1. The Jackson Laboratory, Bar Harbor, Maine 04609, USA
2. Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, Department of Pharmacology, and Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, Texas 78229, USA
3. Institute of Biotechnology/Department of Molecular Medicine, and Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, Texas 78245, USA
4. Department of Physiology and Barshop Institute for Longevity and Aging Studies at The University of Texas Health Science Center at San Antonio, Texas 78229, USA
5. Division of Aging Biology, National Institute on Aging, Bethesda, Maryland 20892, USA
6. Unit for Laboratory Animal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan 48109-2200, USA
7. Environmental Medicine, NY University School of Medicine, New York 10016, USA
8. Wake Forest University School of Medicine, Department of Internal Medicine: Section on Gerontology and Geriatrics Winston-Salem, North Carolina 27157, USA
9. Department of Psychiatry, The University of Texas Health Science Center at San Antonio, Texas 78229, USA
10. Department of Pathology and Geriatrics Center, University of Michigan, and Ann Arbor VA Medical Center, Ann Arbor, Michigan 48109-2200, USA
11. These authors contributed equally to this work.
12. Present address: Department of Aging and Geriatric Research, College of Medicine, Institute on Aging, University of Florida, Gainesville, Florida 32611, USA.

Correspondence to: David E. Harrison^1,11 Correspondence and requests for materials should be addressed to D.E.H. (Email: david.harrison@jax.org).

Abstract

Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies^{1, 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.

1. The Jackson Laboratory, Bar Harbor, Maine 04609, USA
2. Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, Department of Pharmacology, and Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, Texas 78229, USA
3. Institute of Biotechnology/Department of Molecular Medicine, and Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, Texas 78245, USA
4. Department of Physiology and Barshop Institute for Longevity and Aging Studies at The University of Texas Health Science Center at San Antonio, Texas 78229, USA
5. Division of Aging Biology, National Institute on Aging, Bethesda, Maryland 20892, USA
6. Unit for Laboratory Animal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan 48109-2200, USA
7. Environmental Medicine, NY University School of Medicine, New York 10016, USA
8. Wake Forest University School of Medicine, Department of Internal Medicine: Section on Gerontology and Geriatrics Winston-Salem, North Carolina 27157, USA
9. Department of Psychiatry, The University of Texas Health Science Center at San Antonio, Texas 78229, USA
10. Department of Pathology and Geriatrics Center, University of Michigan, and Ann Arbor VA Medical Center, Ann Arbor, Michigan 48109-2200, USA
11. These authors contributed equally to this work.
12. Present address: Department of Aging and Geriatric Research, College of Medicine, Institute on Aging, University of Florida, Gainesville, Florida 32611, USA.

Correspondence to: David E. Harrison^1,11 Correspondence and requests for materials should be addressed to D.E.H. (Email: david.harrison@jax.org).

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