ATF4 activity: a common feature shared by many kinds of slow-aging mice

Abstract

ATF4, a DNA-binding factor that modulates responses to amino acid availability and ribosomal function, has been shown to be altered in both liver and fibroblasts from two strains of long-lived mice, i.e. Snell dwarf and PAPP-A knockout mice. New data now show elevated ATF4 levels, and elevation of ATF4-dependent proteins and mRNAs, in liver of mice treated with acarbose or rapamycin, calorically restricted mice, methionine-restricted mice, and mice subjected to litter crowding. Elevation of ATF4, at least in liver, thus seems to be a shared feature of diets, drugs, genes, and developmental alterations that extend maximum lifespan in mice.

Keywords: acarbose; caloric restriction; longevity; methionine restriction; rapamycin.

Figure 1

Quantitation of protein expression of ATF4 and ATF4 targets. Levels of ATF4 protein (left: A, D, G, J, and M), ATF3 protein (middle: B, E, H, K, and N) and CHOP protein (right: C, F, I, L, and O) in liver of mice exposed to acarbose (top row: A, B, and C), rapamycin (second row: D, E, and F), calorie restriction (third row: G, H, and I), methionine restriction (fourth row: J, K, and L), or crowded litter intervention (bottom row: M, N, and O). Bars show means and SEM for N = 6 mice per age/condition shown. Only male mice were available for testing in the CR and Meth-R condition, and only female mice in the CL condition. Asterisk (*) indicates a significant effect of the intervention, at P < 0.05, using Sidak's post hoc test after a one-factor analysis of variation.

Figure 2

Representative images showing protein expression of ATF4 and ATF4 targets. Protein expression of ATF4 and ATF4 targets by Western blot in livers of mice exposed to acarbose (A: male; B: female), rapamycin (C: male; D: female), calorie restriction (E: male), methionine restriction (F:male), or crowded litter intervention (G:female).

Figure 3

Transcription of ATF4 targets in liver of long-lived mice. Levels of mRNA for ATF3 (left), CHOP (middle), and ASNS protein (right) in liver of mice exposed to acarbose (top row: A, B, and C), rapamycin (second row: D, E, and F), calorie restriction (third row: G, H, and I), methionine restriction (fourth row: J, K, and L), or crowded litter intervention (bottom row: M, N, and O). Bars show means and SEM for N = 6 mice per age/condition shown. Only male mice were available for testing in the CR and Meth-R condition, and only female mice in the CL condition. Data were analyzed by two-factor ANOVA, with tests for effects of intervention, sex, and the [sex × intervention] interaction term. Panels with the ‘Rx’ indicator had a significant overall effect of the intervention, and those with the ‘Int’ indicator had a difference between males and females in the response to the intervention. Asterisk (*) indicates a significant effect of the intervention, at P < 0.05, using Sidak's post hoc test after a one-factor analysis of variation.