(Intro by Life Extension)
What you are about to read is a blueprint by which newly developing technologies may be used to induce biological immortality in human beings.
This research goes far beyond what is normally published in Life Extension.
When perfected, the research findings you are about to learn may enable doctors to inject progenitor cells that will regenerate every tissue in your body, thus restoring you to youthful health and vigor.
Some readers will find this article challenging to comprehend, but I encourage everyone to review it several times to understand how close we may be to achieving meaningful reversal of aging processes.
This article also contains new findings about how easy it is to increase your telomere length, which has been shown to confer longevity and protect against age-related disease.
Targeting the Clockwork of Cell Immortality: A Progress Report
There appears to be a consensus among gerontologists that a significant extension of the healthy human lifespan will require targeting of the clockwork mechanisms that cause aging. We will therefore attempt to explain what this means and what the implications may be for reversing biological aging.
Modern gerontology research can be divided into two camps. In the first camp, researchers are on a quest to understand and control the central mechanisms of the aging “clockwork”. This molecular machinery should be thought of as upstream central regulators (like telomeres) that subsequently trigger mechanisms further downstream. It is these downstream pathological mechanisms, such as chronic inflammation, that inflict age-related changes in specific tissues. 1-3
The second camp of researchers is focused on targeting molecules involved in these downstream mechanisms, as these factors (such as pro-inflammatory cytokines) are the “hatchet men” that directly trigger disease processes. 4,5
If we were to think of the individual mortal human as a ticking time bomb, the upstream mechanisms would be the clocking mechanism of the bomb, perhaps a ticking alarm clock or a burning fuse, and the downstream mechanisms would be the dynamite that is the most direct cause of the damage that follows. The first camp’s approach would therefore be to prevent the explosion itself by stopping the clock, whereas the second camp’s solution would be to let it explode but blunt the force of the explosion by covering it with a dump truck full of sand.
In humans, an example of an upstream clockwork mechanism would be the telomere clock of cellular aging, which counts off how many times a cell has divided and hence determines how old a cell really is. An example of a downstream mechanism would be an inflammatory process that leads to activation of damaging molecules in the coronary arteries as seen in atherosclerosis. 6-8
Many of the downstream processes are those typically addressed in Life Extension articles. This emphasis on the downstream may in part reflect the fact that our current understanding of many of the downstream mechanisms predates our understanding of the “upstream” clocking mechanisms. In addition, interventions into in these downstream events have favorably impacted the severity of age-related diseases.
However, most gerontologists agree that targeting the downstream mechanisms will not sufficiently extend human life expectancy to meet the objectives of those who seek aggressive solutions to pathological aging. By targeting upstream-biology--never before attempted in the practice of medicine--we could potentially create the most powerful impact on the aging process.
But first we should consider the basis for assuming that such a central clockwork exists, or that it would even be feasible to intervene in the inexorable progress of this ticking clock.
In this short progress report, we will attempt to describe the shortest path to a proof-of-principle by referring to a natural type of cellular immortality recently captured in the laboratory dish. This line of reasoning is now taking off in the scientific community.
We will then describe research funded in part by the Life Extension Foundation® that has potential clinical application to combat the deadliest manifestation of cell mortality in the United States, namely, coronary artery disease...the leading cause of heart attack.
The Facts of Life
Let’s begin with the facts of life and remember how an individual human being comes to exist in the first place. The union of a sperm and egg cell leads to a unified cell commonly called a zygote, which then divides into two cells, then four, and so on, until 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 life-functioning cell types such as muscle, blood, or brain cells. This process of cellular commitment is called differentiation.
If pluripotent cells differentiate into sperm or egg cells, scientists say they are remaining in the germ-line. The germ-line is that lineage of cells that connects the generations and is the biological basis of the immortality of the species. They are the cells whose continuous proliferation ensures there are always zebras in Africa. They are the reason why you can go to a local greenhouse and buy fresh young petunias to plant in your garden every spring, year after year. Germ-line cells have the amazing ability to spin off new individuals forever, without the limitations of aging.
When pluripotent germ-line cells commit to become one of the life-functioning cell types of the body, we say they have differentiated into somatic cells. This differentiation seals their fate. These somatic cells are now mortal, even though, up to this point, they have been proliferating continuously for billions of years as germ-line cells. They will now become part of the body that is programmed to die usually within 100 years. Those cells that went the germ-line route have the potential (though not certainty) that they may continue in future generations indefinitely. Because they are not committed to a mortal fate, scientists say the cells are immortal. The use of this term does not mean that the individual cells are indestructible, nor does it mean anything in a religious sense. Instead, the term simply refers to the lack of commitment to the mortality that occurs when these cells differentiate into somatic (functional) cells that have finite lifespans, sometimes measured in maximum amount of doubling times before they die.
For the past few decades, scientists have focused on deciphering the molecular mechanisms of the immortality of germ-line cells in order to find a means of using those insights to restore health to aging somatic (life-sustaining functional) cells. In other words, we have attempted to find a means to rewind the clock of the “ticking time bomb” in our cells back to the beginning of life.
In the past few years, we have learned that, when cells make the decision to become somatic (that is, cells that enable the body to function as opposed to reproductive germ-line cells) 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. This region of the chromosomes is called telomeres, and we refer to it in this article as the “telomere clock of cellular aging”.
Most somatic cells lack sufficient telomerase, and so every time somatic cells proliferate, they progressively shorten their telomeres. This functions as a clock mechanism not unlike the burning of a fuse. However, in contrast to somatic cells, germ-line cells retain telomere length appropriate for the beginning of life, due to an abundance of telomerase activity.
Since there is currently no known way to safely and effectively extend telomere length in the body, our researchers have instead sought means to mimic the natural immortality of germ-line cells in the laboratory dish to make young and healthy cells of all kinds that could potentially be injected into the body. Using this approach, we might be able to repair tissues afflicted with age-related degenerative diseases. The good news is that this technology is now very much operational in the laboratory and is a focus of intensive research around the world.
Embryonic Stem Cells
The first step in understanding how germ-line cell immortality could be used to regenerate aging tissues in the human body was to capture the cells in the laboratory dish. In the mid 1990s, in collaboration with Drs. James Thomson, Roger Pedersen, and John Gearhart, some of us at Geron Corporation launched a project to isolate these cells and grow them as stable cell lines. These cells, called human embryonic stem cells, were the first naturally immortal human cells ever isolated due to their abundant natural expression of telomerase. They had the wonderful property of being able to generate each and every cell type of the human body. For the first time in history, medicine had in its hands a pluripotent stem cell to make every cellular component of the human body. (Pluripotent stem cells are capable of differentiation into any other functional (somatic) cell the body needs.)
These cells generated considerable excitement since they were a means of mass-producing replacement cells for the treatment of a host of degenerative diseases involving the loss or dysfunction of cells, including those in osteoarthritis, macular degeneration, diabetes, heart failure, Parkinson’s disease, and numerous other disorders. The first report of the isolation of these cells marked the birth of the new field called regenerative medicine. When perfected, this technology offered the theoretical potential of rejuvenating an entire human body back to a youthful state.
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.