From: "Dr. D. Kossove" <doctordee@telkomsa.net>
Subject: alpha lipoic acid and Lcarnitine
Date: Sunday, January 11, 2004 12:43 PM

http://www.sciencedaily.com/releases/2002/02/020221073701.htm


   
Source:   Oregon State University 
Date:  
 2002-02-22 

Compounds Rejuvenate Rats, May Aid Humans
CORVALLIS – Researchers in the Linus Pauling Institute at Oregon State University and the University of California at Berkeley have identified a combination of dietary supplements that dramatically improves both the activity, energy level and cognitive function of old rats. 

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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.” 



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This story has been adapted from a news release issued by Oregon State University.

 

 
 
 
———————   Copyright © 1995-2003 ScienceDaily Magazine   |   Contact: editor@sciencedaily.com   ———————
Source: University Of California - Berkeley  
Date: 2002-02-19 
URL: http://www.sciencedaily.com/releases/2002/02/020219075823.htm 

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Dietary Supplements Make Old Rats Youthful, May Help Rejuvenate Aging Humans, According To UC Berkeley Study
Berkeley - Two dietary supplements straight off the health food store shelf put the spark back into aging rats, and might do the same for aging baby boomers, according to a study at the University of California, Berkeley, and Children's Hospital Oakland Research Institute. 

A team of researchers led by Bruce N. Ames, professor of molecular and cell biology at UC Berkeley, fed older rats two chemicals normally found in the body's cells and available as dietary supplements: acetyl-L-carnitine and an antioxidant, alpha-lipoic acid. 

In three articles in the February 19 issue of Proceedings of the National Academy of Sciences, Ames and his colleagues report the surprising results. Not only did the older rats do better on memory tests, they had more pep, and the energy-producing organelles in their cells worked better. 

"With the two supplements together, these old rats got up and did the Macarena," said Ames, also a researcher at Children's Hospital Oakland Research Institute (CHORI). "The brain looks better, they are full of energy - everything we looked at looks more like a young animal." 

"The animals seem to have much more vigor and are much more active than animals not on this diet, signaling massive improvement to these animals' health and well-being," said former UC Berkeley post-doctoral fellow Tory M. Hagen, now an assistant professor at the Linus Pauling Institute at Oregon State University, Corvallis. "And we also see a reversal in loss of memory. That is a dual-track improvement that is significant and unique. This is really starting to explode and move out of the realm of basic research into people." 

Based on the group's earlier studies, the University of California patented use of the combination of the two supplements to rejuvenate cells. Ames, through the Bruce and Giovanna Ames Foundation, and Hagen founded a company in 1999 called Juvenon to license the patent from the university. Juvenon currently is engaged in human clinical trials of the combination. 

One of the three PNAS articles probes the reasons behind this rejuvenation, concluding that the two chemicals "tune up" the energy-producing organelles that power all cells, the mitochondria. Both chemicals are normally used in mitochondria. 

Ames calls mitochondria the "weak link in aging." Evidence has been piling up, he said, that deterioration of mitochondria is an important cause of aging. A significant cause of this deterioration, he believes, is the accumulation of destructive free radicals - byproducts of normal metabolism - that disable enzymes and other chemicals. 

The combination therapy targets mitochondria to get rid of destructive radicals and to boost the activity of a damaged enzyme, carnitine acetyltransferase, that plays a key role in burning fuel in mitochondria. The researchers hoped that the anti-oxidant alpha-lipoic acid would do the former, and that flooding the cell with acetyl-L-carnitine, one of two proteins that the enzyme acts on, would achieve the latter. 

Experiments showed that this regimen worked. Associate researcher Jiankang Liu of CHORI, UC Berkeley postdoctoral fellow David W. Killilea and Ames demonstrated that the enzyme carnitine acetyltransferase is less active in old rats than in young rats, and that it binds less tightly to acetyl-L-carnitine in older rats. 

Supplementation with acetyl-L-carnitine or a combination of acetyl-L-carnitine and alpha-lipoic acid restored the enzyme's activity nearly to that found in young rats and substantially restored binding to acetyl-L-carnitine. 

"The acetyl-L-carnitine is protecting the protein and the higher levels are enabling the protein to work, while alpha-lipoic acid knocks down oxygen radicals," Ames said. "Each chemical solves a different problem - the two together are better than either one alone." 

Ames and Hagen have long had an interest in mitochondria as they relate to aging, and they were intrigued by a 1999 Italian study that showed acetyl-L-carnitine, when fed to old rats, improved mitochondrial activity. 

The two thought this might be a way to reverse the effects of aging on mitochondria, and in various trials found it to work to some degree. Free radicals were still damaging the cell, however, so they decided to pair it with one of the few antioxidants that gets into mitochondria, alpha-lipoic acid. Lipoic acid is produced by mitochondria and boosts levels of other antioxidants. 

In the second of the PNAS studies, Hagen, Ames and colleagues compared 2- to 4-month-old rats to 24- to 28-month-old rats, all fed acetyl-L-carnitine in their water and alpha-lipoic acid in their chow. 

After as much as a month on the supplements, the old and lethargic rats became more peppy, Ames said. 

"We significantly reversed the decline in overall activity typical of aged rats to what you see in a middle-aged to young adult rat 7 to 10 months of age," Hagen said. "This is equivalent to making a 75- to 80-year-old person act middle-aged. We've only shown short-term effects, but the results give us the rationale for looking at these things long term." 

They found also that the combination of lipoic acid and acetyl-carnitine improved mitochondrial activity and thus cellular metabolism, and increased levels of various chemicals known to decline with age, including ascorbic acid, an antioxidant. 

In a third study, Liu, Hagen, Ames and colleagues fed old rats a similar diet of the two supplements and looked at memory function as measured by the Morris water maze test and a peak procedure for assessing temporal or time-based memory developed by Seth Roberts, professor of psychology at UC Berkeley. They found that supplementation improved both spatial and temporal memory, and reduced the amount of oxidative damage to RNA in the brain's hippocampus, an area important in memory. In electron microscope pictures of cells from the hippocampus, mitochondria showed less structural decay in old rats that had a supplemented diet. 

"We did two different tests for cognitive activity in rats, and in both it made a big difference to feed them this mixture," Ames said. "Memory degenerates with age, and this makes them better." 

The analysis of nucleic acid damage in the brain was performed with post-doctoral researcher Elizabeth Head and Carl W. Cotman, professor of neurobiology and behavior, at the Institute for Brain Aging and Dementia at UC Irvine. UC Berkeley psychology graduate student Afshin M. Gharib worked with Liu to conduct the peak performance tests. 

"In aging, you're oxidizing the proteins in mitochondria and they lose activity," Ames explained. "If some of that lost activity is due to binding for substrate or coenzyme - like binding of acetyl-L-carnitine by carnitine acetyltransferase - and you can raise the level of those, then you can reverse some of the loss. 

"We showed, in fact, that that is what's happening with acetyl-L-carnitine. Aldehydes from lipid oxidation are glomming onto that protein, and that is what appears to cause the reduction in binding activity. But if you raise the level of acetyl-L-carnitine, now it works." 

Hagen added, "With aging, we see so many different things that are occurring to mitochondria that then lead to consequences in the cell. If you tune up mitochondria you may have a means of at least delaying the onset of a number of age-related problems that we encounter, or we can in some ways, hopefully, reverse what has already taken place." 



The work was supported by grants from the Ellison Foundation, the National Institute on Aging of the National Institutes of Health, the Wheeler Fund of the Dean of Biology at UC Berkeley, the Bruce and Giovanna Ames Foundation and the National Institute of Environmental Health Sciences Center at UC Berkeley. 



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This story has been adapted from a news release issued by University Of California - Berkeley.

  
 