Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice

Abstract

The National Institute on Aging's Interventions Testing Program was established to evaluate agents that are purported to increase lifespan and delay the appearance of age-related disease in genetically heterogeneous mice. Up to five compounds are added to the study each year and each compound is tested at three test sites (The Jackson Laboratory, University of Michigan, and University of Texas Health Science Center at San Antonio). Mice in the first cohort were exposed to one of four agents: aspirin, nitroflurbiprofen, 4-OH-alpha-phenyl-N-tert-butyl nitrone, or nordihydroguaiaretic acid (NDGA). Sample size was sufficient to detect a 10% difference in lifespan in either sex,with 80% power, using data from two of the three sites. 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. Comparison of the proportion of live mice at the age of 90% mortality was used as a surrogate for measurement of maximum lifespan;neither NDGA (p=0.12) nor aspirin (p=0.16) had a significant effect in this test. Measures of blood levels of NDGA or aspirin and its salicylic acid metabolite suggest that the observed lack of effects of NDGA or aspirin on life span in females could be related to gender differences in drug disposition or metabolism. Further studies are warranted to find whether NDGA or aspirin, over a range of doses,might prove to postpone death and various age-related outcomes reproducibly in mice.

Figure 1

Survival plots for male mice treated with NDGA (upper left), aspirin (upper right), NFP (lower left) or 4-OH-PBN (lower right.) Each symbol represents an individual mouse dying at the age indicated. Log-rank test was used to calculate p-values for differences between treated and control mice.

Figure 2

Survival plots for male mice treated with either NDGA (top panels) or aspirin (bottom panels), compared to control mice, at each of the three test sites. Log-rank test was used to calculate p-values for differences between treated and control mice.

Figure 3

Survival plots for control (untreated) males (left panel) and females (right panel) showing the comparison among the three test sites. Log-rank test was used to calculate p-values for differences among the three test sites.

Figure 4

NDGA levels in plasma of young UM-HET3 mice after four weeks of consumption of food containing NDGA at either 2.5 gm per kg food (“low dose”, upper panel) or 5 gm per kg food (“high dose”, lower panel). Each symbol represents an individual mouse, and median levels are shown by horizontal lines. Statistical significance was evaluated by the Mann-Whitney test.

Figure 5

Ratio of SA to ASA in plasma of young UM-HET3 mice after four weeks of consumption of food containing ASA at either 20 gm per kg food (“low dose”, upper panel) or 60 gm per kg food (“high dose”, lower panel). Each symbol represents an individual mouse, and median levels are shown by horizontal lines. Statistical significance was evaluated by the Mann-Whitney test.