Pregnancy restores the regenerative capacity of the aged liver via activation of an mTORC1-controlled hyperplasia/hypertrophy switch.
Regenerative capacity is progressively lost with age. Here we show that pregnancy markedly improved liver regeneration in aged mice concomitantly with inducing a switch from proliferation-based liver regeneration to a regenerative process mediated by cell growth. We found that the key mediator of this switch was the Akt/mTORC1 pathway; its inhibition blocked hypertrophy, while increasing proliferation. Moreover, pharmacological activation of this pathway sufficed to induce the hypertrophy module, mimicking pregnancy. This treatment dramatically improved hepatic regenerative capacity and survival of old mice. Thus, cell growth-mediated mass reconstitution, which is relatively resistant to the detrimental effects of aging, is employed in a physiological situation and holds potential as a therapeutic strategy for ameliorating age-related functional deterioration.
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Hadassah Medical School, Ein Kerem, Jerusalem, Israel.
Yuval
Y
Gielchinsky
Neri
N
Laufer
Efi
E
Weitman
Rinat
R
Abramovitch
Zvi
Z
Granot
Yehudit
Y
Bergman
Eli
E
Pikarsky
D000375:Aging / Q000502:physiology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D049109:Cell Proliferation; D005260:Female; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D006965:Hyperplasia / Q000378:metabolism; D006984:Hypertrophy / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism* / Q000601:surgery; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes; D011247:Pregnancy; D011506:Proteins; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus