Abstract
Rapamycin extends lifespan and attenuates age-related pathologies in mice when administered through diet at 14 parts per million (PPM). Recently, we reported that daily intraperitoneal injection of rapamycin at 8 mg/kg attenuates mitochondrial disease symptoms and progression in the Ndufs4 knockout mouse model of Leigh Syndrome. Although rapamycin is a widely used pharmaceutical agent dosage has not been rigorously examined and no dose-response profile has been established. Given these observations we sought to determine if increased doses of oral rapamycin would result in more robust impact on mTOR driven parameters. To test this hypothesis, we compared the effects of dietary rapamycin at doses ranging from 14 to 378 PPM on developmental weight in control and Ndufs4 knockout mice and on health and survival in the Ndufs4 knockout model. High dose rapamycin was well tolerated, dramatically reduced weight gain during development, and overcame gender differences. The highest oral dose, approximately 27-times the dose shown to extend murine lifespan, increased survival in Ndufs4 knockout mice similarly to daily rapamycin injection without observable adverse effects. These findings have broad implications for the effective use of rapamycin in murine studies and for the translational potential of rapamycin in the treatment of mitochondrial disease. This data, further supported by a comparison of available literature, suggests that 14 PPM dietary rapamycin is a sub-optimal dose for targeting mTOR systemically in mice. Our findings suggest that the role of mTOR in mammalian biology may be broadly underestimated when determined through treatment with rapamycin at commonly used doses.
Highlights
Rapamycin, a specific inhibitor of the mechanistic Target Of Rapamycin, was the first pharmacological agent reproducibly demonstrated to extend lifespan in multiple organisms including budding yeast, nematodes, flies, and mice (Harrison et al, 2009; Ha and Huh, 2011; Partridge et al, 2011; Choi et al, 2013; Johnson et al, 2013a,b)
Dietary rapamycin reduced developmental weight gain in a dose-dependent manner in control animals, with strength of effect ranging from no observed impact at 14 parts per million (PPM), to a robust and highly significant reduction in body size at 378 PPM that is similar in magnitude to what we previously reported for daily injection of 8 mg/kg (Figure 2)
We present a dose-response profile for dietary rapamycin in a mouse model
Summary
A specific inhibitor of the mechanistic Target Of Rapamycin (mTOR), was the first pharmacological agent reproducibly demonstrated to extend lifespan in multiple organisms including budding yeast, nematodes, flies, and mice (Harrison et al, 2009; Ha and Huh, 2011; Partridge et al, 2011; Choi et al, 2013; Johnson et al, 2013a,b). Rapamycin was first demonstrated to increase murine lifespan by the National Institute on Aging (NIA) Interventions Testing Program (ITP) in a study where genetically heterogeneous UMHET3 mice were fed a diet supplemented with 14 PPM rapamycin in a microencapsulated formula beginning at around 600 days of age (Harrison et al, 2009) This diet was subsequently shown to extend lifespan in UMHET3 mice treated from a young age (Miller et al, 2011) and C57Bl/6 inbred mice when initiated at either 19 months of age (Zhang et al, 2014) or mixed ages (Neff et al, 2013). In addition to increasing lifespan, there is a general consensus that rapamycin attenuates age-associated declines in some measures of cardiac, immune, muscular, and cognitive function, increasing overall healthspan (Spong and Bartke, 2012; Wilkinson et al, 2012; Blagosklonny, 2013; Kaeberlein, 2013; Neff et al, 2013; Zhang et al, 2014). mTOR inhibition by rapamycin has been shown to provide benefit in models of disease such as the murine model of Leigh Syndrome
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