The Hayflick limit, also known as the Hayflick phenomenon, is the amount of times a cell population from a human being can divide before that cell division ceases. When that limit is reached, the next steps are cellular aging and cell death. Here are the details behind that discovery, and what this knowledge may have to do with cutting-edge cancer treatment and the extension of human life.
The Hayflick Limit: Concept and Proof
Leonard Hayflick, an American anatomist, put forth this concept in 1961 while affiliated with the Wistar Institute (located in Philadelphia). He proved that a healthy, normal human cell population (from fetal tissue) experiences between 40 and 60 divisions inside of a cell culture before the cells become senescent cells. Cellular senescence is the state in which cell division ceases.
This refuted the contemporary theory put forth by Alexis Carrel, a Nobel laureate. Carrel postulated that normal human cells were immortal. Hayflick, along with researcher Paul Moorhead, developed a way to prove that human cell proliferation is not unlimited, providing a further understanding of the facets that influence human lifespan.
Studies in the field of gerontology (the study of old age, the aging process, and the unique problems encountered by older adults) have further come to elucidate the role of telomere shortening in aging, which may be the cause behind the Hayflick limit.
Telomeres are structures that make up the end-caps of each chromosome in our cells. When cells divide, these telomeres shorten, and once they reach a certain length, the cells stop dividing. This has led to ongoing research into how telomeres can be preserved and lengthened in different cell types to better extend human life and vitality.
Aging Cell Lines and the Preservation of Human Life
The name "Hayflick limit" was coined in 1974 by Sir Macfarlane Burnet, an Australian Nobel laureate, in recognition of Hayflick's discovery and the understanding that, as cell populations age, so too does the organism to which they belong, which in this case is a human being.
The Myth of Cell Immortality
It would be nice if our cells were infinitely regenerative. It would make science fiction concepts like those seen in Doctor Who much closer to reality.
Prior to the discovery of the Hayflick limit, Alexis Carrel, who was a Nobel prize-winning surgeon, insisted this was true, that the cells in explanted tissue cultures were immortal and that "the lack of continuous cell replication was due to ignorance on how best to cultivate the cells." He said he had cultivated chicken heart fibroblast cells that were able to grow in a cell culture for as long as 34 years, despite the fact that chickens typically live between 5 and 10 years of age.
Unfortunately, other researchers and scientists were not able to replicate these results, which means there could have been some error in the experiment's procedures, such as embryonic chicken stem cells being continuously added in when Carrel provided nutrients to the cells. Whether Carrel was aware of such a mistake or not is still a matter of speculation.
Another theory is that the cells that Carrel selected were so young they contained pluripotent stem cells, cells which could possibly delay replicative senescence if they were given nutrients with telomerase-activation support (for more on the telomerase enzyme, read on). Still, ultimately the cells would succumb to cellular senescence—it's only a matter of time.
The Truth About Time
Hayflick became doubtful of Carrel's assertions when he noticed his own cultures of human fibroblasts from embryonic tissue slowed in their cell division. He at first assumed this was due to a procedural error on his part, but then slowly came to realize that all of the cell cultures he witnessed showed similar slowing. Same containers, same culture medium, and same technician, and yet all cell cultures of a certain age (around their 40th doubling) flagged in the rate of cell division, while younger cultures did not. This scientific observation led Hayflick to team up with cytogeneticist Paul Moorhead to run a dedicated experiment that eliminated potential causative factors.
Moorhead had the ability to identify female vs. male cells in each culture. By mixing equal measures of human male fibroblasts at the tail end of population doubling (their 40th division) with younger female fibroblasts (at their 15th division), he observed them alongside unmixed controlled populations. After 20 more doublings in the mixed cell population, only the female cells were left. This suggested age was the reason for the male cell death, as any contaminating virus or error should have affected both cell populations, not just one, unless it could discriminate between the female and male cells, which is not how a virus operates.
With these results able to be successfully replicated by other researchers and scientists, the Hayflick limit superseded Carrel's claims on cell immortality and became the leading biological theory. Since then, studies into longevity have looked into other factors that may accelerate or slow molecular cell aging.
The Pursuit of Long Life
Hayflick identified three phases of life in the cell cycle.
- Phase one: The primary culture, new and unreplicated.
- Phase two: This is the proliferation stage, which Hayflick referred to as a period of "luxuriant growth."
- Phase three: Hayflick dubbed this the "senescence" stage, wherein cell replication slows and then halts.
Repeated serial cultivation experiments confirmed that normal fetal human cells replicate between 50 and 70 times before they slow and die. Correlated to this aging is the telomere lengths on the ends of chromosomes. As the cells replicate, these caps get shorter and shorter, prompting the theory that longer telomeres could help extend cellular life.
This shortening occurs because, with every division, small segments of DNA information is lost until there's not enough left to copy one more full cell. Evidence has also shown a connection between oxidative stress and telomere length, which has led to the development of therapies to help extend telomeres and in so doing extend life.
Telomeres and Cancer Cells
Guess what: not all cell lines are mortal and fade away with senescence. The only truly immortal cell lines are cancer cells. A cancer cell divides and divides endlessly. It's why they lead to such abnormal tumor growths that they ultimately destroy the life of the host they're proliferating in.
One reason cancer cells have the ability to go on and on is due to their expression of the enzyme telomerase, which prevents the telomeres on their chromosomes from shortening, granting them potentially everlasting life. This knowledge has led to two areas of concentrated research: telomere shortening for cancer cells and telomere lengthening for human cells.
Telomere Shortening for Cancer Cells
One proposed treatment method to interrupt cancer cell growth is to remove their ability to live forever by using telomerase inhibitors. By removing the influence of that enzyme, their telomeres shorten and die just like other cells in the body, allowing them to be eradicated by doctors.
Telomere Lengthening for Human Cells
By the same token, couldn't we introduce telomerase activators to lengthen the life of healthy, normal human cells? This could possibly help repair or lengthen the life of our telomeres, though there's also a concern that it would them give cancerous properties such as endless, counterproductive growth. Perhaps a limited amount could extend the telomeres attached to the cells or our immune systems just enough to resist the development of cancerous cells out of otherwise normal cells, but this is speculation in need of scientific investigation and testing.
The Legacy of the Hayflick Limit
It is without a doubt that the discovery of the Hayflick limit and the knowledge that human cells have a limited capacity to replicate will have a long-lasting impact on the knowledge we hold of human aging. The future discoveries that will result from this understanding could lead us directly to a new phase of human longevity and effective cancer treatment.