অমরত্বের পথে আমরাঃ E̲n̲g̲i̲n̲e̲e̲r̲e̲d̲ ̲S̲t̲e̲m̲ ̲C̲e̲l̲l̲s̲ ̲M̲a̲y̲ ̲E̲n̲a̲b̲l̲e̲ ̲Y̲o̲u̲t̲h̲f̲u̲l̲ ̲I̲m̲m̲o̲r̲t̲a̲l̲i̲t̲y̲. T̲a̲r̲g̲e̲t̲i̲n̲g̲ ̲t̲h̲e̲ ̲C̲l̲o̲c̲k̲w̲o̲r̲k̲ ̲o̲f̲ ̲C̲e̲l̲l̲ ̲I̲m̲m̲o̲r̲t̲a̲l̲i̲t̲y̲:̲ 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. 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. 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. 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. T̲h̲e̲ ̲F̲a̲c̲t̲s̲ ̲o̲f̲ ̲L̲i̲f̲e̲:̲ 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.focus of intensive research around the world. E̲m̲b̲r̲y̲o̲n̲i̲c̲ ̲S̲t̲e̲m̲ ̲C̲e̲l̲l̲s̲: 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.
Posted on: Wed, 26 Nov 2014 23:01:14 +0000
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