Saturday, 25 May, 2013

Radical results

Semi-starve a rat, monkey or yeast, and it’s likely to outlive its free-feeding friends. It’s weird but true: caloric restriction produces longer, healthier lives, although people who restrict their calories do report feeling cold, listless and a certain obsession with food.

But here’s the billion-dollar question: Why does cutting calories by roughly 30 percent produce such benefits if the rest of the diet is sufficient? The best answer is that the lo-cal regime reduces free radicals — molecules and fragments that damage genes, fats and proteins.

A better understanding of this radical-reduction mechanism could support drug discovery. Not to over-dramatize, but the Holy Grail of this research is to find a shortcut to the many benefits of caloric restriction while avoiding that void in the pit of the stomach.

In a study published today in the journal Cell, scientists firmly identified the gene Sirt-3 as essential to some of the benefits of caloric restriction. Sirt-3 is among a group of genes that were already associated with anti-oxidant mechanisms.

Proof in the pudding

“This study is the first direct proof for a mechanism underlying the anti-aging effects we observe under caloric restriction,” says Tomas A. Prolla, a professor of genetics at the University of Wisconsin-Madison, and a senior author of the new study. “We’re getting closer and closer to a good understanding of how caloric restriction works.”

Aging is as hard on mice as it is on people. Both these mice are the same age, but the one in front was genetically engineered to age rapidly for a study led by Tomas Prolla. Photo: Jeff Miller/University of Wisconsin-Madison

The study focuses on mechanisms that control free radicals produced by mitochondria, units in cells that process chemicals so cells can move and perform chemical reactions. Because mitochondria also produce free radicals, the very mechanism that keeps us going in the short run also spells doom in the long run.

But cells have also evolved anti-oxidant mechanisms to defang free radicals, and caloric restriction may be the best way to trigger those defenses.

Bring on the mice

The Cell study focused on age-related hearing loss, a common problem caused by cellular suicide among sensory cells in the inner ear. The scientists compared a control group, which reliably has this loss, to another that lacked the Sirt-3 gene.

Starting at age two months, the mice either stayed on the normal lab diet, or got a 25 percent reduction in calories. At two and 12 months, the mice got hearing tests. As expected, at 12 months, the normal-diet mice, but not the caloric restriction mice, had lost some hearing.

But check this out: the hungry mice without the Sirt-3 gene got absolutely no benefit from the low-cal diet.

The finding was clear, says John Denu, of UW-Madison’s Wisconsin Institute for Discovery. “Caloric restriction no longer prevents age-dependent hearing loss in mice that do not have Sirt-3, and there is thus a clear link between this protein and prevention of age-dependent hearing loss.”

And because hearing loss is considered a legit indicator of the anti-oxidant power of caloric restriction, the study shows that Sirt-3 plays an essential role in the only proven way to retard aging.

Links in the chain

Looking further, the researchers, who included Wei Yu in Denu’s lab and Shinichi Someya in Prolla’s research group, found that Sirt-3 activates an enzyme inside the mitochondria that also participates in a chain reaction that makes the crucial anti-oxidant glutathione, which destroys free radicals.

Even the yeast that fermented this beer live longer if raised under caloric restriction. Photo: cyclonebill

Caloric restriction has many effects, and many genes and proteins are likely to be involved, but Sirt-3 is the first gene proven essential to preserving age-related hearing loss, says Denu, a professor of biomolecular chemistry. “In the mouse, Sirt-3 is one part of the solution.”

Now that Sirt-3 is known to play an essential role, the search is on for a drug that can stimulate it. Finding a key link in caloric restriction is inherently interesting, but the new results may help capture the benefits of caloric restriction, such as better hearing and a longer lifespan, without the pit-of-the-stomach price.

A second approach would be to artificially induce the Sirt-3 stimulating mechanism that caloric restriction uses.

These questions become more pressing now that Sirt-3 is known to be crucial to some of the metabolic benefits of caloric restriction, Denu adds.

Which is just as well, considering that few people can successfully cut calories by 25 percent. “In American culture, it’s more palatable to take a pill than chronically starve yourself,” Denu observes.

We concur. And as the feasts of Thanksgiving approach, we can only say, “Amen. And pass the stuffing!”

Tags: aging, antioxidant, caloric restriction, hearing, John Denu, mitochondria, Tomas Prolla, University of Wisconsin Madison UW-Madison