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The National Institute on Aging has begun a multi-institutional program to evaluate agents (mostly drugs or nutriceuticals) on the aging process in mice. The initial goal is to see if any of the tested interventions increase lifespan; follow-up studies will then look for effects on a wider range of age-sensitive traits, postulated mechanisms of aging, and specific diseases. More information about the program can be found here; information about how to propose an intervention for testing can be found here; and a list of agents already accepted for testing can be found here. A reference to the paper describing the protocol used in the study, and interim results for the first set of tested agents, can be found here.
Key elements of the program include:
1. Use of genetically heterogeneous mice (stock: UM-HET3), in which each mouse is genetically unique, to reduce the chance that the effects seen (or absence of effects) depend on the idiosyncrasies of any particular inbred or F1 hybrid stock.
2. Simultaneous testing at three sites to see to what extent results depend on specific conditions of housing. In addition to our own colony at the University of Michigan, colonies of ITP mice are managed by Dr. David Harrison (Jackson Laboratory, Bar Harbor, ME) and Randy Strong (University of Texas Health Science Center, San Antonio).
3. Interventions can be suggested by anyone, including academic scientists and those working for commercial organizations. Proposals are evaluated once each year by an Access Committee to select those (3 to 5 each year) for entry into the study. Applicants are asked to provide a rationale for selection of the intervention, any published or unpublished data they think should be considered, and information about safety, toxicity, and physiological effects.
4. The initial ("Phase I") study of an agent has lifespan as the primary endpoint, but also provides some data on age-dependent changes in hormones, T cell subsets, and spontaneous activity. Sufficient numbers of male and female mice are tested so that the study has an 80% chance of detecting an increase (or decrease) in lifespan of about 10%, even if only two of the three sites produce usable data.
For more information about the ITP, you can contact Rich Miller (millerr@umich.edu), David Harrison (deh@jax.org), Randy Strong (strong@uthscsa.edu) , or Nancy Nadon (nadonn@exmur.nia.nih.gov).
Cohort 1 (mice born 2004): aspirin, NDGA (nordihydroguiaretic acid), NFP (nitrofluribprofen), and 4-OH-PBN (4-hydroxy alpha-phenyl-N-tert-butyl nitrone).
Cohort 2 (mice born 2005): enalapril maleate, CAPE (caffeic acid phenethyl ester; two doses), rapamycin (from 20 months)
Cohort 3 (mice born 2006): rapamycin (from 9 months), resveratrol (two doses, from 12 months), simvastatin (two doses)
Cohort 4 (mice born 2007): resveratrol (from 4 months), green tea extract, oxaloacetic acid, N-acetyl cysteine, curcumin, and median chain triglyceride oil.
An initial paper [PubMed] describing interim results for Cohort 1 mice, i.e. mice used for the evaluation of the first five test agents, showed that one of the test agents, NDGA (nordihydroguiaretic acid) had a significant positive effect on longevity in male mice, and that a second agent, aspirin, had a marginally significant effect, again in males only. As of December, 2007, 99% of the mice in Cohort 1 have died, and the data pooled across sites show significant positive effects of both NDGA and aspirin on survival of male mice. A paper describing these findings is now in preparation.
UM technicians: Maggie Lauderdale, Jessica Sewald, Melissa Han, Bill Kohler
Collaborators: PIs: David Harrison, Randy Strong
NIA Liaison: Nancy Nadon, Huber Warner
Collaborating scientists: Robert Floyd, Kenneth Hensley, Christiaan Leeuwenburgh, Ennio Ongini, Christy Carter, Krystyna Frenkel, Marco Pahor, Dave Sharp, Clinton Astle, Kevin Flurkey, James Nelson, Martin Javors
Support: NIA U01-AG022303
[last update: December, 2007]
Comparison of survival curves for male mice at the three test sites (Cohort 1)
NDGA improves survival in male mice (pooled across 3 test sites)