for ³immunity´) Synergy is better?
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COX-2 is involved in inflammatory conditions and cancer.
COX-2 can be inhibited by natural products at severaldistinct levels: ± Gene expression (mRNA production) ± Translation (mRNA Protein) ± Enzyme function (prostaglandin production by COX-2)
Synergistic COX-2 inhibition
R esting cell
(no COX-2)
COX-2 mRN A
expression
COX-2 enzyme
production
Prostaglandin
H2/G2 secretion
Lonicera japonica flower Curcumin
Resveratrol
COX-2Inhibition by:
E. Augustifolia root;Phycocyanin from
cyanobacteria
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COMPARISON OF IMMUNE STIMULATINGPROPERTIES OF NATURAL PRODUCTS
Hypotheses to be tested1. Complex cascades of immunity are best
approached in natural medicine by complexmixed formulations of natural agents that havean evidence-base for immune stimulation or
modulation in different areas of immunefunction ± inferred from the complexity of immune cascades.
2. Can the composition of a ³manufacturedsupplement´ (off the shelf) result in the clinical
or laboratory outcome that may be described inliterature that is applied to the marketing andpromotion of the specific immune supplement?
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THE STUDY
In Vitro and Limited In Vivo Observationson the Ability of Two ³Off the Shelf´ DietarySupplements to Alter Natural-Killer CellFunction (NK Cells) and Other Immune
Functions
Independent Laboratory Studies by Gitte S.
Jensen, Aaron N. Hart, sponsored in part byNatural Clinician LLC, New Jersey
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COMPARISON OF IMMUNE STIMULATINGPROPERTIES OF NATURAL PRODUCTS
Method1. Independent in vitro and limited in vivo comparisons of
immune effects of a complex botanical formula (ClinicalImmune Modulator, Natural Clinician LLC) vs. a moresimple natural preparation of fermented mushrooms
(MGN-3 or BRM-4, Daiwa, Japan), containing modifiedarabinoxylan with shitake mushroom derivatives.
2. Products purchased in finished manufactured form3. FDA actions were directed at the marketers of MGN-3
concerning ³treatment claims´, ³making an evaluationof such claims highly relevant´.
4. Estimates are that annual sales of MGN-3 exceeded $47million in retail or professional sales, implying that thisproduct was the most popular ³professional´supplement ever used for the nutritional support of immune function.
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THE TWO PRODUCTS TESTED
MGN-3 (BRM-4): A fermentation productresulting from the enzymatic modification of rice bran with an extract from the mycelium of Shiitake mushroom (Lentinus edodes).
Clinical Immune Modulator
(Biodefense®): A complex nutrient andbotanical formula, utilizing evidence-basedreagents including: Andrographis paniculata,Vit. C, Green Tea, Turmeric, E. senticosus,Zn, Grape seed extract, Ashwangandha,
Oregon Grape, Shiitake mushroom,Echinacea purpurea, Goldenthread root, AloeVera, Garlic, Astragalus, Ginseng Panax,Goldenseal Root, Coriolus mushroom, AHCC,Saccharomyces
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Results1. Culturing human lymphocytes in the presence of extracts of
Clinical Immune Modulator was found to be a potent activator of NK cells (induction of CD69 on almost 100% of peripheralblood NK cells). MGN-3 (BRM-4) produced a weaker activation of NK cells in vitro.
2. Comparisons of serial dilutions of Clinical Immune Modulator vs. MGN-3 (BRM-4) showed that the induction of the CD69 NKactivation required up to 100 fold higher concentrations of MGN-3 extract to produce the same effects as the extracts of Clinical Immune Modulator.
3. Clinical Immune Modulator altered responses to T cellmitogens.
4. MGN-3 (BRM-4) appeared to be able to activate a subset of NK cells but these cells did not express the CD25 marker andinduction of Interferon Gamma was not observed with MGN-3(BRM-4), questioning earlier published data on MGN-3 (BRM-4), used in material to promote the sale of MGN-3 (BRM-4).
Comparison of Immune Stimulating Properties of Natural Products
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Untreated MGN-3 CIM
Activated NK cells Activated NK cells Activated NK cells
Results of CD69 marker expression in response to extracts of the two test substances. Clinical Immune Modulator was a
stronger activator of NK cells, based on dry weight estimates,the complex botanical formula was approximately 50 foldmore efficient.
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Results of CD69 marker expression in response to extracts of thetwo test substances. Clinical Immune Modulator was a stronger activator of NK cells, based on dry weight estimates, the complexbotanical formula was approximately 50 fold more efficient.
NK cell activation
0
5
10
15
20
25
0.2 2 20 200
grams/liter
CIM
NK cell activation
MGN-3
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Results show relative changes in the amount of NK cells in the bloodcirculation after consumption in a human subject. A reduction in NK
cells in the blood is suggestive of increased immune surveillance(trafficking of NK cells to tissue).
Both test products induced similar levels of NK cell trafficking.However, the activation status of NK cells was increased by CIM butdecreased by MGN-3.
NK cells in circulation
0.6
0.65
0.7
0.75
0.8
0.85
0.9
0.95
1
1.0 5
0 2 4 2 4
Hours after consumption of test product
Activation status of circulating NK cells
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
0 2 4 24
Hours after consumption of test product
In vivo effects of test products
MGN-3
MGN-3
CIM
CIM
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Under the conditions of this study,previously reported substantialactivation of NK cells was not apparentwith MGN-3 (BRM-4) off-the-shelf.
In direct comparison with MGN-3, thecomponents of Clinical ImmuneModulator were highly able to promoteNK activation.
The composition of Clinical Immune
Modulator appears to be moreversatile and powerful at modulatingimmunity in comparison with MGN-3(Lane Labs, NJ).
COMPARATIVE STUDY CONCLUSIONS
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Immunesenescence involves more than immunedeficiency, it involves misdirection of immuneresponses and other qualitative changes in immunity.
The contents of a dietary supplement may not be thesame as the material that may have been tested tosupport the sale of a specific, branded dietarysupplement.
Manufacturers of nutraceuticals must provide data to
support their product use that is specific to the productpresented ³on the shelf.´ The popular use of AHCCmay not always fulfill these criteria, especially if thereare different types of AHCC in use?
This presentation supports the notion that goodnutrition or complex lifestyle and nutritionalinterventions will benefit immune function, especially inthe elderly.
Use of complex botanical herbal of nutrient formulaewith wide ranging effects on immune function may workin a more powerful and versatile manner on immunefunction, in comparison with simpler preparations.
CONCLUSIONS