Though they are essential nutrients linked to heart health and brain and cell function, polyunsatured fats (PUFAs) are, by their very chemical nature, highly unstable and vulnerable to oxidation. A team of biochemists at the University of California, Los Angeles (UCLA), however, have discovered a new method to increase the stability of PUFAs, rendering the molecule cell membranes less prone to oxidation without relying on antioxidants to repair damage after it occurs—a method they believe has the potential to not only help combat neurodegenerative disorders such as Parkinson’s disease and perhaps even Alzheimer’s, but also revolutionize the development of a new class of more effective nutritional supplements.
“These compounds (polyunsaturated fatty acids) are so important, yet so fragile,” commented chemistry and biochemistry professor Catherine Clarke in a UCLA-generated press release. “In many diseases, cell membrane function deteriorates, and it’s exciting to think an enhanced class of supplements may be able to correct neurodegenerative diseases, and perhaps even oxidative stress-related aging. It would be a new strategy to treat and reinforce the molecule at the place where it is most prone to damage, instead of taking more antioxidants. This could be a new approach to battling diseases resulting from oxidative stress.
“Our research highlights how vulnerable these essential polyunsaturated fatty acids are,” she continued. “They are so readily damaged. Many neurodegenerative diseases, such as Parkinson’s disease and perhaps Alzheimer’s disease, are tied to oxidative stress.”
Dr. Clarke told Nutraceuticals World that she and her colleagues were initially intrigued by the concept of stabilized PUFAs after being approached by Dr. Mikhail Shchepinov and Robert Molinari, co-founders of Retrotope, Inc., a Los Altos Hills, CA-based privately held company focused on the development of methods capable of controlling metabolic processes associated with oxidative stress.
“Retrotope had synthesized small amounts of the deuterium [an isotope of hydrogen that has double the mass of ordinary hydrogen] substituted, essential fatty acid nutrients, and wished to test an intriguing hypothesis: that these compounds, stabilized at weak link chemical bonds, might provide a safe way to stabilize an organism against oxidative damage to tissue,” recalled Dr. Clarke. “We got excited to test the hypothesis on our co-Q deficient yeast strains that had been previously developed exactly to quantify the effects of such stresses, and measure if various agents like antioxidants could help.”
She said both parties had previously been aware of data linking oxidized fatty acids to certain conditions and diseases of degeneration, and wondered if such stabilized fatty acids, administered as part of diet, could mitigate symptoms or improve health. “The stable isotope deuterium, being the same chemical element as hydrogen, appeared both safe (it is a minor component of natural compounds) and was known for decades to make any bond in which it replaced hydrogen, stronger,” she said.
Through their research, Dr. Clarke and her colleagues demonstrated that polyunsaturated fatty acids could be strengthened by stripping away vulnerable hydrogen atoms and replacing them with much more stable deuterium. The result is the creation of a fatty acid that serves the same function as its predecessor, but without the same susceptibility to oxidation.
Dr. Clarke’s research team—which included four UCLA undergraduates: lead author Shauna Hill, Bradley Kay, Vincent Tse and Kathleen Hirano—conducted experiments with a strain of yeast specially modified to lack antioxidants. They found that colonies treated with normal, naturally occurring polyunsaturated fatty acids died quickly, while those that were treated with the deuterium-reinforced fatty acids displayed resilience on par with wild, unmodified yeast. The replacement of a few hydrogen atoms with deuterium meant the difference between a rapid death and vigorous life for the yeast samples.
“You can think about polyunsaturated fatty acids like an oil-based paint,” explained Dr. Clarke. “When you spread the oil-based paint on the wall, it turns into a hard coat of enamel. That happens because of an oxidation reaction. A hard coat of enamel is great for a wall but lousy for a cell membrane. Cells have to deal with damage continually and have to be able to repair the damage that results from the oxidation.”
Other co-authors of the research included Mikhail Shchepinov, chief scientific officer of Retrotope Inc. in Los Altos Hills, Calif., and Dragoslav Vidovic from the department of chemistry at England's Oxford University.
Because the human body is unable to synthesize its own supply of polyunsaturated fatty acids such as omega 3 and omega 6 fatty acids, supplementation via food and dietary supplements is necessary.
However, Dr. Clarke pointed out that when a polyunsaturated fatty acid is oxidized, a hydrogen atom is stripped away from the molecule, causing it to form a new compound with the oxygen in the bloodstream that impairs the function of the cell membrane. After one polyunsaturated fatty acid molecule is damaged, a chain reaction ensues as the adjacent fatty acids throughout the membrane become similarly degraded. What was once a semi-permeable barrier that regulated cell function becomes a rigid lattice of cross-linked fatty acids that prevents the cell from achieving its purpose—which could be anything from synthesizing a protein to sending a signal to the nervous system.
Antioxidants are typically relied upon to “target the gaps” left in molecules when a hydrogen atom is removed through oxidation. The antioxidants quench the reactive oxidized lipids, forming a new compound that staves off further molecular degredation.
This is where the benefit of reinforced polyunsaturated fatty acids enters the picture, she said, as they could potentially create membranes that are at least somewhat resilient to oxidative damage. A deuterium atom has twice the mass of a hydrogen atom; the carbon-to-deuterium bond in the modified fatty acid is much stronger than the carbon-to-hydrogen bond in the naturally occurring version. Thus, a fatty acid reinforced with deuterium negates the need for protective antioxidants in the first place.
But Dr. Clarke was unsure about how this new research could immediately impact the dietary supplement landscape—or if it even fell under the purview of supplements at all. “Initially, it is unclear if the FDA and other regulatory agencies would deem compounds modified in this way as dietary supplements, or require drug product development,” she said. “Therefore, Retrotope is first examining their effects in specific disease models, which if successful, could lead to drug safety trials in which the compounds could be tested in humans. Since fatty acids turn over from diet rapidly in a number of hard-to-treat tissues, e.g. brain, retina, and the like, the company hopes to offer a whole new class of therapeutic options for largely intractable diseases of tissue degeneration, and has early indications such a plan may work.”
Dr. Clarke said ideally the most likely and immediate application for the research might best be in the realm of neurodegenerative diseases. “We can dream that if the mechanisms of oxidation mitigation work and literature reports of oxidized fatty acids’ roles in disease are all true, we could have a handle on a whole new class of therapeutics for really intractable diseases like Parkinson’s, Alzheimer’s, degenerative retinal diseases, and others,” she said. “We all know the pitfalls of drug discovery, however these compounds, because they actually exist in the body in minute amounts and are required for life, may be safer than others, and certainly appear to down-regulate oxidation in vivo. How such compounds would become generally regarded as safe as a dietary supplement is unclear and we will be entering a dialogue with FDA, but the interim goal of helping in some really bad diseases with a new approach is exciting.”
For now, Dr. Clarke and her colleagues are fine-tuning their attention to focus on the safety of these compounds and how they can work to impact the disease process. “There are many other questions … including how regulatory agencies will respond to what amounts to a blurring line between purified beneficial dietary supplements and highly effective new drugs,” she said. “Indeed, FDA has regulated fatty acid as drugs (e.g Lovaza’s purified omega 3 fatty acids) because of their therapeutic claims and drugs (e.g. Niaspan) are now dietary supplements (‘Slo Niacin’). It won’t be boring as we move forward with the development of these products.”
The UCLA research was federally funded by the National Institutes of Health, and is published in the online edition of the journal Free Radical Biology and Medicine. It is also scheduled for publication in a 2011 print edition.