Longer Lifespan in Male Mice Treated With a Weakly Estrogenic Agonist, an Antioxidant, an α-Glucosidase Inhibitor or a Nrf2-Inducer
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In relatively long-lived C57BL/6 mice and genetic hybrid mice, a similar phenomenon was observed.
“In subsequent recent studies, in the relatively long-lived C57BL/6 mice and genetic hybrid mice, a similar phenomenon was observed [179, 180].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [179]
Despite activating AMPK, metformin has not reproducibly been shown to enhance lifespan in rodents and is notably less effective, or not effective, in older animals, including C. elegans.
“For instance, as discussed in the next section, despite activating AMPK, metformin has not reproducibly been shown to enhance lifespan in rodents and notably less, or not effective in older animals, including C. elegans (66, 72, 74, 75, 77, 78).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [77]
If we accept that metformin, despite inhibiting mTOR, is not a CRM, then metformin would not be expected to extend lifespan.
“If we accept this argument and also accept that metformin, despite inhibiting mTOR, is not a CRM (77, 78) then metformin would not be expected to extend lifespan.”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [77]
Strong et al. were unable to reproduce the positive lifespan data with the 0.1% metformin protocol in mice.
“However, Strong et al. were unable to reproduce the positive lifespan data with the 0.1% metformin protocol in mice, although in combination with rapamycin (14 ppm) lifespan was extended (77).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [77]
Strong et al. provided the explanation that the insulin-sensitizing effect of metformin offsets the negative effects of rapamycin on glucose homeostasis.
“Strong et al. provided the explanation that the insulin-sensitizing effect of metformin offsets the negative effects of rapamycin on glucose homeostasis (77).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [77]
In combination with rapamycin (14 ppm), lifespan was extended in mice.
“However, Strong et al. were unable to reproduce the positive lifespan data with the 0.1% metformin protocol in mice, although in combination with rapamycin (14 ppm) lifespan was extended (77).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [77]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 45 · Cited by 362
- Authors
- Strong, R., Miller, R. A., Antebi, A., Astle, C. M., Bogue, M., Denzel, M. S., Fernandez, E., Flurkey, K., Hamilton, K. L., Lamming, D. W., Javors, M. A., Magalhães, J. P., Martinez, P. A., McCord, J. M., Miller, B. F., Müller, M., Nelson, J. F., Ndukum, J., Rainger, G. E., Richardson, A., Sabatini, D. M., Salmon, A. B., Simpkins, J. W., Steegenga, W. T., Nadon, N. L., & Harrison, D. E.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- University of Michigan (US)
- Max Planck Institute for Biology of Ageing (DE)
- Jackson Laboratory (US)
- 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 78229 USA
- Colorado State University (US)
- University of Wisconsin–Madison (US)
- University of Liverpool (GB)
- University of Colorado Anschutz (US)
- University of East Anglia (GB)
- University of Birmingham (GB)
- Oklahoma City VA Medical Center (US)
- Broad Institute (US)
- West Virginia University (US)
- Wageningen University & Research (NL)
- National Institutes of Health (US)
- Corresponding author
- Strong, Randy
- ORCID
- Strong, Randy
- Miller, Richard A.
- Antebi, Adam
- Bogue, Molly
- Denzel, Martin S.
- Hamilton, Karyn L.
- Lamming, Dudley W.
- Javors, Martin A.
- Magalhães, João Pedro
- Martinez, Paul Anthony
- McCord, Joe M.
- Miller, Benjamin F.
- Müller, Michael
- Nelson, James F.
- Rainger, G. Ed.
- Richardson, Arlan
- Sabatini, David M.
- Salmon, Adam B.
- Steegenga, Wilma T.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2016-06-16
- Volume
- 15
- Issue
- 5
- Pages
- 872-884
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC5013015
- OpenAlex
- W2408643388
- Cited by
- 362
- References
- 45
- Citations by year
- 2026: 26 · 2025: 39 · 2024: 42 · 2023: 38 · 2022: 44 · 2021: 42 · 2020: 32 · 2019: 41 · 2018: 30 · 2017: 20 · 2016: 7 · 2015: 1
- FWCI
- 17.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Aging Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UEA Digital Repository (University of East Anglia) (acceptedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion, cc-by)
- Deep Blue (University of Michigan) (submittedVersion)
- The Research Repository @ WVU (West Virginia University) (submittedVersion)
- The Research Repository @ WVU (West Virginia University) (submittedVersion, cc-by)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Funders
- National Institute on Aging (AG022308, AG022303, AG022307, AG013319, CA034196, AG024824)
- Office of Research and Development
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- lifespan extension, healthy longevity, 17α-estradiol, nordihydroguaiaretic acid, metformin, rapamycin, acarbose, alpha-glucosidase inhibitors, Nrf2 activation, antioxidants, fish oil, ursodeoxycholic acid, sex differences in longevity, dose dependence, genetically heterogeneous mice
- MeSH terms
- alpha-Glucosidases, Animals, Antioxidants, Drugs, Chinese Herbal, Estradiol, Fish Oils, Longevity, Male, Metformin, Masoprocol, Ursodeoxycholic Acid, Survival Analysis, Hand Strength, Sirolimus, Acarbose, Rotarod Performance Test, NF-E2-Related Factor 2, Mice, Glycoside Hydrolase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
