Substances that plants produce to ward off pests stimulate nerve cells in a way that can protect the brain from diseases such as Alzheimer's and Parkinson's/Mark P. Mattson
The article was published with the approval of Scientific American Israel and the Ort Israel network
Plants cannot escape predators, so they have developed an elaborate system of chemical defenses to keep away insects and other creatures that want to eat them. * The toxic chemicals that plants produce to protect against predators, we consume at low levels by eating vegetables and fruits. Exposure to these substances causes a mild stress reaction that gives resilience to the cells in our body. * Adaptation to these stress responses, in a process called hormesis, is responsible for several health benefits, including the protection against brain disorders provided by eating broccoli and blueberries.
Many people believe that eating fruits and vegetables is important for health because of the antioxidants in them. This claim makes sense
Because in most diseases such as cancer, cardiovascular disease and diabetes, chemicals called free radicals cause cellular damage, and antioxidants neutralize them.
As a neurobiologist trying to understand what went wrong in the brain, I have long been aware that free radicals do disrupt and sometimes even kill nerve cells. I also know that people who regularly consume vegetables, fruits and other plant products, which are considered to have high levels of antioxidants, tend to suffer less from neurodegenerative diseases. But the story of antioxidants is not so simple.
And indeed, in rigorously conducted controlled experiments on humans and animals, antioxidants such as vitamin C, E and A have failed in trying to prevent disease or improve the condition of patients. So how do fruits and vegetables improve health?
The answer that emerges is related to the methods that plants have developed over millions of years of evolution to protect themselves from pests. Plants produce bitter-tasting substances that act as pesticides. When we consume plant-based food, we also receive low levels of these toxic substances that cause moderate stress to the body's cells, such as that caused by sports activity or prolonged fasting. The cells do not die, in fact they only get stronger because their response to stress increases their ability to adapt to more difficult conditions. This process of gradually increasing the ability of cellular recovery is called hormesis, and many studies indicate that this process is responsible for the health benefits of consuming fruits and vegetables. Understanding hormesis could even provide new ways to prevent or treat some of the most devastating brain diseases, including Alzheimer's, Parkinson's and stroke.
Aka is a good thing
My colleague and I collected some of the data on hormesis after coming to the subject somewhat indirectly. In the early 90s, while we were at the Sanders-Brown Center on Aging at the University of Kentucky, my team began investigating whether Alzheimer's disease could be treated with antioxidants. We thought they could help because we saw that beta-amyloid, the deadly protein that accumulates excessively in the brains of Alzheimer's patients, makes names in brain cells in culture and we knew that free radicals participate in the destruction process. Unfortunately for us, when we tested the effect of high levels of antioxidants in Alzheimer's patients in clinical trials at various medical centers conducted by Douglas R. Glasgow and Paul Eisen, both from the University of California, San Diego, we found no benefit. So we turned our efforts to what appeared to be another problem that fortunately helped us develop a new hypothesis about why plant foods are good for the brain.
We and others have noticed that people who exercise regularly, consume relatively few calories and experience a variety of intellectual challenges tend to maintain higher brain activity than those whose lifestyle is the opposite. These people are less likely to have Alzheimer's, Parkinson's or stroke. We wondered if diet, sports and intellectual activity influence brain activity and the risk of illness through the same molecular processes.
Our first study, conducted in 1999 by Ondora Bruce-Keller, then a post-doctoral student in my laboratory and now a professor at the Pennington Center for Biomedical Research at the University of Louisiana, revealed that nerve cells in the brains of rats that were intermittently fasting, day and night, were resistant to neurotoxins (neurotoxins). which are known to cause symptoms that mimic falling disease and Huntington's disease, compared to rats that ate normally and were harmed by the toxic substances. Shortly thereafter, I began my role as head of the neurobiology department at the National Institute for Aging Research, where we found that intermittent fasting protects the brains of animals in models of Alzheimer's, Parkinson's, and stroke.
When we tried to understand why starvation is good for the brain, it became clear to us that nerve cells respond to starvation by moving molecules that protect against free radicals and against the accumulation of beta-amyloid. The defense system involves the production of proteins known as neurotrophic factors, such as BNDF, which are essential for the survival of nerve cells, as well as the production of proteins that encourage efficient use of energy and prevent the accumulation of damaged molecules.
From an evolutionary perspective, the fact that intermittent fasting can be beneficial is not at all surprising. Fasting creates a moderate stress that puts the brain in a state where the protection of the nerve cells is extremely essential, a state that allows the animal to operate at a high level and obtain food even when its supply is limited and the animal has to invest a lot of energy to find it.
Our interest in the beneficial effect of stress on brain cells led us, in the end, to look for the neurological effects of plants in the diet. We were intrigued by articles from the 70s that a neurotoxin found in algae, called kainic acid, could cause overactivation of receptors on the surface of brain cells. These receptors bind glutamate, the main signaling molecule that activates nerve cells.
Researchers from our group and others have already shown the paradoxical effect of glutamate in intermittent fasting and sports activity. Excessive stimulation of the receptors may damage or destroy nerve cells. But their milder activity activates a chemical pathway in the nerve cells that has a role in learning, memory and protecting the nerve cells. Such discoveries raise the question of whether low levels of neurotoxins in vegetables and fruits could produce a beneficial health effect by inducing a similar mild stress on brain cells.
"danger! Will Robinson!”
The health benefits of fruits and vegetables are a byproduct of eons of wars that plants wage against creatures that want to eat them, mainly insects. In the course of an evolutionary history of hundreds of millions of years, plants developed ways that allowed them to survive as individuals or species and not become extinct. One way is the production of natural pesticides.
These substances usually don't kill insects: the plant doesn't care if its predator dies, all it wants is for it to go away and never come back. One common way plants repel pests is by targeting the insect's nervous system. The plants produce chemicals that act on the sensilla, nerve cells found in the mouthparts of the insect and similar to the taste buds in the human tongue. These cells send signals to the brain that decides whether to eat that plant or not.
Although insects are the biggest threat to plants, our primitive primate ancestors also looked for ways to feed on roots, leaves and fruits that they found in the tropical forests where they lived. Although plants have become a source of food and medicine, they can cause nausea, vomiting or even death.
In order to adapt, our body has developed a sophisticated warning system, reminiscent of the behavior of a character in the old TV series "Lost in Space", which told about the adventures of nine-year-old Will Robinson and his family who traveled through distant solar systems. When the Robinsons landed on a distant planet and surveyed the area around their spaceship, their traveling companion, a sophisticated robot, warned them of possible dangers. In an episode broadcast in 1968 called "The Great Revolt of the Plants" the robot warned them of the threat of deadly plants.
Just like the robot, our warning system alerts our brain to the presence of toxic substances. The bitter taste of many plants is a warning not to eat too much of the bitter leaves, roots and fruits or simply to avoid them. There seems to be some innate justification, after all, for children who refuse to eat broccoli. To the insects, the toxic chemicals are told to go away and to us they tell us to consume less.
Traditional healers learned through trial and error, which was sometimes fatal, that some of the plants have important medicinal properties. Pharmacists, biochemists, and toxicologists now confirm that toxic plant chemicals can be hormetic, that is, health-beneficial in small amounts.
When the effect of hormesis-inducing substances is measured as a function of dose, and the results are plotted on a graph, a result is obtained that scientists call a two-step response curve: the curve looks like an inverted U. At low doses, the effect line rises indicating that eating a small or moderate amount of plant chemicals confers a health benefit. But at higher doses, the line gradually decreases and indicates that as the amount of substances consumed increases, so does the toxicity. Excessive eating of Brazil nuts can poison the liver and lungs due to the presence of tiny amounts of the element selenium. But eating a few nuts provides an essential ingredient that binds to an enzyme that helps protect the body from heart disease and cancer. This example clarifies how hormesis works and distinguishes it from homeopathy, which claims, without any valid evidence or conceivable mechanism, that small to non-existent amounts of the cause of the disease can cure it.
It appears that chemicals that induce responses characterized by hormesis, meaning just the right amount or not too much, are common in the plant world. Edward G. Calabrese, a toxicologist at the University of Massachusetts at Amherst, has devoted much of his career to identifying chemicals responsible for hormesis. He meticulously analyzed over 30 years more than 10,000 published studies in the fields of biology, medicine and toxicology. Among the substances he found are caffeine, opioids and other compounds that affect the brain. Calabrese founded a scientific society and journal specialized in the study of hormesis. Due to our common interest in the question of how a response to different types of stress was formed during evolution in cells and organisms and how this is important for human health, Calabris and I edited a book on the subject together.
Some researchers are now reevaluating early experiments that suggested the role of antioxidants in fruits and vegetables in protecting the brain and overall health. They are now testing whether hormesis is responsible for the positive results reported in the studies. This test and other works confirm that cellulose extracts infused with plant chemicals can complement the contribution of antioxidants and even overshadow them. This does not mean that antioxidants are completely out of the picture. It is possible that biochemical processes activated by hormetic stress control brain cells' use of antioxidants when they are available.
One example of this new line of research came from Gregory M. Cole, a neurobiologist at the University of California, Los Angeles, who more than ten years ago used one of curry's ingredients, curcumin, to conduct an experiment that he believed could lead to the treatment of Alzheimer's. When we gave curcumin to mice genetically engineered to develop Alzheimer's symptoms, it was found that free radicals damaged their brain cells less and that the cells accumulated less beta-amyloid. Later experiments conducted in my laboratory and conducted by others showed that curcumin actually causes a mild spasm in brain cells. This stress stimulates the production of antioxidant enzymes that eliminate free radicals and prevent the accumulation of toxic proteins. The health benefit of curcumin in the brain is wide-ranging. Studies done with curcumin in other animals suggest that it can reduce the damage caused by a stroke and can even alleviate conditions of depression and anxiety.
Still, other curry ingredients can benefit this organ, which is located inside the skull and weighs a pound and a half. Garlic and hot pepper, for example, both contain a chemical that opens a channel in the outer membrane of nerve cells that allows calcium ions to enter. The opening of such channels causes the electrical activity in the nerve cells to increase, which in animal models seems to protect the cells from the overactivity that occurs in a stroke. In people who live in countries where it is customary to consume garlic and hot pepper, excellent brain activity is measured even in aging, although it is still to be ascertained whether the chemicals in the plants are responsible for it or other aspects of the diet or lifestyle.
In all these studies it seems that hormesis comes into play, and this insight creates a complex and complicated picture of the interplay between free radicals and antioxidants. Curcumin does not work directly in neutralizing free radicals, but calls on enzymes and other reserve units to protect the cell against the harmful radicals. This timed process may explain why antioxidant supplementation is often ineffective or even harmful.
Loading additives on the body can inhibit the natural stress response throughout the body. In a study conducted in 2009 by researchers at the Friedrich Schiller University in Vienna, Germany, and their colleagues, it was found that in tests done a month after a group of people engaged in sports and took antioxidants, there was no improvement in blood glucose regulation and other health markers. In contrast, in people who were only involved in sports, there was an improvement. This means that in fact antioxidant supplements thwart the effect of sports by interfering with hormesis.
Now the biochemical pathways that strengthen the body's resistance to plant chemicals are becoming clear. One of them includes two proteins called Nrf2 and Keap1, which are normally associated with each other in the cytoplasm, the area of the cell outside the nucleus. When these proteins are exposed to plant chemicals such as curcumin or sulforaphane found in broccoli, Keap1 releases Nrf2 which moves to the cell nucleus. In the nucleus it activates genes that contain the code to produce enzymes that eliminate free radicals. Sulfuraphane stimulates the Nrf2 pathway that removes excess free radicals from the body. In a petri dish, it can protect vision cells from damage from ultraviolet radiation that causes macular degeneration.
This connection between plant chemicals and the Nrf2 pathway also motivated my work. About seven years ago, I came across a book entitled: "Insect Antifeedants" (insecticides in plants) by Upender Kool, an Indian scientist and expert in natural insecticides produced in plants. Cole cataloged more than 800 chemicals that have been isolated from plants and prevent insects from eating them. My lab obtained 50 such insecticidal chemicals and tested their ability to activate one or more pathways that signal stress adaptation in cultured neurons. Some chemicals that activate the Nrf2 pathway and exhibit a two-step hormesis response curve. The chemical plumbagin found in a type of tropical flower and black walnut was particularly effective. We found that plumbagin was very effective in reducing brain damage in stroke and improved the outlook for recovery in stroke model mice. The next step I and others are planning is to test chemicals such as sulforaphane and plumbagin, which protect the nerves, in sick humans.
Another important cellular defense involves a family of proteins called sirtuins. Leonard Guaranta from the Massachusetts Institute of Technology (MIT) found that one of the sirtuins, SIRT1, extends life span in yeast and plays a central role in extending life span by restricting calorie intake. Resveratrol, found in red grapes and wine, apparently activates SIRT1, which in turn activates many chemical pathways that mediate the creation of hormesis. In animal experiments, resveratrol protects the brain and spinal cord from damage that results from the cessation of blood flow that occurs in some types of stroke. Not all studies are uniformly positive. Scientists have yet to determine whether one of the pathways activated by resveratrol may actually accelerate the death of some nerve cells.
Other studies, which expanded the picture, show that the benefit a cell can derive from a stress response depends on the timing of the response. Just as vigorous sports, another source of hormetic effects, should be accompanied by periods of rest necessary for cell growth and cell repair, so too, presumably, should rest be made after consuming plant chemicals. When fruits and vegetables are consumed, the body enters a state known as stress resistance, characterized by a general decrease in the construction of new proteins, compared to an increase in the removal of damaged molecules and the production of proteins that are necessary for cell survival.
Cells can last in this state only until they are needed to create new proteins for another purpose, so that they do not enter a state of overstretching and begin to deteriorate. When the stress is over, the cell increases protein production, it grows and repairs damaged molecules. In the case of nerve cells, new intercellular connections can be formed during recovery. The findings suggest that the consumption of fruits and vegetables and the adoption of a sports regimen, when accompanied by a period of rest, can stimulate the production of new nerve cells from stem cells located in the hippocampus, a structure located deep in the brain. The new nerve cells that grow and form connections with existing nerve cells, effectively increase the ability to learn and remember. In fact, a good night's sleep is enough to cause the cells to recover from strenuous sports activity or exposure to plant chemicals consumed during the day.
A possible remedy from Uwhangchungsimwon
Hormesis can pave the way for the search for new drugs and explain the mechanism of some already approved drugs. Snowdrops and snowdrops produce galantamine, a chemical that can improve memory by increasing the levels of acetylcholine, a substance whose molecules are responsible for signaling at synapses, the points of contact between nerve cells. Galantamine, now an approved drug that has a mild effect on Alzheimer's symptoms, creates a mild tension in nerve cells that likely protects them from neurodegeneration and improves their ability to use chemical and electrical signals to communicate with other nerve cells.
A clue to new drugs can come from the theory of medicinal plants. A substance known as uzwhangchungsimwon, which is used in Korean herbal medicine to treat stroke, may protect nerve cells by inducing a stress response that results in the formation of proteins such as Bcl-xl that protect the cells from death. Hallucinogenic plant chemicals can also come into play. When given in moderate doses in a controlled medical setting, they seem promising for the treatment of anxiety, depression and drug addiction.
The idea of hormesis has not escaped controversy. Some researchers question whether scientists have developed adequate methods to distinguish when exactly the beneficial effect ends and the poisoning begins. The exact threshold at which a toxic reaction begins can vary from person to person, making it difficult to use hormesis as a basis for drug therapy. Doubts also arise about expanding the term to include ionizing radiation, such as X-rays, low levels of which have been shown to have a beneficial effect in laboratory animals. However, scientific advisory bodies disallowed the use of radiation in humans even at the lowest levels.
Evaluating the potential health benefit of hormesis requires controlled and careful clinical trials because many herbs are marketed with claims of unproven efficacy. The US National Center for Complementary and Integrative Medicine was founded in 1998, in part to help fund research into such compounds.
These challenges will not stop further experiments in hormesis. Plant chemicals that induce cellular stress may have an advantage over traditional drugs that cause side effects that interfere with the normal activity of nerve cells. Diazepam (Valium) acts on brain cells in a way that prevents anxiety but causes drowsiness. The drug turns off a neural circuit and it stays off until the effect of the drug wears off. At the right dose, drugs that rely on hormesis do not adversely affect neural activity, so it is expected that their use will have fewer side effects.
Several laboratories, including my own, are engaged in the development of hormetic drugs and we have received encouraging results in animals that have undergone genetic engineering to mimic some degenerative diseases of the nervous system in humans. Preliminary studies show that these drugs protect nerve cells from death and increase their resistance to the attack of free radicals and molecular damage that wreaks havoc on the brain. It is possible that apple peel, walnuts and curry powder will be the raw materials for a new generation, fundamentally different, for the treatment of brain diseases.
About the writers
sa0715Matt02
Mark P. Matteson
Head of the Neurobiology Laboratory at the US National Institute on Aging, and Professor of Neurobiology at the Johns Hopkins University School of Medicine. His discoveries advanced the understanding of neural circuits during aging.
One response