It was originally, but erroneously, believed that normal cells also had the potential to divide and function indefinitely in culture, and so it was thought that aging could not be the result of events that occurred within normal cells. Instead, aging was thought to be the result of extracellular events such as radiation or of changes in the extracellular molecules that cement cells to each other.

In 1960, however, it was discovered that no culture conditions exist that will permit normal human cells to divide indefinitely. Rather, cells were found to have a built-in counting mechanism, called the Hayflick Limit, that limits their capacity to replicate. For example, human fibroblast cell populations, found in virtually all tissues, will double only about 50 times in culture when derived from fetal tissue. Fibroblast populations from older adults double fewer times, the exact number of doublings depending upon the age of the donor. Leonard Hayflick and P. S. Moorhead also suggested that only abnormal or cancer cells divide indefinitely. They theorized that the limited capacity for normal cells to divide is an expression of aging and that it determines the longevity of the organism.

In support of this theory, it was found that frozen normal fetal cells "remember" the doubling level at which they were frozen and, after thawing, will undergo additional doublings until the total of fifty is reached. These facts suggested to Hayflick that a replication-counting mechanism existed. Hayflick and coresearcher Woodring Wright later found that this mechanism was located in the nucleus of the cell.

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