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Life Extension Magazine January 2014

Funding Research to Help Fill the Government Void

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

The 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
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
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
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
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.