Compounds inherent in berries, pomegranate juice, wine and green tea have all been cited as having the potential to help people live longer and better.

Compounds inherent in berries, pomegranate juice, wine and green tea have all been cited as having the potential to help people live longer and better. New research is revealing how these compounds—called polyphenols—work, not only as anti-oxidants but also in a neuroprotective capacity in the brain. Down the road, this work could lead to new, more directed treatments for neurodegenerative disorders such as Alzheimer’s Disease, amyotrophic lateral sclerosis (Lou Gehrig’s Disease) and Huntington’s Disease. The Power of Polyphenols But how might something like a glass of pomegranate juice help protect the brain? The secret lies in the substance’s polyphenol molecules. Polyphenols are naturally occurring chemical compounds in plants that can be found in significant amounts in the skins of berries, grapes, beans and nuts. For the most part, the health effects of polyphenols, such as reduced risk of cardiovascular disease and cancer, have been chalked up to their anti-oxidant properties. All cells in the human body need to produce energy to function properly. Unfortunately, one effect of this energy production is oxidative stress, or the release of reactive oxygen and free radicals by the cell into the body. These free radicals can interact with other cell proteins and membranes, leading to cell damage. Such oxidative damage has been associated with cancer, Alzheimer’s disease and other neurodegenerative disorders. The body defends itself against the onslaught of oxidative damage with its own production of anti-oxidants. But studies have shown that people who eat a diet rich in fruits and vegetables that also contain anti-oxidants may be better protected against developing heart disease and some types of cancer. “There’s been a lot of work with polyphenols outside of the nervous system showing anti-inflammatory and anti-atherosclerotic effects,” says David Holtzman, a professor of neurology and molecular biology and pharmacology at Washington University in St. Louis. “The reason isn’t entirely clear.” Holtzman argues that these effects may be due polyphenols’ anti-oxidant properties. But he says they also may be activating some type of cell signaling pathways to stimulate protective effects. This signal activation may be mediated by a group of cellular enzymes called sirtuins. The Role of Sirtuins Sirtuins, including the SIR2 gene found in yeast and fruit flies and its mammalian ortholog SIRT1, are enzymes that appear to pace the aging process and to protect neurons in the brain from stress and damage. “SIRT1 is our holy grail,” says Shin-ichiro Imai, an assistant professor of molecular biology and pharmacology who works in a different laboratory at Washington University. “We are hypothesizing that there may be a universal regulator of aging in our body. SIRT1 could be it.” Leonard Guarente, a biology professor at the Massachusetts Institute of Technology who focuses on the molecular basis of aging, says the regulation could be occurring throughout the whole body. “SIRT1 is expressed everywhere, in all tissues, including the brain,” Guarente says. Guarente and his colleagues have found that sirtuins promote stress resistance in cells. His lab works with a polyphenol and sirtuin-activator called resveratrol, found most commonly in grapes and some red wines. They have found that when mice were fed resveratrol as part of a high-calorie diet, they lived longer. Johan Auwerx, a researcher at the Institute of Genetics and Molecular and Cellular Biology in Strasbourg, France, took that finding one step further by observing that SIRT1, activated by resveratrol, helped cells create more mitochondria, their primary source of energy. “When neurons talk to each other, they need energy,” Auwerx says. “Resveratrol improves mitochondria, can bump up energy levels and make better neurons.” But as mitochondria wear out, the cell produces more reactive oxygen and free radicals that could lead to cell damage. Such damage is linked to the cell dysfunction and death observed in disorders such as Huntington’s disease and Alzheimer’s disease. Polyphenols and Neuroprotection Christian Neri, Research Director of the Neuronal Cell Biology and Pathology unit at the University of Paris, studies the pathology of Huntington’s disease, a rare genetic neurodegenerative disorder that leads to cell dysfunction and death. Recently, in a Caenorhabditis elegans worm model of Huntington’s, resveratrol helped the worm’s neurons resist the effects of the disease, caused by the production of a mutant protein. (For more on the Caenorhabditis elegans worm, see “Simple Creatures Provide Intriguing Findings.”) “We believe that resveratrol activated sirtuins which, in turn, activated a protective program in the cells to help resist the Huntington’s protein,” Neri says. Similarly, Jeffrey Milbrandt, a pathology and immunology professor who works in another laboratory at Washington University, recently published a study showing that resveratrol helped activate sirtuins to resist the degeneration of neural axons, often a precursor to neuron death in disorders such as multiple sclerosis, amyotrophic lateral sclerosis (Lou Gehrig’s disease) and Parkinson’s disease. But resveratrol is not the only polyphenol that can impact neuronal health. Holtzman used pomegranate juice, a substance that contains other polyphenol types, in a mouse model of Alzheimer’s disease. His lab found that the pomegranate juice inhibited both the synthesis and buildup of beta-amyloid peptides, which underlie the brain plaques present in Alzheimer’s. But the protection may go even further than that, Holtzman says, by not only stopping the aggregation and accumulation of those plaques but by helping neurons to resist the damage the plaques cause. “The polyphenol may cause nerve cells to stay healthier even with the cell insult,” Holtzman says. Pomegranate juice was also shown to be neuroprotective in a mouse model of hypoxic-ischemic brain injury, or injury caused by lack of oxygen to the brain. Holtzman’s group fed pomegranate juice to pregnant mice and then later subjected the mother’s seven-day-old babies to a controlled lack of oxygen to the brain. They found that those born from mothers who were given the pomegranate juice had more protection from the stroke-like damage that can occur with hypoxia than those whose mothers were not given the polyphenol. “It was pretty protective,” Holtzman says. “What we’re trying to work out now is whether those effects are due to the ability of the juice components to affect cell signaling.” Further studies showed that resveratrol was also protective in this model, as were the simple polyphenol molecules isolated from the natural compounds. The Promise of Treatment Can these findings be applied to effective treatments for neurodegenerative diseases? The possibility has prompted some researchers to participate in commercial ventures; Guarente founded Elixir Pharmaceuticals, while Auwerx and Milbrandt are both intimately involved with Sirtis Pharmaceuticals. Both companies are focused on creating anti-aging and longevity medications using sirtuins as a target. But the researchers stress that their work is still preliminary. “What is promising is not resveratrol, but rather that we’ve identified the sirtuins,” Neri says. “We now have a very interesting target.” People may benefit in a preventive fashion by increasing their consumption of polyphenol-rich foods. But they should not believe too devoutly in such foods, the researchers agree. “In the best of worlds, these types of compounds will improve you to some degree,” Guarente says. “But they are in no way a substitute for a healthy lifestyle.”

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