Over the past decade, it has become increasingly clear that many aspects of aging are conserved across species. For example: the sirtuins, first discovered in yeast, control lifespan and age-related phenotypes in metazoans. Likewise, the IGF-1 pathway, originally revealed in the worm in studies of the daf-2 mutation, appears to play a significant role in mammalian aging.
But how much do these model systems reveal about what’s going on in human beings? Even the rodents — the laboratory organisms most closely related to us — have very different life histories and have adapted to very different niches over the course of evolution; therefore it would not be surprising if their response to e.g. calorie restriction (CR) were quite different from ours. Indeed, a study from Fontana et al. argues that this is the case for the IGF-1 pathway:
Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans
Reduced function mutations in the insulin/IGF-I signaling pathway increase maximal lifespan and health span in many species. Calorie restriction (CR) decreases serum IGF-1 concentration by ~40%, protects against cancer and slows aging in rodents. However, the long-term effects of CR with adequate nutrition on circulating IGF-1 levels in humans are unknown. Here we report data from two long-term CR studies (1 and 6 years) showing that severe CR without malnutrition did not change IGF-1 and IGF-1 : IGFBP-3 ratio levels in humans. In contrast, total and free IGF-1 concentrations were significantly lower in moderately protein-restricted individuals. Reducing protein intake from an average of 1.67 g kg−1 of body weight per day to 0.95 g kg−1 of body weight per day for 3 weeks in six volunteers practicing CR resulted in a reduction in serum IGF-1 from 194 ng mL−1 to 152 ng mL−1. These findings demonstrate that, unlike in rodents, long-term severe CR does not reduce serum IGF-1 concentration and IGF-1 : IGFBP-3 ratio in humans. In addition, our data provide evidence that protein intake is a key determinant of circulating IGF-1 levels in humans, and suggest that reduced protein intake may become an important component of anticancer and anti-aging dietary interventions.
To understand why this is significant and somewhat surprising, let’s go through the logic: Decreased IGF-1 levels are associated with increased lifespan. Calorie restriction is also associated with increased lifespan. In rodents, CR is associated with decreased IGF-1 levels, leading to the (still unproven) hypothesis that the effects of CR are mediated by modulation of the IGF-1 axis.
In humans, however, the situation is slightly different: As in rodents, the human IGF-1 pathway contains several genes that appear to regulate longevity. The longevity benefits of CR are still under study, but it does appear that certain types of fasting regimens have protective effects against e.g. tumor growth.
According to this new study, however, CR has no effect on the levels of functional, circulating IGF-1 — so while IGF-1 may regulate longevity and CR may protect against cancer and other age-related maladies, it doesn’t appear that CR mediates its effects via IGF-1. And this is true even in the model system that biogerontologists consider to be the best compromise between experimental tractability and evolutionary proximity.
The moral? Just that we can’t ever assume that a result obtained in rodents will hold true in humans: animal model results aren’t clinical facts, just hypothesis generators for studies that will ultimately have to be performed in Our Favorite Species. The devil, as always, is in the details.