Longer lifespan in male mice treated with a weakly estrogenic agonist,an antioxidant,an α‐glucosidase inhibitor or a Nrf2‐inducer |
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| Authors: | Adam Antebi Clinton M Astle Molly Bogue Martin S Denzel Elizabeth Fernandez Kevin Flurkey Karyn L Hamilton Dudley W Lamming Martin A Javors João Pedro de Magalhães Paul Anthony Martinez Joe M McCord Benjamin F Miller Michael Müller James F Nelson Juliet Ndukum G Ed Rainger Arlan Richardson David M Sabatini Adam B Salmon James W Simpkins Wilma T Steegenga Nancy L Nadon David E Harrison |
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| Affiliation: | 1. Max Planck Institute for Biology of Ageing, Cologne, Germany;2. The Jackson Laboratory, Bar Harbor, ME, USA;3. Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;4. Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;5. Colorado State University, Fort Collins, CO, USA;6. Department of Medicine, University of Wisconsin‐Madison, Madison, WI, USA;7. Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;8. School of Biological Sciences, University of Liverpool, Liverpool, UK;9. Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA;10. Norwich Medical School, University of East Anglia, Norwich, UK;11. Department of Physiology and Barshop Center for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;12. Centre for Cardiovascular Sciences, School of Clinical and Experimental Medicine, The Medical School, The University of Birmingham, Birmingham, UK;13. Department of Geriatric Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK, USA;14. VA Medical Center, Oklahoma City, OK, USA;15. Whitehead Institute for Biomedical Research, Cambridge, MA, USA;16. Department of Biology, MIT, Cambridge, MA, USA;17. Howard Hughes Medical Institute, MIT, Cambridge, MA, USA;18. Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA, USA;19. The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA;20. Department of Molecular Medicine and Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;21. Center for Basic & Translational Stroke Research, West Virginia University, Morgantown, WV, USA;22. Division of Human Nutrition, Wageningen University and Research Centre, Wageningen, The Netherlands;23. Division of Aging Biology, National Institute on Aging, Bethesda, MD, USA |
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| Abstract: | The National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin – the latter with and without rapamycin, and two drugs previously examined: 17‐α‐estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17‐α‐estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male‐specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The α‐glucosidase inhibitor, acarbose, at a concentration previously tested (1000 ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies. |
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| Keywords: | acarbose fish oil metformin
NDGA
Protandim rapamycin
UDCA
17‐α ‐estradiol |
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