FGF21 overexpression leads to significant lifespan extension in mice

Jeffrey Serrill, FGF21, growth hormone signaling, starvation response, longevity

An exciting study, published in the new peer-reviewed research journal eLife, has linked a specific mammalian hormone to the process of aging, and showed that the average lifespan of mice who produce large amounts of the substance can potentially increase by up to 40%.  Through their groundbreaking research, investigators from the University of Texas Southwestern Medical Center have provided some intriguing evidence to suggest that the hormone, FGF21, can potentially provide some of the positive benefits of dieting without the need to restrict dietary caloric intake.  Their study provides important information for not only the pharmaceutical and medical professions, but could also be of significant value to the treatment of both age- and weight-related disorders.  As millions of Americans currently suffer from at least one of these two types of illness, these results may provide the rationale needed to successfully develop treatment strategies to combat a wide range of such diseases.

Fibroblast growth factor-21 (FGF21) is typically secreted by the liver as part of the normal “starvation response” elicited by most animals. This response has evolved in diverse animal species as an adaptive mechanism in which biochemical and physiological changes to metabolic strategies occur as a response to a decrease in food intake.  In response to a lack of caloric intake, FGF21 acts to increase insulin sensitivity and decrease baseline insulin levels, as well as increasing fatty acid oxidation and gluconeogenesis (generating glucose from non-carbohydrate substrates).  Collectively, these shifts in physiology allow an organism to shift its metabolic strategy in response to fluctuating caloric intake levels without becoming inordinately stressed.  Though the existence of FG21 has been accepted since 2000, the specific nature of the effects of this hormone on downstream signaling cascades has not yet been adequately addressed; the recent study by UT researchers has shown that alterations to the expression levels of FGF21 can drastically alter certain characteristics of mammalian organisms, due in large part to its effects on the aforementioned metabolic pathways.     

Among these affected characteristics are reductions in overall body size, as well as a decrease in circulating IGF-1 concentrations (a hormone similar to insulin). Most notably however, it was found that when FGF21 is overexpressed by transgenic mice, there seems to be a drastically positive effect on the lifespan of these organisms.  

“Restricting food intake has been shown to extend lifespan in several different kinds of animals. In our study, we found transgenic mice that produced more of the hormone fibroblast growth factor-21 (FGF21) got the benefits of dieting without having to limit their food intake. Male mice that overproduced the hormone had about a 30 percent increase in average life span and female mice had about a 40 percent increase in average life span,” said senior author Dr. Steven Kliewer, professor of molecular biology and pharmacology.

Since 1934, it has been recognized that restricting the diets of laboratory animals to low levels of caloric intake can have a drastic effect on the animals’ lifespans, provided that this restriction is not enough to cause malnutrition.  Since then, decades of caloric restriction studies have recapitulated these results, suggesting that a pharmacological “fountain of youth” may be possible in the future.  The recent findings from the University of Texas study are significant, in that they demonstrate similar increases to organismal longevity without the requirement for caloric restriction.  Conversely, the authors suggest in their paper that the transgenic mice actually seem to eat more food than normal mice, yet do not become sensitive to insulin in the same manner.     

 “Prolonged overproduction of the hormone FGF21 causes mice to live extraordinary long lives without requiring a decrease in food intake. It mimics the health benefits of dieting without having to diet,” said co-author Dr. David Mangelsdorf, chairman of pharmacology and a Howard Hughes Medical Institute (HHMI) investigator at UT Southwestern.

Using microarray and gene expression analyses, the authors provide an adequate explanation for FGF21’s effects on the aging process; namely, they suggest that FGF21 plays a significant role in modulating the balance of growth hormone signaling in the liver.  This modulation appears to directly affect a significant number of genes which have previously been linked to longevity, and results in increases to lifespan at the expense of physical size. With this in mind, the utilization of FGF21-targeted hormone therapy as a therapeutic tool in the future seems to be a very promising idea, and one which will undoubtedly see more attention throughout the coming years.  However, there still seem to be several side effects to the hormone treatments in the laboratory setting which will need to be addressed; these include inadequate development of bone density, as well as potential issues of infertility.  

“Aging and aging-related diseases represent an increasing burden on modern society. Drugs that slow the aging process would be very desirable. These findings raise the possibility of a hormone therapy to extend life span,” said Dr. Mangelsdorf, who runs a research laboratory with Dr. Kliewer.

“FGF21 is not affecting their mobility. These guys are spry. They live nice, long lives,” Dr. Kliewer said. “But the decreased bone density and female infertility will require additional research to determine if it is possible to separate out the hormone’s life span-extending effects from its effect on bone,” he added.        

 

For more information, see the original research article:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466591/pdf/elife00065.pdf

All quotes taken from the University of Texas Southwestern original press release:

http://www.utsouthwestern.edu/newsroom/news-releases/year-2012/october/starvation-hormone-mangelsdorf-kliewer.html

 

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