Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.
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.
Harrison
David E
DE
The Jackson Laboratory, Bar Harbor, Maine 04609, USA. david.harrison@jax.org
Strong
Randy
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Sharp
Zelton Dave
ZD
Nelson
James F
JF
Astle
Clinton M
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Flurkey
Kevin
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Nadon
Nancy L
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Wilkinson
J Erby
JE
Frenkel
Krystyna
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Carter
Christy S
CS
Pahor
Marco
M
Javors
Martin A
MA
Fernandez
Elizabeth
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Miller
Richard A
RA
D000284:Administration, Oral; D000375:Aging / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004032:Diet; D004198:Disease Susceptibility; D005260:Female; D008136:Longevity / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage* / Q000494:pharmacology*; D013047:Specific Pathogen-Free Organisms; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
D002352:Carrier Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus