Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer

Abstract

The National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin - the latter with and without rapamycin, and two drugs previously examined: 17-α-estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17-α-estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male-specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The α-glucosidase inhibitor, acarbose, at a concentration previously tested (1000 ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies.

Keywords: 17-α-estradiol; NDGA; Protandim; UDCA; acarbose; fish oil; metformin; rapamycin.

Figure 1

Survival curves for mice treated with 17‐α‐estradiol (17aE2) or Protandim (Prot) pooled across sites. (A) males treated with 14 ppm 17aE2. (B) females treated with 14 ppm 17aE2. (C) males treated with Prot at 600 ppm (10–17 months of age) followed by 1200 ppm (17 months of age on). (D) females treated with Prot at 600 ppm (10–17 months of age) followed by 1200 ppm (17 months of age on). Each symbol represents one mouse. P‐values reflect log‐rank test, stratified by test site. See Table 1 for statistical results.

Figure 2

Survival curves for mice treated with metformin (Met) with and without rapamycin (Rapa), pooled across sites. (A) males treated with 1000 ppm Met. (B) females treated with 1000 ppm Met. (C) males treated with 1000 ppm Met plus 14 ppm Rapa. (D) females treated with 1000 ppm Met plus 14 ppm Rapa. Each symbol represents one mouse. P‐values reflect log‐rank test, stratified by test site. See Table 1 for statistical results.

Figure 3

Survival curves for mice treated with NDGA, pooled across sites. (A) males treated with 800 ppm. (B) males treated with 2500 ppm. (C) males treated with 5000 ppm. (D) females treated with 5000 ppm. Each symbol represents one mouse. P‐values reflect log‐rank test, stratified by test site. See Table 2 for statistical results.

Figure 4

Effects of NDGA on grip strength and duration and on rotarod performance. Panels A,C,E: males. Panels B,D,F: females. The data are expressed as mean ± SEM of the number of mice shown in parentheses. *significantly different from old NDGA; ^†significantly different from young controls; ***significantly different from old control.

Figure 5

Survival curves for mice treated with fish oil (FO), pooled across sites. (A) males treated with 15 000 ppm (B) females treated with 15 000 ppm. (C) males treated with 50 000 ppm. (D) females treated with 50 000 ppm. Each symbol represents one mouse. P‐values reflect log‐rank test, stratified by test site. See Table 2 for statistical results.

Figure 6

Survival curves for mice treated with ursodeoxycholic acid (UDCA)or acarbose (ACA), pooled across sites. (A) males treated with 5000 ppm UDCA. (B) females treated with 5000 ppm UDCA. (C) males treated with 1000 ppm ACA. (D) females treated with 1000 ppm ACA. Each symbol represents one mouse. P‐values reflect log‐rank test, stratified by test site. See Tables 1 and 2 for statistical results.