Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

• Published in: Nature (London) Vol. 460; no. 7253; pp. 392 - 395
• Main Authors: Nelson, James F, Carter, Christy S, Pahor, Marco, Frenkel, Krystyna, Miller, Richard A, Nadon, Nancy L, Wilkinson, J. Erby, Fernandez, Elizabeth, Javors, Martin A, Flurkey, Kevin, Astle, Clinton M, Sharp, Zelton Dave, Harrison, David E, Strong, Randy
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 16.07.2009
• Subjects: Administration, Oral; Age; Aging - drug effects; Aging - genetics; Aging - physiology; Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - metabolism; Cellular signal transduction; Diet; Dietary supplements; Disease Susceptibility; Female; Females; Genetic aspects; Life expectancy; Life spans (Biology); Longevity - drug effects; Longevity - genetics; Longevity - physiology; Male; Males; Medical sciences; Mice; Mortality; Nematoda; Pharmacology. Drug treatments; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Physiological aspects; Rapamycin; Rodents; Sirolimus - administration & dosage; Sirolimus - pharmacology; Specific Pathogen-Free Organisms; Survival Analysis; Time Factors; TOR Serine-Threonine Kinases; Transgenic animals; United States; Antineoplastic agent; Sirolimus; Rodentia; Lactone; Macrolide; Macrocycle; Vertebrata; Antibiotic; Mammalia; Mouse; Animal; Protein synthesis inhibitor; Immunosuppressive agent; Antibacterial agent
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature08221

Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.