Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

Abstract

The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. Nevertheless, important questions remain regarding the optimal dose, duration, and mechanisms of action in the context of healthy aging. Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodeling of the microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine. We also define a dose in female mice that does not extend lifespan, but is associated with a striking shift in cancer prevalence toward aggressive hematopoietic cancers and away from non-hematopoietic malignancies. These data suggest that a short-term rapamycin treatment late in life has persistent effects that can robustly delay aging, influence cancer prevalence, and modulate the microbiome.DOI: http://dx.doi.org/10.7554/eLife.16351.001

Targeting chromatin aging - The epigenetic impact of longevity-associated interventions

“…Indeed, recent in-vivo evidence suggests that the longevity effects associated with rapamycin persist after transient application and withdrawal in middle aged mice, with the length of longevity gain being proportional to the amount of time spent on rapamycin. This may suggest that some form of epigenetic reprogramming A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT underlies rapamycin's longevity enhancing effects and undoubtedly warrants further investigation (Bitto et al, 2016).Evidence to this effect was observed in a recent study by Gong et al on the brain tissues of young and old mice, compared to those treated with longevity interventions including rapamycin.Brain tissues of young (6 month) and old (22 month) were isolated and analysed for a number of histone modifications. Seven modifications were found to be lost with age.…”

“…Indeed, recent in-vivo evidence suggests that the longevity effects associated with rapamycin persist after transient application and withdrawal in middle aged mice, with the length of longevity gain being proportional to the amount of time spent on rapamycin. This may suggest that some form of epigenetic reprogramming A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT underlies rapamycin's longevity enhancing effects and undoubtedly warrants further investigation (Bitto et al, 2016).…”

“…The fact that in some cases lifespan increases are preserved even after transient application and withdrawal of the intervention, or indeed are to one extent or another inherited by subsequent generations by epigenetic means, is evidence that epigenetic processes have a functional role in determining the rate of age-associated decline (Bitto et al, 2016;Greer et al, 2012).…”

“…underlies rapamycin's longevity enhancing effects and undoubtedly warrants further investigation (Bitto et al, 2016).…”

Oral health in geroscience: animal models and the aging oral cavity

“…Based on published studies of the changes in the gut microbiome during aging in rodents (Flemer et al, 2017;Bitto et al, 2016;Thevaranjan et al, 2017;Langille et al, 2014), we anticipate that large changes in the oral microbiome will also occur in aging mice, but it will require sampling from biologically old animals to detect these important changes. Indeed, a comparative analysis of the oral and gut microbiota as a function of age could be particularly informative.…”