How Engineered Stem Cells May Enable Youthful ImmortalityFebruary 2013
By Michael D. West, PhD
Cloning – A Cellular Time Machine
In 1997, Dolly the sheep was cloned. The way cloning works is that the DNA of a somatic cell is transplanted into an egg (germ-line) cell, whose own DNA has been removed to create a pluripotent cell. This “cloned” cell is capable of differentiating into a new individual with the DNA from an existing individual.
Thus, cloning is an artificial means of generating identical twins differing in age. In the case of nuclear transfer, the DNA in the somatic cells is reprogrammed, meaning its memory of being a skin cell has been erased by a cellular “time machine”, and that cell has now been returned to the germ-line state capable again of making individuals of the same genetic constitution, over and over again…potentially forever!
But one may ask, in the case of cloning, what happens to the aging process of the body cell? Is aging of the cell really reversed, or do we somehow get an embryo and resulting cloned animal that looks young, but is really born old, a kind of “fountain of old age”? At first, the group that cloned Dolly reported that she was born with short telomeres, and cloning had not, reversed the aging process. Dolly was therefore thought to be “born old”; she was a sheep in lamb’s clothing, so to speak.
However, in 2000, our group published a paper demonstrating that, in the case of cow cloning, the telomere clock of cell aging is reset back to the beginning of life. Today, the consensus view is that cloning is capable of reversing cell aging, so animals cloned from aged animals are born young again. If you think about these results, they logically lead to the next question: Would cloning work in humans—not necessarily to make copies of them, but rather as means of reversing the aging of human cells?
Thus, cloning (somatic cell nuclear transfer) could potentially be used to reverse the developmental aging of a human cell. It became a topic of considerable controversy that, for example, a mature skin cell could possibly be transported back in time to the beginning of life. Some of us believe that such a cellular time machine could be used to make young cells of any kind that would be genetically identical to any given patient. This concept came to be called therapeutic cloning, in order to distinguish it from making a cloned human being (the latter process is referred to as reproductive cloning).
Induced Pluripotent Stem (iPS) Cells
Today, the controversy over therapeutic cloning has largely dissipated due to the discovery that the use of just a handful of molecules can effectively replace the use of a whole egg cell in restoring aged somatic cells back to pluripotency (youthful cells capable of differentiation into any other functional (somatic) cell.
In other words, we can take human somatic cells back to the embryonic germ-line state of immortal pluripotency without cloning or ever making an embryo. Since such cells are not isolated from embryos, they are called induced pluripotent stem (iPS) cells, in order to distinguish them from embryonic stem cells.
Most significantly, as reported in Life Extension magazine22 (Biotime’reversing cellular aging-DATE?), we demonstrated that it is possible to utilize these advances to not only revert a cell in the body back to the all-powerful pluripotent stem cell state, but also to activate telomerase and reset the clock of cell aging all the way back to the very beginning of life.
As a result, the stage is now set to lift some cell from the body—perhaps from a sliver of skin, from blood cells, or from a hair pulled from the head—and then genetically manipulate that cell, returning (converting) it to a continuously proliferating youthful line of cells. These rejuvenated cells we believe will be identical to the individual cell they had developed from decades earlier. Since these iPS cells are now reverted back to the germ-line state, they can spin off new somatic cells of all types for an indefinite period of time. A thoughtful person would recognize within these advances the powerful means to potentially regenerate aged tissues with young cells, and a means to do so for periods that extend the normal lifespan of human body cells. All of this new technology targets the upstream clockwork mechanisms of aging. This is possible because life is, in a sense, naturally immortal in that each species has cells capable of regenerating new individuals continuously and for an indefinite period of time.
Applying Regenerative Medicine to Heart Disease
In thinking about where such technologies could be applied, we first considered cardiovascular disease heart failure and stroke are the first and third-ranked causes of death in the United States.
Although epidemiological studies have demonstrated that abnormal lipid profile, diabetes, sedentary lifestyle, and genetic susceptibility are risk factors for coronary disease, hypertension, congestive heart failure, and stroke, advancing age is unequivocally the major risk factor for these diseases. Therefore, we seek a means to target the upstream mechanisms of vascular aging by replacing aged coronary artery cells with the young cells we were born with. This approach could become the most effective means of intervening in heart disease, stroke, and other cardiovascular diseases.
Life Extension’s contribution to this research
In late December 2010, I approached the Life Extension Foundation about the opportunity to accelerate the pace of research that could lead to the reversal of vascular aging using technologies described in this article. Recognizing the potential to cure the most common problem afflicting aging humans, Life Extension provided $2 million of initial funding.
These funds were used to help launch ReCyte Therapeutics, which is focused on regenerating aged vascular function by developing clinical applications based on several of the technologies we have been discussing. The mission is to reverse the developmental aging of a person’s cells and then turn those reprogrammed and rejuvenated cells into primitive vascular progenitors useful in “re-plumbing” an aged vascular system.
ReCyte’s scientists are particularly interested in a cellular component of blood vessels called endothelial cells that reside on the inner lining of the blood vessel. Normal endothelial function and endothelial health are adversely affected by the aging process, presumably due to telomere attrition (and other factors). An aged vasculature is therefore more prone to develop plaques, inflammation, and atherosclerosis. Therefore, myocardial infarction is really not the problem of the heart per se, but rather a problem with the vasculature’s supply of blood to the heart. The goal of ReCyte is to manufacture young vascular progenitor cells capable of repairing aged blood vessels, to target the upstream biology of the aging artery, not the downstream events of inflammation or cholesterol accumulation, arterial calcium deposits, and the formation of atherosclerotic plaques.
Where we are today?
With financial help from the Life Extension Foundation we have been able to improve the efficiency of reprogramming cells using technology licensed from the Wistar Institute in Philadelphia, Pennsylvania, with whom we now collaborate. Wistar scientists discovered that by turning off a gene called SP100, differentiated cells became more susceptible to re-expressing genes normally expressed only in pluripotent stem cells.28
Second, we have formed a similar collaboration agreement with scientists at Cornell Weill College of Medicine in New York City who are focused on the development of vascular endothelium. In collaboration with that group, we have successfully generated purified populations of embryonic vascular cells from induced pluripotent stem cells.29
As a result, we believe the pieces are in place to reverse the developmental aging of an aged person’s cells and then to turn these rejuvenated pluripotent stem cells into young vascular progenitors that should be useful in restoring normal youthful function to the aged vasculature of the heart, brain, and other tissues. Such cells would also be histocompatible with individual patients, which means there would be no need for immunosuppressive drugs. We have already derived these endothelial cells from multiple human embryonic cell lines at clinically applicable scale consistent with Good Manufacturing Practice (GMP).
In summary, at the same moment when we see an aging population placing a strain on our healthcare system and our national budget, we also see the rise of a new technology facilitating the manufacture, on a clinically-feasible scale, of young cells of all types that may allow us to regenerate tissues afflicted with age-related degenerative disease.
At BioTime we are utilizing these breakthroughs in regenerative medicine to target several major diseases. BioTime can be thought of as the hub of a wheel with several subsidiaries focused on different medical specialties such as orthopedics, cardiovascular disease, neuroscience, and so on. Recyte Therapeutics is one of those subsidiaries.
BioTime (NYSE MKT: BTX), both as a company and as individuals, are determined to find the means of rapidly translating this bench-top science into life-saving clinical reality. We are thankful for the support of the Life Extension Foundation for their vision and commitment to advancing human health. We look forward to the day when we can report in Life Extension magazine,the outcomes of the first patients to be treated with reprogrammed young vascular progenitor cells as a novel therapy for cardiovascular disease, the number one cause of mortality in aging humans.
Very early in the course of human development, a small cluster of cells form, each of which has the power to become any of the cell types in the human body. Cells that have this power are said to be pluripotent, meaning they have power (-potent) to become a variety (plurality or pluri-) of cell types. These cells commit to the cell type they will eventually become, that is, each cell will commit to becoming a reproductive (sperm or egg) cell, or one of the body’s many somatic or life-functioning cell types such as muscle, blood, or brain cells. If pluripotent cells differentiate into sperm or egg cells, they are remaining in the germ-line, that lineage of cells that connects the generations and is the biological basis of the immortality of the species. When cells make the decision to become somatic, they turn off telomerase, an enzyme that synthesizes a repeated sequence of DNA over and over again at the end of DNA strands needed to maintain cellular viability.9-12 A recent discovery showed that the use of just a handful of molecules can effectively restore aged somatic cells back to pluripotency. It is possible to utilize these advances to not only revert a cell in the body back to the all-powerful pluripotent stem cell state, but also to activate telomerase and reset the clock of cell aging all the way back to the very beginning of life.
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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