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. 2015 Dec;70(12):1479-89.
doi: 10.1093/gerona/glu190. Epub 2014 Nov 7.

Nordihydroguaiaretic Acid Extends the Lifespan of Drosophila and Mice, Increases Mortality-Related Tumors and Hemorrhagic Diathesis, and Alters Energy Homeostasis in Mice

Stephen R Spindler  1 , Patricia L Mote  2 , Alex L Lublin  2 , James M Flegal  3 , Joseph M Dhahbi  2 , Rui Li
Affiliations

Nordihydroguaiaretic Acid Extends the Lifespan of Drosophila and Mice, Increases Mortality-Related Tumors and Hemorrhagic Diathesis, and Alters Energy Homeostasis in Mice

Stephen R Spindler et al. J Gerontol A Biol Sci Med Sci. 2015 Dec.

Abstract

Mesonordihydroguaiaretic acid (NDGA) extends murine lifespan. The studies reported here describe its dose dependence, effects on body weight, toxicity-related clinical chemistries, and mortality-related pathologies. In flies, we characterized its effects on lifespan, food consumption, body weight, and locomotion. B6C3F1 mice were fed AIN-93M diet supplemented with 1.5, 2.5, 3.5, or 4.5 g NDGA/kg diet (1.59, 2.65, 3.71 and 4.77 mg/kg body weight/day) beginning at 12 months of age. Only the 3.5 mg/kg diet produced a highly significant increase in lifespan, as judged by either the Mantel-Cox log-rank test (p = .008) or the Gehan-Breslow-Wilcoxon test (p = .009). NDGA did not alter food intake, but dose-responsively reduced weight, suggesting it decreased the absorption or increased the utilization of calories. NDGA significantly increased the incidence of liver, lung, and thymus tumors, and peritoneal hemorrhagic diathesis found at necropsy. However, clinical chemistries found little evidence for overt toxicity. While NDGA was not overtly toxic at its therapeutic dosage, its association with severe end of life pathologies does not support the idea that NDGA consumption will increase human lifespan or health-span. The less toxic derivatives of NDGA which are under development should be explored as anti-aging therapeutics.

Keywords: Dose; Lifespan; Longevity; NDGA; Therapeutic; response.

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Figures

Figure 1.
Figure 1.
Shown are the lifespans of mice consuming AIN-93M diet without additions (filled circles; median survival 983 days); mice consuming 1.5g of NDGA/kg AIN-93M diet (open circles; median survival 969 days; Mantel–Cox p = .769; Gehan–Breslow–Wilcoxon p = .991); mice consuming 2.5g of NDGA/kg diet (open squares; median survival 1059 days; Mantel-Cox p = .528; Gehan–Breslow–Wilcoxon p = .490); mice consuming 3.5g of NDGA/kg diet (open upward pointing triangles; median survival 1099 days; Mantel-Cox p = .008; Gehan–Breslow–Wilcoxon p = .009); and mice consuming 4.5g of NDGA/kg diet (open downward pointing triangles; median survival 995 days; Mantel–Cox p = .963; Gehan–Breslow–Wilcoxon p = .647). The controls began with 297 mice and the treatment groups with 18 mice each. The treatments were started at 365 days of age.
Figure 2.
Figure 2.
Food consumption and body weight of the mice shown in Figure 1. Shown is the body weight of the control (closed black circles); 40% CR fed (closed orange circles); 20% CR fed (closed fuchsia circles); 1.5g NDGA/kg diet (closed gold circles); 2.5g NDGA/kg diet (closed green circles); 3.5g NDGA/kg diet (closed purple circles); and 4.5g NDGA/kg diet (closed blue circles). The standard deviations of the weights were omitted for clarity. Food consumption as a percent of the Kcal offered with respect to the Kcals consumed during the preceding month is shown for control, (open black circles); 40% CR fed (open orange circles); 20% CR fed (open fuchsia circles); 1.5g NDGA/kg diet (open gold circles); 2.5g NDGA/kg diet (open green circles); 3.5g NDGA/kg diet (open purple circles); and 4.5g NDGA/kg diet (open blue circles). The significance of differences in body weights between groups are shown in Table 1. A preliminary report of these data from 365 to 1,063 days of age was published previously (14).
Figure 3.
Figure 3.
NDGA dose-responsively extends the lifespan of male Drosophila. Shown is the survival of Drosophila fed diets containing either vehicle alone (closed circles; median survival 20 days), vehicle containing 1.0mg/mL NDGA (upward pointing triangles), or vehicle containing 3.0mg/ml NDGA (downward pointing triangles; median survival 26 days; both Mantel–Cox and Gehan–Breslow–Wilcoxon p < .0001).
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