Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Jul 16;460(7253):392-5.
doi: 10.1038/nature08221. Epub 2009 Jul 8.

Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

David E Harrison  1 , Randy Strong, Zelton Dave Sharp, James F Nelson, Clinton M Astle, Kevin Flurkey, Nancy L Nadon, J Erby Wilkinson, Krystyna Frenkel, Christy S Carter, Marco Pahor, Martin A Javors, Elizabeth Fernandez, Richard A Miller
Affiliations

Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

David E Harrison et al. Nature. .

Abstract

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Survival plots for male (left) and female (right) mice, comparing control mice to those fed rapamycin in the diet starting at 600 days of age, pooling across the three test sites. P-values were calculated by the log-rank test. 4% of the control mice, and 3% of rapamycin-assigned mice were removed from the experiment for technical reasons. Only 5 animals (3 controls, 2 rapamycin) were removed after the start of rapamycin treatment at 600 days. Thus there were no significant differences between groups in censoring.
Figure 2
Figure 2
Survival of control and rapamycin-treated mice for males (top) and females (bottom) for each of the three test sites separately. P-values represent results of log-rank calculations. Vertical lines at age 600 days indicate the age at which the mice were first exposed to rapamycin.
Figure 3
Figure 3
A. Survival plots for male (left) and female (right) mice, comparing control mice to rapamycin-treated mice of a separate (“Cohort 2006”) population, in which mice were treated with rapamycin from 270 days of age. Because at the time of the interim analysis all live mice were between 800 and 995 days of age, we have only limited information about the shape of the survival curve at ages above 900 days, and the apparent change in slope at the oldest ages (> 990 days) reflects this experimental uncertainty. P-values calculated by the log-rank test. B. Effects of dietary rapamycin on an mTORC1 effector in the visceral fat pads from 750- to 880-day-old male and female mice. Ribosomal subunit protein S6 (rpS6) and its phosphorylation status (P-rpS6 - double arrow) were immunoassayed in tissue lysates prepared from mice consuming microencapsulated rapamycin-containing (Rapa) or control diets. Antibodies used are shown to the left. The ratio of intensity values for P-rpS6: rpS6 are shown in the graphs for females and males. Pan-actin was also immunoassayed in the blots to provide an indication of protein loading for each lane. C. Whole blood rapamycin content in 750- to 880-day-old male and female mice.
See this image and copyright information in PMC

Comment in

  • Ageing: A midlife longevity drug?
    Kaeberlein M, Kennedy BK. Kaeberlein M, et al. Nature. 2009 Jul 16;460(7253):331-2. doi: 10.1038/460331a. Epub 2009 Jul 8. Nature. 2009. PMID: 19606132 No abstract available.

Similar articles

  • Ageing: A midlife longevity drug?
    Kaeberlein M, Kennedy BK. Kaeberlein M, et al. Nature. 2009 Jul 16;460(7253):331-2. doi: 10.1038/460331a. Epub 2009 Jul 8. Nature. 2009. PMID: 19606132 No abstract available.
  • Rapamycin extends murine lifespan but has limited effects on aging.
    Neff F, Flores-Dominguez D, Ryan DP, Horsch M, Schröder S, Adler T, Afonso LC, Aguilar-Pimentel JA, Becker L, Garrett L, Hans W, Hettich MM, Holtmeier R, Hölter SM, Moreth K, Prehn C, Puk O, Rácz I, Rathkolb B, Rozman J, Naton B, Ordemann R, Adamski J, Beckers J, Bekeredjian R, Busch DH, Ehninger G, Graw J, Höfler H, Klingenspor M, Klopstock T, Ollert M, Stypmann J, Wolf E, Wurst W, Zimmer A, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Ehninger D. Neff F, et al. J Clin Invest. 2013 Aug;123(8):3272-91. doi: 10.1172/JCI67674. Epub 2013 Jul 25. J Clin Invest. 2013. PMID: 23863708 Free PMC article.
  • Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune-deficient mice.
    Hurez V, Dao V, Liu A, Pandeswara S, Gelfond J, Sun L, Bergman M, Orihuela CJ, Galvan V, Padrón Á, Drerup J, Liu Y, Hasty P, Sharp ZD, Curiel TJ. Hurez V, et al. Aging Cell. 2015 Dec;14(6):945-56. doi: 10.1111/acel.12380. Epub 2015 Aug 28. Aging Cell. 2015. PMID: 26315673 Free PMC article.
  • Longevity, aging and rapamycin.
    Ehninger D, Neff F, Xie K. Ehninger D, et al. Cell Mol Life Sci. 2014 Nov;71(22):4325-46. doi: 10.1007/s00018-014-1677-1. Cell Mol Life Sci. 2014. PMID: 25015322 Free PMC article. Review.
  • Is Rapamycin a Dietary Restriction Mimetic?
    Unnikrishnan A, Kurup K, Salmon AB, Richardson A. Unnikrishnan A, et al. J Gerontol A Biol Sci Med Sci. 2020 Jan 1;75(1):4-13. doi: 10.1093/gerona/glz060. J Gerontol A Biol Sci Med Sci. 2020. PMID: 30854544 Free PMC article. Review.
See all similar articles

Cited by

See all "Cited by" articles

References

    1. Kaeberlein M, et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science. 2005;310:1193–1196. - PubMed
    1. Powers RW, 3rd, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 2006;20:174–184. - PMC - PubMed
    1. Jia K, Chen D, Riddle DL. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development. 2004;131:3897–3906. - PubMed
    1. Kapahi P, et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol. 2004;14:885–890. - PMC - PubMed
    1. Vellai T, et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature. 2003;426:620. - PubMed

Publication types

MeSH terms