Hayflick limit

The Hayflick limit or Hayflick phenomenon is the number of times a normal human cell population will divide until cell division stops. Empirical evidence shows that the telomeres associated with each cell’s DNA will get slightly shorter with each new cell division until they shorten to a critical length.[1][2]

The concept of the Hayflick limit was advanced by American anatomist Leonard Hayflick in 1961,[1] at the Wistar Institute in Philadelphia, Pennsylvania, USA. Hayflick demonstrated that a population of normal human fetal cells in a cell culture will divide between 40 and 60 times. The population will then enter a senescence phase, which refutes the contention by Nobel laureate Alexis Carrel that normal cells are immortal. Each mitosis slightly shortens each of the telomeres on the DNA of the cells. Telomere shortening in humans eventually makes cell division impossible, and this aging of the cell population appears to correlate with the overall physical aging of the human body.

Australian Nobel laureate Sir Macfarlane Burnet coined the name “Hayflick limit” in his book Intrinsic Mutagenesis: A Genetic Approach to Ageing, published in 1974.[3]

History

The belief of cell immortality

Prior to Leonard Hayflick’s discovery, it was believed that vertebrate cells had an unlimited potential to replicate. Alexis Carrel, a Nobel prize -winning surgeon, said that “all cells are explanted in culture are immortal, and that the lack of replication is due to ignorance on how best to cultivate cells.” [3] He supported this hypothesis by claiming to have grown fibroblasts from chicken hearts and growing culture for 34 years. [4] This indicated that cells of vertebratescould continue to divide indefinitely in a culture. However, other scientists have been unable to repeat Carrel’s result. [3]

Carrel’s result is suspected to be an error in experimental procedure. To provide required nutrients, embryonic stem cells of chickens may have been re-added to the daily culture. This would have been easily cultivated in new culture, so it was not an infinite reproduction of the original cells. [1] If it is true, it has been speculated that it has not been admitted. [5] [6]

Also, it has been theorized that the cells used to be pluripotent stem cells , which, if supplied with a supporting telomerase- nutrient activation, would have been capable of replicating replicative senescence, or even possibly reversing it. Cultures not containing telomerase-active pluripotent stem cells would have been populated with telomerase-inactive cells, which would have been subject to 50-60 mitosis cycles until apoptosis occurred in Hayflick’s findings. quote needed ]

Experiment and discovery

Hayflick first became suspicious of Carrel’s theory while working in a lab at the Wistar Institute. Hayflick Was prepaid normal human cells to be exposed to extracts of cancer cells When He Noticed the normal cells HAD stopped proliferating. At first he thought that he had made a technical error in the preparation of the experiment, but later he began to think that the cell division processes had a counting mechanism. Working with Paul Moorhead, a cytogeneticist , he designed an experiment to test Carrel’s theory of cell division. quote needed ]

The experiment proceeded as follows. And mixed human fibroblasts that had divided many times (cells at the 40th population doubling) with female fibroblasts that were divided only at a few times (cells at the 10th population doubling). Unmixed cell populations were kept as controls. When the male control culture was discontinued, the mixed culture was examined and only female cells were found. Ce que la Showed old male 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. [1] [3]

The cells had stopped dividing and had become senescent based on quote needed ]

These results are of great importance to the theory of Carrel and the Hayflick limit as a credible biological theory which, unlike Carrel’s experiment, has been repeated by other scientists. quote needed ]

Cell phases

Hayflick describes three phases in the life of a cell. At the start of his experiment he named the primary culture “phase one”. Phase two is defined as the period when cells are proliferating – Hayflick called it the time of “luxuriant growth”. After months of doubling, the cells eventually reach phase three, a phenomenon of senescence – cell growth diminishes and then cell division stops altogether.

Telomere length

The average cell will divide between 50-70 times before cell death. As the cell divides the telomeres on the end of the chromosome get smaller. The Hayflick limit is the theory that due to the telomeres shortening through each division, the telomeres will eventually no longer be present on the chromosome. This end stage is known as senescence and proves the concept that links the deterioration of telomeres and aging.

The Hayflick limit has been found to correlate with the length of the telomere region 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.[7] This occurs due to the uneven nature of DNA replication, where leading and lagging strands are not replicated symmetrically.[8] The telomere region of DNA does not code for any protein; it is simply a repeated code on the end region of linear eukaryotic chromosomes that is lost. After many divisions, the telomeres become depleted and the cell begins apoptosis. This is a mechanism that prevents replication error that would cause mutations in DNA. Once the telomeres are depleted, due to the cell dividing many times, it will no longer divide. This is when the cell has reached its Hayflick limit.[9][10]

This process does not take place in most cancer cells due to an enzyme called telomerase. This enzyme maintains telomere length, which results in the telomeres of cancer cells never shortening. This gives these cells infinite replicative potential.[11] A proposed treatment for cancer is the usage of telomerase inhibitors that would prevent the restoration of the telomere, allowing the cell to die like other body cells.[12] On the other hand, telomerase activators might repair or extend the telomeres of healthy cells, thus extending their Hayflick limit. Telomerase activation might also lengthen the telomeres of immune system cells enough to prevent cancerous cells from developing from cells with very short telomeres.

Organismal aging

It has been speculated that the limited replicative capability of human fibroblasts in culture may have significance for human aging, even though the number of replications observed in culture is far greater than the number that would be expected for non-stem cells in vivo during a normal postnatal lifespan.[13] Although it had been thought that the replicative capacity of human cell lines was inversely correlated with the age of the human donor from whom the cell lines were derived, it is now clear that no such correlation exists.[13]

Comparisons of different species indicate that cellular replicative capacity correlates primarily with species body mass, not species lifespan.[14] Thus it appears that the limited capacity of cells to replicate in culture may not be directly relevant to organismal aging.

See also

  • Ageing
  • Apoptosis
  • Biological immortality
  • HeLa cells
  • Induced stem cells

References

  1. ^ Jump up to:a b c d Hayflick L, Moorhead PS (1961). “The serial cultivation of human diploid cell strains”. Exp Cell Res25 (3): 585–621. doi:10.1016/0014-4827(61)90192-6. PMID 13905658.
  2. Jump up^ Hayflick L. (1965). “The limited in vitro lifetime of human diploid cell strains”. Exp. Cell Res37 (3): 614–636. doi:10.1016/0014-4827(65)90211-9. PMID 14315085.
  3. ^ Jump up to:a b c d Shay JW, Wright WE; Wright (2000). “Hayflick, his limit, and cellular ageing” (PDF). Nature Reviews Molecular Cell Biology1 (1): 72–76. doi:10.1038/35036093. PMID 11413492. Archived from the original on 2010-07-13.
  4. Jump up^ Carrel A, Ebeling AH (1921). “Age and multiplication of fibroblasts”. J. Exp. Med34 (6): 599–606. doi:10.1084/jem.34.6.599.
  5. Jump up^ Witkowski JA (1985). “The myth of cell immortality”. Trends Biochem. Sci10 (7): 258–260. doi:10.1016/0968-0004(85)90076-3.
  6. Jump up^ Witkowski JA (1980). “Dr. Carrel’s immortal cells”. Med. Hist24 (2): 129–142. doi:10.1017/S0025727300040126. PMC 1082700 . PMID 6990125.
  7. Jump up^ Watson JD (1972). “Origin of concatemeric T7 DNA”. Nature New Biology239 (94): 197–201. doi:10.1038/newbio239197a0. PMID 4507727.
  8. Jump up^ Rousseau, Philippe; Autexier, Chantal (October 2015). “Telomere biology: Rationale for diagnostics and therapeutics in cancer”. RNA Biology12(10): 1078–1082. doi:10.1080/15476286.2015.1081329.
  9. Jump up^ Olovnikov AM (1996). “Telomeres, telomerase and aging: Origin of the theory”. Exp. Gerontol31 (4): 443–448. doi:10.1016/0531-5565(96)00005-8. PMID 9415101.
  10. Jump up^ Olovnikov, A. M. (1971). “Принцип маргинотомии в матричном синтезе полинуклеотидов” [Principles of marginotomy in template synthesis of polynucleotides]. Doklady Akademii Nauk SSSR201: 1496–1499.
  11. Jump up^ Feng F; et al. (1995). “The RNA component of human telomerase”. Science269 (5228): 1236–1241. doi:10.1126/science.7544491. PMID 7544491.
  12. Jump up^ Wright WE, Shay JW (2000). “Telomere dynamics in cancer progression and prevention: Fundamental differences in human and mouse telomere biology”. Nature Medicine6 (8): 849–851. doi:10.1038/78592. PMID 10932210.
  13. ^ Jump up to:a b Cristofalo VJ, Allen RG, Pignolo RJ, Martin BG, Beck JC (1998). “Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation”. Proc. Natl. Acad. Sci. U.S.A95 (18): 10614–9. PMC 27943 . PMID 9724752.
  14. Jump up^ Lorenzini A, Tresini M, Austad SN, Cristofalo VJ (2005). “Cellular replicative capacity correlates primarily with species body mass not longevity”. Mech. Ageing Dev126 (10): 1130–3. doi:10.1016/j.mad.2005.05.004. PMID 15993927.

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