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Hayflick limit

April 09, 2024

The Hayflick limit, or Hayflick phenomenon, is the number of times a normal somatic, differentiated human cell population will divide before cell division stops.[1][2] However, this limit does not apply to stem cells. [citation needed]

Animation of the structure of a section of DNA. The bases lie horizontally between the two spiraling strands. Nitrogen: blue, oxygen: red, carbon: green, hydrogen: white, phosphorus: orange

The concept of the Hayflick limit was advanced by American anatomist Leonard Hayflick in 1961,[3] at the Wistar Institute in Philadelphia, Pennsylvania. Hayflick demonstrated that a normal human fetal cell population will divide between 40 and 60 times in cell culture before entering a senescence phase. This finding refuted the contention by Alexis Carrel that normal cells are immortal.

Each time a cell undergoes mitosis, the telomeres on the ends of each chromosome shorten slightly. Cell division will cease once telomeres shorten to a critical length. Hayflick interpreted his discovery to be aging at the cellular level. The aging of cell populations appears to correlate with the overall physical aging of an organism.[3][4]

Macfarlane Burnet coined the name "Hayflick limit" in his book Intrinsic Mutagenesis: A Genetic Approach to Ageing, published in 1974.[5]

History edit

The belief in cell immortality edit

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, had stated "that all cells explanted in tissue culture are immortal, and that the lack of continuous cell replication was due to ignorance on how best to cultivate the cells".[5] He claimed to have cultivated fibroblasts from the hearts of chickens (which typically live 5 to 10 years) and to have kept the culture growing for 34 years.[6]

However, other scientists have been unable to replicate Carrel's results,[5] and they are suspected to be due to an error in experimental procedure. To provide required nutrients, embryonic stem cells of chickens may have been re-added to the culture daily. This would have easily allowed the cultivation of new, fresh cells in the culture, so there was not an infinite reproduction of the original cells.[3] It has been speculated that Carrel knew about this error, but he never admitted it.[7][8]

Also, it has been theorized[by whom?] that the cells Carrel used were young enough to contain pluripotent stem cells, which, if supplied with a supporting telomerase-activation nutrient, would have been capable of staving off 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 the 50 ± 10 mitosis event limit until cellular senescence occurs as described in Hayflick's findings.[4]

Experiment and discovery edit

Hayflick first became suspicious of Carrel's claims while working in a lab at the Wistar Institute. Hayflick noticed that one of his cultures of embryonic human fibroblasts had developed an unusual appearance and that cell division had slowed. Initially, he brushed this aside as an anomaly caused by contamination or technical error. However, he later observed other cell cultures exhibiting similar manifestations. Hayflick checked his research notebook and was surprised to find that the atypical cell cultures had all been cultured to approximately their 40th doubling while younger cultures never exhibited the same problems. Furthermore, conditions were similar between the younger and older cultures he observed — same culture medium, culture containers, and technician. This led him to doubt that the manifestations were due to contamination or technical error.[9]

Hayflick next set out to prove that the cessation of normal cell replicative capacity that he observed was not the result of viral contamination, poor culture conditions or some unknown artifact. Hayflick teamed with Paul Moorhead for the definitive experiment to eliminate these as causative factors. As a skilled cytogeneticist, Moorhead was able to distinguish between male and female cells in culture. The experiment proceeded as follows: Hayflick mixed equal numbers of normal human male fibroblasts that had divided many times (cells at the 40th population doubling) with female fibroblasts that had divided fewer times (cells at the 15th population doubling). Unmixed cell populations were kept as controls. After 20 doublings of the mixed culture, only female cells remained. Cell division ceased in the unmixed control cultures at the anticipated times; when the male control culture stopped dividing, only female cells remained in the mixed culture. This suggested that technical errors or contaminating viruses were unlikely explanations as to why cell division ceased in the older cells, and proved that unless the virus or artifact could distinguish between male and female cells (which it could not) then the cessation of normal cell replication was governed by an internal counting mechanism.[3][5][9]

These results disproved Carrel's immortality claims and established the Hayflick limit as a credible biological theory. Unlike Carrel's experiment, Hayflick's have been successfully repeated by other scientists.

Cell phases edit

Hayflick describes three phases in the life of normal cultured cells. 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 this the time of "luxuriant growth". After months of doubling the cells eventually reach phase three, a phenomenon he named "senescence", where cell replication rate slows before halting altogether.[citation needed]

Telomere length edit

 
The typical normal human fetal cell will divide between 50 and 70 times before experiencing senescence. As the cell divides, the telomeres on the ends of chromosomes shorten. The Hayflick limit is the limit on cell replication imposed by the shortening of telomeres with each division. This end stage is known as cellular senescence.

The Hayflick limit has been found to correlate with the length of the telomeric region at the end of chromosomes. During the process of DNA replication of a chromosome, small segments of DNA within each telomere are unable to be copied and are lost.[10] This occurs due to the uneven nature of DNA replication, where leading and lagging strands are not replicated symmetrically.[11] The telomeric region of DNA does not code for any protein; it is simply a repeated code on the end region of linear eukaryotic chromosomes. After many divisions, the telomeres reach a critical length and the cell becomes senescent. It is at this point that a cell has reached its Hayflick limit.[12][13]

Hayflick was the first to report that only cancer cells are immortal. This could not have been demonstrated until he had demonstrated that normal cells are mortal.[3][4] Cellular senescence does not occur in most cancer cells due to expression of an enzyme called telomerase. This enzyme extends telomeres, preventing the telomeres of cancer cells from shortening and giving them infinite replicative potential.[14] 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.[15]

Organismal aging edit

Hayflick suggested that his results in which normal cells have a limited replicative capacity may have significance for understanding human aging at the cellular level.[4]

It has been reported that the limited replicative capability of human fibroblasts observed in cell culture is far greater than the number of replication events experienced by non-stem cells in vivo during a normal postnatal lifespan.[16] In addition, it has been suggested that no inverse correlation exists between the replicative capacity of normal human cell strains and the age of the human donor from which the cells were derived, as previously argued. It is now clear that at least some of these variable results are attributable to the mosaicism of cell replication numbers at different body sites where cells were taken.[16]

Comparisons of different species indicate that cellular replicative capacity may correlate primarily with species body mass, but more likely to species lifespan.[clarification needed] Thus, the limited capacity of cells to replicate in culture may be directly relevant to organismal aging.[citation needed]

See also edit

References edit

  1. ^ Rodriguez-Brenes, Ignacio A.; Wodarz, Dominik; Komarova, Natalia L. (December 9, 2015). "Quantifying replicative senescence as a tumor suppressor pathway and a target for cancer therapy". Scientific Reports. 5: 17660. Bibcode:2015NatSR...517660R. doi:10.1038/srep17660. PMC 4673423. PMID 26647820.
  2. ^ Petersen, Thomas; Niklason, Laura (September 2007). "Cellular Lifespan and Regenerative Medicine". Biomaterials. 28 (26): 3751–3756. doi:10.1016/j.biomaterials.2007.05.012. PMC 2706083. PMID 17574669.
  3. ^ a b c d e Hayflick L, Moorhead PS (1961). "The serial cultivation of human diploid cell strains". Exp Cell Res. 25 (3): 585–621. doi:10.1016/0014-4827(61)90192-6. PMID 13905658.
  4. ^ a b c d 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.
  5. ^ a b c d Shay, JW; Wright, WE (October 2000). "Hayflick, his limit, and cellular ageing". Nature Reviews Molecular Cell Biology. 1 (1): 72–6. doi:10.1038/35036093. PMID 11413492. S2CID 6821048.
  6. ^ Carrel A, Ebeling AH (1921). "Age and multiplication of fibroblasts". J. Exp. Med. 34 (6): 599–606. doi:10.1084/jem.34.6.599. PMC 2128071. PMID 19868581.
  7. ^ Witkowski JA (1985). "The myth of cell immortality". Trends Biochem. Sci. 10 (7): 258–260. doi:10.1016/0968-0004(85)90076-3.
  8. ^ Witkowski JA (1980). "Dr. Carrel's immortal cells". Med. Hist. 24 (2): 129–142. doi:10.1017/S0025727300040126. PMC 1082700. PMID 6990125.
  9. ^ a b Hayflick, L (19 May 2016). "Unlike Aging, Longevity is Sexually Determined". In Bengtson, VL; Settersten, RA (eds.). Handbook of Theories of Aging (Third ed.). Springer Publishing Company. pp. 31–52. ISBN 9780826129420.
  10. ^ Watson JD (1972). "Origin of concatemeric T7 DNA". Nature New Biology. 239 (94): 197–201. doi:10.1038/newbio239197a0. PMID 4507727.
  11. ^ Rousseau, Philippe; Autexier, Chantal (October 2015). "Telomere biology: Rationale for diagnostics and therapeutics in cancer". RNA Biology. 12 (10): 1078–1082. doi:10.1080/15476286.2015.1081329. PMC 4829327. PMID 26291128.
  12. ^ Olovnikov AM (1996). "Telomeres, telomerase and aging: Origin of the theory". Exp. Gerontol. 31 (4): 443–448. doi:10.1016/0531-5565(96)00005-8. PMID 9415101. S2CID 26381790.
  13. ^ Olovnikov, A. M. (1971). "Принцип маргинотомии в матричном синтезе полинуклеотидов" [Principles of marginotomy in template synthesis of polynucleotides]. Doklady Akademii Nauk SSSR. 201 (6): 1496–1499. PMID 5158754.
  14. ^ Feng F; et al. (1995). "The RNA component of human telomerase". Science. 269 (5228): 1236–1241. Bibcode:1995Sci...269.1236F. doi:10.1126/science.7544491. PMID 7544491. S2CID 9440710.
  15. ^ Wright WE, Shay JW (2000). "Telomere dynamics in cancer progression and prevention: Fundamental differences in human and mouse telomere biology". Nature Medicine. 6 (8): 849–851. doi:10.1038/78592. PMID 10932210. S2CID 20339035.
  16. ^ 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.A. 95 (18): 10614–9. Bibcode:1998PNAS...9510614C. doi:10.1073/pnas.95.18.10614. PMC 27943. PMID 9724752.


Further reading edit

  • Watts, Geoff (2011). "Leonard Hayflick and the limits of ageing". The Lancet. 377 (9783): 2075. doi:10.1016/S0140-6736(11)60908-2. PMID 21684371. S2CID 205963134.
  • Harley, Calvin B.; Futcher, A. Bruce; Greider, Carol W. (1990). "Telomeres shorten during ageing of human fibroblasts". Nature. 345 (6274): 458–60. Bibcode:1990Natur.345..458H. doi:10.1038/345458a0. PMID 2342578. S2CID 1145492.
  • Gavrilov LA, Gavrilova NS (1991). The Biology of Life Span: A Quantitative Approach. New York: Harwood Academic Publisher. ISBN 3-7186-4983-7.
  • Gavrilov LA, Gavrilova NS (1993). "How many cell divisions in 'old' cells?". Int. J. Geriatr. Psychiatry. 8 (6): 528.
  • Wang, Richard C.; Smogorzewska, Agata; De Lange, Titia (2004). "Homologous Recombination Generates T-Loop-Sized Deletions at Human Telomeres". Cell. 119 (3): 355–68. doi:10.1016/j.cell.2004.10.011. PMID 15507207. S2CID 10686288.
  • Watson, J. M.; Shippen, D. E. (2006). "Telomere Rapid Deletion Regulates Telomere Length in Arabidopsis thaliana". Molecular and Cellular Biology. 27 (5): 1706–15. doi:10.1128/MCB.02059-06. PMC 1820464. PMID 17189431.

April 09, 2024
hayflick, limit, hayflick, phenomenon, number, times, normal, somatic, differentiated, human, cell, population, will, divide, before, cell, division, stops, however, this, limit, does, apply, stem, cells, citation, needed, animation, structure, section, bases,. The Hayflick limit or Hayflick phenomenon is the number of times a normal somatic differentiated human cell population will divide before cell division stops 1 2 However this limit does not apply to stem cells citation needed Animation of the structure of a section of DNA The bases lie horizontally between the two spiraling strands Nitrogen blue oxygen red carbon green hydrogen white phosphorus orangeThe concept of the Hayflick limit was advanced by American anatomist Leonard Hayflick in 1961 3 at the Wistar Institute in Philadelphia Pennsylvania Hayflick demonstrated that a normal human fetal cell population will divide between 40 and 60 times in cell culture before entering a senescence phase This finding refuted the contention by Alexis Carrel that normal cells are immortal Each time a cell undergoes mitosis the telomeres on the ends of each chromosome shorten slightly Cell division will cease once telomeres shorten to a critical length Hayflick interpreted his discovery to be aging at the cellular level The aging of cell populations appears to correlate with the overall physical aging of an organism 3 4 Macfarlane Burnet coined the name Hayflick limit in his book Intrinsic Mutagenesis A Genetic Approach to Ageing published in 1974 5 Contents 1 History 1 1 The belief in cell immortality 1 2 Experiment and discovery 2 Cell phases 3 Telomere length 4 Organismal aging 5 See also 6 References 7 Further readingHistory editThe belief in cell immortality edit 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 had stated that all cells explanted in tissue culture are immortal and that the lack of continuous cell replication was due to ignorance on how best to cultivate the cells 5 He claimed to have cultivated fibroblasts from the hearts of chickens which typically live 5 to 10 years and to have kept the culture growing for 34 years 6 However other scientists have been unable to replicate Carrel s results 5 and they are suspected to be due to an error in experimental procedure To provide required nutrients embryonic stem cells of chickens may have been re added to the culture daily This would have easily allowed the cultivation of new fresh cells in the culture so there was not an infinite reproduction of the original cells 3 It has been speculated that Carrel knew about this error but he never admitted it 7 8 Also it has been theorized by whom that the cells Carrel used were young enough to contain pluripotent stem cells which if supplied with a supporting telomerase activation nutrient would have been capable of staving off 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 the 50 10 mitosis event limit until cellular senescence occurs as described in Hayflick s findings 4 Experiment and discovery edit Hayflick first became suspicious of Carrel s claims while working in a lab at the Wistar Institute Hayflick noticed that one of his cultures of embryonic human fibroblasts had developed an unusual appearance and that cell division had slowed Initially he brushed this aside as an anomaly caused by contamination or technical error However he later observed other cell cultures exhibiting similar manifestations Hayflick checked his research notebook and was surprised to find that the atypical cell cultures had all been cultured to approximately their 40th doubling while younger cultures never exhibited the same problems Furthermore conditions were similar between the younger and older cultures he observed same culture medium culture containers and technician This led him to doubt that the manifestations were due to contamination or technical error 9 Hayflick next set out to prove that the cessation of normal cell replicative capacity that he observed was not the result of viral contamination poor culture conditions or some unknown artifact Hayflick teamed with Paul Moorhead for the definitive experiment to eliminate these as causative factors As a skilled cytogeneticist Moorhead was able to distinguish between male and female cells in culture The experiment proceeded as follows Hayflick mixed equal numbers of normal human male fibroblasts that had divided many times cells at the 40th population doubling with female fibroblasts that had divided fewer times cells at the 15th population doubling Unmixed cell populations were kept as controls After 20 doublings of the mixed culture only female cells remained Cell division ceased in the unmixed control cultures at the anticipated times when the male control culture stopped dividing only female cells remained in the mixed culture This suggested that technical errors or contaminating viruses were unlikely explanations as to why cell division ceased in the older cells and proved that unless the virus or artifact could distinguish between male and female cells which it could not then the cessation of normal cell replication was governed by an internal counting mechanism 3 5 9 These results disproved Carrel s immortality claims and established the Hayflick limit as a credible biological theory Unlike Carrel s experiment Hayflick s have been successfully repeated by other scientists Cell phases editHayflick describes three phases in the life of normal cultured cells 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 this the time of luxuriant growth After months of doubling the cells eventually reach phase three a phenomenon he named senescence where cell replication rate slows before halting altogether citation needed Telomere length edit nbsp The typical normal human fetal cell will divide between 50 and 70 times before experiencing senescence As the cell divides the telomeres on the ends of chromosomes shorten The Hayflick limit is the limit on cell replication imposed by the shortening of telomeres with each division This end stage is known as cellular senescence The Hayflick limit has been found to correlate with the length of the telomeric region at the end of chromosomes During the process of DNA replication of a chromosome small segments of DNA within each telomere are unable to be copied and are lost 10 This occurs due to the uneven nature of DNA replication where leading and lagging strands are not replicated symmetrically 11 The telomeric region of DNA does not code for any protein it is simply a repeated code on the end region of linear eukaryotic chromosomes After many divisions the telomeres reach a critical length and the cell becomes senescent It is at this point that a cell has reached its Hayflick limit 12 13 Hayflick was the first to report that only cancer cells are immortal This could not have been demonstrated until he had demonstrated that normal cells are mortal 3 4 Cellular senescence does not occur in most cancer cells due to expression of an enzyme called telomerase This enzyme extends telomeres preventing the telomeres of cancer cells from shortening and giving them infinite replicative potential 14 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 15 Organismal aging editHayflick suggested that his results in which normal cells have a limited replicative capacity may have significance for understanding human aging at the cellular level 4 It has been reported that the limited replicative capability of human fibroblasts observed in cell culture is far greater than the number of replication events experienced by non stem cells in vivo during a normal postnatal lifespan 16 In addition it has been suggested that no inverse correlation exists between the replicative capacity of normal human cell strains and the age of the human donor from which the cells were derived as previously argued It is now clear that at least some of these variable results are attributable to the mosaicism of cell replication numbers at different body sites where cells were taken 16 Comparisons of different species indicate that cellular replicative capacity may correlate primarily with species body mass but more likely to species lifespan clarification needed Thus the limited capacity of cells to replicate in culture may be directly relevant to organismal aging citation needed See also editAgeing Apoptosis Biological immortality HeLa cells Induced stem cellsReferences edit Rodriguez Brenes Ignacio A Wodarz Dominik Komarova Natalia L December 9 2015 Quantifying replicative senescence as a tumor suppressor pathway and a target for cancer therapy Scientific Reports 5 17660 Bibcode 2015NatSR 517660R doi 10 1038 srep17660 PMC 4673423 PMID 26647820 Petersen Thomas Niklason Laura September 2007 Cellular Lifespan and Regenerative Medicine Biomaterials 28 26 3751 3756 doi 10 1016 j biomaterials 2007 05 012 PMC 2706083 PMID 17574669 a b c d e Hayflick L Moorhead PS 1961 The serial cultivation of human diploid cell strains Exp Cell Res 25 3 585 621 doi 10 1016 0014 4827 61 90192 6 PMID 13905658 a b c d 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 a b c d Shay JW Wright WE October 2000 Hayflick his limit and cellular ageing Nature Reviews Molecular Cell Biology 1 1 72 6 doi 10 1038 35036093 PMID 11413492 S2CID 6821048 Carrel A Ebeling AH 1921 Age and multiplication of fibroblasts J Exp Med 34 6 599 606 doi 10 1084 jem 34 6 599 PMC 2128071 PMID 19868581 Witkowski JA 1985 The myth of cell immortality Trends Biochem Sci 10 7 258 260 doi 10 1016 0968 0004 85 90076 3 Witkowski JA 1980 Dr Carrel s immortal cells Med Hist 24 2 129 142 doi 10 1017 S0025727300040126 PMC 1082700 PMID 6990125 a b Hayflick L 19 May 2016 Unlike Aging Longevity is Sexually Determined In Bengtson VL Settersten RA eds Handbook of Theories of Aging Third ed Springer Publishing Company pp 31 52 ISBN 9780826129420 Watson JD 1972 Origin of concatemeric T7 DNA Nature New Biology 239 94 197 201 doi 10 1038 newbio239197a0 PMID 4507727 Rousseau Philippe Autexier Chantal October 2015 Telomere biology Rationale for diagnostics and therapeutics in cancer RNA Biology 12 10 1078 1082 doi 10 1080 15476286 2015 1081329 PMC 4829327 PMID 26291128 Olovnikov AM 1996 Telomeres telomerase and aging Origin of the theory Exp Gerontol 31 4 443 448 doi 10 1016 0531 5565 96 00005 8 PMID 9415101 S2CID 26381790 Olovnikov A M 1971 Princip marginotomii v matrichnom sinteze polinukleotidov Principles of marginotomy in template synthesis of polynucleotides Doklady Akademii Nauk SSSR 201 6 1496 1499 PMID 5158754 Feng F et al 1995 The RNA component of human telomerase Science 269 5228 1236 1241 Bibcode 1995Sci 269 1236F doi 10 1126 science 7544491 PMID 7544491 S2CID 9440710 Wright WE Shay JW 2000 Telomere dynamics in cancer progression and prevention Fundamental differences in human and mouse telomere biology Nature Medicine 6 8 849 851 doi 10 1038 78592 PMID 10932210 S2CID 20339035 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 A 95 18 10614 9 Bibcode 1998PNAS 9510614C doi 10 1073 pnas 95 18 10614 PMC 27943 PMID 9724752 Further reading editWatts Geoff 2011 Leonard Hayflick and the limits of ageing The Lancet 377 9783 2075 doi 10 1016 S0140 6736 11 60908 2 PMID 21684371 S2CID 205963134 Harley Calvin B Futcher A Bruce Greider Carol W 1990 Telomeres shorten during ageing of human fibroblasts Nature 345 6274 458 60 Bibcode 1990Natur 345 458H doi 10 1038 345458a0 PMID 2342578 S2CID 1145492 Gavrilov LA Gavrilova NS 1991 The Biology of Life Span A Quantitative Approach New York Harwood Academic Publisher ISBN 3 7186 4983 7 Gavrilov LA Gavrilova NS 1993 How many cell divisions in old cells Int J Geriatr Psychiatry 8 6 528 Wang Richard C Smogorzewska Agata De Lange Titia 2004 Homologous Recombination Generates T Loop Sized Deletions at Human Telomeres Cell 119 3 355 68 doi 10 1016 j cell 2004 10 011 PMID 15507207 S2CID 10686288 Watson J M Shippen D E 2006 Telomere Rapid Deletion Regulates Telomere Length in Arabidopsis thaliana Molecular and Cellular Biology 27 5 1706 15 doi 10 1128 MCB 02059 06 PMC 1820464 PMID 17189431 Retrieved from https en wikipedia org w index php title Hayflick limit amp oldid 1171078813, wikipedia, wiki, book, books, library,

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