The US National Institute on Aging currently funds an Intervention Testing Program (ITP) whereby investigators nominate compounds (based on specific molecular ageing theories) to have evaluated with respect to their effects on lifespan and age-related biomarkers in outbred mice.
The principal goal of Phase I elements of the ITP is to identify compounds that delay or decelerate the aging process, using the commonly accepted endpoint of an increase in maximal longevity as a surrogate for an anti-aging effect attributable to a diet, drug, or genetic manipulation.
The ITP investigates treatments with the potential to extend lifespan and delay disease and dysfunction in mice. Such treatments include:
- Dietary supplements
- Plant extracts
- Amino acids
- Redox agents
- Other agents or mixtures of agents
The experiments are conducted in three research laboratories: one at the Jackson Laboratories, one at the University of Michigan, and one at the University of Texas Health Sciences Center at San Antonio.
Agents are administered, usually in the food or water, to groups of specific pathogen-free male and female mice of the UM-HET3 stock. Each mouse is observed until its natural death or until it becomes so severely ill that survival for more than an additional week seems very unlikely. The design includes sufficient numbers of mice (80 in each treatment group and 170 in the control group) to provide 80 percent power to detect a 10 percent increase in average lifespan.
Each mouse also is evaluated for a small set of age-sensitive traits, such as changes in the immune system, spontaneous activity, and lens turbidity. Mice not enrolled in the longevity study are exposed to each intervention to permit assessment of blood and tissue levels of the agents and to help determine if each agent is having its expected metabolic or physiological effect.
This article will focus on the natural compounds (agents) that have been submitted as testing agents to the NIA. These natural agents are listed in the Table below:
Intervention Testing Program Compounds (Natural)
Compound Cohort Year Submitted Status
4-hydroxyl-alpha-phenyl-tert-butyl nitrone (4-OH-PBN) Cohort 1 2004 Study
Beta-guanidinopropionic Acid Cohort 11 2015 In process
Caffeic Acid Phenethyl Ester (CAPE) Cohort 2 2005 In process
Curcumin Cohort 4 2007 Study
Fish Oil Cohort 6 2010 In process
Glycine Cohort 10 2014 In process
Green tea extract Cohort 4 2007 Study
Inulin Cohort 10 2014 In process
Medium Chain Triglyceride Oil Cohort 4 2007 Study
Methylene Blue Cohort 5 2009 In process
MitoQ Cohort 11 2015 In process
Nordihydroguaiaretic acid (NDGA) Cohort 1 2004 Study 1 Study 2 Study 3
Oxaloacetic acid Cohort 4 2007 Study
Protandim® Cohort 7 2011 In process
Resveratrol Cohort 4 2007 Study 1 Study 2
Ursolic Acid Cohort 9 2013 In process
As of the date of publication of this article, the ITP has published studies on the following natural compounds (agents) that have been evaluated with respect to their effects on lifespan and age-related biomarkers in outbred mice:
- 4-OH-alpha-phenyl-N-tert-butyl nitrone (4-OH-PBN)
- Green tea extract (GTE)
- Medium-chain triglyceride oil (MCTO)
- Methlyene Blue (MB)
- Nordihydroguiaretic acid (NDGA)
- Oxaloacetic acid
The results and abstracts of these published studies for these agents are listed in the Table below:
Interventions Testing Programs - Compounds Studied and Published
Interventions Testing Programs - Compounds Studied and Published Compound Abstract of Studies Date of Study References
4-OH-alpha-phenyl-N-tert-butyl nitrone (4-OH-PBN) 4-OH-alpha-phenyl-N-tert-butyl nitrone (4-OH-PBN) did not altered survival March 2008 Study
Curcumin Previous findings were highly suggestive that curcumin would extend life span in our mouse model. The intended concentration of curcumin used in the present study (2000 ppm in the diet) and the method of delivery (in the diet) were the same as those used in previous life-span studies. The actual concentration of curcumin measured in randomly chosen pellets in the present study was reasonably close to 2000 ppm, that is, 1682 ± 126 ppm (data not shown). Moreover, in the present study, curcumin reduced body weights of female mice at all ages. This indicates that at this dose, curcumin has a biological effect, at least in females. Given its reported effects on extending life span in both rats and mice, and the broadly anti-aging effects of curcumin, it is not clear why it had no effect on life span in UM-HET3 mice at any of the three ITP sites. March 2012 Study
Green tea extract (GTE) The pattern of survival in the GTE-treated females, and in the males at TJL and UM, are consistent with the idea that this agent might reduce mortality rate at early ages while at the same time increasing it at later ages. On the other hand, measures of locomotor activity as an indicator of health span did not show any differences between GTE-treated groups and controls. Further studies, in which GTE is provided to young and middle-aged adults but then removed at later ages, might well be justified by these initial observations.
Secondary analysis suggested that GTE might diminish the risk of midlife deaths in females only.
March 2012 Study
Medium-chain triglyceride oil (MCTO) Since no previous studies reported on the effects of MCTO on life span, MCTO was tested in the present study to determine its effects on life span. Despite its many reported health benefits, there was no statistically significant effect of MCT on median or maximum life span in the current study. March 2012 Study
Methlyene Blue (MB) MB did not alter median lifespan of males or females, but did produce a small, statistically significant (6%, P = 0.004) increase in female maximum lifespan. November 2013 Study
Nordihydroguiaretic acid (NDGA) NDGA leads to a significant decline in mortality risk in the first half of the lifespan.
Males in the NDGA group had significantly improved survival (P = 0.0004), with significant effects noted at TJL (P < 0.01) and UT (P < 0.04).
Although we do not yet know whether NDGA will extend maximum lifespan, our data show that this compound does diminish mortality risks among genetically heterogeneous, male, adult mice prior to the last third of the expected lifespan, and thus suggest that further studies of its effects on development and aging are likely to be worthwhile.
March 2008 Study 1
Results showed that NDGA and aspirin each increase survival in male UM-HET3 mice, but not in females.
Pooling data from all three sites, a log-rank test showed that both NDGA (p=0.0006) and aspirin (p=0.01) led to increased lifespan of male mice.
The present results are consistent with previous reports that NDGA increases lifespan in both insects and mammals. Thus, NDGA has been reported to increase lifespan in fruit flies, mosquitoes, and rats
October 2008 Study 2
NDGA increased male median lifespan by 8-10% at three different doses, with P-values ranging from 0.04 to 0.005. Females did not show a lifespan benefit from NDGA, even at a dose that produced blood levels similar to those in males, which did show a strong lifespan benefit. November 2013 Study 3
Oxaloacetic acid In the present study, we evaluated whether OAA could increase life span in mice under the ITP protocol. No indication of a life-span benefit in either sex was found. However, we also determined that OAA is quite labile under the storage conditions used, such that the amount of OAA received by the mice was no more than 25% of the intended amount. March 2012 Study
Resveratrol Resveratrol (at 300 and 1200 ppm food) did not have significant effects on survival in male or female mice.
Our resveratrol data thus serve to confirm the absence of any effect of this agent on mouse life span, using doses two- to eightfold higher than the dose studied by Pearson and colleagues and using genetically heterogeneous mice of both sexes rather than male C57BL/6Nia mice alone.
Clearly more work is called for to identify the pathway(s) by which resveratrol modulates age-sensitive traits in mice and imparts beneficial effects in several rodent models of age-dependent diseases.
February 2011 Study 1
Resveratrol did not have a statistically significant effect on life span of male or female mice, by log-rank test, at the concentrations tested. March 2012 Study 2
Published papers that explain the NIA’s Interventions Testing Program:
Warner, H. R., Ingram, D., Miller, R. A., Nadon, N. L. and Richardson, A. G. (2000) Meeting Report: Program for testing biological interventions to promote healthy aging. Mechanisms of Aging and Development 115:199-208. PubMed
Miller, R. A., Harrison, D. E., 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., and Strong, R. (2007) NIA Interventions Testing Program: Study Design and an Interim Report. Aging Cell 6:565-575. PMID PMC2695675.
Nadon, N. L., Strong, R., Miller, R. A., Nelson, J., Javors, M., Sharp, Z. D., Peralba, J. M. and Harrison, D. E. (2008) Design of Aging Intervention Studies: the NIA Interventions Testing Program. AGE 30:187-199. [AGE online – http://dx.doi.org/10.1007/s11357-008-9048-1 ; NIHMSID47726]
Note: Nordihydroguiaretic acid (NDGA) is not sold to the public as a nutritional supplement. However Chaparral leaf contains a percentage of Nordihydroguiaretic acid (NDGA).
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