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.

Anti-Dementia Research Goes on the Offensive

Rather than fighting a rear-guard action against advancing dementia, some researchers are taking an offensive approach -- a "procognitive" approach. This means that instead of trying to slow down the inevitable decline of dementia, these researchers aim to rebuild brain tissues and brain function. They aim to push back against the decline and reverse it.

Scientists have developed a small peptide that they say can reverse some of the cognitive repercussions of neurodegenerative and potentially trauma-related brain disorders such as Alzheimer’s disease, by increasing synaptogenesis. The peptide, called dihexa, is a stabilized derivative of angiotensin IV (AngIV)...

...Washington State University’s Joseph W. Harding, Ph.D., Alene T. McCoy, Ph.D., and colleagues based their development on prior work demonstrating that the three terminal amino acids of AngIV and its analog Norleucine1-angiotensin IV (Nle1-AngIV) are central to the precognitive activities of the peptides. The team thus set out to develop much smaller, more stable derivatives of Nle1-AngIV that retained the active structure but could be administered orally and cross the blood-brain barrier.

The resulting lead compound, dihexia (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) not only fulfilled these requirements, but proved to be active at picomolar concentrations, and led to dramatic improvements in the cognitive abilities of a scopolamine-treated rat model of learning deficits, and also aged Sprague-Dawley rats.

Importantly, the treatment was effective whether the animals received it directly into the brain, via injection, or orally. Further analyses indicated that dihexia’s precognitive activity was associated with a drug-induced stimulation of dendritic spinogenesis in the hippocampal brain region, and that the newly formed dendritic spins were creating functional synapses. Encouragingly, dihexia was even more potent than brain-derived neurotrophic factor (BDNF), a growth-promoting protein that is used to create neuronal connections, but which hasn’t yet been developed for therapeutic use.

“At its core dementia results from a combination of diminished synaptic connectivity among neurons and neuronal death in the entorhinal cortex, hippocampus, and neocortex,” the researchers note in their published paper in the Journal of Pharmacology and Experimental Therapeutics. However, previous attempts to develop protein neurotrophic factors as therapeutics has been limited by their inability to cross the blood-brain barrier, and the need to manufacture such agents by recombinant methods, which is costly. “The development of dihexa has seemingly overcome these impediments by virtue of its oral activity, demonstrated pro-cognitive/anti-dementia activity, and anticipated low manufacturing costs.” _Gen Engineering News

Another interesting candidate for procognitive therapy is ABT-288, an H3 receptor antagonist.

Another very interesting class of procognitive drugs is the Ampakines. Ampakine CX546 is a recent drug candidate undergoing study.

Here are two different approaches to procognition in the context of developing novel anti-psychotic drugs:

Egis 11150 which has broad spectrum adrenergic, serotenergic, and dopaminergic antagonist activity
New anti-psychotics with 5HT2C receptor agonist and 5HT6 receptor antagonist activity

It is important for neuropharmacologists to take this fateful step, of taking the offensive in the fight against dementia. Repairing and rebuilding the damaged tissues in the brain will likely get better results than a piecemeal promotion of this neurotransmitter, or combating this protein or another. A procognitive approach holds out the possibility of a return to normal function, rather than a mere slowing of inevitable decline.

The technology of the early diagnosis of future dementia is advancing on multiple fronts, from better brain scanners to genetic testing to two recent interesting developments:

Virtual Reality Functional Capacity Assessment Tool (VRFCAT). Not only does VRFCAT promise to provide early diagnosis of cognitive problems, but it should also prove useful for monitoring of different therapeutic regimens.

New mathematical approaches to model the brain as a complex network of interconnected processing nodes Such mathematical modeling approaches should provide new ways of diagnosing normal vs. impaired brain network activity, as well as new ways to monitor effects of therapies on brain network function.

Eventually, what we will want from procognitive treatments, is for all of us to be able to become capable of clearer and deeper thought. For now, we will be happy to watch dementia sufferers coming back into themselves.

But once we see that beginning to happen, we are likely to want to "spread the wealth around" to include more and more people, maybe even ourselves.

Beyond a Personal Sense of Urgency

Each person feels his own sense of urgency -- varying with age and state of health -- regarding his own lifespan, and his ability to live out his remaining lifetime to its fullest.   But it is time for modern human society as a whole to feel an existential sense of urgency, as demographic trends begin to place constraints on humanity's ability to work itself out of a deepening hole.

The problem is one of diminishing human brain power, and one aspect of this problem is the rapid increase in proportion of individuals suffering from dementia -- Alzheimer's dementia and other types.

One illustration of the effect of dementia on the brain of an individual, is the following set of paintings by an American artist living in London, who was diagnosed with dementia at the beginning of the series:

William Utermohlen

The latest global demographic analysis, from a World Health Organization report issued earlier this year, paints the dimensions of that slow-motion catastrophe in quick strokes. An estimated 36 million people worldwide currently suffer from dementia; experts predict the number will double, to approximately 70 million, by 2030 and triple by 2050. (China, India, and Latin America in particular face daunting medico-economic crises.) Since the prevalence of the disease doubles with every five-year age increment after 65, projections for 2050 put the total global population at risk for dementia (people 65 or older) at two billion. The calculus is as grim as it is simple: as more people live longer, more slide into dementia. Care for those patients currently costs $100 billion a year in the United States, with a projected cost over the next 40 years of $20 trillion; by 2050, the cost to U.S. society is projected to be $1 trillion a year.

An even more sobering perspective on the problem comes from a small unpublished pilot study that Granieri and her colleagues at Columbia recently undertook. They did a standard cognitive evaluation of every person 70 or older who was admitted to Allen Hospital for any reason—heart problems, pain, diabetes, breathing difficulties. The results stunned them. "In this hospital, of patients 70 years of age or older, 90 percent have cognitive impairment of some kind, which is much higher than we anticipated," she says.

Not only is dementia distressingly widespread, but the complex overlap of symptoms and possible causes makes addressing the problem broader and trickier than just treating Alzheimer's. The emerging reality, which has become increasingly apparent with better brain imaging, is that the majority of cases among the elderly are so-called "mixed dementias"; the cognitive impairment is due to a combination of vascular problems, such as mini-strokes in discrete parts of the brain, and the more classic Alzheimer's pattern of amyloid plaques. Large-scale international studies in the past three years have shown, according to a recent scientific summary, that dementias caused by blood-vessel lesions in the brain, including vascular dementia and mixed dementia, "together comprise the most common forms of dementia at autopsy in community-based studies." _The Dementia Plague

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At this point, no one knows if medical science is any closer to an effective treatment for dementia than it was 30 years ago. Several competing hypotheses are scrambling for research funds, while the underlying problem itself continues to swell, around the world.

As populations continue to age in most countries except in sub Saharan Africa and tribal areas of Asia, the population proportion susceptible to these dementias will continue to grow. And unfortunately, the regions of the world where young populations will continue to outnumber old populations for the foreseeable future, are also regions with populations possessing rather low average IQ. This means that more and more resources in the developed world will be spent on the tertiary care of dementia patients, while the undeveloped world is likely to sink below its pre-colonial baseline due to overpopulation.

At the same time, the developed world will be suffering from excessive debt, unwise immigration policies, and massively oversized governments of a parasitic nature. All of these problems will converge to make large-scale research programs very difficult to fund.

And so there is a sense of urgency now, not to waste resources on frivolous pursuits of an ideological nature, but to rather focus on problems which are critical and undeniable.

If we allow our best minds to slip away uncontested and un-utilised, we will be throwing away our chances to achieve longer, healthier, more fulfilling, more productive, wide-ranging lives.

We need to move beyond ideology, beyond political correctness, and dedicate ourselves to the very dangerous pursuit of an abundant human future.