Long-lived ames dwarf mice are resistant to chemical stressors

Abstract

To probe the connection between longevity and stress resistance, we compared the sensitivity of Ames long-lived dwarf mice and control littermates with paraquat, diquat, and dobutamine. In young adult animals, 95% of male and 39% of female controls died after paraquat administration, but no dwarf animals died. When the experiment was repeated at an older age or a higher dosage of paraquat, dwarf mice still showed greater resistance. Dwarf mice also were more resistant to diquat; 80% of male and 60% of female controls died compared with 40% and 20% of dwarf mice, despite greater sensitivity of dwarf liver to diquat. Dwarf mice were also less sensitive to dobutamine-induced cardiac stress and had lower levels of liver and lung F(2)-isoprostanes. This is the first direct in vivo evidence that long-lived Ames dwarf mice have enhanced resistance to chemical insult, particularly oxidative stressors.

Figure 1.

Survival of Ames mice after paraquat exposure. Paraquat (50 mg/kg) was administered to 40 male control mice and 30 male dwarf mice (A) as well as to 28 female control mice and 31 female dwarf mice (B). All mice were 4.1–6.3 mo old. In (C), paraquat (50 mg/kg) was administered to 38 male control mice 11.9–17.9 mo of age and 36 male dwarf mice 14.0–19.9 mo of age. In (D), a higher dose of paraquat (75 mg/kg) was administered to 9 control and 15 dwarf female mice 4.1–6.3 mo of age. The dwarf mice are shown in solid triangles, and the control littermates in open triangles. The survival of the mice was followed over 6 days and statistically analyzed using the log-rank test as described in the Experimental Procedures.

Figure 2.

Survival of Ames mice after diquat exposure. Diquat (50 mg/kg) was administered to 24 control and 24 dwarf male mice (A) as well as to 23 control and 20 dwarf female mice (B). All the animals were between 4.2 and 5.8 mo of age. The dwarf mice are shown in solid triangles, and the control littermates in open triangles. The survival of the mice was followed over 6 days and statistically analyzed using the log-rank test as described in the Experimental Procedures.

Figure 3.

Sensitivity of Ames mice to diquat-induced hepatotoxicity. Ames control and dwarf mice were treated with diquat (50 mg/kg), and 6 h after treatment the mice were killed. Hepatotoxicity was measured by the increase in alanine–leucine transaminase (ALT) activity in the plasma and apoptosis in the liver as described in the Experimental Procedures. (A) The mean and SEM ALT activities measured in the plasma of 10 male control mice, 11 male dwarf mice, 8 female control mice, and 8 female dwarf mice (all animals were 12.3–13.9 mo of age). (B) The mean and SEM levels of apoptosis measured in the liver of nine male control mice and nine male dwarf mice (12.3–13.7 mo of age). In (A) and (B), the open bars represent control mice and the solid bars represent dwarf mice. The mean values are displayed on the bars.

Figure 4.

Changes in hepatic isoprostane levels with age, genotype, and calorie restriction. Isoprostane levels were measured in lungs (A) and livers (B) collected from control mice (open bars, n = 5 young and 11 old), control old mice fed a CR diet (stippled bars, n = 4 mice), and dwarf mice (solid bars, n = 5 young and 9 old) as described in the Methods. Each bar represents the mean and SEM for mice of the young (6–8 mo of age) and old (19–33 mo of age) groups. The data were statistically analyzed using the Student’s t test (with Holm’s correction) as described in the Methods, and p values are shown for significant differences.