Heat Shock Protein Levels Predict Insulin Resistance With Aging

Heat shock proteins such as HSP70 are a component of the cellular response to stress: they are generated in greater amounts when a cell is exposed to heat, toxins, starvation, and so forth. They have numerous important roles, but the roles of interest here involve protein quality control, activities that include ensuring that protein machinery folds correctly and misfolded proteins are quickly disposed of before they can cause harm. Misfolded and otherwise broken proteins are a form of damage, and the better the maintenance the less damage there is to impact cells and the organism to which those cells belong.

Heat shock protein activity is thus a noteworthy part of the hormetic response to mild levels of stress, something that contributes to the long-term benefits of calorie restriction, exercise, mild irradiation, and so forth. All of these things spur cells to undertake greater maintenance activities for a period of time, which results in a net benefit. If trying to create a therapy based on mimicking generalized increased levels of hormesis, then boosting levels of heat shock proteins might be a starting point. The mainstream research community hasn't headed in that direction yet with anywhere near the enthusiasm demonstrated for calorie restriction mimetics, however.

Here is an interesting primate study that shows HSP70 levels to predict growth in insulin resistance years later. Given that excess fat tissue and lack of exercise are just as involved as aging in rising insulin resistance in we humans, that raises a number of questions as what is going on here:

Muscle Heat Shock Protein 70 Predicts Insulin Resistance With Aging

Heat shock protein 70 (HSP70) protects cells from accumulating damaged proteins and age-related functional decline. We studied plasma and skeletal muscle (SkM) HSP70 levels in adult vervet monkeys (life span ≈ 25 years) at baseline and after 4 years (≈10 human years). Insulin, glucose, homeostasis model assessment scores, triglycerides, high-density lipoprotein and total plasma cholesterol, body weight, body mass index, and waist circumference were measured repeatedly, with change over time estimated by individual regression slopes.

Low baseline SkM HSP70 was a proximal marker for developing insulin resistance and was seen in monkeys whose insulin and homeostasis model assessment increased more rapidly over time. Changes in SkM HSP70 inversely correlated with insulin and homeostasis model assessment trajectories such that a positive change in SkM level was beneficial. The strength of the relationship between changes in SkM HSP70 and insulin remained unchanged after adjustment for all covariates. Younger monkeys drove these relationships, with HSP70 alone being predictive of insulin changes with aging.

Results from aged humans confirmed this positive association of plasma HSP70 and insulin. In conclusion, higher levels of SkM HSP70 protect against insulin resistance development during healthy aging.

One possible explanation is that this measure, by focusing on a repair and maintenance marker, is a filter for the proportion of insulin resistance caused by low-level biological damage over time, rather than by lifestyle choices. Another possible explanation is that higher levels of HSP70 associate with more physical activity, and in turn with all of the benefits that this brings. So the study could be demonstrating an inverse measure of variations in vervet indolence, which then translates over time to different health trajectories. It would be interesting to see a similar primate study of artificially increased levels of HSP70 - an expensive proposition in a world in which mouse studies can cost millions, and would therefore have to be driven by something more concrete than mere interest.


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