Compounds Rejuvenate Rats, May Aid Humans

The findings were announced today in three articles in a professional journal, the Proceedings of the National Academy of Sciences. The research is supported by grants from the National Institutes of Aging. Small clinical trials are already under way with humans to determine whether these compounds offer the same benefits to people.

The studies were done with a combination of two compounds that occur naturally, acetyl-l-carnitine and an antioxidant, alpha-lipoic acid. Previous work has shown that either of these compounds may have value in addressing some of the physical and mental deterioration associated with aging, but the newest research suggested a combination of the two works far better than either one separately.

"After just a month, older rats whose diet was supplemented with these two compounds were about twice as active as our control rats, which remained largely inactive," said Tory Hagen, an assistant professor in OSU's Linus Pauling Institute. "They also had a much better memory and cognitive performance, measured by their ability to remember objects and spatial orientation."

The researchers found that old rats given the dietary regimen had an activity level about the same as those of middle-aged rats.

The latest findings build on years of research into the aging process and these compounds, the scientists said.

There are many cellular changes associated with aging, and one particularly vulnerable area appears to be the mitochondria where the cell's energy is generated.

Although there are literally hundreds of theories about why animals age and eventually die, the OSU and Cal-Berkeley scientists believe that mitochondria may be an “Achilles heel” for absorbing age-related damage. And there may be ways to influence that process, Hagen said.

“It appears that some compounds, including carnitine and lipoic acid, can mask the metabolic problems caused by cellular aging and the natural oxidative process,” Hagen said. “We’re very excited about the research. This may have relevance to improving people’s quality of life and health.”

Aging is closely related to the major diseases that kill most people around the world – heart disease and cancer – as well as those that can have severe impacts on quality of life, such as Alzheimer’s disease and Parkinson’s disease.

Like many complex metabolic processes there is probably no single, simple answer to the aging process, Hagen said. Some scientists believe the process has a hormonal basis, in which cells no longer “communicate” with each other properly, and others ascribe a genetic basis to aging in which cells become “senescent” after a finite number of programmed divisions.

But the theory being studied at OSU and Cal-Berkeley is that aging is at least partly due to the natural process of oxidation in the body and “free radicals,” that cause cellular damage.

“Oxygen is a double-edged sword,” Hagen said. “We need it to live and it’s essential to cell function. But oxygen can be converted into what we call reactive radical oxygen species, or free radicals. And they have the potential to mutate DNA and damage lipids and proteins.”

The free radicals that are being produced as a result of metabolism are actually the same that result from nuclear radiation. It’s as if humans were being irradiated throughout their lives. And this process is such a natural part of life that cellular repair mechanisms have evolved to help fix or prevent the damage – not the least of which are well-known “antioxidants” such as vitamin C.

“These cellular repair processes are not perfect,” Hagen said. “Oxidative damage does occur, and we think there’s strong evidence that this contributes to aging and some of the other problems associated with it, such as cancer, arteriosclerosis or neurodegeneration.”

A particular weak spot in the body may be the mitochondria in cells – a quasi-independent structure similar to bacteria with its own DNA.

“Mitochondria are the power plants of our cells, where raw fuels are converted into usable forms of energy,” Hagen said. “Up to 90 percent of the oxygen we breathe is used by the mitochondria, as they perform many of the roles critical to cell function, such as producing energy, regulating calcium and even controlling cell life and death.”

But mitochondria, Hagen said, are also the chief source of free radicals. And since they’re right in the neighborhood of the dangerous free radicals they just created, they’re also often the first victims.

“This can be a vicious downward cycle, in which mitochondria create free radicals and then fall victim to them,” Hagen said. “This loss of mitochondrial function and its impact on metabolic function is at least one part of what we call aging.”

In studies of old rats, Hagen’s laboratory has documented a severe decline of mitochondrial function, a slower metabolic rate and reduced cognitive function. He has shown that the antioxidants that help protect mitochondria, especially glutathione, an intracellular antioxidant, decline severely with age. And his studies have shown that the cells of old rats are far more susceptible to age-related oxidative stress than those of young animals.

But the newest studies offer hope. Carnitine is an amino acid that’s involved in fatty acid transport into mitochondria. It's a natural compound produced in the cell and obtained in the diet through meats and vegetables. Previous research showed that rats fed this compound had improved mitochondrial function and overall activity level. In studies done in humans by other researchers, carnitine has been shown to improve balance and short-term memory, Hagen said. And another strong antioxidant, lipoic acid, found in green, leafy vegetables, appears to improve mitochondrial function.

The new study shows that a combination of these two compounds provides all these benefits at even higher levels than either one alone.

“As people age and their mitochondrial function declines, they are even less able to resist the usual metabolic insults of life, just like rats,” Hagen said. “But we’re seeing that an intake of these nutrients in combination seems to restore the ability of cells and mitochondria to deal with environmental stresses, just about as well as they did when they were young.”

“If we can better understand the process of aging and how to influence it,” Hagen said, “we may be able to give people a way to maintain human health for as long as possible.”