"If you're an old rat, it looks very good.
But we still have to wait for the results from the human trials.
There's every reason to think it's going to work in people. I'm very optimistic."
. . . . Dr Bruce Ames, professor of biochemistry at the University of California at Berkeley; 1998


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"the power stations of the cell are called mitochondria... Of the oxygen consumed by an average cell, the mitochondria use most of it to help turn food into energy.

Unfortunately, mitochondria also appear to have a major design flaw — they leak electron electricity. This, in turn, leads to an increase in the production of free radicals.

The antioxidant defenses of your body are usually adequate to prevent substantial tissue damage. However, an overproduction of free radicals (caused, for example, by intense exercise) or a drop in the level of the antioxidant defenses will lead to an imbalance between free radical generation and antioxidant protection.

This imbalance is known as oxidative stress.

Mitochondria are right in the neighborhood of the free radicals they just created. This means they're often the first victims.

It's ironic that the thing we most need to live — oxygen — is the very thing contributing to aging and some of the other problems associated with it, such as cancer and heart disease.

"Oxygen is a double-edged sword," says Tory Hagen. "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."

Bruce Ames and Tory Hagen (researchers in the Linus Pauling Institute at Oregon State University and the University of California at Berkeley) have long had an interest in mitochondria as they relate to aging. They were intrigued by Italian research showing that acetyl-L-carnitine improved mitochondrial activity in older rats .

When Ames and Hagen tried the same experiment, there was a problem . The carnitine did improve mitochondrial health. But it also appeared to increase the level of free radicals. So, they decided to pair it with alpha-lipoic acid.

"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 says. "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."

The University of California have patented the use of acetyl-L-carnitine and alpha-lipoic acid as a way of "enhancing metabolism and alleviating oxidative stress."

Juvenon, a company founded by Ames and Hagen, has licensed the patent from the university. Their first product — Juvenon Energy Formula — contains both alpha-lipoic acid and acetyl-L-carnitine.

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Some biographical info on Dr Bruce Ames, winner of the National Medal of Science, 1998;
aptly named a "Free Radical" by one of his students.


Ames is interested in finding chemicals that can revitalize mitochondria, the power plants of cells, which deteriorate as people age. He formed a company called Juvenon to develop and market cell-rejuvenating supplements based on his research at the University of California, Berkeley.

Ames chairs Juvenon's scientific advisory board but put his founder's stock in a charitable foundation and will take no remuneration from the company.


From "Investor's Business Daily" Wed March 16, 2005 Leaders And Success
"Bruce Ames Pulls It Together" by Patrick Seitz


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Ames was cited "for changing the direction of basic and applied research on mutation, cancer and aging." He established that many cancer-causing chemicals are also mutagens, that is, they cause mutations in cells, and devised a simple, inexpensive test for environmental and natural mutagens. Commonly called the Ames test, it has been used widely in research institutes, industry and regulatory agencies around the world to screen for environmental carcinogens and mutagens and to analyze the mechanisms involved in metabolic activation of carcinogens. It has had a major influence in weeding out mutagenic chemicals before they are introduced into commerce. He also identified the causes and effects of oxidative DNA damage and translated these findings into intelligible public policy recommendations on diet and cancer risk for the American people. Specifically, he concluded that degenerative diseases of aging, such as cancer, cardiovascular disease, cataracts and brain dysfunction, are in good part due to oxidative damage. Dietary antioxidants, such as Vitamins C and E and carotenoids, play a major role in minimizing this damage, he argues. During his career, Ames has tried to dispel the many myths about the causes of cancer, chief among them that trace chemicals in the environment, such as pesticide residues on food, are a significant cause of cancer. The main causes of cancer, he argues, are lifestyle factors, ranging from poor diet to smoking and lack of exercise. A native of New York City, Ames obtained his bachelor's degree in chemistry from Cornell University and his PhD in biochemistry from the California Institute of Technology.


NEWS RELEASE, 12/9/98
http://www.berkeley.edu/news/media/releases/98legacy/12-9-1998b.html


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UC Berkeley biochemist Bruce Ames to receive National Medal of Science, the White House announced today
By Robert Sanders, Public Affairs


Dr Bruce Ames isn't afraid to stir up controversy. He relishes it.

Ames has made a career out of challenging prevailing views in the scientific community.

His primary interest now is on aging, in particular the role of mitochondrial decay as a major contributor to aging and age-related degenerative diseases, such as Alzheimer's.


http://www.juvenon.com/pdfs/ibd_03-16-05.pdf

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In the 1950s, Ames began working at the National Institutes of Health, where he was investigating ways of mutating the DNA of bacteria in order to learn more about gene regulation. His work led him to develop a petri-dish protocol for testing whether a substance can cause such mutations. With that test, Ames and other investigators were able to show that most cancer-causing chemicals act by damaging genes—a finding that now seems obvious only because Ames helped prove it. "This test you can do in an afternoon, whereas an animal cancer test costs a million dollars and takes two years to do," he says. "I never patented it, so I never made any money out of it."

But Ames had made a reputation. In the late 1960s, he took that reputation to Berkeley, where he continued his cancer studies.

Ames got interested in free radicals because they can cause cancer. Like radiation and carcinogens, free-radical oxidation breaks strands of DNA. The breaks are repaired, but some mistakes occur. Mistakes in DNA coding are also known as mutations. And as Ames had helped demonstrate, certain genetic mutations predispose an individual to certain cancers. No one knows why, but the incidence of most cancers increases with age. Ames thought the age-related increase in cancer rates might have something to do with an age-related rise in oxidative damage to DNA.

But no one had shown that DNA oxidation actually does increase with age. In 1990 Ames and his colleagues at Berkeley published the first evidence that it might. They found twice as much DNA oxidation in the tissues of 2-year-old rats as in those from 2-month-old rats.

Ames's research on oxidation led him to look more closely at mitochondria because they are the mother lode of free radicals. In order to burn fats and carbohydrates to make metabolic fuel, mitochondria take electrons from oxygen and shuffle them among a suite of molecules in a complex chain reaction. Invariably, some of the electrons get misplaced, creating free radicals. "People have estimated that [the electron transport chain] is maybe 98 percent efficient, which is much better than a human engineer can do," says Ames. "But it still makes kilos of oxygen radicals per person per year."

Mitochondria produce more oxidants than any other single site in a cell, the main offenders being superoxide, hydrogen peroxide, and hydroxyl radicals. Ames thought mitochondria would therefore be hardest hit by free-radical damage, not only to mitochondrial DNA but also to enzymes in the electron transport chain and lipids in mitochondrial membranes.

It also occurred to him that mitochondria might be an ideal target for intervening in the aging process. Working with postdoctoral student Tory Hagen, Ames characterized the changes that occur in the mitochondria of aging rats. They have shown that old mitochondria consume less oxygen, have stiffer membranes, and shuffle electrons less efficiently than their younger counterparts. Old mitochondria also make a lot more oxidants.

Researchers at the University of Bari in Italy had reported that feeding acetyl-L-carnitine to old rats improves the function of their mitochondria. Stateside, no one but Ames paid much attention to the report. He could see how the supplement might achieve its effects: Acetyl-L-carnitine, also known as Alcar, is a nutrient that helps transport fatty-acid fuel across lipid membranes into mitochondria. Thus the more Alcar a cell has, the better its mitochondria might function.
Ames reasoned that high levels of Alcar might also combat the problems of aging membranes and decrepit enzymes. He began feeding Alcar to his old rats. Within weeks, he and Hagen noticed improvements in the animals' biochemistry and behavior. Their mitochondria were going full bore again, and they had become far more active. But the old rats were still churning out oxidants at a very high rate. In fact, by goosing metabolism, Alcar seemed to slightly increase free-radical production. "We didn't solve the problem of oxidants," Ames says. "In fact, if anything, it was a little worse."
Ames decided to add an agent to the rats' diet to neutralize the oxidants. He tried lipoic acid, a mitochondrial antioxidant. The results were profound. Oxidants and oxidative damage to mitochondrial components dropped dramatically. Both the structure and function of the mitochondria improved. The rats' activity levels doubled. They were, Ames says, "doing the Macarena." The combination of the nutrient and the antioxidant had a synergistic effect. "The two together are better than either one alone."

But the most exciting changes were in the rats' brains. Ames, Hagen, and another postdoc, Jiankang Liu, tested the memory of old rats by training them to find a platform submerged in a swimming tank. Rats are good but reluctant swimmers, so they're motivated to learn. Without supplementation, "the old ones are wandering all over the place before they find the hidden platform," Ames says. "The young ones make a beeline for it." With just a month of Ames's antiaging combo, old rats get to the platform almost as fast as young ones. The old rats' performance on other kinds of memory tests also improves, showing that the swimming-tank test isn't just measuring sharper eyesight. Ames is waiting to see whether they live longer too.

Ames doesn't stand to profit either way. He has no financial stake in Juvenon, and Berkeley gets most of the proceeds from his patents. But Ames unwittingly assured himself a pension several years ago when he wrote a $100,000 check to a former student who was starting a biotech company in California. The company sold for $100 million in 2000. Ames gave $8 million of his newfound wealth to start a genomics and nutrition center. He gave his department at Berkeley a couple million for improvements there, and he doled out thousands more to research projects. With the rest, he set up a foundation to conduct outreach programs to improve nutrition among the poor.

Harvard University epidemiologist Walter Willett says Ames is "obviously playing a role—and somebody in science has to do it—where sometimes you need to state things provocatively to stir up the pot and get people to look critically at issues they weren't looking at before."


Interview with Oxidation Expert Bruce Ames
By Karen Wright,     DISCOVER Vol. 23 No. 10 | October 2002
http://www.imminst.org/forum/index.php?s=&act=ST&f=44&t=3851&


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Interview with Bruce Ames, Professor of Molecular and Cell Biology

Number: 00S03. Issue: Spring 2000
Author[s]: Andrew Hon, Jane Lo, Viet Nguyen, Negar Salehomoum
http://www.ocf.berkeley.edu/~bsj/ bsj@ocf.berkeley.edu

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A Bit More About Aging Mitronchondria:

Mitochondria, little organelles in the cell, are the power plants of the cell: they make all the ATP that powers your brain, your muscles, and your biochemistry. ATP is the high energy molecule that does the work of the body. All that ATP is made in the mitochondria. Basically, the mitochondria are rechargeable batteries. A potential across the membrane is made by burning fat and carbohydrate (which means taking electrons off of them to create that membrane potential). Those electrons are added to oxygen to give water.

With age, the mitochondria becomes very heterogeneous, the membrane potential goes down; cardiolipin, which is the key lipid in the mitochondrial membrane goes down, the oxygen utilized goes down, the ATP formed goes down, and the oxidant leakage goes up, so the cell starts oxidizing it. We think that is a major contributor to aging.

The mitochondria are decaying, so you are not getting enough energy, and your defense systems are not working as well, and you are making more oxidants, and the whole system is a vicious cycle, going downhill. This contributes to cancer, heart disease, impaired brain function and all these degenerate diseases that come along with aging.

your immune system protects you against invaders and saves you from dying an early age from a bacterial infection or viral infection. But every time your white blood cells combat a bacterial infection, they pour out mutagenic oxygen radicals and hypochlorite, to which is the same chemical found in Clorox [liquid bleach]. White blood cells also put out nitrogen oxide, and superoxide. Chronic infection in fact causes about 20% of cancer, probably due in good part to these oxidants.

.....When you "bleed electrons" in the mitochondria, you are making all these powerful oxidants.. superoxide, hydrogen peroxide, and hydroxyl radical....

You are constantly repairing or getting rid of all of these damaged molecules, but your defenses never quite keep up...


excerpted from:
Interview with Bruce Ames, Professor of Molecular and Cell Biology
http://www.ocf.berkeley.edu/~bsj/ bsj@ocf.berkeley.edu
Number: 00S03. Issue: Spring 2000
Author[s]: Andrew Hon, Jane Lo, Viet Nguyen, Negar Salehomoum