Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer

Randy Strong, Richard A. Miller, 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 RichardsonDavid M. Sabatini, Adam B. Salmon, James W. Simpkins, Wilma T. Steegenga, Nancy L. Nadon, David E. Harrison

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)872-884
Number of pages13
JournalAging cell
Volume15
Issue number5
DOIs
StatePublished - Oct 1 2016

Keywords

  • 17-α-estradiol
  • NDGA
  • Protandim
  • UDCA
  • acarbose
  • fish oil
  • metformin
  • rapamycin

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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