Aging does not reduce heat shock protein 70 in the absence of chronic insulin resistance

Abstract

Heat shock protein (HSP)70 decreases with age. Often aging is associated with coincident insulin resistance and higher blood glucose levels, which also associate with lower HSP70. We aimed to understand how these factors interrelate through a series of experiments using vervet monkeys (Chlorocebus aethiops sabaeous). Monkeys (n = 284, 4-25 years) fed low-fat diets showed no association of muscle HSP70 with age (r = .04, p = .53), but levels were highly heritable. Insulin resistance was induced in vervet monkeys with high-fat diets, and muscle biopsies were taken after 0.3 or 6 years. HSP70 levels were significantly greater after 0.3 years (+72%, p < .05) but were significantly lower following 6 years of high-fat diet (-77%, p < .05). Associations with glucose also switched from being positive (r = .44, p = .03) to strikingly negative (r = -.84, p < .001) with increasing insulin resistance. In conclusion, a low-fat diet may preserve tissue HSP70 and health with aging, whereas high-fat diets, insulin resistance, and genetic factors may be more important than age for determining HSP70 levels.

Figure 1.

Scatterplot of skeletal muscle heat shock protein (HSP)70 protein levels across age in 284 adult vervet monkeys maintained on a low-fat diet. Natural life span is approximately 25 years. No relationship is apparent with age (R = .04, p = .52).

Figure 2.

(A) Homeostasis model assessment (HOMA) index scores for insulin resistance in monkeys with lifetime exposure to a low-fat chow diet (n = 284; □), and subsets of middle-aged monkeys fed a high-fat western-type diet for 4 months (n = 24; ■) or 6 years (n = 9; ■). Chronic nutritional stress with a high-fat diet was required to significantly increase HOMA scores (unlike letters indicate p < .05 for the comparison). (B) Muscle HSP70 protein levels in monkeys with lifetime exposure to a low-fat chow diet (n = 284; □) and subsets of middle-aged monkeys fed a high-fat western-type diet for 4 months (n = 24; ■) or 6 years (n = 9; ■). Short-term high-fat western diet exposure increased muscle HSP70 by 72%. However, after chronic nutritional stress, the high-fat diet-induced insulin resistance and depressed HSP70 levels by 77% (unlike letters indicate p < .05 for the comparison). (C) Representative Western blot of HSP70 and GAPDH, demonstrating a positive control (PC) and a random selection of monkey samples. The age of the individual monkey is indicated above each lane.

Figure 3.

(A) Scatterplot with regression line plotted (---) of fasting blood glucose concentrations and muscle HSP70 protein levels in middle-aged monkeys fed a high-fat western-type diet for 4 months (n = 24). Association was strongly positive (R = .44, p = .03).The relationship remained very similar even with removal of monkeys with glucose > 100 mg/dL. (B) Scatterplot with regression line plotted (---) of fasting blood glucose concentrations and muscle HSP70 protein levels in middle-aged monkeys fed a high-fat western-type diet for 6 years (n = 9). Association was very strongly negative (R = −.84, p < .001) in contrast to initial responses to high-fat diet.