Saturday, October 20, 2012

FGF21: Learning to Live Longer from Starving Mice

Biologists have known for several decades that putting mice on a starvation diet leads the mice to live longer -- although not necessarily happier. Humans derive too much pleasure from food to broadly adopt this approach to a longer life, but there may be easier ways to get the same benefit.
In 1934, in a famous experiment at Cornell University, it was discovered that laboratory mice could live twice as long as expected if they were fed a low-calorie diet that included enough nutrients to avoid malnutrition. This phenomenon has since been observed in species ranging from worms to primates, but not in humans. Reducing calorie intake leads to longer lives by modifying a number of the biochemical pathways that sense nutrients, including pathways that involve insulin and various other biomolecules. Chemical and genetic methods can also increase longevity by modifying these pathways, which suggests that it might be possible to develop drugs that can increase lifespan without the reducing calorie intake. _Bioscholar News

"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," says professor Steven Kliewer of UT Southwestern Medical Center. "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." When it comes to maximum life expectancy, the data isn't even all in yet: while none of the untreated mice lived longer than about three years, some of the female mice that overproduced FGF21 will soon reach the age of four. _TGDaily

If the life extension benefits from mice were to transfer to humans, men would live over 20 years longer with more FGF21, and women would live over 30 years longer. And they would be able to eat a normal diet, without starving themselves.

FGF21 is only a part of a complex network of proteins and hormones that affect metabolism and growth. But it appears to be a central part of the network, which may work as a key to unlock some important doors of understanding of metabolic diseases such as diabetes mellitus type 2, mechanisms of growth, as well as providing insights into the ageing process and diseases of ageing.
Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, increases insulin sensitivity, blocks somatic growth and causes bone loss. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting markers of NAD+ metabolism or AMP kinase and mTOR signaling. Transcriptomic analysis suggests that FGF21 acts primarily by blunting the growth hormone/insulin-like growth factor-1 signaling pathway in liver. These findings raise the possibility that FGF21 can be used to extend lifespan in other species. _eLife
There are too many unanswered questions regarding the entire tapestry of hormones involved in growth, metabolism, and ageing, for scientists to recommend use of FGF21 in humans.

The relationship of FGF21 to diabetes and bone density must be teased out and better defined. An intriguing relationship between FGF21 and hibernation should also be better illuminated and clarified.

FGF21 is certainly not THE answer to ageing. But it is very likely to lead us to a number of better questions. And eventually, it may add a decade or two of healthy lifespan to people of the near future.

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