Stephen Holt MD-A4M ImmuneSenesense and Anti-Aging AUG07

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



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.



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.



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



Cells of the Immune System, Reproduced from Vanderhaeghe et al



Immune Cells, Reproduced from Cohen, I.R. Tending Adam¶s Garden



Immune Molecules, Cohen, I.R., Tending Adam¶s Garden



Immune Cell, Functional Directions, Cohen, I.R., Tending Adam¶s Garden



End Organ Distribution: Cohen, I.R., Tending Adam¶s Garden



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.



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



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



IMMUNESENESCENCE: HUMORAL IMMUNIT Y

Antibody specificities change fromforeign to autoantigens

Antibody isotypes change from IgG toIgM

Antibody affinities change from high tolow



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.



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.



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.



Inextricable linkage between malnutrition and aging on immunefunction, Lesourd, B., 1995



Infection-related morbidity is decreased by supplementationwith vitamins and minerals, Chandra, R.K., Lancet, 1992



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?



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



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?



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



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.



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



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



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.



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



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



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



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

Stephen Holt MD-A4M ImmuneSenesense and Anti-Aging AUG07

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