Funding Scientific Research
Since its inception in 1980, the Life Extension Foundation (LEF) has conducted scientific research that goes beyond the scope of academic institutions and biomedical companies. The purpose of this research is to identify and validate technologies that can delay/reverse aging and prevent premature death.
Mainstream research today is focused on how to treat heart attacks, cancer, Alzheimer’s disease and strokes. These are the diseases that we generally assume cause death.
What most doctors don’t yet recognize is that these devastating illnesses are caused mostly by aging. The Life Extension Foundation has provided more than $140 million to scientists across the country to look beyond the disease state and instead search for authentic anti-aging and anti-death solutions. Our objective is to prevent or postpone age-related disease, restore health, and provide much longer and higher-quality human life spans.
This annual report will inform you about the research programs we are funding and detail LEF’s commitment to meaningful scientific discovery. It outlines how Life Extension continues to fund targeted research into killer diseases such as cancer, cardiovascular disorders, immune dysfunction and neurological deficits. These programs are part of a strategic vision to limit or prevent diseases as we mature.
As described in the January 2014 issue of Life Extension Magazine®, the Life Extension Foundation has been funding many researchers who have been denied funding by the federal government. In 2013 the most spectacular example of success by these researchers was the study of naked mole rats by Andrei Seluanov and Vera Gorbunova, who are a husband and wife team at the University of Rochester in Rochester, New York. Dr. Seluanov has the second largest naked mole rat colony in the world. Naked mole rats are about the same size as mice, but live about ten times longer. The two scientists found that naked mole rat cells stop growing when the cells start to crowd each other.1 Cancer is uncontrolled growth of cells, which can quickly lead to crowding of cells ― something naked mole rats prevent. Dr. Gorbunova reported that she and her husband later discovered that naked mole rats secrete a form of hyaluronic acid that is five times larger than what human or mouse cells secrete. When the hyaluronic acid was removed from the naked mole rat cells, they became as vulnerable to cancer as mouse cells.2 That discovery was reported in the July 18, 2013 issue of the journal NATURE as a cover story. Thanks to funding from the Life Extension Foundation, the couple then discovered that naked mole rat protein synthesis is exceedingly error-free.3 Both of those discoveries caused the journal SCIENCE to name the naked mole rat the 2013 "Vertebrate of the Year.”4
The research of Dr. Gorbunova is concerned with how DNA damage and repair contribute to aging and cancer. DNA damage often leads to mutation and cancer, but DNA damage may also contribute to aging.5 She is hopeful that what she can learn about what causes DNA damage and what she can learn about facilitating repair of DNA damage can lead to a reduction of aging and cancer in humans. There has been much interest among life extensionists in resveratrol, a substance found on the skin of red grapes which some scientists believe has been shown to extend the life span of nematode worms.6,7 It was proposed that the ability of resveratrol to activate sirtuin activity is the basis of the benefits of resveratrol.8 There are seven sirtuins in mammals, numbered SIRT1 to SIRT7. The sirtuin in mammals that is activated by resveratrol is SIRT1.9 Resveratrol has been shown to protect obese mice from diabetes.10 SIRT6, on the other hand, is able to protect normal mice from DNA damage,11 and SIRT6 promotes repair of DNA damage. SIRT6 activity increases the DNA repair mechanisms for double-strand breaks. DNA double-strand breaks are dangerous. DNA lesions that can cause cell death or genomic rearrangements are frequently found in aged and cancerous cells. Activation of the SIRT6 gene in mice has been shown to extend their life span.12 Some rodents have a more effective SIRT6 gene than other rodents, so Dr. Gorbunova is seeking to understand the difference. Dr. Gorbunova is looking for chemicals that activate SIRT6 much as resveratrol is thought to activate SIRT1.
Robert Shmookler Reis, Ph.D., who is a professor at the University of Arkansas for Medical Sciences, Little Rock, Arkansas is another researcher who is being funded by the Life Extension Foundation after having been denied funding by the US federal government. His research career has been focused on the influence of genetics on longevity and the diseases of aging. Two decades after it was discovered that a genetic alteration could double the life span of the nematode worm, Dr. Reis was able to achieve a ten-fold increase in nematode life span.13 Humans who live over age 100 have been found to possess a similar gene alteration.14 With funding from the Life Extension Foundation he is hoping to find drugs that can produce similar disease-prevention and life-extending benefits.
João Pedro de Magalhães, Ph.D., is yet another researcher studying genetics for answer to questions concerning extending human health and longevity, but who was unable to do so with government support. Dr. de Magalhães is a Senior Lecturer (equivalent to an Associate Professor in the US) at the University of Liverpool, Liverpool, United Kingdom. Dr. de Magalhães is interested in the fact that the bowhead whale has not only been estimated to live over 200 years, but is able to remain disease-free until much more advanced ages than humans can.15 The mechanisms for the longevity and resistance to aging-related diseases of bowhead whales are unknown, but they must possess aging prevention mechanisms. In particular in the context of cancer, bowhead whales must have anti-tumor mechanisms, because given their large size and longevity their cells must have a massively lower chance of developing into cancer when compared to human cells.16 The Life Extension Foundation has provided funding for sequencing the genome of the bowhead whale. Understanding the bowhead whale’s exceptional longevity and resistance to diseases could lead to techniques to improve human health and longevity.
As described in the September 2011 issue of Life Extension Magazine, the Ellison Medical Foundation (created by software billionaire Larry Ellison) has spent hundreds of millions of dollars funding fundamental research on the biology of aging since 1998. Early in the fall of 2013, the Ellison Medical Foundation announced that this program is being discontinued. No reason has been given. The Life Extension Foundation is now funding three researchers who were previously being funded by the Ellison Medical Foundation.
Howard Chang, MD, PhD is an Associate Professor of Dermatology at Stanford University School of Medicine, Palo Alto, California. Dr. Chang believes that epigenetic (gene expression) changes in stem cells can be made that can reverse aging. Nearly all tissues in the body contain stem cells, which continually maintain tissue function. With age, however, stem cell function declines, causing a decline in tissue function. Dr. Chang has currently succeeded in measuring the gene expression of adult stem cells. He seeks to determine how gene expression changes with age, and then find drugs to reverse those changes. The resulting rejuvenation of tissues should reduce aging-associated diseases and help rejuvenate people for extended youth, health and longevity.
James Shorter, Ph.D., is an associate professor of Biochemistry and Biophysics at the School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania. Dr. Shorter has discovered that various heat shock proteins can prevent or reverse the kind of protein aggregation that leads to Alzheimer's disease, Parkinson's disease, Huntington's disease, and other aging-associated protein aggregation diseases. With funding from the Life Extension Foundation he has been finding or modifying heat shock proteins that are increasingly better able to reverse the amyloid-beta protein aggregation that occurs in Alzheimer's disease. He hopes to apply similar techniques to reverse the other protein that aggregates in Alzheimer’s disease, namely tau protein.
Victoria Belancio, Ph.D., is an assistant professor of Structural and Cellular Biology at Tulane School of Medicine in New Orleans, Louisiana. With funding from the Life Extension Foundation, Dr. Belancio has been studying the molecular biology of transposable elements ("jumping genes"). She has determined that the expression (and damage) of these elements is influenced by the host’s exposure to environmental light in an animal model of human cancer, a concept that has not been previously considered. She wants to determine whether the damage induced by these elements contributes to aging and age-associated diseases, such as cancer. She has also been studying how different light intensities at night influence DNA damage from these elements in rats. By learning how disturbances in circadian rhythm (such as is experienced by shift workers and world travelers) lead to genetic instability, cancer, and aging, Dr. Belancio hopes to demonstrate how intervention can mitigate the negative effects.
Every day in 2013, 1,600 Americans died of cancer,17 victims, to a great extent, of the antiquated but entrenched treatment system that relies on chemotherapy, radiation and surgery. Millions more are still alive, but survive with long-term treatment side effects, shortened life spans, and the omnipresent prospect of a cancer recurrence. Our war on cancer is just beginning.
In our quest to gain complete control over human aging, Life Extension Foundation is committed to reducing these appalling deaths from malignancies. Our support of innovative cancer research is one critical means to this end.
This cancer research progress report, authored by Orn Adalsteinsson, Ph.D., describes highlights of the Life Extension Foundation’s various cancer research initiatives over the past year.
LIT, or laser immunotherapy, uses a combination of local laser irradiation and local administration of GC, or glycated chitosan, at either primary or metastatic tumor site which creates a synergistic photothermal and immunological effect. The GC, which is given by intratumoral injection after laser irradiation of the tumor lesions, exerts an immunoadjuvant effect on metastatic cancers.
During laser irradiation, the treated lesion can reach temperatures of 60–70°C. The irradiated tumor cells swell and break into pieces, creating antigen sources which when combined with GC stimulates the host immune system to generate tumor-specific immune responses. GC is a unique adjuvant class of natural polysaccharides, or a compound that stimulates the immune system and increases the response to a vaccine, without having any specific antigenic effect of its own. GC has been found to enhance both humoral and cell-mediated immune responses.
Interestingly, GC can directly activate dendritic cells (DC), and enhance antigen presentation to DCs, causing proliferation of T cells. The combined thermal treatment and GC stimulation can achieve even higher levels of T cell proliferation which in short upregulates the immune system surveillance.
The key aspect of this approach is that the stimulated immune system attacks not only the primary tumor, but also metastases located anywhere in the body. Because those metastases often bear the same abnormal signal proteins as the primary tumor, they now essentially are marked for the body’s natural defense mechanism to seek out and destroy — no matter where they’ve moved to in the body.
As an added bonus, the immune system “remembers” the identifying markers of the cancer and continuously maintains surveillance to prevent future recurrence. In essence, laser-assisted immunotherapy creates a tiny “vaccine factory” within the victim’s body that throws the entire immune system’s resources at precisely that person’s own tumor.
When compared to existing treatments, which can be a dangerous mix of chemotherapy, radiation, and surgery — which many times do not cure the cancer, but can destroy an individual’s remaining quality of life — LIT is a superior treatment option.
While the initial LIT study has been completed for several years, we continue to follow the trial participants. Of the 15 subjects we reported on last year, 80% remain alive at over four years post-study. Furthermore, 6 of the 15 woman treated are disease free. Of the 15 women, 9 were stage IV or metastatic and 5 of these women are currently disease free. Compared to the typical United States survival rate for women with advanced breast cancer which is 23.8% at 5 years, the results of the LIT study are remarkable.
The Life Extension Foundation is continuing its support for additional laser immunotherapy techniques which allow for even broader applications than we have seen in the breast cancer trials.
Currently, the Life Extension Foundation is sponsoring a phase II clinical trial investigating DCA, short for dichloroacetic acid, for individuals who have stage IV cancer with solid tumors or prostate cancer and have failed conventional or investigational therapies, with limited options for further therapy.
DCA is a metabolic modulator which has been used for the treatment of lactic acidosis and inherited diseases of mitochondrial metabolism in humans for over 30 years. Preclinical in vitro and in vivo models have demonstrated the DCA’s beneficial potential in human cancers and there is 40 years of experience with mechanistic studies looking at human tissues after oral consumption, pharmacokinetic, and toxicity data. There is also data from 6-month randomized studies and 5-year use case reports, all which has supported early-phase clinical trials. Further, prior case studies and clinical trials have reported response to DCA in leukemia and lymphoma, prostate, breast, lung, and brain and nervous system cancers.
The metabolic profile of malignancy, or unopposed cell growth is one associated with various metabolic adaptations that preferentially utilize pathways involved with glycolysis, called the glycolytic phenotype (GP) of cancer. In this adaptation, the cancer cell diminishes, as well as undermines, the metabolic pathways of glucose oxidation (GO) used by normal cells for energy production as well as tumor cell elimination. One such function that is compromised involves the important mitochondrial function of programmed cell death (apoptosis). DCA, in effect, throws the metabolic switch so that cellular metabolism is side-tracked from the GP, and back to GO. In doing so, DCA restores the mitochondria’s apoptotic function and the ability to impair tumor cell proliferation.
To date, the DCA trial has recruited less than ¼ (or 6/40 subjects) of its evaluable 40 subjects mandatory to fulfill the study requirements. While there has been some evidence of tumor response to DCA there has also been some disease progression as well. However, it is early in the study process and there is insufficient data to evaluate or draw any conclusions thus far.
The rapid expansion in the use of Positron Emission Tomography, or PET scans to obtain metabolic information about cancer lesions can provide oncologists and their patients with extremely valuable diagnostic and treatment management information. PET scans use an injected radioactive tracer material like fluorodeoxyglucose (FDG) to produce functional imaging that can help differentiate benign from malignant masses, evaluate tumor stage, monitor response to therapy and detect tumor recurrence in a variety of malignancies.18 Coupled with the precise anatomical imagery produced by computerized tomography, FDG PET/CT can give rapid and accurate information about tumor size, location and rate of growth.
As useful as PET imaging can be, statistical errors can at times result in “false negative” or “false positive” reporting.19 Other issues that may trigger errors include improper PET scanner calibration with patient body weight, and the variability in FDG uptake depending on the elapsed time from when the radiotracer was injected into the patient. But the most egregious errors are perhaps due to incomplete or inconsistent scan interpretations caused by inadequate training and a lack of overall standards for the quantified reporting of results. Incorrect PET scans are common today and can result in improper treatments for cancer patients.
Working with radiologist Richard Black, MD, the International Strategic Cancer Alliance adopted invaluable PET reporting practices in its Life Extension-supported laser-assisted immunotherapy breast cancer trial. Dr. Black has interpreted more than 80,000 PET/CT studies, and his methodology for an across-the-board upgrade in PET scan reporting should be incorporated at the national level to provide oncologists and their patients with the full potential PET technology has to offer. The five key features of Dr. Black’s approach will assure that oncologists receive the same kind and quality of information on each and every scan, regardless of who interpreted the scan, or where it was taken.
Dr. Black presented his initial findings at one of LEF’s Scientific Advisory Board Meetings in 2012; his presentation can be viewed on the Life Extension website at the following URL: www.LEF.org/PET-CT
The critical need to develop superior cancer imaging tools cleared a major hurdle in December 2012, when a U.S. pharmaceutical giant agreed to sell the shelved research and development rights to Combidex, a revolutionary magnetic resonance imaging (MRI) contrast agent. Combidex-enhanced scans can detect metastatic cancer lesions too small to be seen by traditional PET/CT imaging.20
Life Extension continues to be a strong advocate of Combidex since helping with the negotiation of the sale of the Combidex technology package to Radboud University Medical Center in the Netherlands in 2012. In 2013, world-renowned radiologist Jelle Barentsz, MD, with the assistance of Life Extension Foundation through Orn Adalsteinsson, has begun the process of preparing the launching of multi-country research trials, which will ultimately lead to new license applications, a commercialized product and widespread patient access.
Combidex (ferumoxtran-10) is composed of a simple sugar compound, dextran, and superparamagnetic iron oxide, or USPIO.21 These extremely small iron crystals (25-50 nanometers in diameter), become powerfully magnetized when exposed to the magnetic field of an MRI scanner. The injected Combidex contrast fluid is taken up selectively by the macrophages (scavenger cells) that are primarily found in lymph nodes and other inflammatory tissue.21,22
Dr. Barentsz is one of the few physicians in the world to have worked extensively with Combidex technology, predominantly in prostate cancer cases. In one study, Dr. Barentsz and his team compared traditional CT scans and Combidex-enhanced MRI lymphangiography (MRL) for 375 prostate cancer patients, 16% of whom had lymph node metastases. CT imaging detected only 34% of the positive nodes, while Combidex MRL identified a remarkable 82%. The diagnoses were microscopically confirmed by either a lymph-node dissection or a needle biopsy. The study group concluded that Combidex-enhanced MRL is 96% accurate, and can eliminate the need for highly invasive surgical lymph node dissections.23
Combidex scans have also been used to successfully evaluate patients with cancers of the uterus,24 head and neck,25 kidney,26 breast,27 and liver.28
21st Century Medicine (21CM) is a small biotechnology company with large goals, and large accomplishments. Here are some of the recent achievements of 21st Century Medicine, none of which would have been possible without the support received from the Life Extension Foundation.
Organ transplantation could in principle save hundreds of thousands of lives every year in the United States alone, but this will require efficient means for moving organs from donor or from the laboratory to the recipient as well as better means of controlling organ rejection. Organ banking at cryogenic temperatures would solve these problems by a) enabling organs to be put “on hold” until they are needed, allowing for transportation and “just in time” use, b) allowing organs to be transplanted to ideally tissue-matched recipients rather than to poorly-matched recipients, and c) allowing time for recipients to be immunologically conditioned over several months while their specific designated organs are banked to enable the patients to receive the organs without rejection and without the need for lifelong immunosuppression. The problem has been that the technology for banking organs at cryogenic temperatures has been too difficult for most laboratories to entertain, let alone achieve. In 2013, 21CM made three breakthroughs that help to speed the day when the advantages of organ banking can be obtained by tens to hundreds of thousands of patients every year.
21CM has pioneered a technology called “vitrification,” or glass formation, for the cryopreservation of whole organs. Vitrification enables ice formation to be avoided regardless of how much the temperature is lowered. In principle, it is the ideal way to preserve complex systems, whose cell-to-cell arrangements are damaged by the physical intrusion of ice crystals, but the problem in the case of the kidney, 21CM’s main model organ, is that the center of the kidney (the medulla), takes up the agents that prevent ice formation too slowly, which results in over-exposure of the outside of the kidney (the cortex), with resulting toxicity. But in 2013, 21CM demonstrated a new perfusion method (i.e., a method for distributing the protective agents throughout the organ using the vascular system as the means of distribution) that speeds medullary uptake of protective substances without over-exposing the cortex. Detailed comparisons of the concentrations of protective agent (cryoprotectant) that prevent ice in all parts of the kidney versus the concentrations that cause toxicity showed that, based on kidney functional testing after transplanting the kidneys, kidneys can now be made immune to ice formation without increasing toxicity. This is a major breakthrough that has taken a great many years to achieve. It is the culmination of research dating from 1980, brought to fruition only because of Life Extension Foundation support.
Part of the secret of their success was defining in detail the liability of the kidney to ice formation at different warming rates. Because ice requires a certain amount of time to grow, faster warming rates result in less growth and therefore less damage. 21CM found that slow warming could not achieve sufficient ice control even using our new perfusion method, but a solution to this problem was found. Previous researchers had studied electromagnetic warming of frozen and even vitrified (though not viable) organs, but a re-analysis of the problem uncovered a superior approach that we implemented in 2013. Using the new warming technology, 21CM was able to achieve uniform warming at 160°C/min, but their whole kidney transplantation experiments showed that warming at 40-80°C/min would be sufficient for ice control after previous vitrification. 21CM believes they can achieve even faster warming in 2014, but they already have a safety margin of about 2-4 fold, which is extremely encouraging. Another advantage of the new warming method is that it turns itself off when the kidney has reached the ideal temperature for the beginning of cryoprotectant washout: the kidney heats at a maximum rate when it is most liable to form ice, and stops warming when it is free of the danger of ice formation. This technology may have many other applications, and will easily scale up to human organs.
Despite the beauty of vitrification as a method of cryopreservation of whole organs, it introduces a danger of crack formation below the temperature at which the organs revert from the liquid state to the glassy state (the glass transition temperature, at which biological change is essentially arrested as a result of the lack of mobility of the molecules in the living system). At the glass transition temperature, due to the lack of motion of the molecules in the system, thermal contraction stress cannot be relieved, so further cooling builds up stress and may result in cracking of the organ. This problem had been poorly studied in the past, but is essential to ensure the safety of cryogenic organ banking. 21CM found experimentally in 2013 that every organ in the body can be cooled to 6°C below the glass transition temperature without forming any cracks. 21CM even found that we could cool a liter of cryoprotectant solution to the temperature of liquid nitrogen without fracturing, and this liter of solution is expected to be more liable to crack than would be a whole organ, and is about as voluminous as most human organs.
Together, these observations poise 21CM for successful demonstration of kidney banking in 2014. 21CM also developed a pig model at 21CM that will allow them to vitrify and transplant not just rabbit kidneys (their model in 2013), but also pig kidneys, which are as large as human kidneys and should pave the way for application of 21CM technology in human clinical medicine.
Several years ago, 21CM demonstrated successful banking of human corneas, as shown by vital staining, light and electron microscopy, and transplantation into primates. What was missing was a feasible way of translating this accomplishment to the clinic. In 2013, 21CM was approached by a major eye institute about the possibility of performing human clinical trials. 21CM was requested to re-demonstrate their method using another measure of success prior to beginning human transplantation. 21CM chose the ability of the cornea to maintain its hydration during in vitro superfusion for up to about 30 hours, which is a common “acid test” of corneal function in vitro. Vitrified corneas performed nearly as well in this assay system as control corneas obtained from a cooperating eye, opening the door to human transplants in 2014. The benefits of the ability to bring sight to the blind all around the world, which is not presently possible given deterioration of control corneas during transportation outside the US, are self-explanatory. There is no other laboratory, or any other technology, that has been able to reproducibly preserve human corneas after vitrification, and the only theoretically competing method is not practical and is not being commercially pursued. Freezing is no longer used as a method of corneal banking due to its poor long-term effects.
In the last century, major advances in clinical hypothermia enabled previously intractable surgical problems, such as the ability to correct cerebral aneurysms, to be addressed for the first time. Still, the procedure has had its hazards, and, apart from one much older and non-definitive paper, no published method exists that allows the brain and the rest of the body to be put “on hold” for more than 3 hours, which may be inadequate for many purposes. In 2013, 21CM made major breakthroughs on hypothermic brain preservation, on the theory that the brain is both the weakest link in the whole body chain and the least studied organ in the body in terms of the effects of prolonged hypothermia. Through an extensive series of optimizations, and the use of novel pharmacological agents for this purpose, 21CM was able to preserve whole rabbit brains for 15 hours by continuous hypothermic perfusion with complete recovery of electrical in all brain regions, and with no diminution in perfusion rate over 15 hours. Previous investigation of brain ultrastructure showed excellent results even before the current advances, so 21CM believes ultrastructure is well preserved as well. Preliminary results after even 24 hours of preservation have been very encouraging as well, and even equal to non-preserved control brain results. 21CM began construction of equipment to enable testing of whole brain viability after hypothermic preservation in 2013 and will complete and implement this equipment in 2014.
21CM believes these results could enable the rescue of trauma victims and soldiers who cannot be helped with presently available technology. To further explore this possibility, 21CM is establishing a method for 24-hour hypothermic preservation of whole 80-kg pigs, and experiments are imminent. 21CM’s initial results will focus on perfusion rates, edema, histological integrity, and ultrastructural preservation, but 21CM will seek additional funding from an outside funding agency for more detailed studies of energy metabolism and the reversibility of extended hypothermic perfusion in whole large mammals. 21CM’s principle is that if they can preserve whole animals or brain preparations for very prolonged periods, there will be greater comfort in applying these methods under more critical circumstances for lesser periods of time given the very large margin of safety of the technology.