Life Extension Magazine January 2014
Funding Research to Help Fill the Government Void
By Ben Best
Justin Rebo, MD Research Scientist, SENS Foundation
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.
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)
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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