What causes aging? What causes neurodegenerative disorders like Alzheimer’s and Parkinson’s diseases? What can you do to prevent mental decline? These are just a few questions answered by Dr. Stuart Lipton, director of the Center for Neurosciences and Aging at the Burnham Institute for Medical Research, during his Grey Matters lecture at the Natural History Museum. Under the title of “New Drug Treatments and the Future of Stem Cells in the Aging Brain,” Dr. Lipton’s lecture presented an overview of the goals of the Neuroscience Center at the Burnham Institute: to protect the brain by developing neuro-protective drugs and to replace what is lost in the brain by developing new stem cell therapies.
To protect the brain from the detrimental effects of aging and neurodegenerative diseases, scientists have first been investigating the causes of neurodegeneration. It turns out that diseases which cause severe neurodegeneration, such as Alzheimer’s and Parkinson’s disease, may in part reflect events that also occur during normal aging. Dr. Lipton presented the “free radical” theory of aging. He joked, “It’s funny, I was once called a free radical; that was on an Ivy League campus in the early ’70s during the Vietnam War. These are different free radicals.” The free radicals he was referring to in the talk are molecules related to oxygen and nitrogen which are normal products of energy production in the body. Some scientists, such as Dr. Lipton, believe that the accumulation of excess free radicals is one of the major pathways that leads to normal aging. Neurodegenerative diseases, said Dr. Lipton, cause the body to produce more free radicals than normal, leading to nerve damage.
Dr. Lipton went on to discuss ways in which people can reduce the build-up of free radicals, including blueberries, red wine, green tea, hormones, Ibuprofen, extra-virgin olive oil and exercise. Through a combination of some or all of these treatments, it may be possible for people to decrease free radicals in the body and increase lifespan. However, there is not currently enough evidence to provide instructions on exactly what to do.
How do free radicals cause neurodegeneration? Dr. Lipton explained that one characteristic most neurodegenerative diseases share is an excess of mis-folded proteins. Proteins need to fold up into a particular shape in order to function properly. If something causes proteins to lose their shape, they often stop working and clump together into a solid mass. As an example, the heat used when hard-boiling an egg causes proteins in the egg to mis-fold, and then they clump together. Free radicals can cause the same thing to happen to proteins in the brain. These clumps of proteins can then disrupt the function of nerve cells. According to Lipton, “We’ve recently shown that free-radicals can trigger proteins to mis-fold. That enables us to start thinking about different therapeutic strategies to prevent these proteins from mis-folding.”
One therapeutic strategy developed by Lipton involves a drug known as Memantine, which works by turning down the volume of an over-active process that leads to increased free radicals. Unlike many other tested drugs, which cause adverse side-effects because they shut down normal brain activity, Memantine preferentially decreases excessive brain activity that contributes to neurodegeneration, while relatively sparing normal activity. In the words of Lipton, “It only works when you need it to work.” Memantine is the latest treatment available for moderate to severe Alzheimer’s disease (approved by the FDA and marketed in the U.S. under the trade name Namenda). Lipton disclosed that he is the named inventor on patents for the use of Memantine in neurodegenerative disorders, and therefore has a financial interest in the drug, which he developed while at Harvard Medical School.
Even though some drugs, such as Memantine, are available to help prevent neurodegeneration, there will always be cases when prevention is not enough, and it is necessary to repair damaged neurons. For that reason, Lipton is also researching the use of embryonic stem cells to repair damaged tissue. However, much research is needed before stem cells can be used for regenerative medicine. “The trick is, we have to figure out how to make the different cell types and not make a tumor,” said Lipton.
Scientists are just beginning to make progress toward learning that trick. For example, researchers in Lipton’s lab have figured out how to program stem cells to turn into neurons. When injected into a mouse, these cells can grow into correctly functioning neurons and replace some of the cells killed off by a stroke.
Lipton ended the talk with work done in Evan Synder’s lab, another scientist at Burnham. He played a compelling video of a rat that had received a stem cell transplant to treat a spinal cord injury. Before the transplant, the rat could not use its hind legs at all. After the stem cell transplant, the rat was able to walk using its hind legs again. Although the recovery was not 100 percent complete, it was remarkable. Said Lipton, “I think it’s going to become possible, in future years, to harness these treatments, at least if our government allows us to.”
While some progress is being made, a lack of funding is hampering stem cell research. The ban on federal funding imposed by President Bush in 2001 along with lawsuits trying up state funding from the California Institute for Regenerative Medicine both make it very difficult for researchers to find funding for this promising research.
For more information on the Grey Matters Lecture Series, including future lecture dates, visit greymatters.ucsd.edu.