Immune Senescence

and
Anti-Aging Initiatives

Stephen Holt MD, LLD (Hon.) ChB., PhD, DNM,

FRCP (C), MRCP (UK), FACP, FACG, FACN,
FACAM, OSJ
Distinguished 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 with
most body structures.
• Simplistic views of immunity, involving the concepts of
depressed or exaggerated immune functions, has
dominated medical thought.
• Research has underscored the importance of changes in
the direction or quality of immune responses e.g.
autoimmunity.
• Alternative medicine has obsessed about the role of NK
cell function in disease management, used as a key
platform to promote the sale of dietary supplements and
immune-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 what
is right and what is wrong in the body.
• The immune system interprets events,
evaluates results and makes decisions
about how to act.
• The immune system decides how to get
a job done.
• Maintenance of immune function
supports its housekeeping programs of
Recognition, Cognition and Action.
 FUNCTIONS OF IMMUNE AGENTS

• Make cells grow and replicate

• Make cells die
• Make cells move
• Influence cell differentiation,
turning genes “on and off”
• Modify tissue support and
supply systems e.g. scaffolds
and blood vessel growth.
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 that
speak to each other and the body, using
chemical messengers
• Qualitative changes in immune operations
must be considered within the cognitive immune
system
• Complex immune functions require multi-
pronged approaches to change overall functions
• Using a unitary approach to change immune
function may be quite naïve e.g. a single drug.
CONCEPTS OF IMMUNE DEFICIENCY

• Primary: variable deficiencies of T

or 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 and
increased 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 clonal
expansion of T cells, diminishing cell-
mediated immunity
• Reductions in humoral immunity
IMMUNESENESCENCE: HUMORAL IMMUNITY

• Antibody specificities change from

foreign to autoantigens

•Antibody isotypes change from IgG to

IgM

•Antibody affinities change from high to

low
 NATURAL THERAPEUTICS FOR
IMMUNE 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 IMMUNE
FUNCTION
• Nutritional status: antioxidants, vitamins,
minerals, fat ratios in the diet, nutraceuticals.
• Exercise: “A Double-edged Sword”
• Stress reduction, healing attitudes,
interpersonal relationships etc.
• Avoidance of environmental circumstances
that damage immunity, including prevention
of microbial infection.
• Correction of common “states” associated
with impaired immunity e.g. Metabolic
Syndrome 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 has
been slow to evolve.
• Immune deficiency and dysregulation both occur in
Immunesenescence.
• Age associated increase in the presence of
autoantibodies are well recognized and they depress
antibody 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 immune
function, Lesourd, B., 1995
Infection-related morbidity is decreased by supplementation
with vitamins and minerals, Chandra, R.K., Lancet, 1992
NUTRITIONAL AND NUTRACEUTICAL APPROACHES
FOR 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: “A 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 “immunity”) Synergy is better?
 Synergistic COX-2 inhibition
• COX-2 is involved in inflammatory conditions and cancer.

• COX-2 can be inhibited by natural products at several

distinct levels:
– Gene expression (mRNA production)
– Translation (mRNA  Protein)
– Enzyme function (prostaglandin production by COX-2)

Resting cell COX-2 mRNA COX-2 enzyme Prostaglandin

(no COX-2) expression production H2/G2 secretion

COX-2 Lonicera japonica flower E. Augustifolia root;

Curcumin Phycocyanin from
Inhibition by:
Resveratrol cyanobacteria
 COMPARISON OF IMMUNE STIMULATING
PROPERTIES OF NATURAL PRODUCTS
Hypotheses to be tested
1. Complex cascades of immunity are best
approached in natural medicine by complex
mixed formulations of natural agents that have
an evidence-base for immune stimulation or
modulation in different areas of immune
function– inferred from the complexity of
immune cascades.
2. Can the composition of a “manufactured
supplement” (off the shelf) result in the clinical
or laboratory outcome that may be described in
literature that is applied to the marketing and
promotion of the specific immune supplement?
 THE STUDY
In Vitro and Limited In Vivo Observations
on the Ability of Two “Off the Shelf” Dietary
Supplements to Alter Natural-Killer Cell
Function (NK Cells) and Other Immune
Functions

Independent Laboratory Studies by Gitte S.

Jensen, Aaron N. Hart, sponsored in part by
Natural Clinician LLC, New Jersey
COMPARISON OF IMMUNE STIMULATING
PROPERTIES OF NATURAL PRODUCTS
Method
1. Independent in vitro and limited in vivo comparisons of
immune effects of a complex botanical formula (Clinical
Immune Modulator, Natural Clinician LLC) vs. a more
simple natural preparation of fermented mushrooms
(MGN-3 or BRM-4, Daiwa, Japan), containing modified
arabinoxylan with shitake mushroom derivatives.
2. Products purchased in finished manufactured form
3. FDA actions were directed at the marketers of MGN-3
concerning “treatment claims”, “making an evaluation
of such claims highly relevant”.
4. Estimates are that annual sales of MGN-3 exceeded $47
million in retail or professional sales, implying that this
product was the most popular “professional”
supplement ever used for the nutritional support of
immune function.
 THE TWO PRODUCTS TESTED
• MGN-3 (BRM-4): A fermentation product
resulting 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 and
botanical formula, utilizing evidence-based
reagents including: Andrographis paniculata,
Vit. C, Green Tea, Turmeric, E. senticosus,
Zn, Grape seed extract, Ashwangandha,
Oregon Grape, Shiitake mushroom,
Echinacea purpurea, Goldenthread root, Aloe
Vera, Garlic, Astragalus, Ginseng Panax,
Goldenseal Root, Coriolus mushroom, AHCC,
Saccharomyces
Comparison of Immune Stimulating Properties of Natural
Products
Results
1. 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 peripheral
blood 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 NK
activation 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 cell
mitogens.
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 and
induction 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).
 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 fold
more efficient.
 NK cell
NK activation
cell activation
25

20
CIM
15

10

5
MGN-3
0
0.2 2 20 200
grams/liter

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 fold more efficient.
 In vivo effects of test products
NK cells in circulation Activation status of circulating NK cells

1.05 2
1.8
1
MGN-3
0.95
0.9
1.6
1.4 CIM
1.2
0.85
1
0.8
0.75
CIM 0.8
0.6
0.7 0.4
0.65 0.2 MGN-3
0.6 0
0 2 4 24 0 2 4 24

Hours after consumption of test product Hours after consumption of test product

Results show relative changes in the amount of NK cells in the blood

circulation 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 but
decreased by MGN-3.
COMPARATIVE STUDY CONCLUSIONS

• Under the conditions of this study,

previously reported substantial
activation of NK cells was not apparent
with MGN-3 (BRM-4) off-the-shelf.
• In direct comparison with MGN-3, the
components of Clinical Immune
Modulator were highly able to promote
NK activation.
• The composition of Clinical Immune
Modulator appears to be more versatile
and powerful at modulating immunity
in comparison with MGN-3 (Lane Labs,
NJ).
 CONCLUSIONS
• Immunesenescence involves more than immune
deficiency, it involves misdirection of immune
responses and other qualitative changes in immunity.
• The contents of a dietary supplement may not be the
same as the material that may have been tested to
support the sale of a specific, branded dietary
supplement.
• Manufacturers of nutraceuticals must provide data to
support their product use that is specific to the product
presented “on the shelf.” The popular use of AHCC
may not always fulfill these criteria, especially if there
are different types of AHCC in use?
• This presentation supports the notion that good
nutrition or complex lifestyle and nutritional
interventions will benefit immune function, especially in
the elderly.
• Use of complex botanical herbal of nutrient formulae
with wide ranging effects on immune function may work
in a more powerful and versatile manner on immune
function, in comparison with simpler preparations.