NIA Interventions Testing Program: Investigating Putative Aging Intervention Agents in a Genetically Heterogeneous Mouse Model

The Interventions Testing Program (ITP) was established by the National Institute on Aging (NIA) to investigate the potential of dietary interventions to promote healthy aging (https://www.nia.nih.gov/research/dab/interventions-testing-program-itp). The ITP uses a four-way cross genetically heterogeneous mouse model (UM-HET3) to reduce the impact of strain-specific characteristics on outcomes (Nadon et al., 2008Nadon N.L. Strong R. Miller R.A. Nelson J. Javors M. Sharp Z.D. Peralba J.M. Harrison D.E. Design of aging intervention studies: the NIA interventions testing program.Age. 2008; 30: 187-199Crossref PubMed Scopus (104) Google Scholar). Lifespan tests are done in parallel, using the same protocol, at three independent sites to increase robustness of the findings. Population sizes are large enough that the protocol will detect a 10% change in mean lifespan, in either sex, with 80% power, pooling data from as few as two sites. Standard operating procedures were designed to maintain as much consistency as possible among the three sites, including caging, bedding, food, and light/dark cycles; a more in-depth discussion of the SOP has been published (Nadon et al., 2015Nadon N.L. Miller R.A. Strong R. Harrison D.E. NIA interventions testing program: a collaborative approach for investigating interventions to promote healthy aging.in: Kaeberlein M.R. Martin G.M. Handbook for the Biology of Aging. eighth ed. 2015: 287-303Google Scholar). Interventions for testing are proposed by the research community through an annual call-for-proposals, and proposed compounds have ranged from drugs and dietary supplements to micronutrients and metabolic intermediates. Before the ITP embarks on testing a compound, pilot studies are done to maximize the chances of a successful test. Goals of the pilot studies include demonstrating that the compound is stable in food and that it is uniformly mixed in the food, determining blood levels after short-term treatment (bioavailability), showing evidence of an effect from the short-term treatment (bioactivity), and in some cases, testing for toxicity. The testing of mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">rapamycin(definition) is a good case-in-point for analyzing stability of the compound in the food. Pilot analysis showed that about 85% of the rapamycin was degraded by the food preparation process, leading to the use of microencapsulation to deliver stable doses of the compound in food (Harrison et al., 2009Harrison D.E. Strong R. Sharp Z.D. Nelson J.F. Astle C.M. Flurkey K. Nadon N.L. Wilkinson J.E. Frenkel K. Carter C.S. Pahor M. Javors M.A. Fernandez E. Miller R.A. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.Nature. 2009; 460: 392-395Crossref PubMed Scopus (2709) Google Scholar). The list of all compounds tested by the ITP and in progress is on the ITP website at https://www.nia.nih.gov/research/dab/interventions-testing-program-itp/compounds-testing. To date, six compounds have shown significant extension of lifespan:•Aspirin – males only (Strong et al., 2008Strong R. Miller R.A. Astle C.M. Floyd R.A. Flurkey K. Hensley K.L. Javors M.A. Leeuwenburgh C. Nelson J.F. Ongini E. Nadon N.L. Warner H.R. Harrison D.E. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice.Aging Cell. 2008; 7: 641-650Crossref PubMed Scopus (232) Google Scholar);•Rapamycin – males and females (females > males) (Harrison et al., 2009Harrison D.E. Strong R. Sharp Z.D. Nelson J.F. Astle C.M. Flurkey K. Nadon N.L. Wilkinson J.E. Frenkel K. Carter C.S. Pahor M. Javors M.A. Fernandez E. Miller R.A. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.Nature. 2009; 460: 392-395Crossref PubMed Scopus (2709) Google Scholar, Miller et al., 2011Miller R.A. Harrison D. Astle C.M. Baur J.A. deCabo R. Fernandez E. Flurkey K. Javors M.A. Nelson J.F. Pletcher S. Sharp Z.D. Sinclair D. Starnes J.W. Wilkinson J.E. Nadon N.L. Strong R. Rapamycin, but not resveratrol or simvastatin, extends lifespan of genetically heterogeneous mice.J. Gerontology, Biol. Sci. 2011; 66A: 191-201Crossref Scopus (680) Google Scholar, Miller et al., 2014Miller R.A. Harrison D.E. Astle C.M. Fernandez E. Flurkey K. Han M. Javors M.A. Li X. Nadon N.L. Nelson J.F. Pletcher S. Salmon A.B. Sharp Z.D. 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; 13: 468-477Crossref PubMed Scopus (373) Google Scholar);•17αEstradiol – males only (Harrison et al., 2014Harrison D.E. Strong R. Allison D.B. Ames B.N. Astle C.M. Atamna H. Fernandez E. Flurkey K. Javors M.A. Nadon N.L. Nelson J.F. Simpkins J.W. Smith D. Wilkinson J.E. Miller R.A. Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males.Aging Cell. 2014; 13: 273-282Crossref PubMed Scopus (240) Google Scholar);•Acarbose – males and females (males> > females) (Harrison et al., 2014Harrison D.E. Strong R. Allison D.B. Ames B.N. Astle C.M. Atamna H. Fernandez E. Flurkey K. Javors M.A. Nadon N.L. Nelson J.F. Simpkins J.W. Smith D. Wilkinson J.E. Miller R.A. Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males.Aging Cell. 2014; 13: 273-282Crossref PubMed Scopus (240) Google Scholar);•Nordihydroguaiaretic acid (NDGA) – males only (Strong et al., 2008Strong R. Miller R.A. Astle C.M. Floyd R.A. Flurkey K. Hensley K.L. Javors M.A. Leeuwenburgh C. Nelson J.F. Ongini E. Nadon N.L. Warner H.R. Harrison D.E. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice.Aging Cell. 2008; 7: 641-650Crossref PubMed Scopus (232) Google Scholar, Harrison et al., 2014Harrison D.E. Strong R. Allison D.B. Ames B.N. Astle C.M. Atamna H. Fernandez E. Flurkey K. Javors M.A. Nadon N.L. Nelson J.F. Simpkins J.W. Smith D. Wilkinson J.E. Miller R.A. Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse li