Hayflick limit Information & Hayflick limit Links at HealthHaven.com

The Hayflick limit is the number of times a normal cell population will divide before it stops, presumably because the telomeres reach a critical length.^[1]^[2]

[edit] Overview

The Hayflick limit was discovered by Leonard Hayflick in 1961,^[1] at the Wistar Institute (Philadelphia), when Hayflick demonstrated that a population of normal human fetal cells in a cell culture divide between 40 and 60 times. It then enters a senescence phase (refuting the contention by Alexis Carrel that normal cells are immortal). Each mitosis shortens the telomeres on the DNA of the cell. Telomere shortening in humans eventually blocks cell division and correlates with aging. This mechanism appears to prevent genomic instability and the development of cancer.

Carnosine can increase the Hayflick limit in human fibroblasts,^[3] as well as appearing to reduce the telomere shortening rate.^[4]

[edit] Cell Immortality

Prior to Hayflick's discovery it was believed that vertebrate cells had a unlimited potential to replicate. Alexis Carrel, a Nobel prize winning surgeon, stated “that all cells explanted in culture are immortal, and that the lack of continuous cell replication was due to ignorance on how best to cultivate the cells".He supported this hypothesis by claiming to have cultivated chick heart fibroblasts, which had been growing for 34 years.^[5]. Scientists were led to believe that cells of vertebrates could continue to divide indefinitely in a cell. Other scientists were unable to reproduce Carrel's result because of error in Carrel's experiment. The error was due to a daily addition of chick embryonic cells; this allowed for the cultivation of new fresh cells in the culture and not simply the infinite reproduction of the original cells present in the culture^[6]. Some believe that Carrel knew about the error in his experimental procedure, but he never admitted it.^[7]^[8]

[edit] How Hayflick's Limit was Discovered

Leonard Hayflick first became suspicious of Carrel’s theory while working in a lab at the Wistar Institute. Leonard Hayflick was prepping normal human cells to be exposed to extracts of cancer cells when he noticed the normal cells had stopped proliferating. At first Dr. Hayflick thought that he had made a technical error in prepping the experiment, but later he begun to think that cell division processes had a specific counting mechanism. Hayflick, working with Paul Moorhead, designed a experiment that showed the truth about normal cell division. The principle behind these experiments was simple: Hayflick and Moorhead mixed equal numbers of normal human male fibroblasts that had divided many times (cells at the fortieth population doubling) with female fibroblasts that had divided only a few times (cells at the tenth population doubling).Unmixed cell populations were kept as controls. When the male ‘control’ culture stopped dividing, the mixed culture was examined and only female cells were found. This showed that the old cells ‘remembered’ they were old, even when surrounded by young cells, and that technical errors or contaminating viruses were unlikely explanations as to why only the male cell component had died ^[9]. The cells had stopped dividing and become senescent based purely upon how many times the cell had divided. These results disprove the immortality theory of Carrel and establish the Hayflick Limit as accredited biological theory which unlike the experiment of Carrel has been reproduced by other scientists.

[edit] Hayflick's Cell Phases

Hayflick describes three phases of a cell. At the start of his experiment he named the primary culture phase one. In the period when cells are proliferating or as Hayflick calls “luxuriant growth” the cells are in phase two. After so many months of doubling eventually the cells reach what is called “phase three phenomenon” where cell growth is diminished and eventually stopped altogether.^[9]

[edit] Hayflicks limit and Telomere Length

This limit has been found to correlate with the length of the telomeres at the end of a strand of DNA. During the process of DNA replication, small segments of DNA at each end of the DNA strand(telomeres) are unable to be copied and are lost after each time DNA is duplicated ^[10].The telomeres are a region of DNA which code for no proteins; they are simply a repeated code on the end region of DNA that is lost. Eventually, after many divisions, the telomeres become depleted and the cell comenses apoptosis. This a defense mechanism of a cell to prevent replicating error that would cause mutations in DNA. According to Alexey Olovnikov, once the telomeres are depleted due to the cell dividing many times, the cell will no longer divide and the hayflick\ limit has been reached^[11]^[12].This correlation is only true for normal functioning cells.Cancer cells possess an enzyme called Telomerase which is able to restore telomere length. This gives cancer cells their infinite replicative potential and explains why cancer cells are not restricted to Hayflick's limit because their telomere length is never depleted^[13]. A telomerase inhibitor is being proposed as a cancer treatment, this way cancer cells would not have the ability to maintain telomere length and would die like normal body cells^[14].

[edit] See also

[edit] References

^ ^a ^b Hayflick L, Moorhead PS (1961). "The serial cultivation of human diploid cell strains". Exp Cell Res 25: 585-621. PMID 13905659.
^ Hayflick L. (1965). "The limited in vitro lifetime of human diploid cell strains.". Exp. Cell Res. 37 (3): 614–636. doi:10.1016/0014-4827(65)90211-9. PMID 14315085.
^ McFarlan GA.; Holliday R. (1994). "Retardation of the senescence of cultured human fibroblasts by carnosine". Exp. Cell Res. 212 (2): 167–175. doi:10.1006/excr.1994.1132. PMID 8187813.
^ Shao L; Li QH, Tan Z (2004). "L-carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts.". Biochem Biophys Res Commun. 324 (2): 931–936. doi:10.1016/j.bbrc.2004.09.136. PMID 15474517.
^ Carrel, A. & Ebeling, A. H. Age and multiplication of fibroblasts. J. Exp. Med. 34, 599–606 (1921).
^ Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621(1961).
^ Witkowski, J. A. The myth of cell immortality. Trends Biochem. Sci. 10, 258–260 (1985).
^ Witkowski, J. A. Dr. Carrel’s immortal cells. Med. Hist. 24, 129–142 (1980).
^ ^a ^b Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621(1961).
^ Watson, J. D. Origin of concatemeric T7 DNA. Nature New Biol. 239, 197–201 (1972).
^ Olovnikov, A. M. Telomeres, telomerase and aging: Origin of the theory. Exp. Gerontol. 31, 443–448 (1996).
^ Olovnikov, A. M. Principles of marginotomy in template synthesis of polynucleotides. Dokl. Akad. Nauk S.S.S.R.201, 1496–1499 (1971).
^ Feng, F. et al. The RNA component of human telomerase.Science 269, 1236–1241 (1995).
^ Wright, W. E. & Shay, J. W. Telomere dynamics in cancer progression and prevention: Fundamental differences in human and mouse telomere biology. Nature Med. 6, 849–851 (2000).

[edit] Literature

Harley C, Futcher A & Greider C (1990) Telomeres shorten during ageing of human fibroblasts, Nature, 345, 458–460.
Wang R, Smogorzewska A & Lange T (2004) Homologous Recombination Generates T-Loop-Sized Deletions at Human Telomeres, Cell, 119, 355–368.
Watson J & Shippen D (2007) Telomere Rapid Deletion Regulates Telomere Length in Arabidopsis thaliana, Molecular and Cellular Biology, 27(5), 1706-1715.

[edit] External links

Cell immortality and cancer

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[pmid13905659-0] Hayflick L, Moorhead PS (1961). "The serial cultivation of human diploid cell strains". Exp Cell Res 25: 585-621. PMID 13905659.

[1] Hayflick L. (1965). "The limited in vitro lifetime of human diploid cell strains.". Exp. Cell Res. 37 (3): 614–636. doi:10.1016/0014-4827(65)90211-9. PMID 14315085.

[2] McFarlan GA.; Holliday R. (1994). "Retardation of the senescence of cultured human fibroblasts by carnosine". Exp. Cell Res. 212 (2): 167–175. doi:10.1006/excr.1994.1132. PMID 8187813.

[3] Shao L; Li QH, Tan Z (2004). "L-carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts.". Biochem Biophys Res Commun. 324 (2): 931–936. doi:10.1016/j.bbrc.2004.09.136. PMID 15474517.

[4] Carrel, A. & Ebeling, A. H. Age and multiplication of fibroblasts. J. Exp. Med. 34, 599–606 (1921).

[5] Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621(1961).

[6] Witkowski, J. A. The myth of cell immortality. Trends Biochem. Sci. 10, 258–260 (1985).

[7] Witkowski, J. A. Dr. Carrel’s immortal cells. Med. Hist. 24, 129–142 (1980).

[Hayflick.2C_L._1961-8] Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621(1961).

[9] Watson, J. D. Origin of concatemeric T7 DNA. Nature New Biol. 239, 197–201 (1972).

[10] Olovnikov, A. M. Telomeres, telomerase and aging: Origin of the theory. Exp. Gerontol. 31, 443–448 (1996).

[11] Olovnikov, A. M. Principles of marginotomy in template synthesis of polynucleotides. Dokl. Akad. Nauk S.S.S.R.201, 1496–1499 (1971).

[12] Feng, F. et al. The RNA component of human telomerase.Science 269, 1236–1241 (1995).

[13] Wright, W. E. & Shay, J. W. Telomere dynamics in cancer progression and prevention: Fundamental differences in human and mouse telomere biology. Nature Med. 6, 849–851 (2000).

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