Download the PDF-format newsletter at the Methuselah Foundation website: http://www.mfoundation.org/newsletter
We feel it only appropriate to begin this issue of the newsletter by expressing our deepest gratitude to our donors. Your generosity during December and January - with $1,860,000 received or pledged in those two months alone - will allow the Foundation to more than double its spending on SENS research in 2008. As well as strengthening our existing research teams, we are now ready to initiate work in at least two more strands of the SENS program during the coming year; all thanks to the generosity of our supporters.
Understanding Aging
http://www.mfoundation.org/UABBA/
The Methuselah Foundation's world-class conference series continues this year with Understanding Aging: Biomedical and Bioengineering Approaches, running over June 28th and 29th at UCLA.
Understanding Aging will be preceded by a symposium on June 27th entitled Aging: The Disease, The Cure, The Implications, exploring the social implications of robust human life extension. Attendance at this
unique event is free, and we encourage everyone to invite their friends and family!
Ending Aging now Ending Print Run
Ending Aging - co-authored by Dr. de Grey and Michael Rae - is fast approaching the end of its initial 15,000 copy print run. This level of popularity is a notable achievement for a work of scientific non-fiction and has been reflected by the book's reviews:
"de Grey is hardly just another fountain-of-youth huckster... if even one of his proposals works, it could mean years of extended healthy living - not only for unborn generations but also for those of us already casting an uneasy eye toward the mirror."
- Paul Boutin - Wall Street Journal
"de Grey makes state-of-the-art scientific issues accessible to an intelligent layman."
- Arnold Kling, TCS Daily
"Ending Aging isn't an exhortation to change habits in order to live longer. It's a call to do whatever possible to generate interest in anti-aging research and advance the science."
- Janet Cromley, LA Times
A paperback edition of Ending Aging, including a new afterword bringing the scientific content right back up to the leading edge of current research, will be published in September this year. We're exploring options for making this updated content available, for free, to owners of the first edition.
1% For Life
A new donation program was recently launched at the Foundation. A brainchild of Dave Gobel, the 1% For Life program is a committed giving program where individuals or corporations commit 1% of their selected assets to the Foundation. For individuals the asset class would represent 1% of their net worth and would require a minimum $25K donation of liquid assets in order to join the program. For a company the asset class would be negotiated on a company-by-company basis. For example a startup company could donate 1% of their stock. For a larger established firm it could be, for example, 1% of daily/monthly or yearly sales.
Pioneering Artificial Intelligence company Novamente LLC has the distinction of being the first donor in this program having donated one percent of its common stock to the Foundation. Currently in stealth mode, San Francisco-based Novamente is working on revolutionary Artificial Intelligence products. Our very good friend Bruce Klein serves as Novamente's President.
The second donor to the program is Mediox, a Seattle based company, who have designed a high tech multimedia-enabled food service tray, called "SmartTray(tm)". Mediox's President Alex Zhavoronkov has donated 67,500 shares of his private equity to join the "1% For Life" donor group. Alex noted: "Helping extend human lifespan indefinitely has been my goal for many years. The Methuselah Foundation has a strategy and the tools required to combat aging and I am proud to have them as shareholders of Mediox, Inc."
Since many startup companies who will donate stock are privately held and in stealth mode, their donations may need to remain anonymous. Therefore, MF will likely have more donors but be unable to announce the donations. Methuselah Foundation and its subsidiaries will certainly be grateful for such donations and will respect such donor's wishes and needs.
Blogging Up a Storm
Support for longevity research among the internet community has never been stronger. There are two Methuselah Foundation-specific challenges currently underway:
The End Aging Challenge - organised by Foundation volunteer Kevin Dewalt - offers a $10 donation to Foundation research, in return for no more than a YouTube video response describing why you personally support life extension research. Take the challenge at http://www.youtube.com/watch?v=I8lKJCEyRaQ
Second is the Ending Aging owner's challenge - http://tinyurl.com/2uhq8s - which invites those who own Dr. de Grey's book to take a photo of themselves showing off their copy (preferably in a famous place!). Once 50 photos are collected, the organiser will donate $1,000 to SENS research - so if you own a copy, what are you waiting for?
In This Issue
The Foundation currently sponsors research in two of the seven strands of the SENS program: preventing the harm caused by mitochondrial mutations (MitoSENS) and degrading damaging, long-lived cellular debris (LysoSENS).
Our MitoSENS team is moving during this quarter to the laboratory of Dr. Marisol Corral-Debrinski in Paris. Corral-Debrinski's group is unique in the world in focusing specifically on allotopic expression, the technology that will eventually allow us to protect our life-sustaining mitochondrial genes from the mutations resulting from aging. Meanwhile, LysoSENS has continued to generate a stream of exciting results, including the publication of a peer-reviewed paper in the international journal Biodegradation.
Following the style of the first issue, the Progress Report section of this newsletter includes a full summary of our hosted projects. Next, Ben Zealley and Michael Rae present a selection of key advances in areas important to SENS, accomplished by laboratories outside the Foundation. Dr. de Grey then describes a selection of the upcoming projects for which the Foundation is now allocating initial funding. Finally, Elliot Bergman provides us with an update on the Mprize's new Scientific Advisory Board and other recent developments.
We hope you enjoy the newsletter, and welcome any comments or suggestions for the next issue!
Newsletter Editor: Ben Zealley (ben@sens.org)
Progress Report: MitoSENS
Mark Hamalainen
Institut de la Vision, Paris
This March, the Methuselah Foundation has transferred its MitoSENS research program to the lab of Dr. Marisol Corral-Debrinski in the newly opened Institut de la Vision in Paris. Dr. Corral-Debrinski began her career studying mRNA localization to the mitochondria in yeast, a process which she identified as essential for mitochondrial gene therapies. She now heads a lab that is applying the mRNA localization approach to the development of gene therapies for treating inherited mitochondrial diseases.
The same approach can potentially be used to treat the somatic mutations of mitochondrial DNA that play a definitive role in aging. For this reason, we have chosen to collaborate with her to hasten the development of gene therapies that may render such mitochondrial DNA mutations harmless.
Dr. Corral Debrinski's team has already achieved proof-of-principle by using their technique to complement three single gene mutations in cell culture, and has begun in vivo studies in the eyes of rats. The immediate goals of our collaboration will be:
1) to further validate her results by examining the efficiency in which the transgenic proteins are incorporated into mitochondrial complexes (using a technique called 2D Blue-Native PAGE),
2) to use her constructs with Dr. Michele Calos' phage integrase vector, which allows more efficient gene therapy with larger genetic payloads, and will allow us to co-express multiple mitochondrial genes simultaneously.
More details of the strategy underlying the MitoSENS program can be found on our website at http://www.mfoundation.org/mitosens/
Further Reading
Kaltimbacher V, Bonnet C, Lecoeuvre G, Forster V, Sahel JA, Corral-Debrinski M. "mRNA localization to the
mitochondrial surface allows the efficient translocation inside the organelle of a nuclear recoded ATP6 protein."
RNA. 2006 Jul;12(7):1408-17.
Bonnet C, Kaltimbacher V, Ellouze S, Augustin S, Bénit P, Forster V, Rustin P, Sahel JA, Corral-Debrinski M.
"Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts
harboring mitochondrial DNA mutations affecting complex I or V subunits."
Rejuvenation Res. 2007 Jun;10(2):127-44.
Progress Report - LysoSENS
Jacques Mathieu & John Schloendorn
Rice University & Biodesign Institute, Arizona State University
The LysoSENS Project has continued to advance at a rapid pace, both at Rice University in Houston and Arizona State University in Tempe. At Rice University, the focus has been on the elucidation of the 7-ketocholesterol (7KC) degradation pathway in a particular soil bacterium, Rhodococcus sp. RHA1. 7KC is suspected to be a main culprit in atherosclerosis and possibly also contributes to the progression of Alzheimer's disease. Our goal is therefore to identify and produce enzymes capable of degrading this molecule, and test them for the ability to ameliorate either condition.
The majority of the recent work at Rice has revolved around the data that was generated in a microarray study performed in collaboration with the University of British Columbia. Microarray experiments are used to determine changes in gene expression under different conditions, and this tool has revealed a number of genes we believe to be directly involved in degrading 7KC. We are currently in the process of verifying this data using realtime PCR, and plan to publish our findings in the near future. We are also working to clone some of the more promising genes into E. coli, which we will then use to over-express the enzymes for further testing.
In the meantime, the ASU team has identified an enzyme that catalyzes the first step in a degradation pathway of both cholesterol and 7KC. It is important to know the initial step of the process in order to plan therapeutic degradation routes, because the number of therapeutic enzymes that can be delivered is limited. However, it is not clear whether this particular enzyme is useful for therapy, because it also acts on cholesterol - a potentially harmful side reaction. The team is now investigating whether directed evolution methods can be utilized to make the enzyme lose its activity against cholesterol.
In science the saying is "publish or perish". Our first LysoSENS paper, "Microbial degradation of 7-ketocholesterol" - a joint publication between the Rice and ASU teams - has been accepted for publication in the international journal Biodegradation where it will appear in the March 15th issue. The paper reports our initial efforts to isolate and characterize 7KC-degrading bacteria.
More details of the LysoSENS program can be found on our website at http://www.mfoundation.org/lysosens/
Further Reading
Mathieu J, Schloendorn J, Rittmann BE, Alvarez PJ. "Microbial degradation of 7-ketocholesterol."
Biodegradation. 2008 Mar 15. (Epub ahead of print)
Current Goals
Aubrey de Grey
Chairman and CSO, Methuselah Foundation
In the last newsletter, I outlined a couple of the projects within the SENS plan that are ready to be launched as Foundation-sponsored research programs. I am engaged in ongoing discussions with the professors and young researchers whom I have identified as ideal recipients of funding for this work, with a view to initiating the projects this summer. Here I describe two more such projects.
Stimulating the death of exhausted ("anergic") white blood cells:
A key feature of our immune system is the mechanism whereby certain types of white blood cell, including a class called cytotoxic T cells, develop into a form in which they can aggressively attack a very specific class of foreign molecule - a protein on the surface of a virus, for example. If and when they are ever called upon to put that potential into action, they proliferate very rapidly so that there are enough of them in the blood stream to fight off the carriers of the molecule (which may, of course, be proliferating rapidly themselves). Most of these cells die after the invader has been dealt with, but some of them hang around in case the molecule is ever seen again - and they can re-proliferate much more rapidly the second time than the first time. However, probably as a defence against cancer of white blood cells (lymphomas), they eventually stop being able to perform this cycle of proliferation and death.
This is particularly important for T cells that respond to "persistent" viruses (ones that can never be completely removed from the body but instead hide out in a latent form), because viruses like that cause much more frequent reactivation of their cognate T cells than viruses that are only ever re-encountered via reinfection. Many immunologists now think that the accumulation of these exhausted T cells impairs the proliferation of other T cells specific for other foreign molecules, and thereby contributes to the decline of function of the immune system in the elderly. Various ways to eliminate these cells have been proposed, but there is currently no concerted effort to do it. I am in discussions with a top professor in this area with regard to our funding a project to develop such a procedure in mice and potentially thereafter in primates.
Rescuing failing bone marrow with telomerase-negative stem cells:
WILT, the SENS component that addresses cancer, is the most elaborate of all. One part of it is to deprive as many as possible of our cells of the ability to extend their telomeres, so that incipient cancers will wither away before reaching a life-threatening size. The other part, which is needed in order to nullify the side-effects of the first, is periodically to repopulate the stem cell compartments of our continuously-renewing tissues (the blood, skin, gut and lung) with new cells that are similarly unable to extend their telomeres but have initially long enough telomeres to last a decade or so. A big uncertainty in this idea is whether those cells will be competent to repopulate their respective tissues, or whether the absence of telomere elongation ability (specifically, of the enzyme telomerase) may have deleterious effects on either the stem cells themselves or their rarely-dividing neighbours (the "stem cell niche") over and about the telomere length issue. I have been discussing a project to address this question, specifically in the blood of mice, with the world's leading professor in that area.
SENS Around The World
Ben Zealley & Michael Rae
Research Assistants to Dr. de Grey
Alzheimer's Vaccines
Alzheimer's disease (AD) is the most common form of dementia and affects over 24 million people worldwide. Although the details of the disease's development are not completely understood, a significant role is played by the aggregation of amyloid beta (Abeta) proteins into insoluble "senile plaques" whose presence is strongly correlated with disease severity. Abeta plaques are also observed in some forms of Lewy body dementia and in cerebral amyloid angiopathy (CAA), a significant cause of strokes.
Abeta forms due to the sequential proteolytic cleavage of the amyloid precursor protein (APP) by the enzymes beta- and gamma-secretase. Most prospective therapies for AD focus on modulating the activities of these enzymes to reduce the rate of formation of Abeta. However, such approaches cannot prevent the ongoing damage caused by existing plaques. Some researchers consider secretase inhibition to be inherently risky as the enzymes have numerous other functions in the brain, including the processing of the critically important regulatory protein Notch.
An alternative tactic for tackling Abeta utilises the immune system to identify and clear plaques, an approach potentially able to act as a true vaccine by preventing the disease process from ever reaching a pathological level. Initial studies of this approach using the agent AN-1792 (produced by Elan Pharmaceuticals) ran into problems and clinical trials were halted when a small proportion (6%) of patients developed cerebral inflammation. Interestingly, and in spite of the inflammatory side-effects, a significant number of immunised patients did demonstrate stable memory test scores while placebo patients continued to worsen.
To reduce the risk of inflammation, recent immunotherapeutic approaches have focused on passive immunisation - the introduction of a purified antibody that can bind to and clear Abeta without inducing an active immune response. Although safer, passive immunotherapy does require regular injections of antibody to maintain protection. (Some researchers feel that this may in fact be beneficial for patients with existing clinical symptoms, as it avoids any risk of overwhelming the ability of the aged AD brain to clear a sudden rush of antibody-protein complexes.)
The most advanced candidate in this field is bapineuzumab (also known as AAB-001), produced again by Elan, in collaboration with Wyeth Pharmaceuticals. Bapineuzumab is a humanized monoclonal antibody that has received Fast Track designation from the Food and Drug Administration (FDA) for the treatment of mild to moderate Alzheimer's disease. Fast Track designation facilitates development and may expedite regulatory review of drugs that the FDA recognizes as potentially addressing an unmet medical need for serious or life threatening conditions.
On May 21st 2007, Elan and Wyeth announced their intention to begin an 18-month Phase III clinical trial of bapineuzumab in 4,000 patients. This news was received with surprise since the Phase II trials of the agent are still ongoing, with results due to be released later this year. Elan state that the decision to initiate a phase III trial was based on several factors, including a scheduled interim look at data from the ongoing phase II trials, and the continuing follow-up observations of those patients who participated in the earlier AN-1792 trial. It is very unusual for a company to consider funding the far more expensive Phase III process without concrete Phase II results, and many commentators consider this bullish attitude to be a significant show of confidence in bapineuzumab's efficacy and safety.
Despite Elan's enthusiasm there is still an open question regarding the safety of bapineuzumab, especially concerning the significance of FLAIR (fluid-attenuated inversion recovery) data obtained by MRI during the Phase I and II trials of the antibody. High-signal areas in FLAIR data can indicate microhaemorrhages, raising speculation that the vascular side-effects observed in previous passive immunisation experiments may still be an issue with bapineuzumab.
Human AD patients typically have symptoms of CAA, whereas most mouse models of AD typically do not. Cerebral microhaemorrhages have been observed in passive immunotherapy experiments in mice where CAA was present, raising concerns that immunotherapy against Abeta - active or passive - may always carry a risk of vascular complications.
Yet the speculations regarding bapineuzumab's safety are at least partly softened by the findings, by physicians supervising some of the FLAIR-positive patients who participated in the earlier trials, that there are as yet no indications of clinical symptoms. Further research is needed to sort out the issue.
Further Reading
Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K,
Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert
C, Walker S, Wogulis M, Yednock T, Games D, Seubert P. "Immunization with amyloid-beta attenuates
Alzheimer-disease-like pathology in the PDAPP mouse." Nature. 1999 Jul 8;400(6740):173-7.
Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K,
Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B,
Seubert P, Schenk D, Yednock T. "Peripherally administered antibodies against amyloid beta-peptide enter the
central nervous system and reduce pathology in a mouse model of Alzheimer disease." Nat Med. 2000 Aug;6(8):916-9.
Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D. "Passive
immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes
parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage."
J Neuroinflammation. 2004 Dec 8;1(1):24.
Bapineuzumab Phase III trial homepage: http://clinicaltrials.gov/ct2/show/NCT00575055
Knitting with Neurons
Medical nanotechnology - the use of materials with defined structure at the nanometer scale - looks set to become one of the most important areas of research and development in modern medicine. Dr. Ellis-Behnke of MIT's Brain and Cognitive Science department has published some of the most exciting work in the field, much of which was reviewed in his presentation at the SENS3 conference in 2007.
Ellis-Behnke's work has focused on self-assembling peptide nanofibre scaffolds (SAPNS), which have shown remarkable properties in several applications. Excess bleeding caused by trauma or occurring during medical procedures can pose a major risk to health as well as occupying considerable amounts of surgeons' time - in some surgeries, as much as 50% of theatre time can be occupied simply with packing wounds to reduce blood loss. Treatment of open wounds in a wide range of tissues with SAPNS resulted in full haemostasis (cessation of bleeding) in less than 15 seconds, without the use of pressure, cauterisation, desiccation, accelerated coagulation or chemical adhesives, all of which are associated with secondary damage and in some cases reduced effectiveness of long-term healing. Remarkably, SAPNS are non-toxic and non immunogenic, and are broken down and excreted harmlessly within a few weeks from application with no indications of accumulation or secondary toxicity in spleen, brain or lungs.
Promising as their haemostatic applications are, SAPNS have shown even more exciting results in models of severe neural injury. Here the materials benefit from their highly aqueous composition (up to 99.5% water by weight), which permits the injected scaffold to infiltrate arbitrarily shaped lesions and still form tight molecular contacts with the injured tissue.
In order to achieve regeneration after trauma to the central nervous system, multiple problems must be solved. Physical cavities in neural tissue, whether due to primary trauma or to phagocytosis of dead and dying cells after injury, prevents neurons from rejoining across the wound site; indeed, most adult neurons fail to initiate axonal regrowth at all, regardless of the scope of the damage.
SAPNS are able to bridge these gaps and literally re-knit the damaged tissue, while simultaneously providing a permissive environment for axonal regeneration. In hamster models where the optic tract is deeply transected, resulting in a 2mm wide wound, injection of SAPNS solution results in rapid, nearly complete repair of the injury. As well as axonal regeneration, restoration of functional vision (as demonstrated by visually guided behaviour) was observed in 75% of the experimental cohort. (Control animals treated with saline only showed no regeneration and no restoration of vision.)
The optic tract is not the only area where the scaffolds have been successfully applied. In subsequent work, Ellis-Behnke and coauthors have shown that a transection of the dorsal column of rat spinal cords can be similarly bridged by SAPNS, resulting in robust migration of host cells, accompanied by growth of blood vessels and axons into and through the injury site. Although preliminary, these results suggest that SAPNS will have widespread uses in neural injury repair.
The mechanism of regeneration by SAPNS is still not understood, but there are initial indications that the scaffold contracts after assembly, resulting in the physical knitting of damaged tissue and in turn permitting the subsequent regrowth of axons.
In Ellis-Behnke's own words; "This successful outcome gives us a glimpse of what
reconstructive brain surgery may hold for the future."
Further Reading
Ellis-Behnke RG, Liang YX, Tay DK, Kau PW, Schneider GE, Zhang S, Wu W, So KF. "Nano hemostat
solution: immediate hemostasis at the nanoscale." Nanomedicine. 2006 Dec;2(4):207-15.
Ellis-Behnke RG, Liang YX, You SW, Tay DK, Zhang S, So KF, Schneider GE. "Nano neuro knitting: peptide
nanofiber scaffold for brain repair and axon regeneration with functional return of vision."
Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5054-9.
Guo J, Su H, Zeng Y, Liang YX, Wong WM, Ellis-Behnke RG, So KF, Wu W. "Reknitting the injured spinal
cord by self-assembling peptide nanofiber scaffold." Nanomedicine. 2007 Dec;3(4):311-21.
Mprize: Ongoing Developments
Elliot Bergman
Mprize Competitor Development Coordinator
During the first quarter of 2008, Mprize development efforts have been concentrated in four major areas, covering all facets of the Prize competition from scientific governance to consideration of long-term investments in mouse testing facilities.
Firstly, we have established a Scientific Advisory Board (SAB), co-chaired by Professors Andrzej Bartke and Craig Cooney, and including three key Methuselah Foundation researchers as ex officio members. As current competitors, Professors Bartke and Cooney are ideally positioned to help identify, qualify and advise new applicants. Further members are currently being discussed and invited, with the first meeting of the SAB scheduled to occur during the May 30th-June 2nd 2008 meeting of the American Aging Association (AGE) in Boulder, Colorado. AGE's founder, Dr. Denham Harman, is widely known as the "father of the free radical theory of aging," first tested in mice in the 1950s; he would have been the first winner of the Mprize, had it existed at the time.
Secondly, we have begun to roll out a more aggressive business strategy to encourage and magnify the value of mouse studies, including both those involved in the Mprize and those undertaken by other groups. This has notably included work towards reducing the costs of lifespan work, especially the assessment of facilities in India and South Korea which are able to host high-quality, scientifically stringent studies with much lower costs. Professor Cooney has recently performed extensive calculations comparing a range of test formats, which we anticipate will further reduce trial costs and speed the introduction and evaluation of new treatments.
We continue to encourage our competitors to work towards the Rejuvenation arm of the Mprize, reflecting the strong preference our donors have shown for treatments able to help those already in the latter part of life. Our ability to source healthy, middle-aged mice (14-16 months old) at minimal cost will be crucial to the recruitment this year of two new teams working in Australia and the USA.
Thirdly, we have continued our focus on identifying, qualifying and recruiting new competitors, with up to 15 teams anticipated to be actively competing by end of this year. Some of our present competitors, including Professor Bartke, have also disclosed to us new protocols which they will soon introduce. A full list of competitors can be found on the Mprize website, at http://www.mprize.org/competitors.
Finally, we have initiated a pilot program of mentoring in vitro tests of putative lifespan extending compounds as a preliminary stage to more expensive mouse trials. The first results from this program will be announced at AGE 2008.
We're pleased to be able to congratulate competitor Dr. Alan Cash on his recent selection for participation in the National Institute on Aging's Interventions Testing Program, a large scale, multi-institutional study evaluating dietary treatments possibly able to delay aging and aging-related disease in mice. As the ITP accepts only 4-5 new applications per year, Dr. Cash's inclusion represents a major show of confidence in his approach.
