Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies1,2,3,4,5; 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.
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This work was supported by NIA grants AG022303 (R.A.M.), AG025707 and AG022308 (D.E.H.), AG022307 (R.S.) and AG13319 (J.F.N. and R.S.), and the Department of Veterans Affairs (R.A.M. and R.S.) and DoD W81XWH-07-1-0605 (Z.D.S.). We wish to thank P. J. Krason, P. J. Harrison, E. Adler, V. Diaz, J. Sewald, L. Burmeister, B. Kohler, M. Han, M. Lauderdale and D. Jones for reliable technical assistance, S. Pletcher and A. Galecki for statistical assistance, and H. Warner and S. N. Austad for scientific counsel.
Author Contributions D.E.H., R.S. and R.A.M. serve as the principal investigators at the three collaborating institutions; they were responsible for project design, supervision of technical personnel, interpretation of results, and preparation of manuscript drafts. Z.D.S. proposed rapamycin for the study, and was responsible for the measures of mTOR function. J.F.N. and K. Flurkey provided advice on experimental design and interpretation, and comments on the manuscript. Lab manager C.M.A. provided advice, and supervised laboratory procedures and data collection at The Jackson Laboratory site. N.L.N. served as the project officer for the National Institute on Aging, and contributed to program development, experimental design and analysis. J.E.W. conducted and helped interpret the necropsy analyses. K. Frenkel recommended CAPE for the study, and advised on dose and route of administration. C.S.C. and M.P. recommended enalapril for the study, and advised on dose and route of administration. M.A.J. was responsible for the pharmacological analyses. E.F. supervised and conducted laboratory procedures and data collection at the University of Texas site.
This file contains Supplementary Methods, Supplementary Tables S1-S2 and Supplementary Figure 1.
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Inflammation and Regeneration (2018)