How we age has been the subject of debate for decades. An often cited paradox has been the inability of scientist to provide a biological explanation of how eating less extends lifespan.
Indeed, it has been well documented 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, a new laboratory study may have found an answer to the conundrum.
A team of scientists from the University of Wisconsin-Madison and their colleagues have discovered a molecular pathway that is believed to be a key determinant of the aging process.
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.
The study is found in the journal Cell.
“We’re getting closer and closer to a good understanding of how caloric restriction works,” said Dr. 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, gene transcription, programmed cell death 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, Ph.D., 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,” said 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.”
Laboratory researchers used 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,” said Prolla, whose previous work established a genetic link to cell death and age-related hearing loss. “And hearing loss is prevented through caloric restriction.”
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,” said 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, 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.
Source: University of Wisconsin-Madison