Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males

Authors

  • David E. Harrison,

    Corresponding author
    1. The Jackson Laboratory, Bar Harbor, ME, USA
    • Correspondence

      David E. Harrison, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA. Tel.: +1 207 288 6357; fax: +1 207 288 6077; e-mail: david.harrison@jax.org

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    • These three authors contributed equally to this study.
  • Randy Strong,

    1. Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
    2. Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA
    3. Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA
    4. Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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    • These three authors contributed equally to this study.
  • David B. Allison,

    1. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA
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  • Bruce N. Ames,

    1. Children's Hospital Oakland Research Institute, Oakland, CA, USA
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  • Clinton M. Astle,

    1. The Jackson Laboratory, Bar Harbor, ME, USA
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  • Hani Atamna,

    1. Children's Hospital Oakland Research Institute, Oakland, CA, USA
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  • Elizabeth Fernandez,

    1. Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
    2. Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA
    3. Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA
    4. Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Kevin Flurkey,

    1. The Jackson Laboratory, Bar Harbor, ME, USA
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  • Martin A. Javors,

    1. Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
    2. Department of Psychiatry, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Nancy L. Nadon,

    1. Division of Aging Biology, National Institute on Aging, Bethesda, MD, USA
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  • James F. Nelson,

    1. Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
    2. Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Scott Pletcher,

    1. Department of Molecular and Integrative Physiology, and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA
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  • James W. Simpkins,

    1. Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA
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  • Daniel Smith,

    1. Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA
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  • J. Erby Wilkinson,

    1. Unit for Laboratory Animal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
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  • Richard A. Miller

    1. Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA
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    • These three authors contributed equally to this study.

Summary

Four agents — acarbose (ACA), 17-α-estradiol (EST), nordihydroguaiaretic acid (NDGA), and methylene blue (MB) — were evaluated for lifespan effects in genetically heterogeneous mice tested at three sites. Acarbose increased male median lifespan by 22% (P < 0.0001), but increased female median lifespan by only 5% (P = 0.01). This sexual dimorphism in ACA lifespan effect could not be explained by differences in effects on weight. Maximum lifespan (90th percentile) increased 11% (P < 0.001) in males and 9% (P = 0.001) in females. EST increased male median lifespan by 12% (P = 0.002), but did not lead to a significant effect on maximum lifespan. The benefits of EST were much stronger at one test site than at the other two and were not explained by effects on body weight. EST did not alter female lifespan. NDGA increased male median lifespan by 8–10% at three different doses, with P-values ranging from 0.04 to 0.005. Females did not show a lifespan benefit from NDGA, even at a dose that produced blood levels similar to those in males, which did show a strong lifespan benefit. MB did not alter median lifespan of males or females, but did produce a small, statistically significant (6%, P = 0.004) increase in female maximum lifespan. These results provide new pharmacological models for exploring processes that regulate the timing of aging and late-life diseases, and in particular for testing hypotheses about sexual dimorphism in aging and health.

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