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History and Scientific Background
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 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. (This is unlike cancer cells, which are the only "immortal" cells). But the discovery was initially a startling one. Together with Paul Moorhead, Dr. Hayflick published his revolutionary findings, which contradicted current dogma, 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 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.
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 all contribute to "aging", such as cumulative DNA damage and mutation, as well as cross linkage.
Despite the "Hayflick limit", it has also been shown that cells may be immortalized, "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, 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.
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