AAMN Winter 2010 Dr Mark Bartlett

7/28/2019 AAMN Winter 2010 Dr Mark Bartlett

http://slidepdf.com/reader/full/aamn-winter-2010-dr-mark-bartlett 1/6

-AgingdiCL nw

T H e G L O B A L R e s O U R c e f O R A n T I - A G I n G

18TH ANNUAL WORLD CONGRESSON ANTI-AGING MEDICINE AND BIOMEDICAL TECHNOLOGIES

SPECIAL GUEST:

tLor &tLorAS NATURAL THERAPEUTIC

TAR GETS

troGntBoLiITS RISK ON BREAST CANCER

AND MITIGATING EFFECTS

in thi iuwelcme Lee

imme acemeBy nae

nal a Geecaeges lgevy

xb Lsgs

pc cemes

fs ol vs. kll ol

PG 5

PG 10

PG 37

PG 190

PG 190

PG 208


http://slidepdf.com/reader/full/aamn-winter-2010-dr-mark-bartlett 2/6

NUTRITIONAL and GENETIC


http://slidepdf.com/reader/full/aamn-winter-2010-dr-mark-bartlett 3/6WINTER 2010 ANTI-AGING MEDICAL NEWS ❘3

Strategies for LONGEVITY

Abstract

A genomic understanding o

aging is paving the way to iden-

tiy interventions that can have

signifcant impact on the aging process.The polymorphic nature o aging indi-

cates that any anti-aging strategy has

to start with a better understanding o

genes that aect tissue viability.

Our anti-aging approach has always

centered on the oundation o good

macro and micro-nutrition, including

the consumption o plentiul plant-

based antioxidants and phytonutrients.However recent advances, especiallywith the mapping o the human genomeand the subsequent development o DNA microarrays provide (a) an op-

portunity to explore the mechanisms o aging and (b) the tools to begin address-ing aging at its most undamental level. We believe that i we are to widen thegap between chronological and biologi-cal age we must better understand therole o gene expression in aging and howdietary ingredients interact with geneexpression in a positive way.

By Mark R. Bartlet t, PhD


http://slidepdf.com/reader/full/aamn-winter-2010-dr-mark-bartlett 4/638 ❘ANTI-AGING MEDICAL NEWS WINTER 2010

vitamins, minerals, and phytonutrientsnot only fght ree radicals, but theyexert perhaps even more powerul anti-aging eects through a non-antioxidant role. Phytonutrients, many o whichare antioxidants, also inuence the ex-pression or activity o actors involvedin aging including, or example, sirtuins,

AMPK, NFKB and PGC-1 alpha toname a ew.4-6 Thus it is becoming in-creasingly clear that the phytonutrientswe thought were merely antioxidantsare also capable o modulating geneexpression.

Gee xess cece

It is clear that a nutraceutical ap-proach to anti-aging must take into ac-count the polymorphic nature o aging,and that the crosstalk among multiple

genes plays a more important role thanthe action o a single gene in mediat-ing the survival o an organism. Sincethe development o DNA microarraysthat allow scientists to measure thework output o all o the genes in asingle experiment, it is now possible torapidly explore the dierences in theexpression o multiple genes betweentwo or more biological conditions ina single experiment. Our researchand development team at Nu Skinbecame intrigued with the possibility

o measuring the aging process objec-tively at the genetic expression levelater reading some o the exceptionalwork published by Weindruch, Prollaand colleagues (LieGen Technologies,LLC) (LGT) wherein a powerul tech-nique o dierential expression analysiswas being used to conduct genome-wide searches or consistent changesin gene expression patterns that occurduring the aging process.7, 8

Studies using whole-genome tran-

scriptional profling typically identiythousands o genes that are changedin expression with age. Since many o these age-related changes are not univer-sal, but rather are specifc to the geneticbackground o the organism being stud-ied, LGT identifed biomarkers o ageacross seven strains o mice (5 monthsvs. 28-30 months old) so that only themost conserved relevant patterns o age-related gene expression markers wereconsidered. Moreover, these analyseswere perormed in three tissues (heart,

fiGur 1: LGT identifed bimarkers age acrss

seven strains mice (5 mnts vs. 28-30 mnts

ld) s tat nly te mst cnserved relevant

patterns age-related gene expressin markers

were cnsidered. RTqPCR was used t cnfrm a

panel 10-20 genes in eac tissue.

Introduction

Aging is not an episodic process;rather, it is the consequence o a con-tinuum o cumulative damage occur-ring at the molecular, cellular and tissuelevels. The rate o aging rests on actors,internal and external, that can eitherpositively or negatively inuence the

balance between tissue preservation orrepair, and damage. Attenuation o ag-ing is entirely dependent on mitigatingsuch molecular damage by augmentingprotection and compensatory repairmechanisms or slowing the degen-erative processes. In a practical sensewe’ve all probably witnessed cleardiscrepancies between chronologicaland biological age in certain individu-als. And while it has been proposedthat genetic actors contribute to the

phenomenon o people looking old,or young, or their years, most o usintuitively suspect that there are someenvironmental components over whichwe wield a certain amount o control.Thereore, i we are to widen the gapbetween chronological and biologicalage, we must understand the variousmechanisms involved in aging anddevise eective strategies that turnthese mechanisms in avor o tissueprotection or repair and regeneration.The question we are asking is: what

are the liestyle actors and nutritionalcomponents that may assist us in takingcontrol o our own aging process sothat we can age healthily and reduceage-related morbidity?

ac a c n

A major actor in healthy aging

involves what, and how much, we eat.There is ample evidence that poor nu-trition, which includes overeating andpoor nutrient density, is linked with anincreased risk or many degenerativediseases including heart disease, diabe-tes and cancer. It is now also becomingclear that even marginal micronutrient defciencies over time lead to acceler-ated aging.1 Defciencies in severaldierent micronutrients includingolic acid, vitamin D and Magnesium

lead to DNA damage and accelerateage-related mitochondrial dysunction;which in turn leads to urther oxidativedamage to DNA, RNA, proteins andmembrane lipids leading to unctionaldecline in mitochondria, cells, tissuesand organs. Since multiple studies andextensive government-commissionedsurveys point to the widespread natureo inadequate dietary intakes o ruitsand vegetables (and thereore vitaminsand minerals)2 it seems prudent that all

individuals either improve their diets orsupplement their diets with a multi-vitamin mineral supplement to ensurethat there are no shortalls in essentialnutrients.

fee-acal Blgy a xas

A leading hypothesis o aging is basedon the ree radical theory o aging byHarman3 who argued that oxygen-ree radicals produced during normalcellular respiration cause cumulative

damage to molecules which progres-sively leads to loss o unctionality o the organism. Since Harman’s theo-ries were frst proposed, a huge bodyo literature has emerged providingevidence that ree radicals and oxida-tive stress are involved in many diseasestates, especially age-related degenera-tive disease. Although oxidative stressmay be a signifcant actor associatedwith aging, it is clearly not the onlycontributor and recently evidence isemerging to support the concept that


http://slidepdf.com/reader/full/aamn-winter-2010-dr-mark-bartlett 5/6WINTER 2010 ANTI-AGING MEDICAL NEWS ❘3

dysunction associated with agingyields bioenergetic deects within thecell9 that exert proound eects onphysical and mental vitality. Our goalwas to identiy and target unctionalgene clusters associated with mito-chondrial aging.

In our attempt to identiy these gene

pathways we ound that o 20,687gene transcripts measured by the A-ymetrix Mouse Genome array, 1241were associated with the mitochondriaby pathway ontology (using a geneontology database). Ater our murineeeding studies and microarray screen-ing we ound that 172 o these geneschanged in expression during aging incerebral cortex tissue. In gastrocnemiustissue 220 genes changed which age.Cs-4 opposed the age-related changesin 52 o these genes (P<0.05). In addi-

tion, Cs-4 opposed the eects o agingin several gene ontology pathways.In essence we were able to identiymitochondrial-related nuclear encodegenes which changed consistently inexpression with age, or mitochondrialyouth gene clusters (YGC). A numbero natural compounds were screened

or their ability to reset the expressionprofle o these genes to a more youthul level. One ingredient, Cordycepssinensis Cs-4 (Cs-4)10 was shown tomarkedly attenuate these age-relatedgene expression changes in the mito-chondria, suggesting its potential useas a therapeutic intervention o age related vitality loss. Ongoing studies arutilizing this technique to investigatethe eects o a variety o natural ingredients in brain, muscle and other tis-sues, but the sum o such explorations

fiGur 2: Tis eat map illustrates gene expressin tree grups rm a pre-clinical test wit ne

te ageLoC itality ingredients: yung (clumn 1), ld (clumn 2), and ld wit ageLoC science (cl-

umn 3). Eac rw represents ne 52 genes cmprising te mitcndrial ut Gene Cluster (mtG

Clumns 1 and 2 sw tat eac te 52 genes became mre r less active during te aging prceIn clumn 3, te GC activity pattern te ld wit ageLoC science grup as been reset t a gene

expressin pattern similar t te yung grup in clumn 1.

cerebral cortex and gastrocnemius) andreal-time quantitative PCR was usedto confrm a panel o 10-20 genes ineach tissue. Data generated rom such amodel are not only o a higher standardo rigor, but they are more likely tobe applicable to human aging as well.Using this approach statistically robust

patterns, or signatures, o youthul andolder gene expression have emergedwhich enabled us to essentially measureaging at the genetic level. The possibil-ity now existed to screen or ingredientsor ormulations or their ability to retardthe aging process. This is the procedurethat Pharmanex has adopted in collabo-ration with LGT to target aging at thesource, gene expression, in an approachthat we call ageLOC science.

caays, daabases a

Bmacs as a Ge pc

develme

In our frst screening experiment certain ingredients emerged or theirabilities to reset gene expression tothat o a more youthul pattern. Aparticular preparation o pomegranate,or example, was the most eectivecompound tested, opposing 32-65% o the overall aging change depending onthe tissue studied. Other ingredientsand ormulations also emerged as hav-

ing potent eects on gene expressionthat attenuated age-associated patternso expression. The results o our frst round o screening provided an impor-tant insight into ingredients that inu-ence gene expression in a positive wayand served as an important oundationto urther product development.

In addition to helping identiyindividual gene expression signaturesassociated with aging, DNA microar-ray technology in conjunction with

gene databases and bioinormatics canalso be used to identiy the expressionlevels o groups o genes that work together to serve a particular meta-bolic pathway. We added the use o such pathway analyses to our reper-toire o microarray-related gene toolsto help urther guide our product development in ormulating anti-agingproducts by applying it to the concept o age-related vitality loss. One o theearliest maniestations o human agingis a decline in vitality. Mitochondrial


http://slidepdf.com/reader/full/aamn-winter-2010-dr-mark-bartlett 6/640 ❘ANTI-AGING MEDICAL NEWS WINTER 2010

so ar, into the ability o certain naturalproducts to inuence gene expressionin a positive way, has provided strongguidance to our product development process targeted at attenuation o theaging process.

fcal es

The techniques that we have usedor studying gene expression have not disappointed us in their promise as toolsexplore the mechanisms o aging anddrive us towards meaningul product development strategies. We see great promise in the ability o certain nutra-ceutical ingredients and ormulations tohave a marked eect on gene expres-sion to oppose age-related changes. Thenext logical step is to support these geneexpression data with unctional studies.Indeed, the ingredients that we selectedor gene expression screening werebased on promising unctional studiesthat had already been perormed. How-ever, to close the circle, we have ol-

lowed up these promising gene expres-sion data with urther unctional, saetyand efcacy studies in both animalsand humans. Some o these studies arealready completed and have providedpositive correlation and confrmation o the gene expression data; other studiesare still underway.

Ccls

Since aging can be considered asa unction o how genes respond to

diet and environmental perturba-tions through gene expression whilemaintaining their primary unctionto survive, we chose to exploit a geneexpression approach to screen severalnutraceutical ingredients and ormula-tions or their eects on retarding theaging process. We called this approachageLOC science. Our frst oray intothis approach involved targeting age-related vitality loss through an explo-ration o the gene expression changesinvolved in mitochondrial aging. We

identifed tissue-specifc unctionalYGCs, or signatures o gene expressionchanges associated with mitochondrialaging and screened or ingredientsthat restored the more youthul pat-tern o gene expression. Functionalstudies have confrmed the promiseoered by the gene expression studyresults. It is our opinion that whilea oundation sound o nutrition anda positive liestyle are key to healthyaging and compression o morbidity,

there is much to be gleaned rom anunderstanding o gene expression asit relates to the aging process as wepursue the goal dying young - as latein lie as possible.u

RefeRences:

1. Ames BN. Low micronutrient intake may

accelerate the degenerative diseases o aging

through allocation o scarce micronutrients by

triage. Proc Natl Acad Sci U S A 2006 November

21;103(47):17589-94.

fiGur 3: Mainstream anti-aging appraces r years ave centered n te undatin gd

macr and micr-nutritin and antixidants. hwever it is becming increasingly clear tat sme te

pytnutrients we tugt were merely antixidants are als capable mdulating gene expressin

and play a rle in aging.

-agg cece:ee e ee: -agg cece n

2. Site-specifc trends in ruit and vegetable con-

sumption among adults--United States, 2000-

2009. Morbidity and Mortality Weekly Report

(MMWR) 2010;59(35):1125-64.

3. Harman D. Aging: a theory based on ree ra-

dical and radiation chemistry. J Gerontol 1956

July;11(3):298-300.

4. Bengmark S. Curcumin, an atoxic antioxidant

and natural NFkappaB, cyclooxygenase-2, lipo-

oxygenase, and inducible nitric oxide synthase

inhibitor: a shield against acute and chronicdiseases. JPEN J Parenter Enteral Nutr 2006 Ja-

nuary;30(1):45-51.

5. Kim JH, Park JM, Kim EK et al. Curcumin

stimulates glucose uptake through AMPK-p38

MAPK pathways in L6 myotube cells. J Cell

Physiol 2010 June;223(3):771-8.

6. Davis JM, Murphy EA, Carmichael MD, Davis

B. Quercetin increases brain and muscle mi-

tochondrial biogenesis and exercise tolerance.

Am J Physiol Regul Integr Comp Physiol 2009

April;296(4):R1071-R1077.

7. Barger JL, Kayo T, Vann JM et al. A low dose

o dietary resveratrol partially mimics caloric

restriction and retards aging parameters in mice.

PLoS ONE 2008;3(6):e2264.

8. Prolla TA, Weindruch RH, Lee CK, Kayo T; Win-

consin Alumni Research Foundation, assignee.

Methods o screening or compounds that inhibit

expression o biomarker sequences dierentially

expressed with age in mice. Wisconsin patent

7,091,449. 2006.

9. Lanza IR, Nair KS. Mitochondrial unction as

a determinant o lie span. Pfugers Arch 2010

January;459(2):277-89.

10. Zhu JS, Halpern GM, Jones K. The scientifc

rediscovery o a precious ancient Chinese herbal

regimen: Cordyceps sinensis: part II. J Altern

Complement Med 1998;4(4):429-57.

◗ Dr. Bartlett as degrees in Bicemistry and or-

ganic Cemistry rm te Australian Natinal Uni-

versity and a P.D. in Immunlgy and Cell Bilgy

rm te n Curtin Scl Medical Researc

in Canberra, Australia. In Australia e cnducted

researc n cardivascular disease wit an em-

pasis n te rle reactive xygen species and

ree radicals. he als studied te rle bld

platelets in eart disease, and elped publis te

frst scientifc reprt a bicemical link between

cigarette smking and atersclersis.

Later Dr. Bartlett became interested in autim-

mune inammatry diseases and examined anumber plant-derived substances r teir abil-

ity t inibit grat rejectin, inibit cancer metas-

tasis – r spreading – as well as natural prducts

tat were able t inibit autimmune disease.

Bere jining Parmanex Dr. Bartlett was a visiting

scientist at te Natinal Institutes healt, Na-

tinal Cancer Institute in Betesda, MD were, at

te Natinal Cancer Institute, e investigated te

interactin T-cells wit te bld vessel wall, and

te rle varius adesin mlecules tat are

used by tese cells t cmmunicate wit ne an-

ter. he is currently te ice President Glbal

Researc and Develpment r Parmanex.

Documents

AAMN Winter 2010 Dr Mark Bartlett