ITP1: Interventions Testing Program: Effects of various treatments on lifespan and related phenotypes in genetically heterogeneous mice (UM-HET3) (2017)

Miller RA, Strong R, Harrison DE

     
The Interventions Testing Program (ITP, National Institute on Aging) is a multi-institutional study investigating treatments with the potential to extend lifespan and delay disease and dysfunction in heterogeneous populations of UM-HET3 mice. Such treatments include pharmaceuticals, nutraceuticals, foods, diets, dietary supplements, plant extracts, hormones, peptides, amino acids, chelators, redox agents, and other agents or mixtures of agents. The three ITP test sites (with abbreviations as used in these data) are:
  • The Jackson Laboratory (TJL)
  • University of Michigan at Ann Arbor (UM)
  • University of Texas Health Science Center (UT)

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Participants Richard A Miller       University of Michigan,  Ann Arbor, MI
Randy Strong       University of Texas Health Science Center,  San Antonio, TX
David E Harrison       The Jackson Laboratory,  Bar Harbor, ME
ContactRichard A Miller     millerr@umich.edu     Lab web site
AffiliationNational Institute on Aging Interventions Testing Program (ITP)
AcknowledgementsFunding provided by NIH AG022303, AG022307, AG022308
Project type Phenotype archive study
MPD identifiersITP1     MPD:508
Data changelog 1 update/correction.       Initial release date: 06/2017.
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Study results by compound and year

Compound name and (abbreviation) Year
cohort
Dose in food Age at initiation Compound's
effect on lifespan*
Other phenotypes Ref#
17-a-estradiol (17aE2) C2009 4.8 ppm 10 mo View survival analysis
males p = 0.0025
[8]
17-a-estradiol (17aE2) C2011 14 ppm 10 mo View survival analysis
males p < 0.0001
• body weight
• uterus weight (OVX)
[10]
2-(2-Hydroxyphenyl)benzoxazole (HBX) C2012 1 ppm 15 mo View survival analysis
4-OH-a-phenyl-N-tert-butyl nitrone (4-OH-PBN) C2004 315 ppm 4 mo View survival analysis [2]
acarbose (ACA) C2009 1000 ppm 4 mo View survival analysis
males p < 0.0001
females p = 0.0048
[8]
acarbose (ACA) C2012 1000 ppm 16 mo View survival analysis
males p < 0.0001
[10]
acarbose (ACA) C2013 400, 1000, 2500 ppm 8 mo View survival analysis
400 ppm females p = 0.033
400 ppm males p < 0.0001
1000 ppm females p = 0.0027
1000 ppm males p < 0.0001
2500 ppm females p = 0.0061
2500 ppm males p < 0.0001
• fat pads
aspirin (Asp) C2004 20 ppm 4 mo View survival analysis
males p = 0.0106
[2]
caffeic acid phenethyl ester (CAPE) C2005 30 and 300 ppm 4 mo View survival analysis [4]
curcumin (Cur) C2007 2000 ppm 4 mo View survival analysis [6]
enalapril (Enal) C2005 120 ppm 4 mo View survival analysis [4]
fish oil (FO) C2010 15,000 and 50,000 ppm 9 mo View survival analysis • body weight
[10]
green tea extract (GTE) C2007 2000 ppm 4 mo View survival analysis [6]
INT-767 FXR/TGR5 agonist (INT-767) C2012 180 ppm 10 mo View survival analysis
medium-chain triglyceride oil (MCTO) C2007 60,000 ppm 4 mo View survival analysis [6]
metformin (Met) C2011 1000 ppm 9 mo View survival analysis • body weight
[10]
metformin and rapamycin (MetRapa) C2011 Met:1000 ppm and Rapa:14 ppm 9 mo View survival analysis
both sexes p < 0.0001
• body weight
[10]
methylene blue (MB) C2009 28 ppm 4 mo View survival analysis [8]
nitroflurbiprofen (NFP) C2004 200 ppm 4 mo View survival analysis [2]
nordihydroguaiaretic acid (NDGA) C2004 2500 ppm 9 mo View survival analysis
males p = 0.0006
[2]
nordihydroguaiaretic acid (NDGA) C2010 800, 2500, 5000 ppm 6 mo View survival analysis
800 ppm males p = 0.0228
2500 ppm males p = 0.0147
5000 ppm males p = 0.0028
• body weight
• grip strength
• grip duration
• rotarod
[10]
oxaloacetic acid (OAA) C2007 2200 ppm 4 mo View survival analysis [6]
Protandim (Prot) C2011 600 ppm then 1200 ppm 10 mo then 17 mo View survival analysis
males p = 0.0095
• body weight
[10]
rapamycin (Rapa) C2005 14 ppm 20 mo View survival analysis
both sexes p < 0.0001
[4]
rapamycin (Rapa) C2006 14 ppm 9 mo View survival analysis
both sexes p < 0.0001
[5]
rapamycin (Rapa) C2009 4.7, 14, and 42 ppm 9 mo View survival analysis
4.7 ppm females p < 0.0001
14 ppm females p < 0.0001
14 ppm males p = 0.0034
42 ppm both sexes p < 0.0001
[7]
resveratrol (Res) C2006 300 and 1200 ppm 12 mo View survival analysis [5]
resveratrol (Res) C2007 300 ppm 4 mo View survival analysis [6]
simvastatin (Sim) C2006 12 and 120 ppm 10 mo View survival analysis [5]
ursodeoxycholic acid (UDCA) C2011 5000 ppm 5 mo View survival analysis • body weight
[10]
ursolic acid (UA) C2013 2000 ppm 10 mo View survival analysis

* Log-rank test p-value on treated vs. control, shown when p ≤ 0.05 for each sex separately. Statistical definitions








References   (chronological)

1.   Miller RA, Harrison DE, Astle CM, Floyd RA, Flurkey K, Hensley KL, Javors MA, Leeuwenburgh C, Nelson JF, Ongini E, Nadon NL, Warner HR, Strong R. An Aging Interventions Testing Program: study design and interim report. Aging Cell. 2007 Aug;6(4):565-75. Epub 2007 Jun 18.   PubMed 17578509  

2.   Strong R, Miller RA, Astle CM, Floyd RA, Flurkey K, Hensley KL, Javors MA, Leeuwenburgh C, Nelson JF, Ongini E, Nadon NL, Warner HR, Harrison DE. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell. 2008 Oct;7(5):641-50. doi: 10.1111/j.1474-9726.2008.00414.x.   PubMed 18631321     FullText

3.   Nadon NL, Strong R, Miller RA, Nelson J, Javors M, Sharp ZD, Peralba JM, Harrison DE. Design of aging intervention studies: the NIA interventions testing program. Age (Dordr). 2008 Dec;30(4):187-99. doi: 10.1007/s11357-008-9048-Epub 2008 Apr 18.   PubMed 19424842     FullText

4.   Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16;460(7253):392-5. doi: 10.1038/nature0822Epub 2009 Jul 8.   PubMed 19587680     FullText

5.   Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2011 Feb;66(2):191-20doi: 10.1093/gerona/glq178. Epub 2010 Oct 25.   PubMed 20974732     FullText

6.   Strong R, Miller RA, Astle CM, Baur JA, de Cabo R, Fernandez E, Guo W, Javors M, Kirkland JL, Nelson JF, Sinclair DA, Teter B, Williams D, Zaveri N, Nadon NL, Harrison DE. Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2013 Jan;68(1):6-16. doi: 10.1093/gerona/gls070. Epub 2012 Mar 26.   PubMed 22451473     FullText

7.   Wilkinson JE, Burmeister L, Brooks SV, Chan CC, Friedline S, Harrison DE, Hejtmancik JF, Nadon N, Strong R, Wood LK, Woodward MA, Miller RA. Rapamycin slows aging in mice. Aging Cell. 2012 Aug;11(4):675-82. doi: 10.1111/j.1474-9726.2012.00832.x. Epub 2012 Jun 4.   PubMed 22587563     FullText

8.   Harrison DE, Strong R, Allison DB, Ames BN, Astle CM, Atamna H, Fernandez E, Flurkey K, Javors MA, Nadon NL, Nelson JF, Pletcher S, Simpkins JW, Smith D, Wilkinson JE, Miller RA. Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell. 2014 Apr;13(2):273-82. doi: 10.1111/acel.12170. Epub 2013 Nov 19.   PubMed 24245565     FullText

9.   Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, Van Roekel S, Winkleman L, Strong R. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014 Jun;13(3):468-77. doi: 10.1111/acel.12194. Epub 2014 Feb 9.   PubMed 24341993     FullText

10.   Strong R, Miller RA, Antebi A, Astle CM, Bogue M, Denzel MS, Fernandez E, Flurkey K, Hamilton KL, Lamming DW, Javors MA, de Magalhães JP, Martinez PA, McCord JM, Miller BF, Müller M, Nelson JF, et al. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell. 2016 Oct;15(5):872-84. doi: 10.1111/acel.12496. Epub 2016 Jun 16.   PubMed 27312235  

11.   Nadon NL, Strong R, Miller RA, Harrison DE. NIA Interventions Testing Program: Investigating Putative Aging Intervention Agents in a Genetically Heterogeneous Mouse Model. EBioMedicine. 2017 Jul;21:3-4. doi: 10.1016/j.ebiom.2016.11.038. Epub 2016 Dec 2.   PubMed 27923560