Aging does not reduce the hepatocyte proliferative response of mice to the primary mitogen TCPOBOP.
It has been shown that the magnitude of DNA synthesis and the time at which maximal DNA synthesis occurs after two-thirds partial hepatectomy (PH) is greatly reduced in the liver of aged rodents compared to young animals. This reduction could represent an intrinsic defect in proliferation or a more specialized change in the response to PH. We therefore evaluated the proliferative capacity of hepatocytes in aged animals, following treatment with primary liver mitogens. We show that treatment of 12-month-old CD-1 mice with the hepatomitogen 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) caused an increase in hepatocyte proliferation similar to that seen in young (8-week-old) mice. The labeling index was 82% in the livers of aged mice versus 76% in young animals. Histological observation demonstrated that the number of hepatocytes entering mitoses was similar in both groups; the mitotic indices were 2.5 per thousand and 2.7 per thousand, respectively. Additional experiments showed that the timing of DNA synthesis and M phase were nearly identical in both aged and young mice. Stimulation of hepatocyte DNA synthesis was associated with increased expression of several cell cycle-associated proteins (cyclin D1, cyclin A, cyclin B1, E2F, pRb, and p107); all were comparable in aged mice and young mice. TCPOBOP treatment also increased expression of the Forkhead Box transcription factor m1b (Foxm1b) to a similar degree in both groups. In conclusion, hepatocytes retain their proliferative capacity in old age despite impaired liver regeneration. These findings suggest that therapeutic use of mitogens would alleviate the reduction in hepatocyte proliferation observed in the elderly.
Ledda-Columbano
Giovanna M
GM
Department of Toxicology and the Oncology and Molecular Pathology Unit, University of Cagliari, Cagliari, Italy.
Pibiri
Monica
M
Cossu
Costanza
C
Molotzu
Francesca
F
Locker
Joseph
J
Columbano
Amedeo
A
D000375:Aging / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D008115:Liver Regeneration / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D008934:Mitogens / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors / Q000235:genetics
D018797:Cell Cycle Proteins; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D008934:Mitogens; D011725:Pyridines; D012333:RNA, Messenger; D014157:Transcription Factors; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene