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Genes & Dev. 24 (6): 543-548

Copyright © 2010 by Cold Spring Harbor Laboratory Press.

RESEARCH COMMUNICATION

Pregnancy restores the regenerative capacity of the aged liver via activation of an mTORC1-controlled hyperplasia/hypertrophy switch

Yuval Gielchinsky1,2, Neri Laufer2, Efi Weitman3, Rinat Abramovitch4, Zvi Granot1, Yehudit Bergman1,6,, and Eli Pikarsky3,5

1 Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Hadassah Medical School, Ein Kerem, Jerusalem 91120, Israel;
2 Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel;
3 Department of Pathology and the Lautenberg Center for Immunology, Institute for Medical Research Israel-Canada, Hebrew University Hadassah Medical School, Ein Kerem, Jerusalem 91120, Israel;
4 The Goldyne Savad Institute for Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel

Abstract: 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.

Key Words: Liver regeneration • aging • hypertrophy • hyperplasia • mTORC1

Received for publication October 21, 2009. Accepted for publication January 25, 2010.

5 Corresponding authors.

E-MAIL peli{at}hadassah.org.il; FAX 972-2-6426268.

6 E-MAIL Yehudit.Bergman{at}huji.ac.il; FAX 972-2-6414583.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.563110.

Supplemental material is available at http://www.genesdev.org.

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