Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors

Carolina B. Livi, Rulon L. Hardman, Barbara A. Christy, Sherry G. Dodds, Diane Jones, Charnae Williams, Randy Strong, Alex Bokov, Martin A. Javors, Yuji Ikeno, Gene Hubbard, Paul Hasty, Zelton Dave Sharp

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Chronic treatment of mice with an enterically released formulation of rapamycin (eRapa) extends median and maximum life span, partly by attenuating cancer. The mechanistic basis of this response is not known. To gain a better understanding of these in vivo effects, we used a defined preclinical model of neuroendocrine cancer, Rb1+/- mice. Previous results showed that diet restriction (DR) had minimal or no effect on the lifespan of Rb1+/- mice, suggesting that the beneficial response to DR is dependent on pRb1. Since long-term eRapa treatment may at least partially mimic chronic DR in lifespan extension, we predicted that it would have a minimal effect in Rb1+/- mice. Beginning at 9 weeks of age until death, we fed Rb1+/- mice a diet without or with eRapa at 14 mg/kg food, which results in an approximate dose of 2.24 mg/kg body weight per day, and yielded rapamycin blood levels of about 4 ng/ml. Surprisingly, we found that eRapa dramatically extended life span of both female and male Rb1+/- mice, and slowed the appearance and growth of pituitary and decreased the incidence of thyroid tumors commonly observed in these mice. In this model, eRapa appears to act differently than DR, suggesting diverse mechanisms of action on survival and anti-tumor effects. In particular the beneficial effects of rapamycin did not depend on the dose of Rb1.

Original languageEnglish (US)
Pages (from-to)100-110
Number of pages11
JournalAging
Volume5
Issue number2
DOIs
StatePublished - Feb 2013

Keywords

  • MTOR
  • Neuroendocrine tumors
  • Rapamycin
  • Rb1

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Fingerprint Dive into the research topics of 'Rapamycin extends life span of Rb1<sup>+/-</sup> mice by inhibiting neuroendocrine tumors'. Together they form a unique fingerprint.

Cite this