Arches. Photo by Daniel Chia
Jun
26
2010

Dietary Restriction

stress

essential

Judging from common phrases like “breakfast is the most important meal of the day”, “people should eat whenever they are hungry”, and the recently popular “eat five small meals per day instead of three large ones,” public opinion seems to run against going hungry even for short periods of time. However, current research suggests that moderate hunger may actually be healthy. Scientists studying rats and mice on so-called “dietary restriction” have found that these rodents rank significantly better on various measures of health than their counterparts who are fed a more abundant diet.

In addition to studying dietary restriction (DR) in normal rats, scientists have also studied DR in “rodent models” for various neurodegenerative diseases, such as Huntington’s disease (HD), Alzheimer’s disease, and Parkinson’s disease. (In rodent models, researchers either mimic the effects of a given disease via chemicals, or use genetics to actually breed the rodents to manifest an animal form of the disorder.) Here, too, research has demonstrated beneficial effects of dietary restriction: rodent models fed on a dietary restriction system show significant relief from various disease symptoms in comparison to normally fed rodent models. Although more research is needed into the effects of DR on humans, this research suggests the possibility that “cutting back” slightly on traditional daily eating routines could be a benefit to one’s health, especially for people with certain neurodegenerative diseases including HD.

What is meant by dietary restriction? Why is it helpful in rodents? What kinds of things might it do for a person who has HD? This chapter seeks to answer these and other questions, discussing a wide array of topics surrounding the issue of dietary restriction.

The Two Different Types of Dietary Restriction^

The rodents in dietary restriction (DR) studies may be subjected to one of the following dietary restriction schemes: intermittent fasting or daily caloric reduction. (Despite the differences between these two types of dietary restriction, it is important to note from the start that they both maintain a steady intake of vitamins and minerals.) In daily caloric reduction, rodents are fed on a normal, daily schedule, but are fed approximately 50-70% of the calories in the normal lab diet of that species of rodent. In intermittent fasting, rodents are typically placed on an alternating schedule: one day they will fast, then the next day they will be fed. The net number of calories varies, though, for rodents on intermittent fasting. A few rodents will eat a “double meal” on the day they are fed, thus bringing a two-day total (one day fasting, one day eating) to 100% of their normal caloric intake. However, most of the time when intermittent fasting rodents are fed, they will eat roughly what a normal lab rodent eats when fed every day—thus bringing a two-day total to somewhere around 50% of the normal caloric intake. So, the final outcome is similar by either DR scheme: whether through daily caloric reduction or intermittent fasting, mice and rats generally end up with a net reduction in their daily caloric intake.

Interestingly, both forms of DR have been shown to have positive health benefits for rodents. For instance, one study showed that rodents in either DR scheme exhibited “anti-aging” changes (these changes included reduced body temperature and decreased blood glucose and insulin levels). In addition, both types of DR have been shown to have positive effects on the brain (both were shown to combat oxidative stress on proteins and DNA in nerve cells) and to extend rodent life spans. While these results clearly indicate that both types of DR can be quite beneficial, one study suggests that intermittent fasting is more effective at increasing the expression of certain proteins that are very helpful to maintaining the health of nerve cells (these proteins will be described in more detail in the following sections).

How do these two different dietary restriction schemes in rodents correspond to human dietary restriction? Unfortunately, the exact answer to this question has not yet been determined. Some researchers suggest that having a daily intake of 1800-2200 calories (for a moderately active adult) can significantly reduce the risk of age-related neurological disorders like stroke, Alzheimer’s disease, and Parkinson’s disease. (Note: Because HD is passed on in the genes, dietary restriction does not reduce the risk of being genetically predisposed to HD. However, as the rest of this chapter will discuss, research suggests that DR may combat the HD disease process and thus potentially slow down symptom progression.) Other researchers shy away from suggesting an actual number of daily calories, but rather encourage a “low” daily calorie intake (meaning enough calories to fuel all of the functions of the body’s cells, but little or no excess). Still other researchers suggest that foregoing one or two meals per day may be an alternative to reducing the size of each meal. Thus, the lack of a definitive answer to how the rodent research applies to humans should serve as an important disclaimer: one should eat sensibly and not do anything rash like following the rodent studies directly (for instance, researchers warn against the idea of fasting every other day, as was done in some of the rodent trials).

An Evolutionary Explanation for Why Dietary Restriction is Effective^

Despite the fact that it runs counter to some popular beliefs, the concept behind dietary restriction is quite logical. Over the course of human history, access to food was anything but constant, owing to seasonal changes, drought, climate change, migration, etc. Because of a frequent lack of food, the body’s cells evolved mechanisms to cope with the stress that resulted from not having a steady abundance of energy. In fact, over thousands of years, this inconsistent diet actually shaped cellular metabolism, tailoring it to break down food in a way that accounted for the very long time lag between meals. Nowadays, when searching for food is as simple as walking to the grocery store, our frequent and relatively steady intake of food may actually overwhelm our cellular metabolism. The result is that mitochondria, the energy factories of our cells, may begin to produce harmful by-products like free radicals, which can contribute to the degradation and destruction of our cells over time (this can happen in the cells of any person, not simply those with neurological diseases). Thus, one way to think about the link between dietary restriction and healthy cells is that DR allows our cells to metabolize food in manageable amounts, in a manner that is in line with how evolution has programmed the cells’ metabolic machinery to function.

How HD Kills Nerve Cells and How Dietary Restriction Combats It^

Although scientists are uncertain about the exact cause of nerve cell death in HD, they believe that four different harmful phenomena are involved. These phenomena – impaired energy metabolism, oxidative stress, excitotoxicity, and apoptosis – are each believed to be somehow evoked by processes that the mutant huntingtin protein sets in motion. (For background information on the Huntington gene and huntingtin protein, click here.) The exciting news about dietary restriction is that it was shown in rodent studies to be capable of combating all four phenomena, increasing the health and the life span of these nerve cells (and in turn having beneficial effects on disease symptoms, which will be discussed in a later section).

The disease-fighting effects of dietary restriction appear to be the result of its ability to mildly stress the body’s cells. This manipulation encourages cells to produce two special types of proteins that help cells cope with stress: neurotrophic factors and protein chaperones (for more on these proteins, click here and here, respectively). More specifically, brain-derived neurotrophic factor (BDNF) and two protein chaperones known as HSP-70 and GRP-78 appear to play a very large role in opposing the effects of HD on nerve cells. In order to understand how dietary restriction promotes the health of nerve cells, let’s look at each of the four phenomena involved in the degeneration of nerve cells in HD and ask, How do neurotrophic factors and protein chaperones combat their effects?

Impaired Energy Metabolism^

When thinking about cells and metabolism, the first word that comes to mind is mitochondria (singular: mitochondrion), the energy factories of cells. Mitochondria are responsible for using food to make the majority of our cells’ ATP, which is the chemical fuel that our cells’ proteins use to perform their life-sustaining functions. In addition, mitochondria play a key role in maintaining a certain balance of calcium in cells, which is critical to cell survival. Through an unknown mechanism, huntingtin proteins in the nerve cells of people who have HD cause a great deal of problems for mitochondria, interfering with their ability to produce adequate energy and maintain normal calcium levels. (In addition, mitochondria produce dangerous numbers of free radicals, which will be discussed under “Oxidative Stress” below). It is believed that these effects on the cell may play a strong role in the onset of HD, as well as the disease’s progression.

In rodent models of neurodegenerative diseases, the helpful neurotrophic factor BDNF has the ability to increase nerve cells’ resistance to the stress that chemicals put on mitochondria. Two protein chaperones called HSP-70 and GRP-78 are also helpful: they (as well as BDNF) have been shown to stabilize cellular calcium levels. The levels of BDNF, HSP-70, and GRP-78 are all increased in the cells of those rodents in the dietary restriction regimen (in comparison to the normally fed rodents). Thus, these proteins appear to explain why dietary restriction preserves the function of mitochondria. Furthermore, normal mitochondrial function leads to the maintenance of relatively normal levels of ATP production and a safe balance of calcium in cells (as well as reducing the generation of harmful free radicals). This makes cells a lot more resistant to the degeneration that is caused by HD.

Oxidative stress^

In addition to the problems with ATP production and calcium levels that arise when mitochondria are harmed in HD, another major problem arises as well: excessive production of free radicals. It is actually normal for mitochondria to produce some small number of free radicals. However, in HD, the production of free radicals is significantly increased. Over time, this increase of free radicals leads to oxidative stress, which is very harmful to cells and plays a strong role in nerve cell degeneration.

In rodent models of neurodegenerative disorders, where the rodents are given chemicals to elicit oxidative stress in cells, BDNF and HSP-70 are able to increase nerve cell resistance to such stress. It is believed that these proteins induce the production of antioxidant enzymes in order to combat the oxidative stress. Since dietary restriction increases the levels of these proteins, it is not surprising that the number of free radicals in the cells of dietary restriction rats was significantly less than that of normally fed rats. Through the stimulation of BDNF and HSP-70 (and likely other proteins that play a part), dietary restriction suppresses free radical production by a significant amount, thus reducing oxidative stress and making cells much healthier.

Excitotoxicity^

Nerve cells communicate with one another using certain chemicals called neurotransmitters. Typically, the message that is communicated between “sender nerve cell” and “receiver nerve cell” is encoded by two different things: the type of neurotransmitter that is released and how much of this neurotransmitter is released (another aspect of communication – the type of receptors on the receiver neuron – is also involved, but this topic is beyond the scope of this discussion). When a sender nerve cell overstimulates a receiver nerve cell by consistently sending too much neurotransmitter, the receiver nerve cell becomes damaged and may ultimately die. This overstimulation resulting in nerve cell harm is known as excitotoxicity. Scientists believe that excitotoxicity may take place due to certain events: after a stroke, after trauma to the central nervous system (for instance, after a car accident), or during the course of a neurodegenerative disease like HD.

With regard to neurodegenerative diseases, two very important compounds can influence a nerve cell’s vulnerability to excitotoxicity: glutamate and glucose. Glucose is a sugar that is involved in many cellular processes, one of which is to allow nerve cells to adequately send and receive glutamate. Glutamate is a neurotransmitter and is typically the culprit in excitotoxicity. Thus, efficient transport of these two compounds across cell membranes is essential to not only making nerve cell communication effective, but also to protecting nerve cells against excitotoxicity. Indeed, in rodent models of neurodegenerative diseases, chemicals that impaired glucose and glutamate uptake by nerve cells were believed to make the cells more vulnerable to excitotoxicity and degeneration.

Dietary restriction is beneficial in combating this method of cellular degradation because it decreases the impact of the chemicals that impair glucose and glutamate uptake. The result of this action is that levels of glucose and glutamate transport remain closer to normal, resulting in a decreased vulnerability to excitotoxicity. In addition to their other beneficial effects in cells, BDNF and HSP-70 appear again to be the heroes in protecting nerve cells against excitotoxicity (although it is quite possible that other proteins induced by dietary restriction also play a role in protecting against this phenomenon).

Apoptosis^

Apoptosis means “programmed cell death;” it is a mechanism by which a cell can lead to its own destruction. In the development of human brain (and the brains of other animals), apoptosis is frequently used to get rid of nerve cells that are unhealthy or improperly placed and allow for better-suited nerve cells to thrive. In this regard, apoptosis is a very natural event. However, the huntingtin protein in people who have HD can start a cascade of events that leads to apoptosis in otherwise perfectly good cells. Thus, in HD, apoptosis is not only one of the mechanisms by which the disease can degrade nerve cells, but it is often the thing that ultimately kills nerve cells (with impaired energy metabolism, oxidative stress, and excitotoxicity being contributors to a cell’s vulnerability to apoptosis).

As indicated by the fact that they are much more prevalent in nerve cells of mice with HD than mice without the disease, one of the key components in the apoptosis cascade in HD cells appears to be a group of proteins known as caspases. This is where dietary restriction comes into play: in nerve cells from HD mice fed normally, there was a significantly greater amount of caspase-1 (one of the caspase proteins) than in nerve cells from HD mice fed according to the dietary restriction regimen. BDNF, produced in large quantities in rodents on dietary restriction, induces the expression of certain “anti-apoptotic” proteins (specifically, Bcl-2 proteins), which most likely accounts for these effects. Thus, dietary restriction’s ability to interfere with the programmed cell death of nerve cells allows these nerve cells to stay alive and perform their physiological functions for a longer period of time. (For more on caspases, click here.)

How Dietary Restriction Reduces Huntingtin Protein Aggregation^

Although impaired energy metabolism, oxidative stress, excitotoxicity, and apoptosis are the phenomena that actually degrade nerve cells, the more fundamental issue in nerve cells of people with HD is huntingtin protein aggregation. Despite the fact that recent research has dispelled the idea that mutant huntingtin aggregates directly cause nerve cell death, scientists believe that they may have potentially critical indirect effects on the disease process. For instance, researchers have found a correlation between increased aggregation of huntingtin and nerve cell death via apoptosis (click here for more information on correlation and causation). Thus, the neuronal inclusions composed of huntingtin proteins (and other proteins that huntingtin captures) are a truly important aspect of HD. This is why, in addition to its other tremendous benefits, another beneficial effect of dietary restriction is its ability to decrease the number of neuronal inclusions in nerve cells.

The way that dietary restriction reduces neuronal inclusions may be through the initiation of a process called autophagy, which captures the huntingtin protein aggregates and disposes of them. But DR’s initiation of autophagy is somewhat complex. As mentioned previously in the section about excitotoxicity, glucose is a very important compound and its transport into cells of people with HD is somehow hindered. (In fact, because of this difficulty of moving glucose from the blood into cells, many people with HD suffer from a condition called hyperglycemia, which means that their blood sugar is too high.) Dietary restriction (through the induction of BDNF and HSP-70) improves the transport of glucose into cells. The presence of higher amounts of glucose in cells has been shown to decrease the activity of a protein called mTOR, which is a negative regulator of autophagy. Thus, by decreasing mTOR’s activity, the cell’s high glucose concentrations effectively “release the brake” on autophagy, allowing it to do its job of clearing huntingtin aggregates from the cell. This process is summarized in the schematic below:

DR -> BDNF + HSP-70 -> improved glucose transport -> less mTOR activity -> more autophagy -> more huntingtin aggregates cleared from cell

(Interestingly, in addition to this long process of reducing neuronal inclusions, a much shorter mechanism accomplishes the same task: HSP-70, which is produced in large quantities in dietary restriction, has been shown to directly interact with the mutant huntingtin protein and thus reduce the number of aggregates in cells.)

The reduction of aggregates is positively correlated with reducing cell death. Clearly, this is a very positive result for individuals with HD because the more nerve cells that survive, the better.

The Effects of Dietary Restriction on the Onset and Progression of HD^

As explained in the previous two sections, dietary restriction has a wonderful ability to combat nerve cell degeneration in rodent models of HD. Since the disease is characterized by its ability to kill nerve cells (and thus lead to the recognizable symptoms of the disorder), it is quite logical to expect that by combating nerve cell degeneration, dietary restriction would delay the onset of disease symptoms and slow the progression of HD. Indeed, this has been the case in rodent models of the disease. In a study of mice with HD, at age 8 weeks these mice were split into two groups, one that was fed according to a dietary restriction regimen and the other that was fed normally. In comparison to normally fed mice, the onset of behavioral symptoms of HD in the dietary restriction mice was delayed by an average of 12 days. With regard to survival times, by age 21 weeks, all of the normally fed mice had died, while only 40% of the dietary restriction mice had died. On average, the dietary restriction regimen increased survival time by about 2 weeks. Considering the short life of mice (which is approximately 2-3 years for normal mice, and even shorter for mice with HD), 12 days and 2 weeks are relatively long lengths of time, which indicates that dietary restriction has a profound effect on delaying symptom onset and increasing the survival time of those individuals with HD.

The Effects of Dietary Restriction on the Symptoms of HD^

In addition to increasing the survival time of individuals with HD and delaying the symptoms of the disease, dietary restriction also has been shown to significantly reduce the severity of HD symptoms. In order to understand how dietary restriction accomplishes this task, let us discuss the disease symptoms in the context of the parts of the body with which they are associated.

Not every nerve cell in the body is affected by HD; only those nerve cells in the basal ganglia (especially the striatum) and the cerebral cortex are degenerated by the disease. The basal ganglia play a strong role in the brain’s regulation of motion (for more information about the neurobiology behind HD, click here). Or, if you’d like to see a general overview of the brain and its parts, click here). Thus, since nerve cells in the basal ganglia of dietary restriction rodents showed increased resistance to degeneration (due to the processes described in section 3), we can now understand why these rodents showed significant improvements in their motor performance in comparison to normally fed rodents. Indeed, by promoting the health and survival of nerve cells in the basal ganglia, dietary restriction allows these cells to perform their normal duties, which results in relatively strong motor performance despite having HD.

The cerebral cortex also plays a role in regulating the body’s movements, often working with the basal ganglia to perform this task. In addition, the cerebral cortex is involved in many other functions, such as cognitive tasks (like learning and memory) and emotional tasks. In HD mice, brain atrophy (the wasting away of nerve cells after they die) results in the thinning of the cerebral cortex. However, one study showed that the atrophy in dietary restriction rats was much less significant in comparison to normally fed rats, a fact that is explained by dietary restriction’s ability to combat the disease process and keep nerve cells alive. Although the HD researchers performing this study did not make a direct link between the reduced brain atrophy and the cognitive and emotional symptoms of HD, some other research on aging suggests that this reduced atrophy may help HD symptoms as well. These aging studies indicate that dietary restriction rodents perform better than normally fed rodents on learning and memory tasks as they age (the aging process is thought to partially damage nerve cells, albeit to a far less degree than neurodegenerative diseases do). Thus, although learning and memory alterations are not specifically linked to HD, it is possible that other cognitive (and perhaps even emotional) tasks that are related to HD may also be improved by dietary restriction. (However, regardless of whether or not this turns out to be true, surely everyone would welcome improvements in learning and memory!)

Aside from neurological symptoms of HD, one ailment that people with HD often have is hyperglycemia, a dangerous condition involving high blood sugar. By helping to improve the transport of glucose in cells (which is described above in the section on “Excitotoxicity”), dietary restriction helps to normalize blood sugar levels and take away the hyperglycemia.

Finally, the last non-neurological symptom of HD that we will discuss is weight loss. Since we typically associate eating more calories with gaining more weight, one study of HD mice produced a seemingly paradoxical result: mice who practiced dietary restriction actually lost less weight than those who were fed normally! However, if one looks at the typical story of humans who have HD, these results are not so perplexing after all: despite eating more and more calories each day, people with HD often find that they still cannot combat their progressive weight loss. Thus, perhaps the weight loss in HD is not an issue of calories, but instead an issue of tissue “wasting” (that is to say, large amounts of cell death). As illustrated in section 3, dietary restriction is able to combat the disease process, thus allowing cells to be healthy and survive for a far greater amount of time. The more tissue that remains healthy, the less weight will be lost. Thus, one can solve the problem of HD-induced weight loss by actually eating less instead of more.

The Use of Drug Therapy in Place of Dietary Restriction^

In some of the rodent studies mentioned in the sections above, a substance called 2-deoxy-D-glucose (abbreviated “2-DG” or “2DOG”) was shown to produce levels of HSP-70 and GPR-78 that were similar to those produced by dietary restriction. In addition, 2-DG was shown to be even more effective at inducing autophagy and decreasing huntingtin protein aggregation than a high level of glucose in cells. These results indicate that the helpful effects of dietary restriction on cells may also be obtainable through the use of a dietary supplement like 2-DG. However, scientists have not yet determined whether or not long-term use of 2-DG might lead to harmful side effects. More research is necessary to determine whether or not the use of a supplement like 2-DG for an extended period of time is safe.

Important Cautionary Note^

The rodent research on dietary restriction has produced encouraging results for combating Huntington’s disease. However, as mentioned in the first section, exactly how the rodent research translates into dietary restriction recommendations for people is not yet clear. Thus, rather than starting a dietary restriction regimen on one’s own, we at HOPES urge people to first consult their physician to see if dietary restriction might be safe and effective for them.

Seeing as weight loss is a dangerous symptom of HD, dietary restriction is unlikely to be a helpful strategy for patients with the disease.

For further reading^

  1. Duan W, Guo Z, Jiang H, Ware M, Li XJ, Mattson MP. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2911-6. Epub 2003 Feb 14. PMID: 12589027 [PubMed - indexed for MEDLINE]
    A technical paper that illustrates the many beneficial effects of dietary on combatting the symptoms of HD. Covers the topic from many levels, including cell biology, neuroanatomy, and physiology.
  2. Guo Z, Ersoz A, Butterfield DA, Mattson MP. Beneficial effects of dietary restriction on cerebral cortical synaptic terminals: preservation of glucose and glutamate transport and mitochondrial function after exposure to amyloid beta-peptide, iron, and 3-nitropropionic acid. J Neurochem. 2000 Jul;75(1):314-20. PMID: 10854276 [PubMed - indexed for MEDLINE]
    A technical paper about the effects of HSP-70 and GRP-78 on combating neurodegeneration in HD (as well as Parkinson’s disease and Alzheimer’s disease).
  3. Mattson MP, Duan W, Guo Z. Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms. J Neurochem. 2003 Feb;84(3):417-31. Review. PMID: 12558961 [PubMed - indexed for MEDLINE]
    A technical paper that provides an overview of dietary restriction’s ability to induce the production of proteins like neurotrophic factors and protein chaperones. Also discusses how these proteins combat neurodegeneration.
  4. Ravikumar B, Stewart A, Kita H, Kato K, Duden R, Rubinsztein DC. Raised intracellular glucose concentrations reduce aggregation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy. Hum Mol Genet. 2003 May 1;12(9):985-94. PMID: 12700167 [PubMed - indexed for MEDLINE]
    A technical paper that shows how an increase in cellular glucose concentration (or the administration of 2-DG) reduces huntingtin protein aggregation in cells.

-M. Stenerson, 1/6/04