Calorie restriction and IGF-1, in rodents vs. humans

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.

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11 comments

  1. Very good analysis, and good points. You can not assume what you learn from one organism will translate to another. We might have to start somewhere to do our basic research (e.g. rodents) but then we have to see if the findings hold true in the organism you are trying to treat.

    brainhealthhacks.com

  2. I agree with your point that we can only derive so much from the study of the little furry animals. Since not having access to the full study I wonder if the following variables have been accounted for in the study:
    1. Nutrient composition
    2. Level of physical activity
    Both of these exert a strong effect on Insulin/IGF-1 production.

  3. 1. They did not feed the humans lab mouse chow.
    2. I’d be curious to know how one could normalize physical activity between two organisms of such disparate sizes. Anyone have any ideas?

  4. “They did not feed the humans lab mouse chow.”
    No kidding. Same composition of Carb/Protein/Fat would be nice.
    Regarding the level of exercise: I’m sure the furry animals will be naturally active. We may need to crack the whip on the humans especially if they’re cal. restricted.

  5. I seem to remember Michael Rae not worrying about a higher protein diet while practicing caloric restriction. Mainly because he also did not think CR effects were mediated by IGF-1. However, we do know of some population groups that have lower IGF-1 levels because of their diet (just look at chinese and japanese diets). Do they seemingly have good longevity (yes!)

  6. In 1977, my pituitary gland was 100% resected due to a craniophyrngioma. Since then I have suffered from profound HGH deficiency with zero IGF levels for 31 years. I am currently considering HGH replacement therapy due to osteoporosis. I understand the only risk of HGH replacement is incipient neoplasms will start to grow. In terms of aging, it has been the observation of my family and friends that I am aging much slower than life-long friends my same age. In 2000, at the age of 45, I married for the first time. My bride was 27, she is now 35 and we appear the same age to the people who now meet us for the first time.
    The main reason I am replying is let you know there was a study on the pituitary and aging in 1978 which is seminal to your discussion. Unfortunately, I do not remember the name of the biologist. I believe I saw the study on 60 minutes 1978-1980. The biologist induced twins rats and mice who were siamesed to assure monozygotic status. He surgically removed the pituatary of one animal instituting Thyroid and glucosteroid hormone replacement therapy but leaving the other twin animal biologically intact. He found the Panhypopituitary animals in the study lived 3-4 times longer than their intact monozygotic twined siblings. At that time, he had not postulated HGH was the key. In fact, the study never even mentioned HGH. I immediately realized HGH was the key to his study but no one was replacing HGH at the time, and studies on IGF were at least 15 years in the future. Since 1984, I have not been able to find the study and have forgotten then name of the biologist. If anyone is familiar with this study, please direct me to the source. I would like to write the biologist.

  7. Thank you for your patience. I understand that the topic of this discussion on the relationship between CR & IGF pathway is far move advanced than the simple removal of a pituitary gland to see what happens. Yet, I am a living clinical case in point. There maybe other clinical manisfestations of low IGF that co-occur with the reduction in the rate of aging, that will help guide further studies. Especially, the rate of cell turnover rate in the hippicampus and it’s neuropsycholocial manisfestation of altered memory and perception.
    This is about as far as I can go with this as an informed lay person…who has a personal interest in the topic at hand.

  8. Well, the story on IGF and CR in rodents is somewhat more complicated. If CR is imposed on a young rat (i.e. young enough to be growing rapidly), then IGF-I levels fall, somewhat. (They do not fall nearly as much as in a mouse with a pituitary mutation, though.) These data are consistent with the idea that low IGF-I may contribute to the anti-aging effects of CR, but don’t prove it.

    2. Aging in rodents leads to a decline in IGF-I. But since CR is anti-aging, it also blocks the fall in IGF-I. Thus in old age, control rodents have lower IGF-I than CR rodents – the opposite of the effect seen in the same animals when they are young.

    3. To see if rodents resemble humans in the response of IGF-I levels to CR, you’d need an experiment where the CR is started in fully grown adults. I don’t know if that has been done, yet.

    4. CR extends the lifespan of Ames dwarf mice, which have a severe, lifelong deficit of IGF-I. This is a strong argument against the idea that lowering IGF-I is the main pathway by which CR extends lifespan.

  9. Has there ever been testing of whether rodent/human body temperatures (controlled by the pituitary gland)were also lowered during CR? Some time ago it was believed that lower body temperatures contributed to extended life span.

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