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Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors
Carolina B Livi1, Rulon L Hardman, Barbara A Christy
1Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
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 thesein 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.
Insights
Enterically released rapamycin (eRapa) significantly extended lifespan and reduced tumors in Rb1+/- mice, challenging previous assumptions about rapamycin
Area of Science:
- Gerontology and Cancer Biology
- Molecular and Cellular Oncology
Background:
- Chronic rapamycin treatment extends lifespan and attenuates cancer in mice.
- Diet restriction (DR) has minimal effect on Rb1+/- mouse lifespan, suggesting pRb1 dependence.
- Enterically released rapamycin (eRapa) was predicted to have minimal effect in Rb1+/- mice, similar to DR.
Purpose of the Study:
- To investigate the in vivo effects of eRapa on lifespan and neuroendocrine cancer in Rb1+/- mice.
- To determine if eRapa's anti-aging and anti-cancer effects are dependent on pRb1.
Main Methods:
- Rb1+/- mice were fed a diet with or without eRapa (14 mg/kg food) from 9 weeks of age until death.
- Rapamycin blood levels were measured to confirm dosage.
- Lifespan, tumor incidence (pituitary and thyroid), and tumor growth were monitored.
Main Results:
- eRapa dramatically extended median and maximum lifespan in both male and female Rb1+/- mice.
- eRapa slowed the appearance and growth of pituitary tumors and decreased thyroid tumor incidence.
- The beneficial effects of eRapa were independent of pRb1 levels.
Conclusions:
- eRapa demonstrates significant lifespan-extending and anti-tumorigenic effects in a preclinical neuroendocrine cancer model.
- eRapa's mechanisms of action on survival and tumor suppression appear distinct from diet restriction and are not dependent on pRb1.
- These findings suggest rapamycin has diverse biological activities independent of pRb1.
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