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Stem Cell Stress Causes Gray Hair

Cell, June 12, 2009

In a new study which examines the cellular mechanisms that cause gray hair, scientists learn more about the mammalian aging process.

Cellular stress has long been known to accelerate aging, and more specifically it is the damage incurred by DNA which causes all the characteristics that are associated with advanced age. Now, scientists are one step closer to elucidating precisely what these various cellular and molecular mechanisms might be.

Led by Dr. Emi Nishimura, researchers at the Tokyo Medical and Dental University have examined the association between environmentally imposed chemical damage and graying hair. Graying hair is associated with aging not only in humans but also in other mammals, and is often the focus of cellular studies. In Dr. Nishimura's experiment, laboratory mice were subjected to a variety of cellular assaults which included chemical injections and whole-body x-rays. The mice then began growing gray hair, which revealed permanent damage to the stem cells of their hair follicles upon analysis.

The cellular DNA of every living species is constantly under attack by damaging agents that include chemical pollutants, ultraviolet light and ionizing radiation, among others. A single mammalian cell can experience as many as 100,000 stressful "events" per day, any one of which would be enough to damage the cell's DNA. This relentless assault throughout life by innumerable natural as well as manmade environmental stressors inevitably results in permanent damage to the DNA. The cummulative effects of this "DNA weathering" will eventually, beyond a certain point, become externally visible. When a certain amount of DNA damage is inflicted upon the stem cells of hair, graying is the resulting external sign.

Hair follicles contain stem cells which mature into melanocytes, which are the cells that produce melanin, which is the pigment that gives hair its color. These stem cells are especially vulnerable to cellular stress, however, which is why very few people make it to an advanced age without succumbing to gray hair. For the first couple decades of life, the stem cells in hair follicles are plentiful enough that there is simultaneously an abundance of those stem cells which differentiate into pigment cells, and those that merely reproduce into identical "daughter" stem cells. Consequently, pigment is continually being added to new, growing hair. But as the decades of life continue to accumulate, so do the cellular assaults, and an increasing percentage of the stem cells in the hair follicles will continue to mature until finally there are no more pigment cells left. Hair without pigment is gray.

In the past, the exact mechanisms by which the number of pigment cells in hair decreased were not fully elucidated, although DNA damage has been understood to play a key role. As Dr. Nishimura explains, the accelerated maturation of hair follicle stem cells may be the body's "more sophisticated way" of purging the damaged stem cells, rather than just forcing the cells to die through more ordinary apoptotic (cellular death) mechanisms.

The topic of aging is a complex one, and it has implications for a number of medical and scientific fields, including not only stem cell therapies but cancer. How and why we age has always been a topic of general human interest. The exact mechanisms by which particular cells age, die, and either are or are not replaced by new cells, is of increasing scientific interest as well. Dr. Leonard Hayflick, the renowned cell biologist and founder of "molecular gerontology", played a key role in our understanding of these cellular mechanisms. By his discovery of the built-in limitations of cellular longevity, he established the fact that there exists a limit to the number of times that normal (noncancerous) cells can divide. This limit is known as the "Hayflick limit". While employed in cell biology and mycoplasmology at Wistar in the 1950s, Dr. Hayflick noticed that each cultured human and animal stem cell has a predetermined number of times that it can replicate in order to create another stem cell. Prior to his discovery of this, it had been commonly and erroneously believed for at least sixty years, since the turn of the previous century, that cells would continue to divide indefinitely. Dr. Hayflick discovered that cells stop growing after about 50 divisions, or population doublings. As he described, "They continued to eat, excrete waste, and perform all the metabolic housekeeping necessary to stay alive. They just didn't replicate anymore. Eventually, debris attached to them, and they ultimately suffered 'degeneration'." (From Stephen S. Hall, "Merchants of Immortality", 2003). It is now commonly understood that normal cells in culture have a finite limit to the number of times they can divide - unlike cancer cells, which are the only "immortal" cells, and can continue to divide indefinitely. But the discovery was initially a startling one. Together with Paul Moorhead, Dr. Hayflick published his revolutionary findings, which contradicted the current dogma of that era, first in Experimental Cell Research in 1961, and again in an updated version in Experimental Research, in 1965. Entitled, "The limited in vitro time of human diploid cell strains," this seminal paper introduced the new idea that the number of times a human cell is capable of dividing is innately limited. The paper had previously been rejected by the Journal of Experimental Medicine, and Dr. Hayflick still possesses the now famous rejection letter, in which the journal's editor wrote, "The largest fact to have come out from tissue culture in the last fifty years is that cells inherently capable of multiplying will do so indefinitely if supplied with the right milieu in vitro." (Ibid.) Time will tell exactly how many other dogmatic pillars shall be overturned by future discoveries. Meanwhile, Dr. Hayflick's discovery not only shattered conventional "wisdom", but it also focused attention on the cell as the fundamental location of aging. Dr. Hayflick was able to demonstrate for the first time that both mortal and immortal mammalian cells exist. Much of modern cancer and stem cell research today is based upon this distinction.

The cellular senescence (from the Latin, "senex", meaning "old man" or "old age"), or cellular death, discovered by Dr. Hayflick is now known to involve the successive shortening of chromosomal telomeres with each cell cycle as cells repeatedly divide. This feature of replicative cell senescence has become an established principle in biogerontology, the field of aging, although the exact mechanisms behind this process are still not yet fully understood. In addition to the successive shortening of telomeres, other factors in the process of DNA replication during cell division also contribute to "aging", such as cumulative DNA damage and mutation, as well as cross linkage. Despite the "Hayflick limit", however, it has also been shown that cells may be immortalized, thereby "crashing right through the Hayflick limit and continuing for dozens more cell doublings", by the extension of telomeres with telomerase. ("Hayflick Unlimited: Extension of Life Span by Introduction of Telomerase into Normal Human Cells." Science, 1997). In 1998, although it was somewhat disappointing as a commercial venture, the Geron Corporation developed techniques for extending telomeres, thereby demonstrating the ability of lengthened telomeres to prevent cellular senescence. Clearly, more work in this field will no doubt impact clinical applications of cancer and stem cell therapies.

Meanwhile, at least regarding the subject of gray hair, a number of interesting commercial and entrepreneurial opportunities continue to present themselves. Since it is virtually impossible to avoid DNA and stem cell damage throughout life, a global market exists for a procedure that would immortalize melanocytes, perhaps by extending the telomeres of these cells with telomerase. As Dr. Linzhau Cheng of the Johns Hopkins Institute of Cell Engineering has hypothesized, "We may soon have anti-graying creams for aging populations."

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