Rapamycin slows aging in mice

Wilkinson, John E.; Burmeister, Lisa; Brooks, Susan V.; Chan, Chi Chao; Friedline, Sabrina; Harrison, David E.; Hejtmancik, J. F.; Nadon, Nancy L.; Strong, Randy; Wood, Lauren K.; Woodward, Maria A.; Miller, Richard A.

doi:10.1111/j.1474-9726.2012.00832.x

Cited by 589 publications

(540 citation statements)

References 31 publications

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“…A well‐known side effect of rapamycin treatment in humans and mice is testicular degeneration (Wilkinson et al ., 2012), and we observed that both the intermittent rapamycin and daily rapamycin treatment regimens significantly decreased testes mass (Fig. 3C).…”

Section: Resultsmentioning

confidence: 60%

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

et al. 2015

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SummaryInhibition of the mechanistic target of rapamycin (mTOR) signaling pathway by the FDA‐approved drug rapamycin has been shown to promote lifespan and delay age‐related diseases in model organisms including mice. Unfortunately, rapamycin has potentially serious side effects in humans, including glucose intolerance and immunosuppression, which may preclude the long‐term prophylactic use of rapamycin as a therapy for age‐related diseases. While the beneficial effects of rapamycin are largely mediated by the inhibition of mTOR complex 1 (mTORC1), which is acutely sensitive to rapamycin, many of the negative side effects are mediated by the inhibition of a second mTOR‐containing complex, mTORC2, which is much less sensitive to rapamycin. We hypothesized that different rapamycin dosing schedules or the use of FDA‐approved rapamycin analogs with different pharmacokinetics might expand the therapeutic window of rapamycin by more specifically targeting mTORC1. Here, we identified an intermittent rapamycin dosing schedule with minimal effects on glucose tolerance, and we find that this schedule has a reduced impact on pyruvate tolerance, fasting glucose and insulin levels, beta cell function, and the immune system compared to daily rapamycin treatment. Further, we find that the FDA‐approved rapamycin analogs everolimus and temsirolimus efficiently inhibit mTORC1 while having a reduced impact on glucose and pyruvate tolerance. Our results suggest that many of the negative side effects of rapamycin treatment can be mitigated through intermittent dosing or the use of rapamycin analogs.

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Section: Resultsmentioning

confidence: 60%

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

et al. 2015

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“…In mice, rapamycin treatment increased testicular degeneration and cataract incidence (101) , and caused insulin resistance in some mouse strains. In a set of elegant studies, it was recently reported that the longevity effects of DR (via inhibition of mTORC1) can be uncoupled from the insulin-resistant effects (via inhibition of mTORC2 (89) ).…”

Section: Rapamycinmentioning

confidence: 99%

Dietary restriction and the pursuit of effective mimetics

Selman

2014

Proc. Nutr. Soc.

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Dietary restriction (DR) has been shown to extend both median and maximum lifespan in a range of animals, although recent findings suggest that these effects are not universally enjoyed across all animals. In particular, the lifespan effect following DR in mice is highly strain-specific and there is little current evidence that DR induces a positive effect on all-cause mortality in non-human primates. However, the positive effects of DR on health appear to be highly conserved across the vast majority of species, including human subjects. Despite these effects on health, it is highly unlikely that DR will become a realistic or popular life choice for most human subjects given the level of restraint required. Consequently significant research is focusing on identifying compounds that will bestow the benefits of DR without the obligation to adhere to stringent reductions in daily food intake. Several such compounds, including rapamycin, metformin and resveratrol, have been identified as potential DR mimetics. Although these compounds show significant promise, there is a need to properly understand the mechanisms through which these drugs act. This review will discuss the importance in understanding the role that genetic background and heterogeneity play in mediating the lifespan and healthspan effects of DR. It will also provide an overview of the most promising current DR mimetics and their effects on healthy lifespan.

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“…The inhibition of mTOR signaling with chronic, systemic 2.24-mg/kg (14 ppm) administration of rapamycin, a product of the soil bacteria Streptomyces hygroscopicus, extends life span in mice, even when introduced late in life (Harrison et al 2009). Rapamycin 4.7, 14, and 42 ppm in food also slows age-dependent pathology of the liver, heart, and tendons (Wilkinson et al 2012). A recent study demonstrated that chronic 2.24-mg/kg rapamycin inhibits age-associated cognitive decline (Halloran et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

Kusne

Goldberg

Parker

et al. 2013

AGE

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The chronic and systemic administration of rapamycin extends life span in mammals. Rapamycin is a pharmacological inhibitor of mTOR. Metformin also inhibits mTOR signaling but by activating the upstream kinase AMPK. Here we report the effects of chronic and systemic administration of the two mTOR inhibitors, rapamycin and metformin, on adult neural stem cells of the subventricular region and the dendate gyrus of the mouse hippocampus. While rapamycin decreased the number of neural progenitors, metforminmediated inhibition of mTOR had no such effect. Adult-born neurons are considered important for cognitive and behavioral health, and may contribute to improved health span. Our results demonstrate that distinct approaches of inhibiting mTOR signaling can have significantly different effects on organ function. These results underscore the importance of screening individual mTOR inhibitors on different organs and physiological AGE

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Rapamycin slows aging in mice

Cited by 589 publications

References 31 publications

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

Dietary restriction and the pursuit of effective mimetics

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

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