Further Investigations into FGF21 in Calorie Restriction

In most species examined to date reducing caloric intake while maintaining optimal levels of required dietary micronutrients extends healthy life spans and maximum life spans. In laboratory mice the effect can extend maximum life spans by up to 40% or more, but the consensus is that in humans lifelong calorie restriction would perhaps add just a few years to life spans even through the effects on health are quite similar. Even regular exercise is not quite as impressive in its benefits to long term health, however, which raises the question as to why it is that calorie restriction doesn't have the same effect on life span in humans as it does in mice.

The evolutionary argument for this conclusion is pretty straightforward: the calorie restriction response evolved in the deep past as a way to better survive periods of seasonal famine. A season is long for a mouse, short for a human, and therefore only the mouse evolves a very plastic life span. There are other considerations that pertain only to primates, as well. We humans are long lived in comparison to our neighboring species such as chimpanzees and gorillas, and that is a fairly recent development in the grand sweep of evolutionary time. It is thought that our growing intelligence and culture led to new selection effects that extended life because the old could contribute to the success of their grandchildren. Out of the set of switches and dials available to evolution on a shorter time frame, it is possible that many that would be affected by calorie restriction are already turned on all the time in our species, as it were.

I can speculate wildly in this way without great fear of contradiction because the metabolic response to calorie restriction is fantastically complex and still only understood in broad outline. The short summary is that near everything that can be measured in the operation of cell metabolism changes when there are fewer calories coming in. This makes it a real challenge to pull apart exactly what is going on in detail: what is important, what is secondary, which systems are driving which changes. A cell is a big mess of feedback loops based on changing abundances of various proteins, and everything interacts with everything else in a constant, dynamic dance of change. The research community has put serious time and money into the attempt to understand how calorie restriction works over the past fifteen years, and there isn't much to show for it yet - one can argue that most of that money and time has been spend on what turned out to be interesting dead ends. A vast amount of data has been generated, and yet just a few sentences can now be added to the summary of what was known at the turn of the century. A lot more work lies ahead.

One of the proteins implicated in the calorie restriction response is fibroblast growth factor 21 (FGF21). More of it extends life in mice, and more of it is generated during methionine restriction. Some researchers are looking on it as a possible calorie restriction mimetic due to these results. In general its ability to produce life extension on its own makes it seem worthy of further investigation, and here is a typical result of such investigation, which is to say that the situation is rendered more complicated than prior work suggested, and more questions are raised than answers are provided:

Fibroblast Growth Factor 21 Is Not Required for the Reductions in Circulating Insulin-Like Growth Factor-1 or Global Cell Proliferation Rates in Response to Moderate Calorie Restriction in Adult Mice

Calorie restriction (CR), reduced caloric intake without malnutrition, increases maximum lifespan and delays the onset of many age-related diseases in organisms ranging from worms to rodents, and possibly non-human primates. Decreased signaling through the somatotropic axis is one mechanism that has been suggested to mediate these effects of CR, perhaps through a reduction in cell proliferation, which is predicted to contribute to lifespan extension by delaying cellular replicative senescence and inhibiting the promotional phase of carcinogenesis. Several lines of evidence contribute to a strong case for this hypothesis. First, CR in mice leads to a reduction in circulating levels of insulin-like growth factor-1 (IGF-1) in association with reduced rates of proliferation in a number of cell types. Second, repletion of circulating IGF-1 levels in CR rodents attenuates the CR-induced reduction in cell proliferation. Last, disruption of IGF-1 signaling in several mouse models mimics many of the effects of CR including, increased maximum lifespan, reduced tumor progression, delayed cellular replicative senescence and reduced rates of cell proliferation. Thus, identifying mechanisms that regulate IGF-1 signaling and cell proliferation in response to CR in mice could provide insight into the biology of aging and offer therapeutic targets for treating age-related diseases.

Using FGF21-knockout mice, we asked directly whether FGF21 was necessary for the IGF-1 and cell proliferation responses to moderate CR in adult mice. In order to capture possible circadian fluctuations in mRNA and circulating levels of factors of interest, mice were euthanized at two different time points. We found that the relative levels of circulating FGF21 and hepatic FGF21 mRNA in ad libitum (AL) vs. CR mice exhibited characteristic circadian fluctuations. The pattern of FGF21 expression in response to CR was unexpected in light of previous observations that FGF21 expression is robustly up-regulated in fasted mice. In contrast to these studies, we found that at 1500 h, CR mice, which had essentially been without food for more than 20 h, had lower hepatic FGF21 mRNA levels and a trend towards lower circulating levels of FGF21 compared to AL mice. Furthermore, at 1900 h, CR mice, which were in a postprandial state, had higher circulating FGF21 and hepatic FGF21 mRNA levels compared to AL mice. These data underscore the fact that CR is not simply repeated fasting and that CR and fasting are two distinct dietary paradigms.

Interestingly in humans, long-term (1-6y) CR does not reduce circulating IGF-1 levels and a very low calorie diet in obese diabetics actually reduces circulating FGF21 levels, with the caveat that baseline circulating FGF21 levels are elevated in this population. More studies are needed to confirm and clarify the effect of varying degrees of CR on circulating IGF-1 and FGF21 levels and the potential interplay between these two hormones in healthy humans.

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