9. What is ageLOC? SIGNS Developing products that address the sources of aging, not just the signs and symptoms.
10. D. James Morré, PhDDepartment of Medicinal Chemistry and Molecular Pharmacology andDorothy M. Morré, PhD Department of Foods and Nutrition Purdue University, West Lafayette, Indiana ARNOX, AN AGING ENZYME: 1ST AGELOC SOURCE OF AGING
11. Identified a NOX which increases with age Nicotinamide adenine dinucleotideOXidase, a hydroquinone oxidase
12. 1/2 O2 H2O NOX 2 O2 S SH Protein Protein Outside S SH Plasma Membrane Q10 Q10H2 Inside Quinone Reductase NAD(P)+ NAD(P)H + H+ arNOX Generates Superoxide O2- - 2 O2 A powerful free-radical generator
13. GENESIS OF AGELOC The arNOX discovery helped explain… Why Some People Look Years Younger Than They Really Are.
14. HUMAN GENOME Our genome encodes for: our looks our size how our bodies work our health our behaviors Our longevity
26. Which genes are turned on and off does change (e.g. gene expression).
27.
28.
29. Elastin arNOX To better understand aging, we need to know the expression level for every gene. …in a single experiment.
30. Gene Expression Profiling 101 Young Skin Fibroblast (Hypothetical) Gene 1 arNOX Gene 2 Elastin Gene 3 Collagen Gene 4 MMP DNA mRNA Microarray (e.g. Gene Chip) Young Skin Key arNOX (0) Elastin (8) - High Activity - Medium Activity - Low Activity Collagen (6) MMP (2) - Off
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32. Elastin arNOX The expression level for every gene in a single experiment! DNA Microarray Gene Map Key Over 25000 Genes - High Activity - Medium Activity - Low Activity - Off
33.
34. Target - Investigate the effect different ingredients have on YGC’s.
39. In additional to understanding the genetic basis of aging in Humans, mice, fruit flies, yeast and roundworms are also fruitful models for the genetic/aging scientist
41. Gene Expression Profiling 101 Young Skin Old Skin arNOX (0) Elastin (8) arNOX (8) Elastin (0) Changes with Aging Collagen (6) MMP (2) Collagen (2) MMP (4) By comparing the two, you can understand the genetic changes associated with aging Key - High Activity - Medium Activity Down regulation Up regulation No Change - Low Activity - Off
48. Targeting - Cataloging the effect different ingredients have on YGC’s.
49.
50. Identifying Changes (Old vs. Young YGC Profile) Old Skin Young Skin A B A B D C C D By comparing the two, you can understand the genetic changes associated with aging Key - High Activity - Medium Activity - Low Activity - Off
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52. Targeting & Resetting YGC Once you map the changes, you can screen for ingredients and formulas that reverse these changes Young Skin A B Old Skin A B AGING Post Application C D A B ageLOC D C C D Key - High Activity - Medium Activity - Low Activity - Off
53.
54. Targeting - Cataloging the effect different ingredients have on YGC’s.
55.
56. Gene Activity in Skin Cells DNA Microarray Gene Map Over 25000 Genes
58. ageLOC Science Four YGCs Identified Pigment Signs of Aging Hydration Fine Lines & Wrinkles Youth Gene Clusters Cellular Turnover Youthful SkinStructure Discoloration Skin Structure Skin Tone Hydration Texture, Smoothness Radiance Pore Size
59. Changes in gene activity patterns yield tissue changes as we age “Interventions can impact gene activity patterns even late in life and may reverse skin aging”* *Adler, Chang et al. Cell Cycle 2008;7(5):556-559
60. “THE PROOF IS IN THE PUDDING” Meaning: The true value or quality of something can only be judged when it's put to use. “Nu Skin has never developed a product that delivers these kindof results before (both in clinical results and user perception” Dr. Helen Knaggs, PhD VP of NuSkin R&D
61. ageLOC Summary Nu Skin Enterprises Center for Anti-Aging Research (NSE:CAAR) brings together experts in the field of anti-aging genetics Only we can Identify Youth Gene Clusters (YGC) AgeLOC Science Targets the Ultimate Sources of Aging Only Nu Skin understand how to Reset Youth Gene Clusters to their youthful state Over the next 10 years as the ageLOC approach matures, its full impact will be realized on many more products - enabling Nu Skin to stay years ahead of our competition
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63. Nutritional Intervention affects age related gene expression and can Reverse Aging Lee et al, Science 1999;285(5432):1390-3; Colman et al, Science 2009;325:201-204
I often get the question, “What is ageLOC”? Simply put it is our new approach to [read slide]But what is the ultimate source of aging? As we got all of our scientists together we began reviewing what we have learned over the last 25 years of product development.
Our first foray into this “sources of aging” area involved a really cool discovery by Dr. James Morre and Dr. Dorothy Morre at Purdue University. …
The Morre Professors discovered an enzyme which increases with age…
…which is bad, because this enzyme generates nasty free-radicals which damage the skin…
Studies at stanford university correlated the appearance of age with the levels of this enzyme being expressed in the skin.
If we want to target the sources of aging, then we need to look at the genes, because the genes are the source of all proteins in the body. The structure and the functioning of our bodies begins at the genetic level. We know that our genes contain the codes for all of the above…But exactly how, and which genes are important, have eluded us. For starters, we didn’t even know the full code until recently.
But one thing we did learn is that there seems to be a program that takes place causing the aging processGenes, of course, determine the structure and function of our bodies. As they’re expressed, the gene products are structural (like collagen and elastin) and functional (enzymes, hormones) proteins.For this reason, gene expression patterns must be the source of aging. In fact, as we age, the patterns of gene expression change. Is it possible to affect the red line – the inevitable slow progression of aging symptoms towards death??
But in a major breakthough, at the turn of this century, the human genome was finally fully sequenced. Freely available to all. What would you do with it?
So, it’s been cracked. We have the code! All of it. What does it look like? Mostly a bunch of GATC! How is that going to benefit you! Sure, it can and will be used by scientists to help understand the genetic nature of various serious diseases. But again, you personally, can you benefit also? What do you think of when you think of your DNA? Who’s your daddy? But can you change your DNA? You’re stuck with it, right?
With Genes and Gene Expression having been defined as the ultimate source of aging, we faced a dilemma. While we have a lot of scientists and PhDs at Nu Skin, however not a lot of expertise in genetics. We therefore had to reach out to experts in the field, and identify those who were the experts in the field of anti-aging genetics.This is why we are so proud to announce the formation of the NSE:CAARObviously you all know we have over 100 scientists in house, and a network of research partners around the world. That is represented by the Nu Skin logo here. We then partnered with some of the world leaders in the field of anti-aging research. We brought together researchers from Stanford, as well as engaging LifeGen to create a team dedicated to the study of anti-aging research.
The Center for Anti-Aging Research has five new scientists that I would like to introduce today. [Give names and affiliations of each] Stuart Kim, Howard Chang, Anne Chang, Richard Weindruch, Tomas Prolla[CLICK]Together they have published over 300 scientific papers, and their insights have changed the way aging is viewed.
Touch on each of the 3 bullet points above
Since we are obviously going to be to be talking about genetics, I think it important to give at least a basic introduction to genes, and their significance. However I promise that the material I will cover will only be at a 5th grade level – so everyone of you can easily understand.Cells are the building block of us! Our heart, lungs, brain, skin, bone, etc… are all made from cellsInside each cell is the nucleus, considered the brain of the cell. Inside the nucleus of each cell is a copy of our genome (e.g. the blueprints for our entire body). This is found on the DNA within the nucleus, which when compacted is called our chromosomes.
Here are pictures of chromosome three. Each is of one of a set of twins. On the left twin A. On the right twin B. Genes that expressed the same (e.g. same pattern of genes turned on and off) are highlighted in yellow.Genes that are differently expressed are shown in green and red. Clearly the expression pattern of young (3 year old) twins are quite similar. However older twins (50 year old), there is very little similarity.
Wouldn’t it be great if we had a way to instantly know the expression levels of every one of the genes in the nucleus at once? Well that technology does exists – it is called either a Gene Chip or a DNA microarray.
I want to explain the tools that the genetic researchers use, because this will help you to understand what we have done to help create our new anti-aging skin care products.Lets say we’re studying four different genes in the skin. Each gene produces a certain amount of gene product, depending upon whether the switch is turned up or down on that gene.On this piece of glass (the gene chip) we have four quadrants, and each quadrant attracts (is sticky for) specifically, each of the genes of interest.Then the magic of the gene chip is that the more product, the brighter the light shines, so we have a sort of brightness map representing the relative activity of that gene in your skin cells.
But such a chip exists – not just for four genes – but for all of the human genes. All 25,000 of them!
Here is a picture of one of these on the left. If you add cells to the chip, and look at the blue square in the center with a high powered microscope, you will get an image like this (center)See all of these dots? Each one represents the expression level of a single gene. If the gene is turned off it will show up in dark blue – like this one here for arNOX. If the gene is very active, then it will show up almost white – like this one here for Elastin.This is obviously a Gene Chip performed on a young cell. If it had been older, the arNOX would be white, and the Elastin would show low activity.But what is important to know is that in a single experiment we can now know the exact expression level of every gene in the body – isn’t that cool?
OK, so now that you know the basics of genes, and understand what a Gene Chip is, let me outline Nu Skin’s ageLOC approach.Touch on each of the three bullet pointsFirst I am going to talk about how we go about identifying YGC’s
The first question you might have is, “what is a Youth Gene Cluster”These are groups of genes (e.g. clusters) that work together to exert a specific function in a tissue associated with youthfulness.They are tissue specific, in that the YGC’s associated with aging in the heart, are completely different that those found in the brain or skin.In practice, these groups act as the master regulators of aging in a specific tissue.
This slide represents the same person as she ages. Well her genes haven’t changed right? So the physical changes we observe are due to changes in the expression profile of the genes as you age. Using gene chip technology, and a rigorous analysis of the data (I’ll talk about later), we can pinpoint the gene expression pattern changes with age, and identify the genes that work together for youthful vs aging attributes.
We are also very interested in studying the expression profile of those individuals that age gracefully (like those that were in our contest). I only use their pictures to illustrate the concept, these actual people have not been used in our genetic studies (at least not yet??).
In additional to understanding the genetic basis of aging in Humans, mice, fruit flies, yeast and roundworms are also fruitful models for the genetic/aging scientist.
Now lets carry this a bit further…We have two samples of human skin. One is young, the other older. If aging changes the expression pattern of the genes in skin, then you will agree that…Some genes will express more or less than it’s younger counterpart so…If we generate a gene array map for each tissue sample, they’ll differ somewhat from each other.
Like this!You can actually generate a second sort of gene array map based on the difference between the two.If the gene of the older skin expresses at a relatively lower level – the color will be blue or green or whatever you choose.If the gene of the older skin expresses at a higher level – the color will be red.
And the 25000 or so genes would create a map like this – called a heat map.
But this heat-map, representing 25,000 genes, would be awfully complex. Can you imagine how long it would take to sort out all of this information? You’d need a complex and intelligent database programmed by scientists expert in the field of bioinformatics. That, we have! And using this system we can determine which genes are relevant to the aging process, and thus find youth gene clusters. Genes that are functionally related to aging.
All of this genetic information that goes into our database, will provide us with a detailed map of what is happening during the aging process. After all, without a map (e.g. a knowledge of where you are and where you are going), you are never going to reach your destination – and even if you did reach it, you wouldn’t even know that you had arrived. It is by studying this map, that we have been able to identify the master genetic regulators of the aging process in skin (e.g. youth gene clusters). Or in other words, groups of genes (e.g. clusters) that work to direct the aging process, and how they change (up or down regulated, and to what level).
OK, I hope that this has helped you understand how we are going about identifying the YGC’s (e.g. those master regulators of aging) – so that step is done [click]Now lets focus on Targeting and Resetting these YGC’s
We also use Gene Chips to Target and Reset the YCG’s
Now if I compare the two gene chips, I can determine the genetic changes associated with aging in the skin (in this example with regard to aging skin structure). Here we have identified the YGC’s, and then evaluated at how they change with age.
Remember the older twins? Gene expression patterns can change depending upon our environment, our nutrition, and what we put on our skin.
Now that we have this information, we can screen for ingredients and formulas that reverse these changes (as illustrated above). Here I demonstrate what it means to reset a youth gene cluster.
OK, so now we have talked about the three step process of ageLOC (Identifying, Targeting, and then Resetting).
So how have we been able to apply this science to our new products?
Again, as I described earlier, gene Chip technology allows us to examine the genes expressed in human skin.Heat maps can be generated to show the difference between old and young skin in terms of that gene expressionAnd also, between treated and untreated skin, to determine if the pattern of gene expression can be reset to that of younger skin again.
Our Nu Skin scientists have identified 4 such Youth Gene Clusters in the skin
These Youth gene clusters, depending upon their pattern of expression, affect the signs of aging on the right.
It is summarized rather nicely by one of our partners, Howard Chang in his Cell Cycle paper from 2008.Changes in gene activity patterns yield tissue changes as we ageInterventions can impact gene activity patterns even late in life and may reverse skin aging.
So these are the cornerstones of ageLOC science.First, we’ll learn about the genesis of the ageLOC approach and how we have a unique ability to target the ultimate sources of aging. Second, we’ll learn how Nu Skin can identifyarSuperMarkers - more specifically, Youth Gene Clusters. Third, we’ll learn how only Nu Skin can reset Youth Gene Clusters to promote more youthful aging.
These scientists have been studying that red line, or that genetic program of aging. What genes are expressed during youth, and which ones change as you grow older? Which ones cause aging, and which ones are the result of aging? Can certain lifestyle or dietary habits change the expression of those genes? Can we keep the youthful pattern longer? If we do, will we live longer or avoid aging diseases?Two landmark studies published in the journal Scienceby our research partners, Dr Richard Weindruch and Tomas Prolla, have shown that nutritional intervention can have a great impact on the expression of the genes. They showed in a study published several years ago, then followed up with a hugely important recent study earlier this year, that a specificdietary intervention, merely the reduction of caloric intake, not only positively influenced gene activity, but more importantly delayed the onset of age-related conditions and extend lifespan. In other words, they found that certain nutritional interventions can send us into ageLOC mode. They found that the power is in our genes, with the right influence, to slow or even reverse the aging process. Aging is not fixed. And the work of our collaborators at Stanford are studying the same processes, the pattern of gene expression as we age, but have focused on those changes that occur in the skin.Dr. Weindruch has pioneered this important anti-aging research; he and Dr. Prolla bring over 30 years of research and over 200 scientific publications to Nu Skin. Their groundbreaking research has already caught the attention of major mass media outlets in the US, including the New York Times, the Wall Street Journal, the Oprah Winfrey Show, and CBS 60 Minutes.Their research proves that (1) specific interventions can positively influence gene activity patterns and (2) as a result of these gene activity changes, meaningful anti-aging benefits can be achieved. Can you see why we are so excited about this partnership? This knowledge is ours to leverage and in fact served as foundational research for Nu Skin’s ageLOC Science approach.
So we’re beginning to see that the red line (which is the genetic program of aging – or the pattern of gene expression as age) can be affected by lifestyle, topical or nutritional intervention. In essence, for the first time, these scientists can measure aging at the genetic level, and map the changes along the path of aging. Only with this information, can we expect to be able to influence the process by testing topical and nutritional intervention strategies.
