Scientists ferret out a key pathway for aging

November 18, 2010 by Terry Devitt, University of Wisconsin-Madison

For decades, scientists have been searching for the fundamental biological secrets of how eating less extends lifespan.

It has been well documented in species ranging from spiders to monkeys that a diet with consistently fewer calories can dramatically slow the process of aging and improve health in old age. But how a reduced diet acts at the most basic level to influence metabolism and physiology to blunt the age-related decline of tissues and cells has remained, for the most part, a mystery.

Now, writing in the current online issue (Nov. 18) of the journal Cell, a team of scientists from the University of Wisconsin-Madison and their colleagues describe a molecular pathway that is a key determinant of the . The finding not only helps explain the cascade of events that contributes to aging, but also provides a rational basis for devising interventions, drugs that may retard aging and contribute to better health in old age.

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

The Wisconsin study focuses on an enzyme known as Sirt3, one of a family of enzymes known as sirtuins, which have been implicated in previous studies in the aging process, , programmed and stress resistance under reduced calorie conditions. In mammals, including humans, there are seven sirtuins that seem to have wide-ranging influence on cell fate and physiology.

Sirt3 has been less studied than other members of the sirtuin family, but the new study provides "the first clear evidence that sirtuins have anti-aging effects in mammals," according to John M. Denu of UW-Madison's Wisconsin Institute for Discovery and a senior author of the report.

The Sirt3 enzyme, Denu explains, acts on mitochondria, structures inside cells that produce energy and that are the sources of highly reactive forms of oxygen known as free radicals, which damage cells and promote the effects of aging. Under reduced-calorie conditions, levels of Sirt3 amp up, altering metabolism and resulting in fewer free radicals produced by mitochondria.

"This is the strongest and most direct link that caloric restriction acts through mitochondria," says Prolla, who has studied the effects of reduced calorie diets on aging and health for more than a decade. "Sirt3 is playing a surprisingly important role in reprogramming mitochondria to deal with an altered metabolic state under caloric restriction."

The lead authors of the new study are postdoctoral fellows Shinichi Someya, of UW-Madison and the University of Tokyo, and Wei Yu of UW-Madison. The work involved a mouse model that exhibits age-related hearing loss, a phenomenon associated with free radical damage to the cells of the cochlea, a structure in the inner ear that converts sound vibrations to nerve impulses. Age-related hearing loss is common in humans, and is newly exemplified by such things as ultrasonic cell phone ring tones that only the very young can hear as the cells that capture the highest frequencies are the first to go.

"Hearing loss is associated with the loss of specific cell types in the cochlea," notes Prolla, whose previous work established a genetic link to cell death and age-related hearing loss. "And hearing loss is prevented through ."

In companion experiments in cultured cells and detailed in the Cell report, the Wisconsin team and their colleagues show that elevated levels of Sirt3 protect cells from cell stress and death caused by free radicals.

"Sirt3 is sufficient to provide protection against oxidative damage," says Denu.

Although sirtuins have been studied extensively and are believed by many scientists to play a role in aging, the new study is the first to conclusively link the enzymes to slowing the aging process in mammals. According to Denu, who is also a professor of biomolecular chemistry in the UW School of Medicine and Public Health, knowing the molecular basis of how the sirtuin enzymes work may ultimately lead to the rational development of drugs that activate the pathways of enzymes like Sirt3 to slow down the process of aging.

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not rated yet Nov 19, 2010
Can I get a prescription for that?
1 / 5 (1) Nov 19, 2010
The body is a machine, the more you use it, the more it wears out. Eating causes so many metabolic actions it isn't hard to understand that it causes aging. The body goes into overdrive to digest food. My guess is that there are many 'mechanisms'.
not rated yet Nov 19, 2010
Is there anything else that effects Sirt3? Yes, if a low calorie diet increases Sirt3 activity what would a normal diet with high levels of exercise do?

A more active lifestyle that consumes any excess calories might do the same sort of thing?

So what would be better for Sirt3: Eat 800 calories a day and sit watching TV or eat 3000 calories a day and run 20 miles before breakfast?

Eat well, work hard, live a long life?
not rated yet Nov 19, 2010
The body-as-a-machine-wearing-out was noted by Dr. Roy Wolford in one of his books on maximizing life span through caloric restriction. He likened the human body to a furnace designed to burn about 80 million calories, at the end of which it is worn out. Spend the budget however you like. That's a million calories a year for an 80 yr old, 2740 c/day, pretty generous. One would have to be very physically active to avoid weight gain and degenerative disease.

He recommended lopping off 25% of calories, but starting from a lower base for the less active. His mice may have been always hungry, but they became supermice with incredibly long and disease-free life spans.
not rated yet Nov 19, 2010
Trans-reserveratrol (red wine molecule) is the only known substance that has experimentally reproduced similar experimental effects as caloric restriction. It has demonstrated similar genetic affects on the Sirtuin gene (mice) complex. However, like caloric restriction it doesn't likely extend the genetic life span limits, though it probably will extend the average life span significantly, reducing age related disease. Our life span limits are genetically controlled, but since those limits are far past reproductive age - there are no direct genetic feed back loops to selectively extend our life spans. Shortly past sexual maturity, a slow genetic cascade (chain reaction) begins that effectively shuts down specific cellular metabolic, replacement and repairs - the process we call aging. If we are to significantly extend our max life spans then we will have to intervene in this genetic cascade - effectively tricking our genes into thinking we are teenagers - forever. Easy to say.

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