Article

Metformin improves healthspan and lifespan in mice

  • Nature Communications 4, Article number: 2192 (2013)
  • doi:10.1038/ncomms3192
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Abstract

Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced low-density lipoprotein and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging.

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Acknowledgements

We thank Federico Butelman from Farmhispania S.A., a FDA-approved cGMP company, for providing us with the metformin used in C57BL/6 mouse study; W. Wood and E. Lehrmann for microarray assistance; D. Phillips-Boyer, D. Nines and J. Lucas for animal care; and O. Carlson for insulin measurements. This research was supported, in part, by the Intramural Research Program of the NIA, NIH, and parts of this work was done under a CRADA with SIRTRIS, a GlaxoSmithKline (GSK) company. A.P.G. is the recipient of an individual fellowship from the Portuguese Foundation for Science and Technology (SFRH/BD//44674/ 2008). S.J.M. is supported by a National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (RIMS Project ID 2010-01671).

Author information

Author notes

    • Alejandro Martin-Montalvo
    •  & Evi M. Mercken

    These authors contributed equally to this work

Affiliations

  1. Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, Maryland 21224, USA

    • Alejandro Martin-Montalvo
    • , Evi M. Mercken
    • , Sarah J. Mitchell
    • , Hector H. Palacios
    • , Theresa M. Ward
    • , Robin K. Minor
    • , Michel Bernier
    •  & Rafael de Cabo
  2. Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia

    • Sarah J. Mitchell
  3. Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia

    • Sarah J. Mitchell
  4. Department of Biochemistry, University of California Riverside, 3401 Watkins Drive, Riverside, California 92521, USA

    • Patricia L. Mote
    •  & Stephen R. Spindler
  5. Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, Maryland 21224, USA

    • Morten Scheibye-Knudsen
    •  & Vilhelm A. Bohr
  6. Department of Genetics, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA

    • Ana P. Gomes
    •  & David A. Sinclair
  7. Department of Medicine and Oncology, McGill University, Montreal, Quebec H3A 2B3, Canada

    • Marie-José Blouin
    •  & Michael Pollak
  8. Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Auerbachstrasse 112, Stuttgart 70376, Germany

    • Matthias Schwab
  9. Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, Maryland 21224, USA

    • Yongqing Zhang
    •  & Kevin G. Becker
  10. Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, Maryland 20892, USA

    • Yinbing Yu
  11. Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA

    • Donald K. Ingram
  12. Department of Pathology, University of Washington, Seattle, Washington 98195-7470, USA

    • Norman S. Wolf

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Contributions

All experiments were designed by A.M.-M., R.K.M., D.K.I. and R.de C. The experiments were carried out by A.M.-M., H.H.P., T.M.W., E.M.M., S.J.M., M.S.-K. and A.P.G. S.R.S. and P.L.M. performed the longevity study in B6C3F1 mice. Y.Z. and K.G.B. developed and applied the computational methods for analysis of microarray data. M.P. and M.-J.B. determined metformin concentration in plasma and liver tissues. N.S.W. determined cataract development. Y.Y. applied the statistical analysis of survival. A.M.-M., M.B., R.de C., V.A.B., D.A.S. and M.P. interpreted the data. A.M.-M., M.B. and R.de C. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Rafael de Cabo.

Supplementary information

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    Supplementary Information

    Supplementary Figures S1-S6, Supplementary Tables S1-S9, Supplementary Methods and Supplementary References

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