Activating AMPK In One Organ Slows Whole Body Aging

Activating AMPK in one organ could slow whole body aging

Tuesday, September 16, 2014. An article published online on September 4, 2014 in Cell Reports reveals the outcome of research conducted at the University of California, Los Angeles which found that activation of adenosine monophosphate-activated protein kinase (AMPK) in one organ decelerated the aging process elsewhere in the bodies of fruit flies.

AMPK is a gene that is activated when cellular energy levels are low. The gene has also been found to be activated by the antidiabetic drug metformin. AMPK stimulates a process known as autophagy that enables cells to degrade and eliminate damaged components, which helps protect against aging. "We have shown that when we activate the gene in the intestine or the nervous system, we see the aging process is slowed beyond the organ system in which the gene is activated," commented senior author David Walker, who is an associate professor of integrative biology and physiology at UCLA.

For their research, Dr Walker, along with lead author Matthew Ulgherait and colleagues, examined over 100,000 genes in Drosophila melanogaster, the fruit fly that has been the subject of numerous other experiments in the field of gerontology. The team found that increasing AMPK in the flies' intestines increased life span by 30% and lengthened the portion of their lives spent healthy.

"A really interesting finding was when Matt activated AMPK in the nervous system, he saw evidence of increased levels of autophagy in not only the brain, but also in the intestine," Dr Walker reported. "And vice versa: activating AMPK in the intestine produced increased levels of autophagy in the brain—and perhaps elsewhere, too."

"Matt moved beyond correlation and established causality," he added. "He showed that the activation of autophagy was both necessary to see the antiaging effects and sufficient; that he could bypass AMPK and directly target autophagy."

"Instead of studying the diseases of aging—Parkinson's disease, Alzheimer's disease, cancer, stroke, cardiovascular disease, diabetes—one by one, we believe it may be possible to intervene in the aging process and delay the onset of many of these diseases," Dr Walker predicted. "We are not there yet, and it could, of course, take many years, but that is our goal and we think it is realistic."

What's Hot

Aspirin, metformin share common mechanism

A report by scientists from McMaster University, the University of Dundee and the University of Melbourne, published online on April 19, 2012 in the journal Science suggests a common mechanism for salicylate—aspirin's active compound—and the drug metformin in decreasing the risk of several diseases.

"Salicylate, a plant product, has been in medicinal use since ancient times," Simon A. Hawley and colleagues write in their introduction to the article. "More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both rapidly broken down to salicylate in vivo."

The authors explain that salsalate or aspirin administered in high doses result in the activation by salicylate of adenosine monophosphate-activated protein kinase (AMPK), a regulator of cell growth and metabolism. AMPK is known to be activated by exercise as well as the antidiabetic drug metformin. "We're finding this old dog of aspirin already knows new tricks," commented co-principle investigator Dr Greg Steinberg, who is an associate professor of medicine in the Michael G. DeGroote School of Medicine at McMaster University and the Canada Research Chair in Metabolism and Obesity. "In the current paper we show that, in contrast to exercise or metformin which increase AMPK activity by altering the cells' energy balance, the effects of salicylate are totally reliant on a single Ser108 amino acid of the beta 1 subunit.

"We show that salicylate increases fat burning and reduces liver fat in obese mice and that this does not occur in genetically modified mice lacking the beta1 subunit of AMPK," he noted.

The fact that both metformin and aspirin activate AMPK suggests that their recently publicized benefits in reducing the risk of cancer could be due to a shared mechanism. However, only further studies can confirm the validity of this interesting hypothesis.

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Health Concern

Calorie Restriction

Caloric restriction (CR) is a general strategy for improving wellbeing and lifespan. It is more than a simple limitation of calories for maintenance of body weight; CR is the dramatic reduction of caloric intake to levels that may be significantly (up to 50% in some cases) below that for maximum growth and fertility, but nutritionally sufficient for maintaining overall health ("undernutrition without malnutrition").It remains one of the most researched and successful approaches to life extension in laboratory settings. Although the effects of CR on health are diverse, its mechanisms are not fully understood, and are thought to involve the activation of survival mechanisms that have been evolutionarily conserved to protect organisms from stress.

The practical challenge of long-term or lifetime CR has recently generated interest in caloric restriction mimetics (CRMs), an alternative to CR which may provide the pro-longevity benefits without an actual reduction in caloric intake. CRMs are a broad class of compounds and interventions that may promote life- and health-span by a diversity of mechanisms, ranging from induction of genes that protect against stress, to antioxidation and anti-inflammation.

The glucoregulatory agent metformin can produce many of the gene expression changes found in mice on long-term caloric restriction, in particular, it can decrease the expression of chaperones; a set of proteins which, in addition to their other functions, can reduce apoptosis (self-destruction of damaged or malignant cells) and promote tumorigenesis. Metformin has increased mean lifespan in the worm C elegans. Along with the related antidiabetic biguanide drugs phenformin and buformin, metformin extended the mean life span of mice by up to 37.9 percent and their maximum life span by up to 26 percent in multiple studies while significantly decreasing the incidence and size of mammary tumors.