Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males

Abstract

Four agents--acarbose (ACA), 17-α-estradiol (EST), nordihydroguaiaretic acid (NDGA), and methylene blue (MB)--were evaluated for lifespan effects in genetically heterogeneous mice tested at three sites. Acarbose increased male median lifespan by 22% (P < 0.0001), but increased female median lifespan by only 5% (P = 0.01). This sexual dimorphism in ACA lifespan effect could not be explained by differences in effects on weight. Maximum lifespan (90th percentile) increased 11% (P < 0.001) in males and 9% (P = 0.001) in females. EST increased male median lifespan by 12% (P = 0.002), but did not lead to a significant effect on maximum lifespan. The benefits of EST were much stronger at one test site than at the other two and were not explained by effects on body weight. EST did not alter female lifespan. 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. 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. These results provide new pharmacological models for exploring processes that regulate the timing of aging and late-life diseases, and in particular for testing hypotheses about sexual dimorphism in aging and health.

Keywords: NDGA; acarbose; estradiol; heterogeneous mice; lifespan; methylene blue.

Figure 1

Survival curves comparing controls and mice fed Acarbose (ACA) for males (A) and females (B) pooled across the three sites. On this and other figures here, significance of differences between control and test mice are given as ‘P’ values on each set of curves.

Figure 2

Survival curves comparing controls and mice fed Acarbose (ACA) for males (A,B,C) and females (D,E,F) from each of the three sites: TJL (A,D), UM (B,E), and UT (C,F).

Figure 3

Data from an independent group of mice fed the standard Acarbose (ACA) diet starting at 4 months of age, tested at UM only. (A–E) Results from blood tests at 9 months of age: HbA1c, fasting glucose, FGF21, IGF1, and fasting insulin. (F) Activity, scored at 11 months as the number of beam interruptions in 50 h, adjusted for each mouse as a change score with reference to activity at 5 months for the same mouse. Diet restriction (C,F) was started at 4 months; mice were fed 60% of their normal consumption after a 2-week transitional period at 80%. Each bar shows mean and standard error of the mean. Numbers of mice: (A,B,D,E) n = 17–20 of each sex; (C) n = 10 per group, sexes pooled because there was no sex difference; (F) n = 17–18 males, 20 females.

Figure 4

Weights are given for males (A) and females (B) at 6-month intervals for controls and mice fed Acarbose (ACA), EST, and MB. Data were pooled from the three sites.

Figure 5

Survival curves comparing controls and mice fed EST for males pooled from the three sites (A) and for males at each site: TJL (B), UM (C), and UT (D). Survival curves for males and females fed MB pooled from the three sites are (E) and (F), respectively.

Figure 6

Survival curves comparing male controls and male mice fed NDGA at three different doses (A). Data for female controls and female mice fed the high dose of NDGA (B). Data were pooled from the three sites.