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From the desk of Methuselah Foundation chair, Aubrey de Grey:
I'll be writing soon to update you on the progress we're making at the Methuselah Foundation. Following the successful conclusion of the third SENS conference in Cambridge, and the recent publication of my book, "Ending Aging", which has received uniformly favourable reviews, I feel that we're turning the corner - the plausibility of retarding and eventually reversing aging is beginning to percolate into the public consciousness.
A telling sign of increasing mainstream acceptance of our work at the Methuselah Foundation is the invitation I recently received to speak at the prestigious Stem Cell Summit to be held in Boston on October 2nd and 3rd. On 3rd October I will be attending the session on aging, followed by heading a table at the "Conversations with Experts" luncheon.
http://www.thestemcellsummit.com
http://www.thestemcellsummit.com/pdf/Agenda.pdf
Perhaps I might see you in Boston !
Since we last welcomed new supporters to the Methuselah Foundation's Three Hundred, both SENS3 and the launch of Ending Aging have taken place, bringing a flurry of donations and new faces. Please welcome this brace of new members to the Three Hundred, philanthropists of vision and modest means who see a way clear to the defeat of aging: Neil Kauffman, Michael Yamashita, Erik Dumas, Art Fritzson, Julie and Mark Connard, SychDeli, Prometheus, John Onysko, and Joseph P Jackson III.
In chemistry, a catalyst is a substance that vastly accelerates the rate of a chemical reaction by lowering the activation energy required; wonderful things (like life) then occur which would otherwise take an eternity or not happen at all! The Mprize is just such a "social catalyst," one that can shake humanity from its pro-aging stupor. Today, each human born on this earth is sentenced. Not sentenced to death, since perhaps we could come to terms with eventual oblivion. No, the horrible truth is that we are sentenced to live. Built to break down, and made to wither away, we are forced to witness our own demise - first a gradual decay then an accelerating spiral of frailty. On top of this biological damage, society imposes an equally devastating plague - social aging - the rigid hierarchies, labels, and roles that have co-evolved to "ease" the transition into obsolescence. Enough! This cycle of despair ends now, in the first few decades of the 21st century. Never doubt that the powers of creativity, intelligence, and love can triumph over any adversity. It is a joy and privilege to join a group whose mission is nothing less than to heal the world.
Well said, and welcome aboard.
Here is a second report from Michael Rae on the third Strategies for Engineered Negligible Senescence conference (SENS3):
Attendees at SENS3 heard first-hand about an extremely exciting approach to cancer treatment that has not yet hit the scientific literature or the press. In 2003, Dr. Zheng Cui and his colleagues at the Comprehensive Cancer Center of Wake Forest University reported the discovery of mice with immune cells that rendered them invulnerable to cancer: they had been intentionally giving mice cancer by injecting them with virulent cancer cells as part of a separate study, when they discovered a single mouse in the colony that was completely immune to the invasive cells.
His curiosity piqued, Dr. Cui went on to show that it could resist multiple rounds of such injections, and were so impressed that they used him to father a whole colony of mice, all of whom shared this remarkable invulnerability to cancer. Based on that ability, he calls them spontaneous regression/complete resistance (SR/CR) mice.
Last year, Dr. Cui electrified the world when he showed that the new strain's cancer-fighting abilities were caused by a particular subset of their immune cells -- members of a class of white blood cell known as neutrophil granulocytes. These cells are from the innate immune system, meaning that they don't have to "learn" to identify a narrowly-defined enemy, but are constantly on the lookout for broadly-defined "foreign" cells. They are a kind of phagocytic cells, surrounding, engulfing, and digesting their targets when they find them.
Dr. Cui tested the ability of these cells to fight off cancer by transfusing them into normal mice with cancers. Surprisingly, the simple transfusion of the cancer-fighting immune cells from the resistant mice effectively transfered the same remarkable protection to the normal mice. And even more excitingly, the treatment didn't just prevent cancers from forming, but actually fought off existing cancer: when researchers transfused the anti-cancer white blood cells into normal mice with existing skin tumors, the tumors regressed completely in a matter of weeks. Moreover, a single dose of the cancer-fighting immune cells gave the normal animals a cancer immunity that often lasted for the rest of their lives.
At SENS3, Dr. Cui presented the next logical step in his research: work demonstrating the existence of, and characterizing, high-potency cancer-killing granulocytes in humans.
Dr. Cui's team first went looking for the existence of potent cancer-killing granulocytes in a group of healthy volunteers. This was done by testing the volunteers' granulocytes' ability to destroy cancer cells in a petrie dish. They found that, unlike in mice (who seem to have an all-or-nothing effect), there appears to be a classical bell-shaped distribution of cancer-killing ability in the granulocytes of people in the population: a few people have white blood cells extremely weak cancer-killing activity, the great majority have an 'average' competence, and a very small group of outliers have the kind of overwhelming search-and-destroy activity (at least in a test tube!) that is seen in the SR/CR mice.
Surprisingly, they found that the ability of peoples' granulocytes to kill cancer is very sensitive to the season. Looking at the efficacy of granulocytes drawn at samples taken year round, he found that the activity is strong in the sunnier months (May to September) and falls off dramatically in the gloomier ones (November through April). The reason for this effect is unknown, but it could be connected to other things that vary with the number of hours of daylight and that are connected to cancer risk, such as the circadian-rhythm hormone melatonin or the "sunshine vitamin," vitamin D3.
He also found that the cancer-killing capacity could be "abolished" by stress: in one anecdote, a grad student from his lab at Wake Forest had been tested just after making his first presentation at a scientific conference, and the normally high level of cancer-fighting activity in his granulocytes was severely depressed. Re-testing him several days later, the activity of his granulocytes had bounced back to normal.
And, unsurprisingly, preliminary evidence suggests that cancer-fighting ability appears to fall off with biological aging, and is even lower in cancer patients. An interesting question for future research will be whether low cancer-fighting activity precedes cancer incidence (suggesting that the lack of resistance was a key factor in developing cancer) or followed it (suggesting that the disease process weakens their natural immune resistance sufficiently to overwhelm these cells' cancer-killing activity).
Based on these promising findings, Dr. Cui applied to test the transfusion of granulocytes from highly cancer-resistant people into people with existing cancer -- a potential therapy he calls "GIFT" (for "Granulocyte InFusion Therapy"). He now has approval from both the IRB and FDA to move ahead with the trial, and the next step is to raise the necessary funding.
Z. Cui, I. Molnar, M.C. Willingham, G.J. Pomper, J.R. Stehle, M. Blanks
From a newly discovered innate anticancer immune response in mice to a new treatment for human cancers http://www.sens.org/sens3/abs/Cui.htm
Michael Rae reports from the proceedings at SENS3:
Among the most exciting presentations at the third conference on Strategies for Engineered Negligible Senescence (SENS3) were those in Friday's session on the rescue of mitochondrial mutations. This is a subject to which Conference organizer and Methuselah Foundation Chief Science Officer Dr. Aubrey de Grey has made widely-recognized contributions.
Unlike most other parts of the cell, mitochondria house many of the genes encoding their essential proteins within themselves. These genes are vulnerable to the constant assault of free radicals produced by the mitochondria as a side-effect of their role as cellular power plants. When mitochondrial DNA is damaged, it cannot make the proteins needed to carry on the essential business of generating energy for the cell; the ensuing metabolic damage is the driver of age-related rise in oxidative stress. This oxidative stress fuels free radical damage and interferes with essential signaling pathways in cells far from the original site of the damage.
Dr. de Grey first proposed an 'engineering' solution to this form of aging damage in 1998: the use of allotopic expression -- the creation of 'backup copies' of those genes in the safer confines of the nucleus -- in 1998. In Friday's SENS3 session, several researchers presented their recent work aimed at advancing this and other potentially useful approaches to mitochondrial damage.
PhD candidate Mark Hamalainen of Cambridge University presented the initial success in his Methuselah Foundation-funded work on allotopic expression, showing evidence that his allotopically-expressed genes could encode the relevant proteins and that these were taken up into the mitochondria. In this case, the genes encode healthy and defective versions of the protein that is miscoded in Neuropathy, Ataxia and Retinitis Pigmentosa (NARP), a hereditary mitochondrial disease characterized by blindness and weak and uncoordinated muscles. Well done! It is good to see Foundation-funded research make such solid progress; many thanks go to the generous donors who have made this possible.
Dr. Marisol Corral-Debrinski, of Paris' Quinze-Vingts National Center of Ophthalmology, presented a dramatic step forward with a technique whose effectiveness she had preliminarily confirmed with several allotopically-expressed proteins, that result published in Rejuvenation Research. The technique involves shifting the production site of such proteins closer to the mitochondria themselves, allowing the cell's machinery to thread the proteins through the narrow straits of the mitochondria's import channels as quickly as they are produced. This prevents the proteins from folding back up on themselves, which makes them harder to import. In her recently-published work, she tested her technique by using it to allotopically express several proteins in cells defective for the relevant genes, restoring their ability to generate energy and sustain cellular life. Now Dr. Corral-Debrinski has leapt forward into a living organism, inserting an allotopic version of the defective human gene that causes the mitochondrial disease Leber Hereditary Optic Neuropathy (LHON) into mice retinas. LHON causes blindness in humans, and allotopic expression of the gene caused the same cell loss and abnormal lack of cell communications branching that appears in the disease. Dr. Corral-Debrinski next hopes to take this to the next level, and cure the disease in mice by introducing the healthy gene.
Another way of easing the entry of twisted-up (and thus hard to import) allotopically-expressed proteins is through the introduction of special 'bracing bars' called inteins into the proteins. The inteins hold apart their snarling bends and kinks -- an idea first proposed by Dr. de Grey in a 2000 paper in Trends in Biotechnology. After some preliminary work by Japanese scientists, the University of Zaragoza's Dr. Antonio Enriquez has now picked up the ball, and described his early work with mitochondrial protein inteins during this session.
In addition to the work on allotopic expression, two presentations were given summarizing soon-to-be-published progress on entirely novel ways of overcoming the problem of mitochondrial mutations: the import of whole new mitochondria into the cell by Dr. Volkmar Weissig of Northeastern University. Reviewers initially found his results unbelievable, until he pointed out that it had actually previously been reported - and then forgotten! - by Israeli scientists in 1984. Remarkably, Dr. Enriquez was able to confirm that both he and a Cambridge University lab had independently confirmed this result in recent years, but had never been able to follow through with the additional work required to publish the result in a journal.
Finally, Dr. Samit Adhya of the Division of Molecular and Human Genetics at the Indian Institute of Chemical Biology is pursuing yet another innovative approach. He proposes to dispense with the need for mitochondrial DNA altogether, by instead providing the mitochondrial protein-making machinery directly with the "working instructions" (messenger RNA) that it normally receives in the form of a transcribed copy taken from the mitochondrial DNA originals. This would allow the mitochondria to continue their protein production even if the mitochondrial DNA were completely destroyed: they would still have their marching orders, even if the general himself were incommunicado. Dr. Adhya is accomplishing this goal by borrowing a trick used by a single-celled organism called Leishmania tropica. This organism, unlike mammals, generates another kind of RNA in the main cell body, and uses a specialized protein to move it into the mitochondria. Dr. Adhya reasoned that he could bind copies of our own RNA to the same protein and use it to deliver both kinds of RNA into mammalian mitochondria, bypassing the need for a DNA original. Very clever.
Using a tagging protein, Dr. Adhya first showed that he could in fact move such RNA into mammalian cells. But how to show that it was working? A normal cell already has the needed RNA, so the functionality of such cells would not be improved by adding more. This means that you can't distinguish a cell whose mitochondria has integrated and used such imported RNA to make proteins from one that hasn't.
Like Dr. Corral-Debrinski, Dr. Adhya decided to work backwards as a preliminary test. Instead of delivering more of the functional RNA, Dr. Adhya introduced antisense RNA -- RNA that is designed as a mirror-matched copy of the original, to which it binds and inactivates. He chose antisense RNA that would block the action of the RNA that delivers instructions copied from the gene whose mutations cause a human mitochondrial congenital disorder called Myoclonal Epilepsy with Ragged Red Fibers (MERRF). If Dr. Adhya's protocol could cause mitochondria to take up and translate the antisense RNA, it would interfere with the animals' mitochondrial function in exactly the same way as occurs in the human disease, recreating the muscle-wasting symptoms to which victims are subjected.
While we can't yet draw definitive conclusions, all of Dr. Adhya's results are consistent with success. In some of the most visually arresting presentations of the conference, Dr. Adhya showed how injecting the RIC-linked antisense RNA into the legs of rats quickly caused the same kind of leg muscle degeneration seen in MERRF; when examined under a microscope, muscle cells from such animals showed the death of muscle fibers and the loss of mitochondrial function.
The next step will be to introduce functional RNA into animals with dysfunctional mitochondrial genes. If this restores normal mitochondrial function and blocks the symptoms and pathology associated with the disease, we'll know for sure that the RNA import technology works. This would allow us to sidestep not only the mutations in the mitochondrial DNA of those rare and unfortunate souls who suffer with congenital mitochondrial diseases, but those responsible for the universal mitochondrial failures of aging.
We live in exciting times! You can read the summaries of the conference presentations at the SENS website; references are below:
PhD candidate Mark Hamalainen
Holt IJ, Bokori-Brown M, Hamalainen M.
Allotopic expression: mitochondrial to nuclear gene transfer.
Rejuvenation Res. 2007 Sep;10(Suppl1):S32(Abs53).
http://www.sens.org/sens3/abs/Holt.htm
Dr. Marisol Corral-Debrinski
S. Ellouze, C. Bonnet, S. Augustin, V. Kaltimbacher, V. Forster, M. Simonutti, J-A. Sahel, M. Corral-Debrinski
Allotopic mRNA localization to the mitochondrial surface: a tool for rescuing respiration deficiencies
Rejuvenation Res. 2007 Sep;10(Suppl1):S24(Abs 23).
http://www.sens.org/sens3/abs/Corral.htm
Dr. Antonio Enriquez
J.A. Enriquez
Inteins and allotopic expression of mtDNA encoded proteins
Rejuvenation Res. 2007 Sep;10(Suppl1):S28(Abs 36).
http://www.sens.org/sens3/abs/Enriquez.htm
Dr. Volkmar Weissig
V. Weissig, E. Katrangi, S.V. Boddapati, G.G.M. D'Souza
Manipulating the mitochondrial genome
Rejuvenation Res. 2007 Sep;10(Suppl1):S50(Abs 124).
http://www.sens.org/sens3/abs/Weissig.htm
Dr. Samit Adhya
S. Mukherjee, B. Mahata, B. Mahato, S. Adhya
Use of a parasite-derived protein complex to modulate the function of mitochondria in human cells
Rejuvenation Res. 2007 Sep;10(Suppl1):S19(Abs 2)
http://www.sens.org/sens3/abs/Adhya.htm
Scientists and volunteers attending SENS conferences traditionally get together for a group picture before punting on the river Cam. Here are a few pictures of that gathering from the third conference on Strategies for Engineered Negligible Senesence (SENS3), held earlier this month:
As I'm sure you all know, the third conference on Strategies for Engineered Negligible Senesence (SENS3) is underway; a full schedule of presentations on rejuvenation, aging and longevity research research for those attending.
The purpose of the SENS conference series, like all the SENS initiatives (such as the journal Rejuvenation Research and the Methuselah Mouse Prize), is to expedite the development of truly effective therapies to postpone and treat human aging by tackling it as an engineering problem: not seeking elusive and probably illusory magic bullets, but instead enumerating the accumulating molecular and cellular changes that eventually kill us and identifying ways to repair -- reverse -- those changes, rather than merely to slow down their further accumulation.
Methuselah Foundation COO David Chambers has once again provided us with pictures of longevity-minded scientists in their natural habitat: between presentations, catching up on news and discussing prospects for the future. As for SENS2, it's quite a crowd - to go along with the impressive list of abstracts and talks.
Members of the Methuselah Foundation's Three Hundred gathered for the second Three Hundred dinner in Cambridge on the evening of the 5th. This was just prior to the SENS 3 conference, presently in full swing.
I'm told a good time was had by all. David Chambers, Foundation COO, smuggled out some pictures of the event: here they are, capturing our generous donors, Foundation volunteers, a good dinner and numerous signed copies of Ending Aging:
Aubrey de Grey, Methuselah Foundation chair, and Michael Rae see their new book "Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime" launch today. Congratulations are due to all those whose hard work helped make this possible.
Nearly all scientists who study the biology of aging agree that we will someday be able to substantially slow down the aging process, extending our productive, youthful lives. Dr. Aubrey de Grey is perhaps the most bullish of all such researchers. As has been reported in media outlets ranging from 60 Minutes to The New York Times, Dr. de Grey believes that the key biomedical technology required to eliminate aging-derived debilitation and death entirely - technology that would not only slow but periodically reverse age-related physiological decay, leaving us biologically young into an indefinite future - is now within reach.
In Ending Aging, Dr. de Grey and his research assistant Michael Rae describe the details of this biotechnology. They explain that the aging of the human body, just like the aging of man-made machines, results from an accumulation of various types of damage. As with man-made machines, this damage can periodically be repaired, leading to indefinite extension of the machine's fully functional lifetime, just as is routinely done with classic cars. We already know what types of damage accumulate in the human body, and we are moving rapidly toward the comprehensive development of technologies to remove that damage. By demystifying aging and its postponement for the nonspecialist reader, de Grey and Rae systematically dismantle the fatalist presumption that aging will forever defeat the efforts of medical science.
If you'd like a better understanding of the research program funded by the Methuselah Foundation and our generous donors, then this is the book for you.
Methuselah Foundation Announces the Re-entry of Former Prize Winner Professor Andrzej Bartke, PhD, into the Mprize Competition
The Methuselah Foundation is pleased to announce that Professor Andrzej Bartke has again taken up the challenge to compete in the Mprize competition. Professor Bartke is Professor of Physiology and Internal Medicine, Director of Geriatric Medicine and Distinguished Scholar at Southern Illinois School of Medicine. The Mprize, a scientific research prize aimed at encouraging scientists to find a way to reverse the aging process, is a primary activity of the Methuselah Foundation. The Mprize fund continues to grow and currently stands at close to $4.5 Million. Prizes will be awarded to research groups that can most successfully extend the life span of laboratory mice.
"Few people not directly involved in gerontological research are fully aware of the exciting developments in the study of aging, and what I feel is the very real prospect of devising effective means of postponing age-related disease and functional decline and, yes, prolonging life."
- Professor Andrzej Bartke
Professor Bartke won the Longevity Mprize in 2004 when a Growth Hormone Receptor gene knockout mouse bred in his laboratory, from animals developed by Professor John Kopchick, reached a record age of nearly five years. Professor Bartke remains very active in anti-aging and age-related diseases medicine. He holds a confirmed belief and strong interest in continuing to use mice as proxies for humans to speed up aging research.
Since winning the Mprize for Longevity, Professor Bartke has continued his mouse aging research in several new directions including:
- the interactions of mouse longevity genes with caloric restriction
- the role of altered insulin signaling in mediating the effects of growth hormone on longevity
- the effects of hormonal therapy during development
- the characterization of novel mutants affecting GH-IGFI axis
Of particular note is Professor Bartke's research into the importance of insulin, Growth Hormone ("GH") and Caloric Restriction ("CR") on the aging processes. Work at his laboratory on the phenotypic characteristics of long-lived mouse mutants, enhanced sensitivity to insulin actions, combined with reduced insulin secretion and organ-specific alterations in the expression of genes related to IGFI and insulin signaling, as well as his collaborative studies on increased stress resistance are important scientifically, representing a bridge between the information obtained from lower organisms and the quest to understand the mechanisms of human aging.
Professor Bartke's beliefs in the value of mouse research can be summed up in his recent observation:
The mouse is unique for accelerating aging research because it provides a very workable mammalian system for the study of genetic, hormonal and nutritional influences on aging, age-related disease and longevity
The Methuselah Foundation is delighted that Professor Bartke has decided to re-enter the Mprize competition and wishes him and his team success in their ground-breaking research.
About the Methuselah Foundation
The Methuselah Foundation is a non-profit 501(c)(3) organization dedicated to accelerating the development of foreseeable, science-based therapies to combat aging. Its main activities are the funding of SENS research, and the Methuselah Mouse Prize, which is being offered to the scientific research teams that significantly extend the lifespan of middle-aged laboratory mice. Further details of the Methuselah Foundation can be found at: www.methuselahfoundation.org
About Professor Andrzej Bartke
Professor Bartke is currently Professor of Physiology and Internal Medicine, Director of Geriatric Medicine & Distinguished Scholar at Southern Illinois School of Medicine. Professor Bartke earned his MSc in Biology at the Jagiellonian University, Krakow, Poland and his PhD in Zoology (Genetics) at the University of Kansas. He was Assistant Professor of Genetics at his Krakow alma mater, Post-doctoral Fellow and later Scientist and Senior Scientist at the Worcester Foundation for Experimental Biology, and Associate and then Professor at The University of Texas Health Sciences Center at San Antonio. Since 1984, Professor Bartke has been Professor and Chairman, Department of Physiology, Southern Illinois University, assuming his current position in 2002.
Professor Bartke has received numerous honors and awards from a broad array of prestigious scientific societies, conferences and publications. He has been an Officer and Director of some of these organizations and Editor of some of their scientific journals. His awards include an Honorary PhD from Lodz Medical University, Poland in 2007 and the coveted Denham Harman Lifetime Achievement in Research from the American Aging Association ("AGE") in 2005, an organization of which he was President during 2004-2005.
Professor Bartke's scientific contributions also include:
- Training and qualifying many PhD, MSc and Post- doctoral students
- Extensive publications: 507 papers, 113 review articles and book chapters, and 11 books.
His research work has been supported by agencies such as the NIH, The Ellison Medical Foundation and The Glenn Foundation for Medical Research.
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