Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance

Abstract

A diet deficient in the amino acid methionine has previously been shown to extend lifespan in several stocks of inbred rats. We report here that a methionine-deficient (Meth-R) diet also increases maximal lifespan in (BALB/cJ x C57BL/6 J)F1 mice. Compared with controls, Meth-R mice have significantly lower levels of serum IGF-I, insulin, glucose and thyroid hormone. Meth-R mice also have higher levels of liver mRNA for MIF (macrophage migration inhibition factor), known to be higher in several other mouse models of extended longevity. Meth-R mice are significantly slower to develop lens turbidity and to show age-related changes in T-cell subsets. They are also dramatically more resistant to oxidative liver cell injury induced by injection of toxic doses of acetaminophen. The spectrum of terminal illnesses in the Meth-R group is similar to that seen in control mice. Studies of the cellular and molecular biology of methionine-deprived mice may, in parallel to studies of calorie-restricted mice, provide insights into the way in which nutritional factors modulate longevity and late-life illnesses.

Figure 1

Survival curves for control and methionine‐restricted (Meth‐R) groups. Each symbol represents one mouse dying at the age indicated. The left panel shows all mice and the right panel shows only those mice that survived at least 365 days. At the time of writing, there are 2/40 survivors in the Meth‐R group, and 0/40 survivors in the control group.

Figure 2

Body weight in control and methionine‐restricted mice, shown as mean and standard deviation at monthly intervals; n = 40 mice per group at the outset.

Figure 3

Levels of MIF mRNA in liver cell lysates (upper panel) of Meth‐R, CR and their respective controls, and (lower panel) of serum MIF protein concentrations in Meth‐R and control mice. Bars show mean levels ± SEM; mRNA is in arbitrary units. There were seven or eight mice per group for the Meth‐R samples and four mice per group for the CR samples. Significance tests for the serum protein used the Student's t‐test, and the Mann–Whitney test was used (with log2‐transformed values) for the mRNA comparisons.

Figure 4

Meth‐R diet diminishes liver cell vulnerability to acetaminophen (APAP) toxicity. Symbols show mean and standard error for n = 6 mice in each group at the indicated time points. Student's t‐test indicates P < 0.05 for the 8‐h and 24‐h time points for each enzyme, except for LDH at 24 h, for which P = 0.08.