May 12, 2005




††††††††††††††††††††††††††††††††††††††††† (SRF)

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Thank you, Aubrey.

I want to thank Arthur, Andrzej, and Donna for the opportunity to tell you about the Supercentenarian Research Foundation, which I'll just refer to as the SRF.




††††† ††††††††††††††††††††††† HANDOUTS

††††† RESPONSE FORM†††††††††††




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These are the handouts you've been given.Each is one sheet except for the last one.


The history of the SRF is the history of an organization that doesn't exist -- not yet, but it will shortly.


At the Integrative Medical Therapeutics for Anti-Aging Conference at the Hilton Hotel in Las Vegas last October, 18 of us met for breakfast at 6:30 AM to discuss the topic Supercentenarians.This meeting was organized by Steve Coles and Elliot Bergman and included some others who are here at this Meeting, including Aubrey de Grey and Chris Heward.Robert Young and Louis Epstein described their work in identifying and validating Supercentenarians (110+).This work is publicized by Steve Coles on the Gerontology Research Group website and in newspapers.The consensus was that this was a good base to build on, but that we needed to do much more.Out of that beginning was born the plan for a foundation that would accept tax-deductible donations that would be disbursed for research into aging, and that research would focus initially on the oldest amongst us, the Supercentenarians.We also intend to investigate younger age groups, particularly the offspring and siblings of Supercentenarians.The organizing committee is listed on this slide.




Elliot Bergman, Ph.D.

Steve Coles, M.D., Ph.D.

Doros Platika, M.D.

Aubrey de Grey, Ph.D.

Karlis Ullis, M.D.

Dave Gobel

Robert Young

Stanley Primmer

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I want to emphasize at the outset that the intent of the SRF is not to compete with other groups and individuals with similar interests, but to cooperate and collaborate with them.


The N.I.A. only funds about 15 percent of grant applications that it receives.Now I presume that the noted scientists here this afternoon are more frequently in the 15% who get funded than among those who don't.Still it just might be worthwhile to you to have an additional source of funding for your invaluable projects.We hope that the SRF can become such a source.Our vision is that after a few years the SRF will be able to provide millions of dollars in research grants for the study of aging.


But why Supercentenarians?I'm glad you asked that.Nature has performed an aging experiment in humans in which the vast majority of us die by the time we are 80 something.Only a few live to 100, and it is even more rare for someone to live to 110 or beyond.These Supercentenarians may hold not only the secret of longevity, but also the secret of aging.


Our concept is for the research to be conducted in 2 phases:



††††† ††††††††††††††††††††††† RESEARCH PHASES

††††† 1. Diagnostic Phase - to determine the causes and effects of aging in Supercentenarians

††††† 2. Intervention Phase - to attempt to prevent, ameliorate, and reverse the causes and effects of aging

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When I invited a friend to join the SRF, he responded that he didn't need to study Supercentenarians because he already knew the cause of aging, and he then proceeded to describe his theory.This interchange prompted me to write the last half of the Mission Statement in which I acknowledged some of the leading theories of what causes aging.I borrowed heavily from Aubrey's Seven Deadly "SENS" when I made this list.However, while the SRF will consider all reasonable theories during analyses of the data obtained, it will seek to be informed by the facts discovered rather than adopting a priori any postulated theory of aging.This is a key element of our philosophy:before we can solve a problem, we need to define the problem.Before we conduct research into methods for intervening in aging, we must diagnose those aging processes for which intervention is needed.


For the diagnostic phase we will seek answers to 2 questions.



††††† ††††††††††††††††††††††† DIAGNOSTIC PHASE

††††† 1. Why do Supercentenarians live longer than most?

††††† 2. Why don't they live longer than they do?

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[Pictures of four Supercentenarian ladies]

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The answer to the 2nd question may be even more important than the 1st.When you look at pictures of these Supercentenarian ladies, you won't mistake any of them for 20-year-old beauty queens.It doesn't take a renowned gerontologist with 50 years of experience to see that these ladies aren't in the best condition.Now, if you were hoping for pictures of beauty queens, I'm afraid you'll have to get them somewhere else.But what happened to these ladies that caused their morbidity?[Slide listing possible causes of morbidity/aging]Was it due to:




††††† ††††††††††††††††††††††† POSSIBLE CAUSES OF MORBIDITY/AGING

        Free radicals? (ROS)

        Cellular loss and atrophy?

        Cellular replicative senescence?

        Accumulation of somatic nuclear DNA mutations?

        Accumulation of somatic mitochondrial DNA mutations?

        Intracellular accumulation of lipofuscin?

        Accumulation of amyloid fibrils?

        Alteration of intracellular long-lived proteins?

        Glycation induced cross-linking of extracellular long-lived proteins?

        Alteration in regulation of IGF-1/insulin pathway?

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All of these are well-founded theories of aging, but which of them are most significant in causing the debilitated condition of even those who have known very little illness during their lives?We need to examine the tissues and cells from Supercentenarians to objectively answer this question.


Many kind-hearted gerontologists seek ways to compress the period of morbidity and suffering at the end of life, but in Supercentenarians this period may be longer than for those who die at younger ages.So how would you shorten their morbidity?Not let them live as long?They just might object to that.It would be better to delay the beginning of morbidity, prevent it, or even reverse it.If there are such things as core factors of aging, they may be more clearly exhibited in Supercentenarians who have overcome, delayed, or escaped the diseases of old age to which most of us succumb.Having survived without submitting to disease, what is left but basic factors of aging?This is the natural selection experiment that nature has performed for us.We hope to learn from that experiment.We may also ask, if the consequences of morbidity can be overcome, will the incidence of diseases of old age be reduced??


Finding the answers to the questions, "Why do Supercentenarians live longer than most?" and "Why don't they live longer than they do?" will require two courses of action:



††††† ††††††††††††††††††††††† COURSES OF ACTION

††††† 1. Obtain medical and biological data from living Supercentenarians by non-invasive means.

††††† 2. Obtain autopsies and tissue samples from the deceased.

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Dave Gobel has proposed developing the Jeanne Calment Clinic that would have mobile teams.He and Dr. Karlis Ullisplan to develop this project.The Jeanne Calment Clinic will be a virtual clinic and brain trust to assist the personal physicians of the Supercentenarians to provide for their medical care.By doing so we would hope not only to help them, but also to gain their trust and cooperation.They would then be more willing to allow non-invasive procedures to characterize their current physiological status as fully as possible and to agree to an autopsy and post mortem tissue sampling.


Clearly we need more autopsies of Supercentenarians.Steve Coles arranged for and participated in the autopsy of Elma Grace Corning who died last year at the age of 112.He has also arranged for the future autopsy of Marion Higgins who is 112.You may have seen the article about her on the front page of the Wall Street Journal on Feb. 25.We may have some surprises as to what causes the death of Supercentenarians.Did you know that 2 out of 3 autopsies of Supercentenarians have found that systemic amyloidosis was the cause of death? - well, all right, 2 of the 3 autopsies that I know of found this to be true.Obviously we need a larger sample than 3.


We not only need autopsies of Supercentenarians, but we also need to collect tissue samples.A few limited samples were collected from Elma Grace Corning.Greg Fahy has prepared a detailed protocol for collection of tissue samples in a manner designed to preserve the maximum data.


In order to maximize the benefits from the data collected we need to develop a two-part scientific database.The 1st part would be to hold the demographic data - who the Supercentenarians are, the validation criteria met by them, birthdates, family information, etc.The 2nd part would be designed to contain the medical and biological data obtained from living subjects, autopsies, and tissue samples.It would contain the data developed in the research projects funded by the SRF.The two parts would be linked by a unique ID in order to protect the privacy of the individuals involved.Considerable demographic data have been collected by the Gerontology Research Group directed by Steve Coles, and these data would be entered into the database where a search capability would facilitate extraction of information.


We are fully aware of the fact that we are dealing with a small population of subjects and that we face the challenge of obtaining statistically significant data.There are several ways of coping with this problem:


††††† ††††††††††††††††††††††† STATISTICALLY SIGNIFICANT DATA FROM A

††††† ††††††††††††††††††††††† SMALL SAMPLE OF SUPERCENTENARIANS


††††††††††† 1.Emulate search for rare genetic diseases


2.Search for longevity associated genetic polymorphisms found in other studies


3. Find more Supercentenarians


4.Extend the age range downward from 110

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    1. The mutations causing several genetic diseases have been successfully identified in spite of the rare occurrence of these diseases.  For example mutations in Lamin A were found to be the cause of Hutchinson-Gilford Progeria in three different studies in April of 2003.  One of these studies was based on a sample of only 20 individuals.  The other two consisted of much smaller samples.  They did have a clue in knowing the approximate location of the mutations.  Subsequently atypical Werner's Syndrome was found in Lamin A mutations in only 3 or 4 individuals. Considering the small samples in these examples, we might have some hope of identifying genetic polymorphisms that are associated with the extreme longevity of Supercentenarians.

    2. We also may have clues indicating which genes may permit Supercentenarians to live so long.Several studies have identified specific gene variations that are associated with longevity.  I would postulate that only one or two of these variations might be required for an individual to live to 100, but that a combination of several might occur in Supercentenarians.  Therefore, we should list all such longevity gene polymorphisms and examine Supercentenarians for some combination of them as well as additional, previously unidentified variations.

    3. Currently there are about 64 Supercentenarians known to exist worldwide, with approximately 20 of these in the U.S.  Estimates are that a few hundred are probably alive in the world.  With financial support the numbers of identified and validated Supercentenarians could be extended beyond those currently obtained with limited resources.Every year as some die off, others enter the ranks of Supercentenarians, adding to the numbers potentially available for study.

    4.  If necessary, the age range for genetic and other studies can be extended downward.  In a recent study Kojima T., et al. (Exper Geront 2004; 39:1595-1598) utilized 122 Japanese "semiSupercentenarians" aged 105 and more to provide a sufficient sample size to identify SNPs in the introns of the insulin receptor gene that were associated with the longevity of the subjects.  This approach could also be utilized in our anticipated investigations.


Before we can ask Mr. or Mrs. Zillionaire for their money, we need to have a well thought out Scientific Plan for how to proceed with aging research.This must be a plan that is not just dreamed up by one or two people.It must have your support and your endorsement.In fact we want you to help develop this plan.I have prepared an Outline for Scientific Research of Supercentenarians with the help of my colleagues which is included in the handout given you.We would like you to review this outline, suggest whatever changes you think are appropriate, and then take the specific items that are in your area of interest and expertise and expand the few lines to a paragraph or apage that describes how you think research for that project should proceed.You may think that this list is too long, but it is more likely too short.In order to define the causes and effects of aging we need to perform a very thorough examination that characterizes the biology and physiology of the subjects down to the cellular and molecular level.Realistically we won't be able to do everything on this list, but we should collect samples in such a way that future analyses can be performed as resources become available.We will ask the Scientific Advisory Board to complete this Scientific Plan and to select a few top priority projects for initial funding.They will need to develop a full research proposal for these few projects, including a schedule, a budget, and the selection of a Principal Investigator.Note that this is a targeted approach in which the Scientific Advisory Board recommends which projects should be funded.It is also targeted initially to Supercentenarians.The directed nature of how research will be funded will differentiate the SRF from other sources of funding.When the Scientific Plan is complete, the fundraisers can then take it to wealthy potential benefactors and show them exactly what we propose to do with their donations.



††††† ††††††††††††††††††††††† SUCCESS OF THE SRF DEPENDS ON:


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In order for the Supercentenarian Research Foundation to succeed, the activities of four groups must be effective:the management of the SRF, scientists of gerontology, financial supporters, and the Supercentenarians and their families.If any one of these groups does not fulfill its role, then the effectiveness of the SRF will suffer.In order to succeed we need your help.Here's what you can do:



††††† ††††††††††††††††††††††† WHAT YOU CAN DO:


††††† 1. Help develop the Scientific Plan

††††† 2. Volunteer to help the Directors and officers in the many tasks that are required

††††† 3. Volunteer to serve on the SAB

††††† 4. Suggest names of individuals to serve as Directors or officers

††††† 5. Ask your rich uncle to donate a few hundred million dollars

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A one-page response form has been included with the handout given you.In order to join us, please print your name, your E-mail address, your areas of interest and expertise, whether you would be willing to serve on the Scientific Advisory Board, the Board of Directors, or the Honorary Board.A pledge of money to help defray our startup costs would also be greatly appreciated.We will then E-mail you copies of the documents handed to you and keep you up-to-date on developments in the SRF.You can then return modified copies and your comments and suggestions to us.


We are currently in the process of selecting Directors for the SRF.It is our intent to achieve a balance between M.D.ís, scientific researchers, and business people for the BOD.Those who have agreed to serve if selected include:


SLIDES 12 - 15:

††††††††††††††††††††††††††††† DIRECTOR CANDIDATES


††††††††††† Doros Platika, M.D.

††††††††††† ††††††††††† President & CEO of the Pittsburgh Life Sciences Greenhouse

††††††††††† ††††††††††† Scientific advisor at MPM Capital

President & CEO of Centagenetix (worked with Tom Perls)

††††††††††† ††††††††††† President & CEO of Curis, Inc.

††††††††††† ††††††††††† President & CEO of Ontogeny, Inc.

††††††††††† Steve Coles, M.D., Ph.D.

††††††††††† ††††††††††† Director of the Gerontology Research Group -

provides a link to GRG work in identifying & validating Supercentenarians

participated in the autopsy of Elma Grace Corning

Assistant Researcher, Stem-Cell Technology and Longevity Medicine, Department of Surgery, UCLA David Geffen School of Medicine

Dave Gobel

††††††††††† Executive Director of the Methuselah Mouse Foundation

Founded Worlds Inc. that worked with Spielberg's Starbright Foundation

††††††††††† Co-founded Knowledge Adventure

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We have discussed several other names, but have not contacted them as yet.We would also welcome your suggestions


Those who would be willing to serve on the SAB include:



††††† ††††††††††††††††††††††† SCIENTIFIC ADVISORY BOARD CANDIDATES


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When we began our endeavor to organize the SRF, some of us tended to think in terms of a small organization that might eventually grow into a larger foundation.This has been called a "cottage industry," in which a small organization is run by a few friends with small goals.It didn't take long for us to realize that we should think BIG.And so, we want to look not at the little cottage (picture), but up at the skyscraper (picture) that we figuratively envision for the Supercentenarian Research Foundation.




[In two parts:Picture of a little cottage from Brazil;

picture of a large skyscraper from San Francisco.]