Aging is associated with decreased pancreatic acinar cell regeneration and phosphatidylinositol 3-kinase/Akt activation

Hiroaki Watanabe, Hiroshi Saito, Piotr G. Rychahou, Tatsuo Uchida, B. Mark Evers

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Background & Aims: The effects of aging on pancreatic acinar cell proliferation have not been clearly defined. Phosphatidylinositol 3-kinase (PI3K)-mediated phosphorylation of Akt is a critical step for proliferation of various cell types and insulin secretion from pancreatic endocrine cells; however, its role in acinar cell proliferation is not known. The purpose of this study was to (1) delineate the effects of aging on pancreatic regeneration after partial pancreatectomy (Px) and (2) define the involvement of the PI3K/Akt pathway in pancreatic regeneration. Methods: Following partial Px, pancreatic regeneration and activation of the PI3K pathway were compared in young and aged mice. Activation of the PI3K/Akt pathway was evaluated by Akt phosphorylation (pAkt). The role of the PI3K pathway in pancreatic regeneration after partial Px was assessed by effects of a pharmacologic PI3K inhibitor wortmannin or small interfering RNA (siRNA) to the p85α regulatory subunit. To confirm further the critical role of the PI3K/Akt pathway in pancreatic acinar cell proliferation, IGF-1-mediated cell proliferation was determined in cultured acinar cells pretreated with wortmannin or p85α siRNA. Results: Pancreatic regeneration and pAkt expression after partial Px were significantly decreased with aging. Treatment with wortmannin or p85α siRNA reduced pancreatic regeneration after partial Px. The IGF-1-mediated cell proliferation in vitro was completely blocked by wortmannin or p85α siRNA but not by the MEK/ERK inhibitor PD98059. Conclusions: PI3K/Akt activation plays a critical role in the regeneration of pancreatic acini after resection. Furthermore, pancreatic regeneration is markedly attenuated in the aged pancreas most likely because of decreased PI3K/Akt activation.

Original languageEnglish
Pages (from-to)1391-1404
Number of pages14
JournalGastroenterology
Volume128
Issue number5
DOIs
StatePublished - May 2005

Bibliographical note

Funding Information:
Supported by grants R37AG10885, R01DK48498, and P01DK35608 from the National Institutes of Health.

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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