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Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

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Abstract

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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Figure 1: Survival plots for male and female mice, comparing control mice to those fed rapamycin in the diet starting at 600 days of age, pooling across the three test sites.
Figure 2: Survival of control and rapamycin-treated mice for males and females for each of the three test sites separately.
Figure 3: Characterization of mice receiving rapamycin from 270 days of age.

Change history

  • 16 July 2009

    A present address author affiliation was added to C.S.C. on 16 July 2009.

References

  1. 1

    Kaeberlein, M. et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193–1196 (2005)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Powers, R. W., Kaeberlein, M., Caldwell, S. D., Kennedy, B. K. & Fields, S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 20, 174–184 (2006)

    CAS  Article  Google Scholar 

  3. 3

    Jia, K., Chen, D. & Riddle, D. L. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131, 3897–3906 (2004)

    CAS  Article  Google Scholar 

  4. 4

    Kapahi, P. et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885–890 (2004)

    CAS  Article  Google Scholar 

  5. 5

    Vellai, T. et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426, 620 (2003)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Kohn, R. R. Principles of Mammalian Aging 2nd edn 151 (Prentice-Hall, 1978)

    Google Scholar 

  7. 7

    Miller, R. A. Extending life: scientific prospects and political obstacles. Milbank Q. 80, 155–174 (2002)

    Article  Google Scholar 

  8. 8

    Olshansky, S. J., Perry, D., Miller, R. A. & Butler, R. N. In pursuit of the longevity dividend. Scientist 20, 28–35 (2006)

    Google Scholar 

  9. 9

    Schneider, E. L. & Miller, R. A. in Brockelhurst's Textbook of Geriatric Medicine (eds Tallis, R., Fillit, H. & Brockelhurst, J. C.) 193–199 (Churchill Livingstone, 1998)

    Google Scholar 

  10. 10

    Archer, J. R. & Harrison, D. E. l-deprenyl treatment in aged mice slightly increases lifespans, and greatly reduces fecundity by aged males. J Gerontol. Biol. Sci. 51A, B448–B453 (1996)

    CAS  Article  Google Scholar 

  11. 11

    Schneider, E. L. & Reed, J. D. Life extension. N. Engl. J. Med. 312, 1159–1168 (1985)

    CAS  Article  Google Scholar 

  12. 12

    Phelan, J. P. & Austad, S. N. Selecting animal models of human aging. Inbred strains often exhibit less biological uniformity than F1 hybrids. J. Gerontol. 49, B1–B11 (1994)

    CAS  Article  Google Scholar 

  13. 13

    Klebanov, S. E. et al. Maximum life spans in mice are extended by wild strain alleles. Exp. Biol. Med. 226, 854–859 (2001)

    CAS  Article  Google Scholar 

  14. 14

    Flurkey, K., Currer, J. M. & Harrison, D. E. in The Mouse in Biomedical Research 2nd edn, Vol. III (eds Fox, J. G. et al.) 637–672 (Academic, 2007)

    Book  Google Scholar 

  15. 15

    Miller, R. A. et al. An aging interventions testing program: study design and interim report. Aging Cell 6, 565–575 (2007)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Nadon, N. L. et al. Design of aging intervention studies: the NIA interventions testing program. AGE 30, 187–199 (2008)

    CAS  Article  Google Scholar 

  17. 17

    Strong, R. et al. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell 7, 641–650 (2008)

    CAS  Article  Google Scholar 

  18. 18

    Roderick, T. H. Selection for radiation resistance in mice. Genetics 48, 205–216 (1963)

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Wang, C., Li, Q., Redden, D. T., Weindruch, R. D. & Allison, B. Statistical methods for testing effects on “maximum lifespan”. Mech. Ageing Dev. 125, 629–632 (2004)

    Article  Google Scholar 

  20. 20

    Petroulakis, E., Mamane, Y., Le Bacquer, O., Shahbazian, D. & Sonenberg, N. mTOR signaling: implications for cancer and anticancer therapy. Br. J. Cancer 96 (Suppl.). R11–R15 (2007)

    Article  Google Scholar 

  21. 21

    Masoro, E. J. Overview of caloric restriction and ageing. Mech. Ageing Dev. 126, 913–922 (2005)

    CAS  Article  Google Scholar 

  22. 22

    Sharp, Z. D. & Bartke, A. Evidence for down-regulation of phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR)-dependent translation regulatory signaling pathways in Ames dwarf mice. J. Gerontol. A 60, 293–300 (2005)

    Article  Google Scholar 

  23. 23

    Hsieh, C. C. & Papaconstantinou, J. Akt/PKB and p38 MAPK signaling, translational initiation and longevity in Snell dwarf mouse livers. Mech. Ageing Dev. 125, 785–798 (2004)

    CAS  Article  Google Scholar 

  24. 24

    Dhahbi, J. M. et al. Temporal linkage between the phenotypic and genomic responses to caloric restriction. Proc. Natl Acad. Sci. USA 101, 5524–5529 (2004)

    ADS  CAS  Article  Google Scholar 

  25. 25

    Garber, K. Rapamycin’s resurrection: a new way to target the cancer cell cycle. J. Natl Cancer Inst. 93, 1517–1519 (2001)

    CAS  Article  Google Scholar 

  26. 26

    Lorberg, A. & Hall, M. N. TOR: the first 10 years. Curr. Top. Microbiol. Immunol. 279, 1–18 (2004)

    CAS  PubMed  Google Scholar 

  27. 27

    Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006)

    CAS  Article  Google Scholar 

  28. 28

    Reiling, J. H. & Sabatini, D. M. Stress and mTORture signaling. Oncogene 25, 6373–6383 (2006)

    CAS  Article  Google Scholar 

  29. 29

    Sonenberg, N. & Hinnebusch, A. G. New modes of translational control in development, behavior, and disease. Mol. Cell 28, 721–729 (2007)

    CAS  Article  Google Scholar 

  30. 30

    Bradford, M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248–254 (1976)

    CAS  Article  Google Scholar 

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Acknowledgements

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.

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Correspondence to David E. Harrison.

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Harrison, D., Strong, R., Sharp, Z. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009). https://doi.org/10.1038/nature08221

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