258:
222:, 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.
210:
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.
193:-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
31:
261:
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
209:
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
329:
during a normal postnatal lifespan. 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
244:
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
333:
Comparisons of different species indicate that cellular replicative capacity may correlate primarily with species body mass, but more likely to species lifespan. Thus, the limited capacity of cells to replicate in culture may be directly relevant to the overall physical aging of an organism.
278:
are unable to be copied and are lost. This occurs due to the uneven nature of DNA replication, where leading and lagging strands are not replicated symmetrically. The telomeric region of DNA does not code for any protein; it is simply a repeated code on the end region of linear eukaryotic
181:
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. It has been speculated that Carrel knew about this error, but he never admitted it.
231:
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.
213:
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
226:
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
235:
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.
177:
However, other scientists have been unable to replicate Carrel's results, and they are suspected to be due to an error in experimental procedure. To provide required nutrients,
314:
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.
279:
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.
127:
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.
282:
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.
905:
Olovnikov, A. M. (1971). "Принцип маргинотомии в матричном синтезе полинуклеотидов" [Principles of marginotomy in template synthesis of polynucleotides].
205:
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
166:
are immortal, and that the lack of continuous cell replication was due to ignorance on how best to cultivate the cells". He claimed to have cultivated
298:. This enzyme extends telomeres, preventing the telomeres of cancer cells from shortening and giving them infinite replicative potential. A proposed
985:
Wright WE, Shay JW (2000). "Telomere dynamics in cancer progression and prevention: Fundamental differences in human and mouse telomere biology".
1499:
215:
270:
The
Hayflick limit has been found to correlate with the length of the telomeric region at the end of chromosomes. During the process of
1413:
299:
330:
variable results are attributable to the mosaicism of cell replication numbers at different body sites where cells were taken.
17:
1332:
1133:
Harley, Calvin B.; Futcher, A. Bruce; Greider, Carol W. (1990). "Telomeres shorten during ageing of human fibroblasts".
1358:
1194:
762:
753:
Hayflick, L (19 May 2016). "Unlike Aging, Longevity is
Sexually Determined". In Bengtson, VL; Settersten, RA (eds.).
1479:
1535:
1378:
1368:
1033:"Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation"
907:
1423:
306:
that would prevent the restoration of the telomere, allowing the cell to die like other body cells.
1325:
79:
379:"Quantifying replicative senescence as a tumor suppressor pathway and a target for cancer therapy"
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8:
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263:
246:
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113:
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947:
496:
Hayflick L, Moorhead PS (1961). "The serial cultivation of human diploid cell strains".
394:
377:
Rodriguez-Brenes, Ignacio A.; Wodarz, Dominik; Komarova, Natalia L. (December 9, 2015).
174:(which typically live 5 to 10 years) and to have kept the culture growing for 34 years.
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for the definitive experiment to eliminate these as causative factors. As a skilled
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Also, it has been theorized that the cells Carrel used were young enough to contain
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611:
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549:
540:
Hayflick L. (1965). "The limited in vitro lifetime of human diploid cell strains".
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is far greater than the number of replication events experienced by non-stem cells
303:
94:
90:
830:
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582:
Shay, JW; Wright, WE (October 2000). "Hayflick, his limit, and cellular ageing".
271:
1474:
1243:
1226:
1222:
219:
163:
1227:"Homologous Recombination Generates T-Loop-Sized Deletions at Human Telomeres"
862:
Olovnikov AM (1996). "Telomeres, telomerase and aging: Origin of the theory".
718:
1514:
1204:
Gavrilov LA, Gavrilova NS (1993). "How many cell divisions in 'old' cells?".
1186:
1057:
223:
155:
117:
83:
955:
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1303:
1270:"Telomere Rapid Deletion Regulates Telomere Length in Arabidopsis thaliana"
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815:"Telomere biology: Rationale for diagnostics and therapeutics in cancer"
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59:
39:
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It has been reported that the limited replicative capability of human
1154:
934:
Feng F; et al. (1995). "The RNA component of human telomerase".
595:
348:
257:
89:
The concept of the
Hayflick limit was advanced by American anatomist
30:
275:
55:
43:
1096:
Watts, Geoff (2011). "Leonard
Hayflick and the limits of ageing".
998:
326:
228:
171:
1031:
Cristofalo VJ, Allen RG, Pignolo RJ, Martin BG, Beck JC (1998).
249:", where cell replication rate slows before halting altogether.
1444:
757:(Third ed.). Springer Publishing Company. pp. 31–52.
343:
291:
51:
47:
376:
1459:
105:
102:
1030:
150:
Prior to
Leonard Hayflick's discovery, it was believed that
358:
162:-winning surgeon, had stated "that all cells explanted in
1203:
1177:
35:
1216:
748:
746:
495:
108:
cell population will divide between 40 and 60 times in
933:
813:
Rousseau, Philippe; Autexier, Chantal (October 2015).
743:
674:
Witkowski JA (1985). "The myth of cell immortality".
245:
eventually reach phase three, a phenomenon he named "
1132:
624:
436:
Petersen, Thomas; Niklason, Laura (September 2007).
101:, Pennsylvania. Hayflick demonstrated that a normal
42:
lie horizontally between the two spiraling strands.
778:Watson JD (1972). "Origin of concatemeric T7 DNA".
274:of a chromosome, small segments of DNA within each
135:
1340:
984:
1183:The Biology of Life Span: A Quantitative Approach
145:
1512:
812:
435:
1500:Strategies for engineered negligible senescence
154:cells had an unlimited potential to replicate.
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1024:
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491:
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487:
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116:phase. This finding refuted the contention by
1326:
1267:
438:"Cellular Lifespan and Regenerative Medicine"
133:coined the name "Hayflick limit" in his book
861:
700:
673:
197:occurs as described in Hayflick's findings.
1021:
539:
524:
478:
200:
34:Animation of the structure of a section of
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1319:
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577:
575:
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1414:Reliability theory of aging and longevity
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838:
777:
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650:
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402:
82:human cell population will divide before
27:Limit to divisions of a normal human cell
752:
256:
29:
627:"Age and multiplication of fibroblasts"
568:
189:, which, if supplied with a supporting
14:
1513:
1268:Watson, J. M.; Shippen, D. E. (2006).
1314:
1095:
584:Nature Reviews Molecular Cell Biology
309:
24:
1359:Antagonistic pleiotropy hypothesis
1089:
454:10.1016/j.biomaterials.2007.05.012
252:
74:, is the number of times a normal
25:
1547:
1480:List of longest-living organisms
978:
927:
898:
855:
806:
771:
1274:Molecular and Cellular Biology
1189:: Harwood Academic Publisher.
694:
667:
618:
429:
370:
239:
146:The belief in cell immortality
13:
1:
1110:10.1016/S0140-6736(11)60908-2
831:10.1080/15476286.2015.1081329
755:Handbook of Theories of Aging
703:"Dr. Carrel's immortal cells"
625:Carrel A, Ebeling AH (1921).
364:
1379:Free-radical theory of aging
1037:Proc. Natl. Acad. Sci. U.S.A
876:10.1016/0531-5565(96)00005-8
688:10.1016/0968-0004(85)90076-3
554:10.1016/0014-4827(65)90211-9
510:10.1016/0014-4827(61)90192-6
7:
1206:Int. J. Geriatr. Psychiatry
337:
302:is the usage of telomerase
10:
1552:
1369:DNA damage theory of aging
1244:10.1016/j.cell.2004.10.011
908:Doklady Akademii Nauk SSSR
140:
1432:
1424:Stem cell theory of aging
1349:
1179:Gavrilov LA, Gavrilova NS
719:10.1017/S0025727300040126
1058:10.1073/pnas.95.18.10614
290:due to expression of an
201:Experiment and discovery
1399:Network theory of aging
956:10.1126/science.7544491
286:does not occur in most
1490:Regeneration (biology)
1450:Biological immortality
792:10.1038/newbio239197a0
354:Biological immortality
267:
187:pluripotent stem cells
120:that normal cells are
63:
18:Replicative senescence
1409:Programmed cell death
1394:Negligible senescence
701:Witkowski JA (1980).
260:
137:, published in 1974.
33:
1495:Rejuvenation (aging)
1286:10.1128/MCB.02059-06
643:10.1084/jem.34.6.599
300:treatment for cancer
179:embryonic stem cells
1536:Cellular senescence
1470:Indefinite lifespan
1374:Evolution of ageing
1344:(biology of ageing)
1219:Smogorzewska, Agata
1147:1990Natur.345..458H
1049:1998PNAS...9510614C
948:1995Sci...269.1236F
942:(5228): 1236–1241.
676:Trends Biochem. Sci
395:2015NatSR...517660R
284:Cellular senescence
264:cellular senescence
195:cellular senescence
170:from the hearts of
72:Hayflick phenomenon
1217:Wang, Richard C.;
780:Nature New Biology
383:Scientific Reports
268:
112:before entering a
64:
1508:
1507:
1485:Maximum life span
1440:Adaptive mutation
825:(10): 1078–1082.
448:(26): 3751–3756.
404:10.1038/srep17660
131:Macfarlane Burnet
16:(Redirected from
1543:
1419:Selection shadow
1404:Plant senescence
1389:Immunosenescence
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1141:(6274): 458–60.
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915:(6): 1496–1499.
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310:Organismal aging
95:Wistar Institute
93:in 1961, at the
91:Leonard Hayflick
21:
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1223:De Lange, Titia
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1090:Further reading
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1043:(18): 10614–9.
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987:Nature Medicine
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1280:(5): 1706–15.
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1104:(9783): 2075.
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993:(8): 849–851.
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321:observed in
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134:
129:
126:
110:cell culture
99:Philadelphia
88:
71:
67:
65:
819:RNA Biology
631:J. Exp. Med
590:(1): 72–6.
319:fibroblasts
240:Cell phases
207:fibroblasts
168:fibroblasts
160:Nobel prize
1531:Senescence
1515:Categories
1465:DNA repair
1364:Catabiosis
1351:Senescence
1342:Senescence
1098:The Lancet
365:References
359:HeLa cells
304:inhibitors
296:telomerase
247:senescence
191:telomerase
152:vertebrate
114:senescence
60:phosphorus
1212:(6): 528.
1126:205963134
707:Med. Hist
389:: 17660.
349:Apoptosis
62:: orange.
58:: white,
54:: green,
1521:Genetics
1304:17189431
1261:10686288
1253:15507207
1225:(2004).
1187:New York
1181:(1991).
1118:21684371
1015:20339035
1007:10932210
892:26381790
849:26291128
661:19868581
604:11413492
562:14315085
518:13905658
472:17574669
423:26647820
338:See also
276:telomere
172:chickens
122:immortal
56:hydrogen
46:: blue,
44:Nitrogen
1295:1820464
1171:1145492
1163:2342578
1143:Bibcode
1077:9724752
1045:Bibcode
972:9440710
964:7544491
944:Bibcode
936:Science
921:5158754
884:9415101
840:4829327
800:4507727
737:6990125
728:1082700
652:2128071
612:6821048
463:2706083
414:4673423
391:Bibcode
327:in vivo
294:called
229:viruses
141:History
86:stops.
76:somatic
50:: red,
1445:Ageing
1302:
1292:
1259:
1251:
1193:
1169:
1161:
1135:Nature
1124:
1116:
1075:
1065:
1013:
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970:
962:
919:
890:
882:
847:
837:
798:
761:
735:
725:
659:
649:
610:
602:
560:
516:
470:
460:
421:
411:
344:Ageing
292:enzyme
52:carbon
48:oxygen
38:. The
1460:Death
1257:S2CID
1167:S2CID
1122:S2CID
1068:27943
1011:S2CID
968:S2CID
888:S2CID
608:S2CID
106:fetal
103:human
70:, or
40:bases
1300:PMID
1249:PMID
1231:Cell
1191:ISBN
1159:PMID
1114:PMID
1073:PMID
1003:PMID
960:PMID
917:PMID
880:PMID
845:PMID
796:PMID
759:ISBN
733:PMID
657:PMID
600:PMID
558:PMID
514:PMID
468:PMID
419:PMID
158:, a
66:The
1290:PMC
1282:doi
1239:doi
1235:119
1151:doi
1139:345
1106:doi
1102:377
1063:PMC
1053:doi
995:doi
952:doi
940:269
913:201
872:doi
835:PMC
827:doi
788:doi
784:239
723:PMC
715:doi
684:doi
647:PMC
639:doi
592:doi
550:doi
506:doi
458:PMC
450:doi
409:PMC
399:doi
97:in
36:DNA
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