Funding Research to Help Fill the Government Void

Jonas Salk, MD
His pioneering research
spared hundreds of
thousands from paralysis
and premature death.

The National Institutes of Health is the world’s largest supporter of biomedical research.

Due to deep budget cuts, scientists who may be on the cusp of significant advances are finding it difficult to obtain federal funding.¹

Rather than see vital projects fall by the wayside, the Life Extension Foundation® has stepped up to provide grants to scientists involved in promising fields of research.

While Life Extension Foundation^® support of multi-million dollar research programs remains intact, we report here on seven individual scientists who are efficiently working in biomedical arenas overlooked by the mainstream. What’s remarkable is how much these talented individuals can do with so few dollars.

To put these small grants in context, we looked at the early career of Jonas Salk, the discoverer of the polio vaccine. Polio was the most frightening public health problem in the United States in the early 1950s.^2,3

Jonas Salk graduated from medical school, but his interest went beyond practicing medicine.³ Dr. Salk applied for research positions at universities, but found these were closed to him because of the “Jewish quotas” that prevailed in much of the medical establishment at the time.⁴

Dr. Salk was relegated to a cramped, unequipped quarters in the basement of an old municipal hospital. As time went on, however, Salk was able to secure private grants to build a working virology laboratory, where he helped develop flu vaccines.

Jonas Salk’s talents were eventually recognized, and he was later asked by the National Foundation for Infantile Paralysis to participate in the foundation’s polio project.³

On April 12, 1955, the results of a huge human trial of Salk’s polio vaccine were announced: It was safe and effective.³ In the two years before the vaccine was widely available, the average number of polio cases in the U.S. was more than 45,000. By 1962, that number had dropped to 910.²

Salk never patented the vaccine, nor did he earn any money from his discovery, preferring to see it distributed as widely as possible.³

It is impossible to know if the small grants Life Extension Foundation^® is making to these young scientists will result in medical breakthroughs, but there are interesting parallels to the cramped laboratory that Dr. Salk was initially relegated to and what some of these individuals did with their own limited funds to advance cancer and aging research.

The scientists that Life Extension Foundation^® have recently funded describe their work here, along with their stories about having been unable to obtain funding from government sources. We want to warn that some of the following research descriptions are technical in nature and may not be fully comprehendible to all our readers.

John Schloendorn, PhD. Independent Stem Cell Researcher (PhD in Molecular Biology)

John Schloendorn, PhD

I study human embryonic stem cells as a means to develop meaningful life-extending rejuvenation therapies. Federal government funding of stem cell research is still far too restrictive, even under President Obama. State and private funding are generally more interested in pedigree and reputation, rather than risk-taking and innovation. My grant applications to mainstream funding agencies were virtually always declined with words like “unproven” or “too speculative.” However, my view is that if we are to create tomorrow’s life extension medicine, then a certain amount of “unproven” and “speculative” work is going to be required. Therefore, I left my academic position and set out to do this work on my own. Fortunately, my skills and accomplishments are better appreciated in the life extension community.

In 2010, I was able to raise a small amount of venture capital for my first startup company, ImmunePath, Inc. At ImmunePath, we derived immune cells from mouse progenitor cells, and were able to use those cells to save the lives of mice that had been administered what would have otherwise have been fatal infectious pathogens. There were no immune system incompatibilities, and no immunological matching was required. The next step for ImmunePath would have been human clinical trials. But this would have required $15 million, a sum of money we ultimately failed to raise.

After ImmunePath failed, I have re-built my stem cell laboratory. I had to learn to obtain used laboratory equipment from failing biotechnology companies for cents on the dollar, or even for free. Nonetheless, I had to spend most of my personal savings to re-build my stem cell laboratory in this way. I am able to keep my lab operational by renting out access to my equipment, doing contract research for others, or producing biological components for universities involved in stem cell research. But it’s still difficult to make the economics work and takes a lot of my time. The $50,000 grant Life Extension Foundation^® provided will be sufficient to put my laboratory on a self-sustaining path. Thus I would become free to focus entirely on my “unproven” stem cell research, where I can potentially make a very large impact on extending our healthy life span.

I am therefore very grateful to the Life Extension Foundation^® for granting me $50,000. I believe that with that seed money I can fairly rapidly develop self-sustaining infrastructure that will give me the means to concentrate on regenerative medicine. My goal is to substantially extend human life and health. I am hopeful that I can soon concentrate on research that will achieve these ends. Citations to some of my scientific research papers, along with papers of my colleagues appear at the end of this article.^5-11

Andrei Seluanov, PhD. Assistant Professor at the University of Rochester, Rochester, New York

Andrei Seluanov, PhD

Because of my research into the molecular mechanisms of aging and cancer, I maintain the second largest colony of naked mole rats in the world. Naked mole rats are the size of mice, but they live about ten times longer than mice. In protected environments mice normally can live up to three years, usually dying of cancer. Naked mole rats have never been observed to develop cancer. Nor do they show much sign of aging or aging-associated disease. Understanding the reasons for the exceptional longevity of naked mole rats, and the means by which they avoid cancer, has been the focus of my recent research.

In 2009 I published an article in the Proceedings of the National Academy of Sciences of the United States of America in which I demonstrated that naked mole rats avoid cancer through contact inhibition.¹² In some species, cancer cells can multiply without restraint, ultimately becoming big masses of tumor cells that crowd-out normal functioning cells. Contact inhibition is the impediment of excessive growth of cells by neighboring cells.¹² The National Academy of Sciences also awarded me the Cozzarelli prize for having the most exceptionally excellent paper on the subject of biomedical sciences for the year 2009.¹³

After further research I determined that the contact inhibition and cancer resistance in naked mole rats is due to high levels of a molecule called hyaluronan between the cells.¹⁴ A similar, although less potent compound, has already been applied in the clinic and as a food supplement. I have been wanting to determine the molecular mechanisms by which hyaluronan prevents contact inhibition, establish whether hylauronan also plays a role in extending life by means other than contact inhibition, and explore the potential for making the benefits of hyaluronan available to humans through research on mice.

But when I applied to the Federal Government (the National Institutes of Health) for funding, my grant application was declined. One of the reviewers advocating the decline argued that there is no need for further research with naked mole rats because that animal’s genome has been sequenced. Without grant money I would be unable to continue my research. I turned to the Life Extension Foundation^® for support. I am greatly pleased that the Life Extension Foundation^® is giving me $50,000 every six months, with progress reports required before each new six-month grant. These grants will enable me to look for ways to extend human life and health.

Robert Shmookler Reis, PhD. Professor at the University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Robert Shmookler Reis, PhD

My research career has been focused on the influence of genetics on longevity and the diseases of aging. Although we have known for the better part of a century that calorie restriction slows aging in rodents¹⁵ and that life span is largely under genetic control in many or all species,^16,17 it is only in the last two decades that the genes and pathways regulating life span have been discovered. A mutation in the age-1 gene was shown to increase the average life span of nematode worms by 40–65%¹⁸ and daf-2 mutations double their life span.¹⁹ These genes were later found to lie in the same genetic pathway, which when manipulated in mice can stretch their life span by half.²⁰

Two decades after the first long-lived mutant in age-1 was characterized,¹⁸ I found that more thorough elimination of this gene’s PI3K gene product can actually extend nematode life span tenfold.²¹ I believe that this benefit can extend far beyond worms. Suppression of PI3K in mouse heart muscle slows many measures of heart aging and improves their overall survival.²² Crippling just one of the normal two copies of PI3K in all tissues of the mouse is bad for juvenile mice but improves fitness, metabolism, and survival after maturity.²³ Humans who live past age 100 show an inherent genetic bias that produces the same effects.²⁴

My goal is to identify the molecules that are directly affected by the most beneficial genetic modification, and to find drugs that can knock out PI3K and mimic the life-extending benefits observed in previous studies. Nematode worms are an ideal biochemical laboratory for life span studies of this nature, but I also expect to experiment with human cells and mice, with which I have many years of experience.

Several applications to the Federal Government for support to conduct this and related research have not been successful. The Summaries of Discussion indicated that reviewers were sharply divided, which inevitably results in a score that is not fundable even though two of the three critiques were positive. Just a single comment can be fatal, even an obviously biased one such as that little new could be added by this study “in light of the fact that the age-1 pathway has been extensively characterized by a number of groups.”

Another reviewer required that I show evidence of the effectiveness of the drugs I am seeking before I can be funded to look for them. Fortunately, the people at the Life Extension Foundation^® have a remarkably positive attitude to supporting research that can make a significant difference to human longevity. Life Extension Foundation^® is giving me $50,000 every six months for at least two years as long as progress reports (before each new six-month period) indicate that my research is productive. This open-ended funding arrangement benefits everyone, because Life Extension Foundation^® is assured that their money is put to good use, while the grant recipient knows that funding can continue as long as the results warrant it.

Vera Gorbunova, PhD. Professor in the Department of Biology at the University of Rochester, Rochester, New York.

Vera Gorbunova, PhD

My research 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.²⁵ I am hopeful that what I can learn about what causes DNA damage and what I 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.^26,27 It was proposed that the ability of resveratrol to activate sirtuin activity is the basis of the benefits of resveratrol.²⁸

There are seven sirtuins in mammals, numbered SIRT1 to SIRT7. The sirtuin in mammals that is activated by resveratrol is SIRT1.²⁹ Resveratrol has been shown to protect obese mice from diabetes.³⁰ SIRT6, on the other hand, is able to protect normal mice from DNA damage,³¹ 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.³² Some rodents have a more effective SIRT6 gene than other rodents, so I am seeking to understand the difference.

I would like to find a chemical that activates SIRT6 much as resveratrol is thought to activate SIRT1. I would like to understand what makes some SIRT6 genes better than others in order to get the best effect. Our laboratory has developed assays of SIRT6 biochemical activity, which we will optimize to be able to screen large numbers of chemicals including natural compounds and identify those that activate SIRT6.

Although program officers at the National Institute on Aging are supportive of my work, the budgets are shrinking, and outside reviewers can have divergent opinions. My application for funding was declined because the reviewers believed that SIRT6 may not be the only means by which DNA repair may be better or worse between species.

Fortunately, the Life Extension Foundation^® has granted me the research money I need to learn how SIRT6 can best be utilized to protect against DNA damage. Life Extension Foundation^® is giving me $50,000 every six months, with progress reports required before each new six-month grant. Life Extension Foundation^® appreciates that if I can find one means of protecting against aging and cancer today, that will not stop me from finding another means tomorrow.

Justin Rebo, MD Research Scientist, SENS Foundation

Justin Rebo, MD

My goal has always been to help people live longer, healthier, lives. To that end after I received my MD I moved to Silicon Valley and co-founded a regenerative medicine startup. We made blood cells from embryonic stem cells and used them successfully in a preclinical model, and I developed methods to induce total immune system tolerance of transplanted tissue mismatched on all MHC loci (Major Histocompatibility Complex) using simple blood stem cell transplants. The expertise I’ve developed through the research I’ve accomplished so far is linked in that it all uses the blood system as a means of promoting or allowing some kind of rejuvenation. This work is exactly what Life Extension Foundation^® is helping me to continue.

Blood, the fluid that transports nutrients, gases, immune cells, and a host of other factors throughout our bodies, declines in function with age. For example, hematopoietic stem cells (HSCs) from older mice, which give rise to the cellular component of blood, have multiple functional defects, including lineage changes, reduced self-renewal, homing efficiency, and a delayed proliferative response.³³ The acellular component of blood, plasma, also declines in function; young mice injected intravenously with plasma from old mice exhibit decreased neurogenesis.³⁴ Blood’s decline exacerbates the age-related functional decline of all other human organs and systems, since these are exposed to and depend on blood. For example, CCL11, a normal eosinophil associated chemokine, increases in plasma with age and when administered to young mice reduces neurogenesis.³⁴ Heterochronic parabiosis, the joining of the circulatory systems of two animals of different ages, has been used for decades to study the effects of circulating factors both on the young parabiont and the old.³⁵ The exposure of young blood to old animals has been found to rejuvenate aged muscle, and restore hepatocyte proliferation to levels seen in young animals.³⁶ This indicates that the restoration of a young systemic environment can at least partially rejuvenate old tissues and stem cells.

It follows that any intervention that can functionally rejuvenate blood may also have some rejuvenating effect on the rest of the body’s systems.

With Life Extension Foundation^® funding, I will test the effects of replacing old components in blood with young ones so the tissues can exist in a young systemic environment. This can mean the cellular or acellular components of blood, or some combination. Similar technologies have already been successfully applied in humans for treating several diseases, but no one has yet extended these methods to treat the pathological effects of aging.

In particular, I will study the rejuvenating effects of plasma exchange. This means transfusing the plasma of young animals into tissue-typed older animals. Further I will directly remove specific aged factors from plasma including those factors already known and also those elucidated during the course of this study using high throughput proteomics of young vs. aged plasma.

After as little as two years the goal is to begin human clinical development.

This research has thus far remained completely un-fundable through traditional funding sources, which is why it’s so important that Life Extension Foundation^® is stepping forward to fill the gap to help bring these potentially lifesaving therapies to the clinic. Life Extension is funding $130,000 towards my research.

João Pedro de Magalhães, PhD Senior Lecturer (equivalent to an Associate Professor in the US) at the University of Liverpool, Liverpool, United Kingdom.

João Pedro de Magalhães, PhD

My Integrative Genomics of Ageing Group broadly aims to help understand the genetic, cellular, and molecular mechanisms of ageing. Although our research integrates different strategies, its focal point is developing and applying experimental and computational methods that help bridge the gap between genotype and phenotype, a key challenge of the post-genome era, and help decipher the human genome and how it regulates ageing and longevity. In the long-term, I would like our work to contribute to the development of interventions that preserve health and combat disease by manipulating the ageing process.

Biomedical research, including most research on human diseases, is usually based on animal models that develop the disease under study at a higher incidence and rate than normal. An unexplored paradigm in biomedical research, however, is the use of disease-resistant organisms to identify genes, mechanisms, and processes that protect against (rather than cause) disease. While disease models may be useful to develop treatments, models of resistance to disease may prove valuable for human disease prevention. In this context, we are interested in studying the unique genetics, physiology, and cell biology of long-lived animals. For example, we have employed next-generation sequencing platforms to study the long-lived naked mole-rat.³⁷

The bowhead whale (Balaena mysticetus) has not only been estimated to live over 200 years, making it the longest-lived mammal, but clearly these animals remain disease-free until much more advanced ages than humans can.³⁸ The mechanisms for the longevity and resistance to aging-related diseases of bowhead whales are unknown, but it is clear they must possess aging prevention mechanisms. In particular in the context of cancer, bowhead whales must have anti-tumour 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.³⁹

In this project supported by the Life Extension Foundation^®, we are sequencing the genome of the bowhead whale. We are also performing analyses to identify promising candidate genes for further study and identify possible mechanisms that may explain the long life span and resistance to age-related diseases of bowhead whales. Overall, this project will provide a key resource for studying the bowhead whale’s exceptional longevity and resistance to diseases. Studying a species so long-lived and with such an extraordinary resistance to age-related diseases will help elucidate mechanisms and genes conferring longevity and disease resistance in mammals that in the future may be applied to improve human health.

This is the sort of high-risk, high-reward project that is rarely supported by government funding bodies, and indeed my grant applications to study long-lived organisms have been invariably rejected (including by the National Institutes of Health and NHGRI, in spite of widespread support from the research community⁴⁰) for being too risky and often labelled as “overambitious.” I am therefore very grateful to the Life Extension Foundation^® for contributing $23,000 for this project. All data and results from this project will be made available to the scientific community to encourage research using data from long-lived species.

Maximus Peto Independent Protein Manufacturer (BBA Finance, MBA, Undergraduate Biochemistry)

Maximus Peto, MBA

Most stem cell research requires the use of recombinant cytokines in the stem cell growth media. But current retail prices are very high, which markedly inhibits the advance of stem cell therapies that could save human lives.

I currently work at developing very low-cost recombinant cytokines (a specialized type of protein), because these proteins are used ubiquitously in stem cell research.

I first learned how to successfully produce recombinant proteins in my work at the SENS Foundation. “SENS” stands for “Strategies of Engineered Negligible Senescence” and is headed by Dr. Aubrey de Grey.

At SENS Foundation, I worked on making enzymes for their LysoSENS program for two years. Prior to joining SENS Foundation in 2010, I published a peer-reviewed research paper on iron and aluminium accumulation in humans with age, and how to remove these metals.⁴¹ During my time at SENS Foundation, I also experimented with producing recombinant cytokines in my personal lab, which I invested several thousand dollars of my own funds into building. After some initial successes on a small scale using techniques I developed, I was very surprised at how inexpensively these proteins can be synthesized. However, with my cheap, small-scale equipment, I was unsuccessful in making and purifying enough cytokines for distribution to scientists in need. I discovered that a large proportion of the budget (10-50%) of many stem cell labs is spent on these recombinant cytokines. Upon the realization that the high cost of these cytokines was hampering life saving research, I decided that it would be greatly beneficial in accelerating stem cell research if I made these proteins inexpensively on a larger scale. I currently intend to lower the retail cost of recombinant cytokines by 50-90%, and plan to give away cytokines to avant garde stem cell researchers working directly in the fields of life-extending research.

I approached the Life Extension Foundation^® for funding my development processes. I am thankful and excited Life Extension has understood the far-reaching implications of my work for advancing stem cell research. After about five months of discussions, Life Extension Foundation^® has committed $100,000 of funding to this project that I envision will help lead to technologies that will slow and reverse human aging processes.

If you have any questions on the scientific content of this article, please call a Life Extension^® Health Advisor at 1-866-864-3027.

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