IGF‐1, nutrition and aging: the big picture

Abstract

We appreciate the views expressed by Dr Pollak regarding our recent article concerning caloric restriction (CR) and serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) concentrations. We knew that in large population studies dealing with people eating Western diets, protein intake, but not energy intake, is associated with serum IGF-1 concentration. However, one of the goals of our research is to determine whether severe CR with adequate nutrition is associated with the same metabolic and hormonal adaptive response in healthy lean humans as observed in CR rodents, in which CR slows aging and protects against cancer. We have shown that severe long-term CR without malnutrition powerfully prevents obesity, inflammation and hypertension, and lowers fasting glucose, insulin and triiodothyronine concentrations in humans (Fontana & Klein, 2007). However, unexpectedly, we found that, unlike its effect in rodents, chronic severe CR does not reduce serum IGF-1 concentrations in humans. Reducing protein intake for 3 weeks in volunteers practicing severe CR resulted in lower serum IGF-1 levels, similar to those of mildly protein-restricted vegans. These data suggest that, unlike in rodents, protein intake is more powerful than calorie intake in modulating circulating IGF-1 concentration in humans (Fontana et al., 2008). We are aware of the epidemiological data linking lower IGF-1 levels and increased cardiovascular mortality. However, we think that association does not prove causality. Several confounding factors (e.g. abdominal obesity, insulin resistance, inflammation) may distort the association between IGF-1 and mortality. As we get older IGF-1 drops, but abdominal fat deposition, insulin resistance and inflammation increase (Fontana & Klein, 2007). For example, an antagonistic relationship between inflammatory cytokines and IGF-1 is generally observed during degenerative conditions (Wolf et al., 1996; De Benedetti et al., 1997). The problem is that metabolic factors are not isolated from each other, but are interrelated. CR prevents abdominal obesity, insulin resistance, and inflammation, but at the same time lowers IGF-1, insulin, testosterone and other growth factors in long-lived CR animals (Fontana & Klein, 2007). To understand the complex interactions that regulate aging and the CR-mediated anti-aging and anti-cancer effects, we need to use a new perspective that favors integration instead of only reductionism.