Journal Article

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

Vizzini, Nicholas, Ito, Takashi K, LeTexier, Nicolas J, Smith, Kaleb, Beyer, Richard P, Treuting, Piper M, Chen, Belle, Kaeberlein, Matt, Snyder, Jessica M, Meza, Daniel, Kerr, Kathleen F, Davis, Daniel J, Huang, Heather Z, Tung, Herman, Yajima, Masanao, Sutlief, Elissa, Pineda, Victor V, Bitto, Alessandro, Gillespie, Catherine H

2016

Overview

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. Old age is the single greatest risk factor for many diseases including heart disease, arthritis, cancer and dementia. By delaying the biological aging process, it may be possible to reduce the impact of age-related diseases, which could have great benefits for society and the quality of life of individuals. A drug called rapamycin, which is currently used to prevent organ rejection in transplant recipients, is a leading candidate for targeting aging. Rapamycin increases lifespan in several types of animals and delays the onset of many age-related conditions in mice. Nearly all of the aging-related studies in mice have used the same dose of rapamycin given throughout the lives of the animals. Lifelong treatment with rapamycin wouldn’t be practical in humans and is likely to result in undesirable side effects. For example, the high doses of rapamycin used in transplant patients cause side effects including poor wound healing, elevated blood cholesterol levels, and mouth ulcers. Before rapamycin can be used to promote healthy aging in humans, researchers must better understand at what point in life the drug is most effective, and what dose to use to provide the biggest benefit while limiting the side effects. Now, Bitto et al. show that treating mice with rapamycin for a short period during middle age increases the life expectancy of the mice by up to 60%. In the experiments, mice were given two different doses of rapamycin for only three months starting at 20 months old (equivalent to about 60-65 years old in humans). After receiving the lower dose, both male and female mice lived about 50% longer than untreated mice, and showed improvements in their muscle strength and motor coordination. When given the higher dose, male mice showed an even greater increase in life expectancy, but the female mice did not. These female mice had an increased risk of developing rare and aggressive forms of blood cancer, but were protected from other types of cancer. Both drug treatments also caused substantial changes in the gut bacteria of the male and female mice, which could be related to effects of rapamycin on metabolism, immunity and health. More studies are needed to uncover precisely how such short-term treatments can yield long-term changes in the body, and how such changes are related to lifespan and healthy aging.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Age / Aging / Animals / Anti-Bacterial Agents - administration & dosage / Antibiotics, Antineoplastic - administration & dosage / Blood cancer / Cancer / Cancer Biology / Deoxyribonucleic acid / Developmental Biology and Stem Cells / DNA / Drug dosages / Females / Filamentous bacteria / Food / Gastrointestinal Microbiome - drug effects / Health aspects / healthspan / Life expectancy / Life span / longevity / Longevity - drug effects / Males / Mice / microbiome / Middle age / mTOR / Neoplasms - prevention & control / Rapamycin / Rodents / Sirolimus - administration & dosage / Small intestine