Insulin sensitivity as a key mediator of growth hormone actions on longevity

Abstract

Reduced insulin sensitivity and glucose intolerance have been long suspected of having important involvement in aging. Here we report that in studies of calorie restriction (CR) effects in mutant (Prop1(df) and growth hormone receptor knockout [GHRKO]) and normal mice, insulin sensitivity was strongly associated with longevity. Of particular interest was enhancement of the already increased insulin sensitivity in CR df/df mice in which longevity was also further extended and the lack of changes in insulin sensitivity in calorically restricted GHRKO mice in which there was no further increase in average life span. We suggest that enhanced insulin sensitivity, in conjunction with reduced insulin levels, may represent an important (although almost certainly not exclusive) mechanism of increased longevity in hypopituitary, growth hormone (GH)-resistant, and calorie-restricted animals. We also report that the effects of GH treatment on insulin sensitivity may be limited to the period of GH administration.

Figure 1.

(A) Survival plots of Ames dwarf (Df) and normal (N) mice fed ad libitum (AL) or subjected to 30% calorie restriction (CR) starting at 2 months of age and maintained for the remainder of life span. From Bartke and colleagues (12). (B) Insulin tolerance test performed in N and Df mice indicated improved insulin sensitivity after CR in both genotypes. All groups were randomly fed (100% AL) overnight. Mice were injected intraperitoneally with insulin (0.75 U/kg of body weight). Glucose was measured in samples collected from the tail vein at specified time points. a, b, c—values that do not share the same letter are significantly different (p < .05).

Figure 2.

(A) Kaplan–Meier survival plot of normal (N) and growth hormone receptor knockout (GHRKO) mice that were fed ad libitum (AL) or subjected to 30% calorie restriction (CR) starting at 2 months of age and maintained for the remainder of life span. Data from males and females are combined. From Bonkowski and colleagues (13). (B) Results of insulin tolerance test in normal and GHRKO mice that were fed AL or subjected to 30% CR between 2 and 12 months of age. All groups were randomly fed (100% AL) overnight. Mice were injected intraperitoneally with insulin (0.75 U/kg of body weight). Glucose was measured in samples collected from the tail vein at specified time points. *p < .05 compared with AL controls within phenotype. From Bonkowski and colleagues (13).

Figure 3.

Chi-square test of independence representing the distribution of data for the Ames dwarf (df/df), growth hormone receptor knockout (GHRKO), and their respective normal controls on ad libitum (AL) or calorie-restricted diets into quartiles representing all possible combinations of long and short median longevity (Long+, Long−) and high (smaller area under the curve, AUC−) and low (bigger area under the curve, AUC+) insulin sensitivity (see Materials and Methods section). Notes. CR = calorie restriction. *Expected count/observed count.

Figure 4.

Insulin tolerance test performed in Ames dwarf mice after 6 weeks of growth hormone (GH) injections, and in control Ames dwarf and normal animals. (A) One day after the last injection of GH, insulin sensitivity of Ames dwarf mice was decreased to the level measured in normal mice. (B) One month after the last injection, insulin sensitivity of dwarf mice improved and returned to the level measured in control Ames dwarf mice. a, b—values that do not share the same letter in the superscript are significantly different (p < .05).