247:
211:, 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.
199:
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.
182:-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
20:
250:
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
198:
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
318:
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
233:
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
322:
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.
267:
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
170:
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.
220:
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.
202:
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
215:
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
224:
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.
166:
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,
303:
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.
268:
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.
116:
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.
271:
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.
894:
Olovnikov, A. M. (1971). "Принцип маргинотомии в матричном синтезе полинуклеотидов" [Principles of marginotomy in template synthesis of polynucleotides].
194:
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
155:
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
287:. This enzyme extends telomeres, preventing the telomeres of cancer cells from shortening and giving them infinite replicative potential. A proposed
974:
Wright WE, Shay JW (2000). "Telomere dynamics in cancer progression and prevention: Fundamental differences in human and mouse telomere biology".
1488:
204:
259:
The
Hayflick limit has been found to correlate with the length of the telomeric region at the end of chromosomes. During the process of
1402:
288:
319:
variable results are attributable to the mosaicism of cell replication numbers at different body sites where cells were taken.
1321:
1122:
Harley, Calvin B.; Futcher, A. Bruce; Greider, Carol W. (1990). "Telomeres shorten during ageing of human fibroblasts".
1347:
1183:
751:
742:
Hayflick, L (19 May 2016). "Unlike Aging, Longevity is
Sexually Determined". In Bengtson, VL; Settersten, RA (eds.).
1468:
1524:
1367:
1357:
1022:"Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation"
896:
1412:
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that would prevent the restoration of the telomere, allowing the cell to die like other body cells.
1314:
68:
368:"Quantifying replicative senescence as a tumor suppressor pathway and a target for cancer therapy"
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102:
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1037:
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485:
Hayflick L, Moorhead PS (1961). "The serial cultivation of human diploid cell strains".
383:
366:
Rodriguez-Brenes, Ignacio A.; Wodarz, Dominik; Komarova, Natalia L. (December 9, 2015).
163:(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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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
292:
83:
79:
819:
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571:
Shay, JW; Wright, WE (October 2000). "Hayflick, his limit, and cellular ageing".
260:
1463:
1232:
1215:
1211:
208:
152:
1216:"Homologous Recombination Generates T-Loop-Sized Deletions at Human Telomeres"
851:
Olovnikov AM (1996). "Telomeres, telomerase and aging: Origin of the theory".
707:
1503:
1193:
Gavrilov LA, Gavrilova NS (1993). "How many cell divisions in 'old' cells?".
1175:
1046:
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144:
106:
72:
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1443:
1292:
1259:"Telomere Rapid Deletion Regulates Telomere Length in Arabidopsis thaliana"
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804:"Telomere biology: Rationale for diagnostics and therapeutics in cancer"
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179:
140:
48:
28:
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It has been reported that the limited replicative capability of human
1143:
923:
Feng F; et al. (1995). "The RNA component of human telomerase".
584:
337:
246:
78:
The concept of the
Hayflick limit was advanced by American anatomist
19:
264:
44:
32:
1085:
Watts, Geoff (2011). "Leonard
Hayflick and the limits of ageing".
987:
315:
217:
160:
1020:
Cristofalo VJ, Allen RG, Pignolo RJ, Martin BG, Beck JC (1998).
238:", where cell replication rate slows before halting altogether.
1433:
746:(Third ed.). Springer Publishing Company. pp. 31–52.
332:
280:
40:
36:
365:
1448:
94:
91:
1019:
139:
Prior to
Leonard Hayflick's discovery, it was believed that
347:
151:-winning surgeon, had stated "that all cells explanted in
1192:
1166:
24:
1205:
737:
735:
484:
97:
cell population will divide between 40 and 60 times in
922:
802:
Rousseau, Philippe; Autexier, Chantal (October 2015).
732:
663:
Witkowski JA (1985). "The myth of cell immortality".
234:
eventually reach phase three, a phenomenon he named "
1121:
613:
425:
Petersen, Thomas; Niklason, Laura (September 2007).
90:, Pennsylvania. Hayflick demonstrated that a normal
31:
lie horizontally between the two spiraling strands.
767:Watson JD (1972). "Origin of concatemeric T7 DNA".
263:of a chromosome, small segments of DNA within each
124:
1329:
973:
1172:The Biology of Life Span: A Quantitative Approach
134:
1501:
801:
424:
1489:Strategies for engineered negligible senescence
143:cells had an unlimited potential to replicate.
1015:
1013:
524:
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516:
480:
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476:
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105:phase. This finding refuted the contention by
1315:
1256:
427:"Cellular Lifespan and Regenerative Medicine"
122:coined the name "Hayflick limit" in his book
850:
689:
662:
186:occurs as described in Hayflick's findings.
1010:
528:
513:
467:
189:
23:Animation of the structure of a section of
1322:
1308:
570:
566:
564:
562:
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1403:Reliability theory of aging and longevity
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1045:
893:
827:
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715:
639:
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71:human cell population will divide before
16:Limit to divisions of a normal human cell
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245:
18:
616:"Age and multiplication of fibroblasts"
557:
178:, which, if supplied with a supporting
1502:
1257:Watson, J. M.; Shippen, D. E. (2006).
1303:
1084:
573:Nature Reviews Molecular Cell Biology
298:
13:
1348:Antagonistic pleiotropy hypothesis
1078:
443:10.1016/j.biomaterials.2007.05.012
241:
63:, is the number of times a normal
14:
1536:
1469:List of longest-living organisms
967:
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887:
844:
795:
760:
1263:Molecular and Cellular Biology
1178:: Harwood Academic Publisher.
683:
656:
607:
418:
359:
228:
135:The belief in cell immortality
1:
1099:10.1016/S0140-6736(11)60908-2
820:10.1080/15476286.2015.1081329
744:Handbook of Theories of Aging
692:"Dr. Carrel's immortal cells"
614:Carrel A, Ebeling AH (1921).
353:
1368:Free-radical theory of aging
1026:Proc. Natl. Acad. Sci. U.S.A
865:10.1016/0531-5565(96)00005-8
677:10.1016/0968-0004(85)90076-3
543:10.1016/0014-4827(65)90211-9
499:10.1016/0014-4827(61)90192-6
7:
1195:Int. J. Geriatr. Psychiatry
326:
291:is the usage of telomerase
10:
1541:
1358:DNA damage theory of aging
1233:10.1016/j.cell.2004.10.011
897:Doklady Akademii Nauk SSSR
129:
1421:
1413:Stem cell theory of aging
1338:
1168:Gavrilov LA, Gavrilova NS
708:10.1017/S0025727300040126
1047:10.1073/pnas.95.18.10614
279:due to expression of an
190:Experiment and discovery
1388:Network theory of aging
945:10.1126/science.7544491
275:does not occur in most
1479:Regeneration (biology)
1439:Biological immortality
781:10.1038/newbio239197a0
343:Biological immortality
256:
176:pluripotent stem cells
109:that normal cells are
52:
1398:Programmed cell death
1383:Negligible senescence
690:Witkowski JA (1980).
249:
126:, published in 1974.
22:
1484:Rejuvenation (aging)
1275:10.1128/MCB.02059-06
632:10.1084/jem.34.6.599
289:treatment for cancer
168:embryonic stem cells
1525:Cellular senescence
1459:Indefinite lifespan
1363:Evolution of ageing
1333:(biology of ageing)
1208:Smogorzewska, Agata
1136:1990Natur.345..458H
1038:1998PNAS...9510614C
937:1995Sci...269.1236F
931:(5228): 1236–1241.
665:Trends Biochem. Sci
384:2015NatSR...517660R
273:Cellular senescence
253:cellular senescence
184:cellular senescence
159:from the hearts of
61:Hayflick phenomenon
1206:Wang, Richard C.;
769:Nature New Biology
372:Scientific Reports
257:
101:before entering a
53:
1497:
1496:
1474:Maximum life span
1429:Adaptive mutation
814:(10): 1078–1082.
437:(26): 3751–3756.
393:10.1038/srep17660
120:Macfarlane Burnet
1532:
1408:Selection shadow
1393:Plant senescence
1378:Immunosenescence
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1144:10.1038/345458a0
1130:(6274): 458–60.
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1007:
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904:(6): 1496–1499.
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299:Organismal aging
84:Wistar Institute
82:in 1961, at the
80:Leonard Hayflick
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1212:De Lange, Titia
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1079:Further reading
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1032:(18): 10614–9.
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976:Nature Medicine
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1269:(5): 1706–15.
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1093:(9783): 2075.
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1444:CGK733 fraud
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431:Biomaterials
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310:observed in
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251:is known as
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99:cell culture
88:Philadelphia
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60:
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808:RNA Biology
620:J. Exp. Med
579:(1): 72–6.
308:fibroblasts
229:Cell phases
196:fibroblasts
157:fibroblasts
149:Nobel prize
1520:Senescence
1504:Categories
1454:DNA repair
1353:Catabiosis
1340:Senescence
1331:Senescence
1087:The Lancet
354:References
348:HeLa cells
293:inhibitors
285:telomerase
236:senescence
180:telomerase
141:vertebrate
103:senescence
49:phosphorus
1201:(6): 528.
1115:205963134
696:Med. Hist
378:: 17660.
338:Apoptosis
51:: orange.
47:: white,
43:: green,
1510:Genetics
1293:17189431
1250:10686288
1242:15507207
1214:(2004).
1176:New York
1170:(1991).
1107:21684371
1004:20339035
996:10932210
881:26381790
838:26291128
650:19868581
593:11413492
551:14315085
507:13905658
461:17574669
412:26647820
327:See also
265:telomere
161:chickens
111:immortal
45:hydrogen
35:: blue,
33:Nitrogen
1284:1820464
1160:1145492
1152:2342578
1132:Bibcode
1066:9724752
1034:Bibcode
961:9440710
953:7544491
933:Bibcode
925:Science
910:5158754
873:9415101
829:4829327
789:4507727
726:6990125
717:1082700
641:2128071
601:6821048
452:2706083
403:4673423
380:Bibcode
316:in vivo
283:called
218:viruses
130:History
75:stops.
65:somatic
39:: red,
1434:Ageing
1291:
1281:
1248:
1240:
1182:
1158:
1150:
1124:Nature
1113:
1105:
1064:
1054:
1002:
994:
959:
951:
908:
879:
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836:
826:
787:
750:
724:
714:
648:
638:
599:
591:
549:
505:
459:
449:
410:
400:
333:Ageing
281:enzyme
41:carbon
37:oxygen
27:. The
1449:Death
1246:S2CID
1156:S2CID
1111:S2CID
1057:27943
1000:S2CID
957:S2CID
877:S2CID
597:S2CID
95:fetal
92:human
59:, or
29:bases
1289:PMID
1238:PMID
1220:Cell
1180:ISBN
1148:PMID
1103:PMID
1062:PMID
992:PMID
949:PMID
906:PMID
869:PMID
834:PMID
785:PMID
748:ISBN
722:PMID
646:PMID
589:PMID
547:PMID
503:PMID
457:PMID
408:PMID
147:, a
55:The
1279:PMC
1271:doi
1228:doi
1224:119
1140:doi
1128:345
1095:doi
1091:377
1052:PMC
1042:doi
984:doi
941:doi
929:269
902:201
861:doi
824:PMC
816:doi
777:doi
773:239
712:PMC
704:doi
673:doi
636:PMC
628:doi
581:doi
539:doi
495:doi
447:PMC
439:doi
398:PMC
388:doi
86:in
25:DNA
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