THe GLOBAL ResOURce fOR AnTI-AGInG    anti-Aging        -Aging    m e d i Ca L n e w s                                    ...
Strategies for       LONGEVITY                                                               By Mark R. Bartlett, PhD     ...
Introduction                                        are the lifestyle factors and nutritional   vitamins, minerals, and ph...
cerebral cortex and gastrocnemius) andreal-time quantitative PCR was usedto confirm a panel of 10-20 genes ineach tissue. ...
anti-aging science:                                                                               2.    Site-specific tren...
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Anti Aging Medi Ca L News

  1. 1. THe GLOBAL ResOURce fOR AnTI-AGInG anti-Aging -Aging m e d i Ca L n e w s estroGen metaBoLism ITS RISK ON BREAST CANCER AND MITIGATING EFFECTS teLomeres & teLomerase AS NATURAL THERAPEUTIC TARGETS in this issue welcome Letter PG 5 immune enhancement By nature PG 10 nutritional and Genetic strategies for longevity PG 37 exhibitor Listings PG 190 product announcements PG 190 SPECIAL GUEST: fish oil vs. krill oil PG 208 suzanne somers 18TH ANNUAL WORLD CONGRESS ON ANTI-AGING MEDICINE AND BIOMEDICAL TECHNOLOGIES
  3. 3. Strategies for LONGEVITY By Mark R. Bartlett, PhD Abstract based antioxidants and phytonutrients. A However recent advances, especially genomic understanding of with the mapping of the human genome aging is paving the way to iden- and the subsequent development of tify interventions that can have DNA microarrays provide (a) an op- significant impact on the aging process. portunity to explore the mechanisms of The polymorphic nature of aging indi- aging and (b) the tools to begin address- cates that any anti-aging strategy has ing aging at its most fundamental level. to start with a better understanding of We believe that if we are to widen the genes that affect tissue viability. gap between chronological and biologi- Our anti-aging approach has always cal age we must better understand the centered on the foundation of good role of gene expression in aging and how macro and micro-nutrition, including dietary ingredients interact with gene the consumption of plentiful plant- expression in a positive way.WINTER 2010 ANTI-AGING MEDICAL NEWS ❘ 37
  4. 4. Introduction are the lifestyle factors and nutritional vitamins, minerals, and phytonutrients Aging is not an episodic process; components that may assist us in taking not only fight free radicals, but theyrather, it is the consequence of a con- control of our own aging process so exert perhaps even more powerful anti-tinuum of cumulative damage occur- that we can age healthily and reduce aging effects through a non-antioxidantring at the molecular, cellular and tissue age-related morbidity? role. Phytonutrients, many of whichlevels. The rate of aging rests on factors, are antioxidants, also influence the ex-internal and external, that can either macro and micro nutrition pression or activity of factors involvedpositively or negatively influence the in aging including, for example, sirtuins, A major factor in healthy agingbalance between tissue preservation or AMPK, NFKB and PGC-1 alpha to involves what, and how much, we, and damage. Attenuation of ag- name a few.4-6 Thus it is becoming in- There is ample evidence that poor nu-ing is entirely dependent on mitigating creasingly clear that the phytonutrients trition, which includes overeating andsuch molecular damage by augmenting we thought were merely antioxidants poor nutrient density, is linked with anprotection and compensatory repair are also capable of modulating gene increased risk for many degenerativemechanisms or slowing the degen- expression. diseases including heart disease, diabe-erative processes. In a practical sense tes and cancer. It is now also becomingwe’ve all probably witnessed clear Gene expression science clear that even marginal micronutrientdiscrepancies between chronological deficiencies over time lead to acceler- It is clear that a nutraceutical ap-and biological age in certain individu- ated aging.1 Deficiencies in several proach to anti-aging must take into ac-als. And while it has been proposed different micronutrients including count the polymorphic nature of aging,that genetic factors contribute to the folic acid, vitamin D and Magnesium and that the crosstalk among multiplephenomenon of people looking old, lead to DNA damage and accelerate genes plays a more important role thanor young, for their years, most of us age-related mitochondrial dysfunction; the action of a single gene in mediat-intuitively suspect that there are some which in turn leads to further oxidative ing the survival of an organism. Sinceenvironmental components over which damage to DNA, RNA, proteins and the development of DNA microarrayswe wield a certain amount of control. membrane lipids leading to functional that allow scientists to measure theTherefore, if we are to widen the gap work output of all of the genes in a decline in mitochondria, cells, tissuesbetween chronological and biological single experiment, it is now possible to and organs. Since multiple studies andage, we must understand the various rapidly explore the differences in the extensive government-commissionedmechanisms involved in aging and expression of multiple genes between surveys point to the widespread naturedevise effective strategies that turn two or more biological conditions in of inadequate dietary intakes of fruitsthese mechanisms in favor of tissue a single experiment. Our research and vegetables (and therefore vitaminsprotection or repair and regeneration. and development team at Nu Skin and minerals)2 it seems prudent that allThe question we are asking is: what became intrigued with the possibility individuals either improve their diets or supplement their diets with a multi- of measuring the aging process objec- vitamin mineral supplement to ensure tively at the genetic expression level that there are no shortfalls in essential after reading some of the exceptional work published by Weindruch, Prolla nutrients. and colleagues (LifeGen Technologies, LLC) (LGT) wherein a powerful tech- free-radical Biology and antioxidants nique of differential expression analysis A leading hypothesis of aging is based was being used to conduct genome- on the free radical theory of aging by wide searches for consistent changes Harman3 who argued that oxygen- in gene expression patterns that occur free radicals produced during normal during the aging process.7, 8 cellular respiration cause cumulative Studies using whole-genome tran- damage to molecules which progres- scriptional profiling typically identify sively leads to loss of functionality of thousands of genes that are changed the organism. Since Harman’s theo- in expression with age. Since many of ries were first proposed, a huge body these age-related changes are not univer- of literature has emerged providing sal, but rather are specific to the genetic evidence that free radicals and oxida- background of the organism being stud- tive stress are involved in many disease ied, LGT identified biomarkers of agefiGure 1: LGT identified biomarkers of age across states, especially age-related degenera- across seven strains of mice (5 monthsseven strains of mice (5 months vs. 28-30 months tive disease. Although oxidative stress vs. 28-30 months old) so that only theold) so that only the most conserved relevant may be a significant factor associated most conserved relevant patterns of age-patterns of age-related gene expression markerswere considered. RTqPCR was used to confirm a with aging, it is clearly not the only related gene expression markers werepanel of 10-20 genes in each tissue. contributor and recently evidence is considered. Moreover, these analyses emerging to support the concept that were performed in three tissues (heart,38 ❘ ANTI-AGING MEDICAL NEWS WINTER 2010
  5. 5. cerebral cortex and gastrocnemius) andreal-time quantitative PCR was usedto confirm a panel of 10-20 genes ineach tissue. Data generated from such amodel are not only of a higher standardof rigor, but they are more likely tobe applicable to human aging as well.Using this approach statistically robustpatterns, or signatures, of youthful andolder gene expression have emergedwhich enabled us to essentially measureaging at the genetic level. The possibil-ity now existed to screen for ingredientsor formulations for 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.microarrays, databases andBioinformatics as a Guide to productdevelopment In our first screening experimentcertain ingredients emerged for theirabilities to reset gene expression tothat of a more youthful pattern. Aparticular preparation of pomegranate,for example, was the most effectivecompound tested, opposing 32-65% ofthe overall aging change depending on fiGure 2: This heat map illustrates gene expression of three groups from a pre-clinical test with one ofthe tissue studied. Other ingredients the ageLoC vitality ingredients: young (column 1), old (column 2), and old with ageLoC science (col-and formulations also emerged as hav- umn 3). Each row represents one of 52 genes comprising the mitochondrial youth Gene Cluster (mtyGC). Columns 1 and 2 show that each of the 52 genes became more or less active during the aging potent effects on gene expression In column 3, the yGC activity pattern of the old with ageLoC science group has been reset to a genethat attenuated age-associated patterns expression pattern similar to the young group in column 1.of expression. The results of our firstround of screening provided an impor-tant insight into ingredients that influ- dysfunction associated with aging tion, Cs-4 opposed the effects of agingence gene expression in a positive way yields bioenergetic defects within the in several gene ontology pathways.and served as an important foundation cell9 that exert profound effects on In essence we were able to identifyto further product development. physical and mental vitality. Our goal mitochondrial-related nuclear encoded In addition to helping identify was to identify and target functional genes which changed consistently inindividual gene expression signatures gene clusters associated with mito- expression with age, or mitochondrialassociated with aging, DNA microar- chondrial aging. youth gene clusters (YGC). A numberray technology in conjunction with In our attempt to identify these gene of natural compounds were screenedgene databases and bioinformatics can pathways we found that of 20,687 for their ability to reset the expressionalso be used to identify the expression gene transcripts measured by the Af- profile of these genes to a more youth-levels of groups of genes that work fymetrix Mouse Genome array, 1241 ful level. One ingredient, Cordycepstogether to serve a particular meta- were associated with the mitochondria sinensis Cs-4 (Cs-4)10 was shown tobolic pathway. We added the use of by pathway ontology (using a gene markedly attenuate these age-relatedsuch pathway analyses to our reper- ontology database). After our murine gene expression changes in the mito-toire of microarray-related gene tools feeding studies and microarray screen- chondria, suggesting its potential useto help further guide our product ing we found that 172 of these genes as a therapeutic intervention of age re-development in formulating anti-aging changed in expression during aging in lated vitality loss. Ongoing studies areproducts by applying it to the concept cerebral cortex tissue. In gastrocnemius utilizing this technique to investigateof age-related vitality loss. One of the tissue 220 genes changed which age. the effects of a variety of natural ingre-earliest manifestations of human aging Cs-4 opposed the age-related changes dients in brain, muscle and other tis-is a decline in vitality. Mitochondrial in 52 of these genes (P<0.05). In addi- sues, but the sum of such explorationsWINTER 2010 ANTI-AGING MEDICAL NEWS ❘ 39
  6. 6. anti-aging science: 2. Site-specific trends in fruit and vegetable con- where we were: anti-aging science now 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 free 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 chronic diseases. 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, DavisfiGure 3: Mainstream anti-aging approaches for years have centered on the foundation of good B. Quercetin increases brain and muscle mi-macro and micro-nutrition and antioxidants. however it is becoming increasingly clear that some of the tochondrial biogenesis and exercise tolerance.phytonutrients we thought were merely antioxidants are also capable of modulating gene expression Am J Physiol Regul Integr Comp Physiol 2009and play a role in aging. April;296(4):R1071-R1077. 7. Barger JL, Kayo T, Vann JM et al. A low dose of dietary resveratrol partially mimics caloricso far, into the ability of certain natural diet and environmental perturba- restriction and retards aging parameters in mice.products to influence gene expression tions through gene expression while PLoS ONE 2008;3(6) a positive way, has provided strong maintaining their primary function 8. Prolla TA, Weindruch RH, Lee CK, Kayo T; Win-guidance to our product development to survive, we chose to exploit a gene consin Alumni Research Foundation, assignee. Methods of screening for compounds that inhibitprocess targeted at attenuation of the expression approach to screen several expression of biomarker sequences differentiallyaging process. nutraceutical ingredients and formula- expressed with age in mice. Wisconsin patent tions for their effects on retarding the 7,091,449. 2006.functional studies aging process. We called this approach 9. Lanza IR, Nair KS. Mitochondrial function as ageLOC science. Our first foray into a determinant of life span. Pflugers Arch 2010 The techniques that we have used January;459(2):277-89. this approach involved targeting age-for studying gene expression have not 10. Zhu JS, Halpern GM, Jones K. The scientific related vitality loss through an explo-disappointed us in their promise as tools rediscovery of a precious ancient Chinese herbal ration of the gene expression changes regimen: Cordyceps sinensis: part II. J Alternexplore the mechanisms of aging and involved in mitochondrial aging. We Complement Med 1998;4(4) us towards meaningful product identified tissue-specific functionaldevelopment strategies. We see great YGCs, or signatures of gene expressionpromise in the ability of certain nutra- ◗ Dr. Bartlett has degrees in Biochemistry and or- changes associated with mitochondrial ganic Chemistry from the Australian National Uni-ceutical ingredients and formulations to aging and screened for ingredients versity and a Ph.D. in Immunology and Cell Biologyhave a marked effect on gene expres- that restored the more youthful pat- from the john Curtin School of Medical Researchsion to oppose age-related changes. The in Canberra, Australia. In Australia he conducted tern of gene expression. Functionalnext logical step is to support these gene research on cardiovascular disease with an em- studies have confirmed the promiseexpression data with functional studies. phasis on the role of reactive oxygen species and offered by the gene expression study free radicals. he also studied the role of bloodIndeed, the ingredients that we selected results. It is our opinion that while platelets in heart disease, and helped publish thefor gene expression screening were a foundation sound of nutrition and first scientific report of a biochemical link betweenbased on promising functional studies cigarette smoking and atherosclerosis. a positive lifestyle are key to healthythat had already been performed. How- aging and compression of morbidity,ever, to close the circle, we have fol- Later Dr. Bartlett became interested in autoim- there is much to be gleaned from an mune inflammatory diseases and examined alowed up these promising gene expres- understanding of gene expression as number of plant-derived substances for their abil-sion data with further functional, safety it relates to the aging process as we ity to inhibit graft rejection, inhibit cancer metas-and efficacy studies in both animals tasis – or spreading – as well as natural products pursue the goal dying young - as lateand humans. Some of these studies are that were able to inhibit autoimmune disease. in life as possible. ualready completed and have provided Before joining Pharmanex Dr. Bartlett was a visitingpositive correlation and confirmation of scientist at the National Institutes of health, Na-the gene expression data; other studies RefeRences: tional Cancer Institute in Bethesda, MD where, atare still underway. the National Cancer Institute, he investigated the interaction of T-cells with the blood vessel wall, and 1. Ames BN. Low micronutrient intake mayConclusion accelerate the degenerative diseases of aging the role of various adhesion molecules that are through allocation of scarce micronutrients by used by these cells to communicate with one an- Since aging can be considered as triage. Proc Natl Acad Sci U S A 2006 November other. he is currently the vice President of Globala function of how genes respond to 21;103(47):17589-94. Research and Development for Pharmanex.40 ❘ ANTI-AGING MEDICAL NEWS WINTER 2010