Funding Scientific Research
Since its inception in 1980, Life Extension (LE) 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. Life Extension has provided more than $175 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 LE’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.
Every day in 2013, 1,600 Americans died of cancer,1 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 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 Life Extension’s various cancer research initiatives over the past year.
Life Extension is funding a pancreatic cancer trial at City of Hope Hospital in Los Angeles, California with a 21-person target enrollment. The clinical trial includes a supplementation package to be used with standard pancreatic cancer drugs. The clinical trial continues to accrue patients with a targeted completion date set for 2018.
Study title: A Pilot Study of Gemcitabine, Abraxane, Metformin and a Standardized Dietary Supplement (DS) in Patients With Unresectable Pancreatic Cancer
Patients receive gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) on days 1, 8, and 15. Patients also receive metformin hydrochloride orally (PO) twice daily (BID) starting day -6 and dietary supplement PO BID starting day -3. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months.
This pilot phase I trial studies the side effects of gemcitabine hydrochloride, paclitaxel albumin-stabilized nanoparticle formulation, metformin hydrochloride, and a standardized dietary supplement in treating patients with pancreatic cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Metformin hydrochloride, used for diabetes, may also help kill cancer cells. Dietary supplements (curcumin, vitamin D, vitamin K2, vitamin K1, B-6, high selenium broccoli sprouts, epigallocatechin gallate, L-carnitine, garlic extract, genistein, zinc amino chelate, mixed toxopherols, ascorbic acid, D-limonene) can block different targets in the cancer cell simultaneously and may slow down cancer growth. Giving gemcitabine hydrochloride, paclitaxel albumin-stabilized nanoparticle formulation, and metformin hydrochloride with a dietary supplement may work better in treating patients with pancreatic cancer that cannot be removed by surgery.
Pancreatic Adenocarcinoma Unresectable Pancreatic Carcinoma
Drug: Gemcitabine Hydrochloride Drug: Paclitaxel Albumin-Stabilized Nanoparticle Formulation Drug: Metformin Hydrochloride Dietary Supplement: Therapeutic Dietary Intervention Other: Laboratory Biomarker Analysis Other: Quality-of-Life Assessment
Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment Masking: None (Open Label)
Primary Purpose: Treatment
Primary Outcome Measures:
Secondary Outcome Measures:
Other Outcome Measures:
Study Start Date:
Estimated Study Completion Date:
Estimated Primary Completion Date:
January 2018 (Final data collection date for primary outcome measure)
Dichloracetate , GcMAF, and Chemotherapy
Based on the results of the DCA study and work looking at the combination of DCA and GcMaf, Örn Adalsteinsson, Ph.D., of the International Strategic Cancer Alliance (ISCA) and his associates, have launched a Phase I/II clinical trial to determine if the generic drug dichloracetate (DCA), combined with a low dose or metronomic chemotherapy, and a vitamin D cofactor called Gc macrophage activating factor (GcMAF) are able to induce partial &/or complete remissions in cancer subjects with a variety of malignancies. The three-month trial is taking place at a highly-regarded private clinic in the Caribbean, and is open to 20-40 participants who have failed conventional or investigational cancer therapies and have few options for further treatment. The DCA and chemotherapy are orally administered once daily for 12 weeks, while the GcMAF is injected subcutaneously once a week for 12 weeks. Participants also receive optimized nutritional supplements.
DCA is a metabolic modulator that retards the breakdown of glucose to lactic acid, interfering with the glucose uptake that is crucial to cancer cell survival. By suppressing the enzyme PDK (pyruvate dehydrogenase kinase), DCA disrupts aerobic glycolysis and essentially starves cancer cells of glucose, their primary fuel, which in turn induces apoptosis (normal cell death), decreases cancer cell proliferation, and inhibits tumor growth.2 DCA's low toxicity produces only mild side effects at effective doses, with peripheral neuropathy being the most commonly reported adverse side effect.3 Of the hundreds of studies published about DCA in the past 30 years, most relate to its use in treating the rare childhood disease congenital lactic acidosis. Only about a dozen, mostly in vitro, studies have documented DCA's efficacy as an anti-cancer agent, with several in vivo studies showing that DCA can induce apoptosis in epithelial ovarian cancer cells4 and malignant brain tumors.5 DCA was able to upregulate the apoptotic function by depolarizing the mitochondria and increasing mitochondrial reactive oxygen species.6
GcMAF has demonstrated some complete remissions on its own in patients who participated in three separate trials on breast,7 prostate,8 and colorectal cancer.9 The mechanism of action involves resupplying the Gc protein (also known as vitamin D binding protein), which cancer cells destroy by secreting an abundance of the enzyme Nagalase.10 GcMAF restores the deficiency, which is a critical component in activating the macrophages, the immune system's cancer scavengers, that in turn exert a tumoricidal action on cancer cells.11
Traditional chemotherapy regimens utilize the maximum tolerable dose with the highest acceptable toxicity (side effects) which in turn requires rest periods between cycles - a practice that not only involves re-growth of tumor cells, but also growth of selected clones resistant to the therapy. Metronomic chemotherapy (MC) is the continuous, equally spaced administration of low doses of chemotherapeutic drugs without extended rest periods. The MC treatment modality has not only been shown to be an efficacious antitumoral with very low toxicity, but also a cell target switch, aiming at tumor endothelial cells as an anti-angiogenic agent.12
While DCA , GcMAF, and MC have very different mechanisms of action - DCA restores mitochondrial metabolism which antagonizes tumor growth, metastases and survival, while GcMAF activates tumoricidal macrophages and MC acts as both an antitumoral and anti-angiogenic agent - the combination may prove to be a potent anti-cancer weapon by fighting the war simultaneously on three fronts.
Photodynamic Immunotherapy (PDIT)
For the last 8 years, Orn Adalsteinsson, Ph.D., and his research team have been conducting clinical trials exploring Laser Immunotherapy (LIT) as a possible breast cancer treatment and the results have been very promising.
In a Phase I, proof-of-concept study, 10 patients with advanced breast cancer received at least one LIT treatment. Eight patients were available for evaluation. Of those patients, one patient had a complete response (CR), four patients had a partial response (PR), two patients had progressive disease (PD) and one patient had stable disease (SD). The objective response rate was 62.5% and the clinical beneficial response rate was 75%.13
An unpublished Phase II clinical trial conducted in the Bahamas by Dr. Adalsteinsson and his research team enrolled 15 breast cancer patients who received between one and four LIT treatments. Among all 15 subjects in the study, 73.3% remain alive today. Compare that with the typical survival rate in the United States for women with advanced breast cancer, which is only 25% at 5 years.14 Currently, six subjects have surpassed the five-year milestone and of the surviving 73.3%, the average survivorship is 59.8 months or 4.9 years and counting!
Of the 15 subjects who were treated, four subjects are deceased, 11 subjects remain alive, and of those subjects four are disease free and two are in remission, which equates to a 73.3% total subject survival rate. However, of the 15 study subjects only 6 subjects completed the trial. Of those six subjects, one subject is deceased, five subjects remain alive, and of those five subjects four subjects remain disease-free, which equates to an 83.3% survival rate for subjects who completed the study.
Currently Dr. Adalsteinsson and his research team are recruiting and conducting a Phase III clinical trial examining an improved LIT technique referred to as Photodynamic Immunotherapy (PDIT). By combining a sensitizer with a corresponding laser application which is then followed by an immunoadjuvant agent and adjuvant nutritional supplements. Researchers are confident that PDIT, an enhanced LIT procedure, will greatly improve response rates in women in all stages and with varying types of breast cancer.
PDIT utilizes a photosensitizing agent which is activated by a unique wavelength of light causing one of the oxygen molecules to spin in the opposite direction in an ever-increasing arc before it returns home. This single oxygen molecule otherwise known as Singlet Oxygen or Reactive Oxygen Species (ROS) produces localized damage and moderate inflammation leading to primary tumor cell damage and the creation of tumor specific antibodies resulting in potentiation of adaptive immunity.15-17
Directly after the laser treatment, an immunoadjuvant is administered, and in the presence of localized damage and moderate inflammation created by the treatment, an immune response is initiated. The immunoadjuvant, simulated by tumor tissue fragments and cellular molecules dispersed throughout the body, act as potent inflammatory mediators rousing the body's "self-defense" system18 enabling a massive recruitment of immune cells to the damaged site.
Within minutes the mobilization of cell mediated immunity triggers a large number of neutrophils to invade the area19,20 followed by the arrival of mast cells, lymphocytes, monocytes, and macrophages with increased phagocytic capacities.19-22 Over time, after phagocytosis and tumor cell debris processing has occurred, macrophages function as antigen presenting cells23 shifting cell-mediated immunity to humoral immunity with the production of cytotoxic antibodies. These antibodies provide immunity against neoplastic cellular multiplication resulting in the destruction of locally remaining tumor cells and metastatic tumor cells as well as preventing the occurrence of new distant metastases.24-29
While the PDIT Phase III clinical trial has just begun, the research team is confident with the initial results of the work conducted thus far and are looking forward to reporting the long-term results in subsequent publications.
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.30 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.31 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.lifeextension.com/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.32
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 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.49 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.33,34
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.35
Combidex scans have also been used to successfully evaluate patients with cancers of the uterus,36 head and neck,37 kidney,38 breast,39 and liver.40
For many years Life Extension has been funding cryobiological research that would allow for increasingly long-term, low-temperature maintenance or storage of transplantable organs. Too often vitally-needed transplantable organs from accident victims do not reach needy patients soon enough because the organs deteriorate so rapidly. The demand for transplantable organs greatly exceeds the supply. Just as refrigerators and freezers preserve food, low-temperatures could preserve transplantable organs. The lower the temperature, the longer the organs could be preserved. But because freezing damages all biological tissues, cryoprotectants (anti-freeze solutions) must be developed to prevent ice formation. 21st Century Medicine (21CM) is the major cryobiological research company that Life Extension has been funding. 21CM has developed a relatively non-toxic cryoprotectant solution. The word "relatively" must be emphasized, because all cryoprotectant solutions have some toxicity. For that reason, cryobiologists try to use just enough cryoprotectant to prevent ice formation, but not enough to damage tissues as a result of toxicity. Unfortunately, the organ that is in greatest demand for transplant, the kidney, has posed serious problems for cryobiologists. The outer layers of the kidney receive high blood flow, whereas the inner layers receive low blood flow. So the challenge has been to get enough cryoprotectant into the kidney from the bloodstream to prevent ice formation in the inner layer without causing toxic damage to the outer layer of the kidney. The year 2016 has seen major technical breakthroughs by 21CM on this problem. 21CM can now substantially reduce or eliminate ice formation in the inner layers of the kidney without toxic damage to the outer layers of the kidney.
Up to 900,000 organ transplants are needed each year in the United States alone, compared to about 30,000 transplants actually carried out each year. Many exciting advances are leading to ways to eliminate the organ shortage, but an avalanche of new organs will create a new problem – how to manage all of the resulting transplants. Even without the added stress of a 30-fold increase in the number of transplants, transplantation today is a frenetic endeavor, with Lear jets rushing human hearts to their recipients before their short survival times outside the body expire, surgeons performing transplants in the middle of the night, families constantly on standby, waiting to go to the hospital at a moment’s notice to receive a life-saving organ, and with kidneys and other organs being transplanted with considerable storage damage and with less than perfect matches because the alternative is to discard the poorly matched organs as their viable storage times expire.
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 Life Extension.
The ability to preserve, or bank, living human organs at very low temperatures for unlimited times would offer many advantages for human organ transplantation. As it is today, organs are frequently rushed from donor to recipient by jet, just barely reaching the recipient before losing viability, and often requiring transplantation in the wee hours of the night. Potential organ recipients can’t go on vacation while they wait, and must often move to the city of their nearest transplant center, due to fear that the organ assigned to them will suddenly become available for a very brief time, and then be gone before they can report for the operation. On top of this, with such limited shelf lives for donor organs, there is no time to do immunological cross matching for most organs, and even for kidneys, which can be preserved the longest, the matches achieved are rarely ideal. All of these problems, and more, could be eliminated if organs could be cryopreserved, i.e., if they could be preserved at cryogenic temperatures without time limits.
21st Century Medicine has set for itself the goal of demonstrating the feasibility of cryopreserving whole organs in a non-frozen, glassy state, through a technique called vitrification. We have been working on kidneys specifically, but with the goal of eventually being able to bank all organ types. For vitrification, most water in the organ must be replaced with chemicals called cryoprotective agents, to prevent the water from freezing. That has not been easy to do without causing significant damage to the organ, but last year, we reported here that we had finally succeeded.
Having solved the problem of water replacement, the next step, initiated in 2017, was to begin cooling kidneys to deep subzero temperatures to assess the effect on the kidney of deep cooling per se. This is necessary to understand the effects of actually banking and warming the kidney, and to work out ideal protocols for cooling and warming that minimize injury.
In the past, we were able to cool kidneys to -45°C with consistent survival, but these kidneys were seriously injured by the cooling and warming process. This year, after investigating multiple protocols for getting kidneys to and from -45°C, we were able to achieve an 80% survival rate, and the amount of injury observed in the survivors was about 40% less than what we had seen before, and the kidneys returned to normal after 10 days rather than after 19 days in our previous experiments. As of this writing, we are working on an improvement of this protocol that seems to be giving us better results still, and that may improve results after much deeper cooling.
The other side of the vitrification problem is warming. Going to -45°C and back is not very complicated because ice can’t form in the kidney at this temperature, but when we go to -130 to -140°C and then try to warm the kidney back up again, ice can form in the kidney during warming and potentially cause significant injury. To suppress that, we need rapid warming methods. Recently, there was a big splash about publication of a paper on “nano-warming” of 50 ml volumes of cryoprotectant containing blood vessels and heart valves, but what the reports didn’t mention is that to apply this to a human kidney would cost $100,000 per kidney. We have been working on our own rapid warming method whose cost of application to a human kidney would be very low because it doesn't require adding costly foreign materials to organs. This year we finished upgrading to higher power equipment with better control characteristics, and we hope to begin application to rabbit kidneys near the end of the year.
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 completed and implemented 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.