December 22, 2009  —  A report appearing in the December 2009 issue of the American Psychological Association journal Behavioral Neuroscience revealed that diets that fail to provide enough of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may negatively affect the nervous system. The finding could impact the understanding of information-processing deficits that occur in schizophrenia, bipolar disease, obsessive-compulsive disorder, attention deficit-hyperactivity disorder (ADHD), Huntington’s disease and other nervous system disorders.

Norman Salem Jr, PhD of the Laboratory of Membrane Biochemistry and Biophysics at the National Institute on Alcohol Abuse and Alcoholism and his associates gave one of the four following diets to pregnant mice and their offspring: omega-3 fatty acid deficient, low alpha-linolenic acid, high alpha-linolenic acid, or a diet enriched with EPA and DHA. DHA is the primary omega-3 fatty acid in the nervous system, including the brain. While DHA is metabolized from alpha-linolenic acid in the diet, the conversion is minimal, rendering a dietary source of DHA and EPA, such as fish oil or an algae source, of vital importance. “Humans can convert less than one percent of the precursor into DHA, making DHA an essential nutrient in the human diet,” coauthor Irina Fedorova, PhD noted.

Adult offspring of the mice in the four groups were tested for nervous system function by exposing them to a loud noise preceded by a softer warning tone. Animals normally flinch upon hearing a loud tone, however, the degree of flinching is reduced when the animals are first exposed to a warning tone: an adaptive process known as sensorimotor gating. Weak sensorimotor gating in humans is associated with a number of nervous-system disorders.

While mice that were raised on EPA and DHA demonstrated normal sensorimotor gating, animals given the other diets were more startled by the loud noise. The finding suggests that a sensory overload state could result from DHA deficiency.

The ability of DHA and EPA to help maintain nerve cell membranes may be responsible for the protective effects observed in the current study. “It is an uphill battle now to reverse the message that ‘fats are bad,’ and to increase omega-3 fats in our diet,” Dr Salem commented. “It only takes a small decrement in brain DHA to produce losses in brain function.”



December 22, 2009  —  A growing body of scientific literature is helping parents and doctors better understand the link between fatty acids and behavioral disorders such as ADHD. The ratio between omega-3 and omega-6 fatty acids (such as arachidonic acid) seems especially important. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 fatty acids found in flaxseed oil and cold water fish. In the typical Western diet, we tend to consume more omega-6 fatty acids relative to omega-3 fatty acids. The ratio of omega-3 to omega-6 fatty acids has been shown to influence the development of neurotransmitters and other chemicals that are essential for normal brain function. Increased intake of omega-3 fatty acids has been shown to reduce the tendency toward hyperactivity among children with ADHD (Haag M 2003).

Several studies have examined the role of essential fatty acids in ADHD, with very encouraging results:

  • § A study examined the effects of flaxseed oil and fish oil, which provide varying degrees of omega-3 fatty acids, on adults with ADHD. The patients were given supplements for 12 weeks. Their blood levels of omega-3 fatty acids were tracked throughout the 12 weeks. Researchers found that high-dose fish oil increased omega-3 acids in the blood relative to omega-6 acids. An imbalance between arachidonic acid and omega-3 fatty acids is considered a risk factor for ADHD (Young GS et al 2005).

One study compared 20 children with ADHD who were given a dietary supplement (that included omega-3 fatty acids) to children with ADHD who were given methylphenidate. The dietary supplement was a mix of vitamins, minerals, essential fatty acids, probiotics, amino acids, and phytonutrients. Amazingly, the groups showed almost identical improvement on commonly accepted measures of ADHD (Harding KL et al 2003).



December 22, 2009  —  Attention deficit/hyperactivity disorder (ADHD) is a distressing diagnosis for any parent to hear. It’s well known that children with ADHD are at a disadvantage in school and that ADHD can have long-term effects. In addition, a number of powerful pharmaceuticals have been used to treat the condition.

Fortunately, newer findings in nutrition and wellness, and newer generations of pharmaceuticals, have been developed that can help children with ADHD gain control over their lives. The Life Extension Foundation has conducted an extensive survey of the scientific literature to uncover the safest and best approaches for families affected by this increasingly common condition.

ADHD is defined as a persistent lack of attention to tasks (attention deficit) and/or a lack of ability to control impulses and an increase in physical activity (hyperactivity) that is not typical of others at a similar stage of development (National Institutes of Health 2006). ADHD is most prevalent in children and teens, although it can occur in adults. ADHD occurs in 3 to 6 percent of all children in the United States, with rates as high as 15 percent in some areas (Kasper DL et al 2005).

According to the fourth edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), ADHD is now the most commonly diagnosed behavioral disorder of childhood. Boys with ADHD outnumber girls 3 to 1. Some children outgrow ADHD, but 60 percent continue to have symptoms (Biederman J et al 2000).

ADHD: A Typical Profile

The behavior of children who have ADHD typically is affected in many settings such as at home and school or when they are with friends. The most prominent feature of ADHD is a consistent pattern of developmentally inappropriate levels of attention, concentration, distractibility, hyperactivity, and impulsivity. It is important to note that these problems must be inappropriate to a child’s developmental level to be considered ADHD. One concern among physicians is rampant overdiagnosis of ADHD, in part because the condition has been so hard to define.

Children who have attention deficits are unable to remain on-task for extended periods of time. They may appear forgetful, in part because their inability to attend to information prevents them from understanding it in the first place. Such children may also have cognitive and language delays. Children with hyperactivity may fidget, have difficulty engaging in quiet activities, be excessively talkative, and always seem to be on the go. Children who have impulse control problems may be impatient (for example, they may blurt out an answer before the question has been finished). They may have difficulty waiting their turn and are often perceived to be intruding on others. All of these manifestations can cause difficulties in academic and social settings (Warner-Rogers J et al 2000).

It is common for children with ADHD to be misdiagnosed as having learning disorders because they often perform poorly on tests that require information processing and concentration (Hartman CA et al 2004; Weiler MD et al 2000). There is also evidence that adults with ADHD are more likely to have a variety of addictive behaviors, among them alcoholism (Ponce AG et al 2000), smoking (Levin ED et al 2001), and cocaine use (Bandstra ES et al 2001).

What Causes ADHD?

Although the exact causes of ADHD are unknown, it is most likely caused by an interaction of genetic, environmental, and nutritional factors, with a strong focus on the interaction of multiple genes (genetic loading) that together cause ADHD.

There is some evidence that people with ADHD do not produce adequate quantities of certain neurotransmitters, among them dopamine, norepinephrine, and serotonin. Some experts theorize that such deficiencies lead to self-stimulatory behaviors that can increase brain levels of these chemicals (Comings DE et al 2000; Mitsis EM et al 2000; Sunohara GA et al 2000).

There may also be some structural and functional abnormalities in the brain itself in children who have ADHD (Pliszka SR 2002; Mercugliano M 1999). Evidence suggests that there may be fewer connections between nerve cells. This would further impair neural communication already impeded by decreased neurotransmitter levels (Barkley R 1997). Evidence from functional studies in patients with ADHD demonstrates decreased blood flow to those areas of the brain in which “executive function,” including impulse control, is based (Paule MG et al 2000). There may also be a deficit in the amount of myelin (insulating material) produced by brain cells in children with ADHD (Overmeyer S et al 2001).

Diagnosing ADHD

Establishing a diagnosis of ADHD is a considerable challenge, largely because of the lack of reliable and specific testing and firm criteria. ADHD has become a high-profile condition (which may result in it being both overdiagnosed and under diagnosed), depending on pressures from parents, teachers, and others. Although DSM-IV contains diagnostic criteria, they are often not followed by health professionals. Because of the lifelong implications of a diagnosis of ADHD, most experts recommend a multidisciplinary team approach to both diagnosis and treatment. Such an approach should involve physicians, child behavior experts, and parents. Nutritional experts may also be valuable members of the treatment team.

The core symptoms of ADHD in children are listed below. This list was adapted from the Centers for Disease Control. It is important to note that the diagnosis of ADHD cannot be made unless the patient has experienced these symptoms in ways that are disabling for a 6-month period. The DSM-IV diagnosis includes:

I. Either A or B:

A. Six or more of the following symptoms of inattention have been present for at least 6 months to a point that is disruptive and inappropriate for developmental level:

  1. Often does not give close attention to details or makes careless mistakes in schoolwork, work, or other activities.
  2. Often has trouble keeping attention on tasks or play activities.
  3. Often does not seem to listen when spoken to directly.
  4. Often does not follow instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions).
  5. Often has trouble organizing activities.
  6. Often avoids, dislikes, or does not want to do things that take a lot of mental effort for a long period of time (such as schoolwork or homework).
  7. Often loses things needed for tasks and activities (such as toys, school assignments, pencils, books, or tools).
  8. Is often easily distracted.
  9. Is often forgetful in daily activities.

B. Six or more of the following symptoms of hyperactivity/impulsivity have been present for at least 6 months to an extent that is disruptive and inappropriate for developmental level:


  1. Often fidgets with hands or feet or squirms in seat.
  2. Often gets up from seat when remaining in seat is expected.
  3. Often runs about or climbs when and where it is not appropriate (adolescents or adults may feel very restless).
  4. Often has trouble playing or enjoying leisure activities quietly.
  5. Is often “on the go” or often acts as if “driven by a motor.”
  6. Often talks excessively.


  1. Often blurts out answers before questions have been finished.
  2. Often has trouble waiting his/her turn.
  3. Often interrupts or intrudes on others (such as butts into conversations or games).

II. Some symptoms that cause impairment were present before age 7 years.

III. Some impairment from the symptoms is present in two or more settings (such as at school or work and at home).

IV. There must be clear evidence of significant impairment in social, school, or work functioning.

V. The symptoms do not happen only during the course of a pervasive developmental disorder, schizophrenia, or other psychotic disorder. The symptoms are not better explained by another mental disorder (such as a mood disorder, anxiety disorder, dissociative disorder, or personality disorder).

Traditional Medical Treatment

In addition to behavioral management, medical treatment of ADHD includes stimulant and nonstimulant medications.

Stimulant drugs. Effective prescription drugs are primarily the so-called stimulant drugs. These agents are known to increase brain concentrations of a variety of brain neurotransmitters, most importantly dopamine, and exert a calming effect on people who have ADHD. Since dopamine enhances signaling between nerve cells that are involved in task-specific activities and also decreases “noise,” or “nonsense signaling,” increased concentrations of dopamine are thought to help individuals stay focused and on-task.

Despite their limitations, stimulants are still considered first-line treatment for ADHD. They are effective in 70 to 80 percent of patients. Stimulants are highly effective at alleviating core ADHD symptoms (such as inattention, hyperactivity, or impulsivity). Original stimulant preparations had very short periods of action that could result in dramatic rises and falls in drug levels. Newer long-acting preparations have been developed to even out these swings.

Even with the newer formulations, some adverse effects are inevitable. Long-term effects, although unusual, can occur. There is some evidence, for example, that long-term use of stimulants, especially methylphenidate (Ritalin®), can cause a delay in growth (Holtkamp K et al 2002). It is understandable that many parents are hesitant to give their young children this medication.

While they are effective, stimulant drugs are members of the amphetamine class, which means they can have significant adverse effects and hold some potential for abuse. Unfortunately, methylphenidate has gained popularity as a recreational drug, especially among adolescents and college students. While methylphenidate paradoxically acts as a calming drug among people diagnosed with ADHD, it acts as a stimulant among people who do not have ADHD. Surveys have indicated that more than 90 percent of college students and adolescents who abuse prescription drugs identified methylphenidate as their drug of choice (White BP et al 2006).

Nonstimulant drugs. The negative effects of stimulant drugs have led to an intensive search for better alternatives. Atomoxetine is the first nonstimulant drug approved by the US Food and Drug Administration (FDA) for treatment of ADHD and the only agent approved by the FDA for treatment of ADHD in adults.

Atomoxetine therapy for ADHD controls symptoms and maintains remission, and has comparable efficacy with methylphenidate, a favorable safety profile, and noncontrolled substance status (Christman AK et al 2004). Atomoxetine is safe and well tolerated (Kelsey DK et al 2004). It effectively reduces ADHD symptoms and improves social functioning in school-aged children, adolescents, and adults. As with stimulant medications, atomoxetine should be used with caution in patients who have hypertension or a cardiovascular disorder (Christman AK et al 2004).

In addition to atomoxetine, other drugs that increase brain concentrations of dopamine and/or serotonin have been used with varying degrees of success. Among these are the anticonvulsant gabapentin (Hamrin V et al 2001), the dopamine-enhancing antidepressant bupropion (Daviss WB et al 2001), the wakefulness-promoting drug modafinil (Taylor FB et al 2000), and donepezil, an acetylcholinesterase inhibitor that increases brain levels of acetylcholine. Studies, however, have cast doubt on donepezil’s effectiveness (Wilens TE et al 2005).



The drug takes its name from the Polynesian name, Rapa Nui, for Easter Island                   
Credit: Comstock Images/Jupiter Images)

Timesonline.co.uk, Mark Henderson, Science Editor  —   A drug used by transplant patients can extend the lives of mice by about a third, according to research that raises the prospect of a life-prolonging pill for people.

Male mice given rapamycin lived on average 28 per cent longer than a control group of animals, while the effect on females was greater still, with a 38 per cent increase in life expectancy. The animals were treated at an age of 20 months, which is the equivalent of 60 years in humans.

The study, led by David Harrison, of the Jackson Laboratory in Maine, is the first to identify a drug that can lengthen the lives of mammals, and suggests that similar medical techniques might be capable of doing the same thing in people.

Scientists warned, however, that nobody should take rapamycin in the hope of living longer. The drug, originally identified in soil samples from Easter Island, is a powerful suppressor of the immune system, commonly given to patients to help to prevent the rejection of transplanted organs, and its dangers to healthy people would far outweigh any potential benefit.

The hope is that rapamycin’s effects might highlight biological pathways involved in the ageing process, which could then be targeted with a safer drug. Details of the research have been published in the journal Nature.

Randy Strong, of the University of Texas and a member of the study team, said: “We believe this is the first convincing evidence that the ageing process can be slowed and lifespan can be extended by a drug therapy starting at an advanced age.”

Matt Kaeberlein and Brian Kennedy, of the University of Washington, wrote in a commentary on the work: “Certainly, healthy individuals should not consider taking rapamycin to slow ageing. The potential immunosuppresive effects of this compound are sufficient to caution against this.

“It may be possible to develop pharmacological strategies that provide the health and longevity benefits without unwanted side effects.”

Lynne Cox, researcher in ageing at the University of Oxford, said: “This is a very exciting study. It is especially interesting that the drug was effective even when given to older mice – equivalent to 60-year-old humans – as it would be much better to treat ageing in older people rather than using drugs long term through life. What the study does is to highlight an important molecular pathway that new, more specific drugs might be designed to work on.”

Research into the ageing process has previously identified two mechanisms that can prolong mammalian lifespans, but neither is easily applicable to humans. Mice are known to live longer if fed a calorie-restricted diet that is close to starvation levels, but this would be very difficult for a person to maintain. The other option is genetic manipulation.

Dr Harrison’s team began to investigate rapamycin because it seems to affect the same biological pathway as calorie restriction, making it a candidate for anti-ageing therapy. The drug, which takes its name from Easter Island’s Polynesian name, Rapa Nui, is used to tone down the immune system of transplant patients so that their organs are not rejected, and to improve the performance of stents implanted to keep arteries open. It has also started trials as a cancer therapy.

Arlan Richardson, director of the Barshop Institute at the University of Texas, which contributed to the research, said: “I’ve been in ageing research for 35 years and there have been many so-called ‘anti-ageing’ interventions over those years that were never successful.

“I never thought we would find an anti-ageing pill for people in my lifetime; however, rapamycin shows a great deal of promise to do just that.”

Disease Mechanism I: Protein Aggregation

A Protein Build-up Remover


Drug summary: Rapamycin, also known as sirolimus, is an FDA-approved antibiotic and immunosuppressant. It is already being used in organ transplant patients and is currently being tested in phase II and III clinical trials in cancer patients for its antitumor activity. Rapamycin inhibits the activity of a protein called mTOR which, among its other functions, inhibits a process called autophagy. Autophagy is the process by which a cell breaks down its own molecules and other components that are no longer needed. Since mTOR functions to inhibit autophagy, by inhibiting mTOR, rapamycin promotes autophagy, allowing for the breakdown of unnecessary components of the cell. Researchers have shown in fly and mouse models of HD that by inducing autophagy, rapamycin helps nerve cells break down huntingtin aggregates.

Whether these protein aggregates are a cause or result of the HD disease process is not yet known. However, nerve cells that build up huntingtin aggregates in the brains of people with HD often die. (To read more about huntingtin protein aggregation and its role in HD, click here.) Thus, rapamycin may help prevent cell death by helping nerve cells clear out huntingtin aggregates. Rapamycin could be an especially promising treatment if started before or shortly after the onset of symptoms in people with HD, when the levels of huntingtin aggregates in the nerve cells are still manageable.

What is autophagy, the cellular mechanism affected by rapamycin?

Rapamycin prevents the protein mTOR from performing its normal functions in the cell. mTOR is a member of a whole family of “TOR” (“target of rapamycin”) proteins. While mTOR is involved in many different cell functions, it mainly helps regulate when the cell makes and breaks down proteins. The decision to make or break down proteins depends on what proteins are needed by the cell at specific times and on the conditions around the cell. If the cell has enough available amino acids, which are the building blocks of proteins, mTOR is free to signal to other molecules that will tell the cell to build new proteins. On the other hand, if the cell is running low on nutrients, it has to break down already existing proteins and other cell components to free the building blocks so that they can be reused.


The process by which the cell breaks down its own components is called autophagy, which basically means “eating of the self.” The part of the cell that is to be degraded is first engulfed by a double membrane to separate it from the rest of the cell; the resulting membrane-enclosed bubble of cytosol (and the proteins it contains) becomes what is called the autophagosome. The autophagosome eventually fuses with a cellular organelle called a lysosome, a much larger membrane-enclosed bubble that contains a variety of enzymes that can break down all sorts of cellular components (which is why lysosomes are sometimes referred to as the “garbage disposals” of the cell). In order to protect the rest of the cell from being degraded, these enzymes only work in a very acidic environment, so the pH inside lysosomes is much lower than the neutral pH in the rest of the cell. This pH barrier protects the rest of the cell from being degraded should the enzymes somehow leak out. Once the contents of the autophagosome are delivered to the lysosome, the lysosomal enzymes break down the new contents, which can then be recycled for new use within the cell.

mTOR comes into this picture because it inhibits the process of autophagy; since mTOR signaling means that the cell has plenty of nutrients to build with, autophagy is not necessary to break down already existing molecules. The discovery that rapamycin inhibits mTOR prompted researchers to see if its ability to stimulate autophagy could also help nerve cells get rid of huntingtin aggregates.

How could rapamycin be used to help prevent build-up of huntingtin aggregates?

Until a couple of years ago, it was believed that the main mechanism by which the cell got rid of huntingtin aggregates involved what is called the ubiquitin-proteasome system, which is responsible for tagging and degrading improperly formed proteins. However, recent research shows that proteins with abnormally expanded stretches of the amino acid glutamine, like the altered huntingtin protein (which causes HD), are also disposed of through a particular kind of autophagy. In this process, the proteins are gathered up and transported to the lysosome, where they are broken down and their component amino acids recycled. Studies of nerve cells have shown that huntingtin can often be found in autophagosomes, the membrane-bound sacs that carry cell parts to the lysosome for degradation.


Rapamycin could potentially be used to treat HD by taking advantage of the autophagy process. The drug has been shown to induce autophagy and to help prevent toxicity caused by huntingtin aggregates in both cell and animal models of HD. The basic process by which this occurs can be summarized as follows: Rapamycin inhibits the protein mTOR -> mTOR can no longer inhibit autophagy -> autophagy is activated -> huntingtin aggregates are broken down in the lysosome.

Unfortunately, the mechanism by which rapamycin could help people with HD is more complicated than the process outlined above. Researchers that tested rapamycin’s ability to reduce huntingtin aggregates in cell cultures and animal models found that the drug only works in cells that have been expressing the altered (HD-causing) huntingtin protein for a short time. In cells and animals that have already had time to build up huntingtin aggregates, rapamycin fails to stimulate autophagy enough to clear out the aggregates. The current explanation for this finding is that mTOR is actually sequestered, or trapped, by the huntingtin aggregates themselves. (For more information about huntingtin aggregates, click here.) This reasoning could help explain the typical late onset of Huntington’s disease: early in life, the huntingtin aggregates sequester mTOR and in doing so induce autophagy, which initially helps get rid of the aggregates. However, as more and more huntingtin aggregates form, the autophagy that is set off by inactivation of mTOR can no longer keep up the pace as aggregates begin to form faster than they can be degraded – and the symptoms of HD begin to appear.

When rapamycin is administered to cells that already contain a lot of huntingtin aggregates, there is no visible improvement because the aggregates in these cells have already inactivated mTOR. Further inactivation of mTOR by rapamycin cannot clear out aggregates which have already become too numerous to be totally cleared out by the resulting autophagy. However, rapamycin does have protective effects in cells that don’t yet have much aggregate build-up. Researchers found that the drug decreases death in cell cultures, fruit flies, and in a mouse model of HD that mimics the late onset of the disease in humans. The severity of symptoms can also be decreased in mice treated with rapamycin. This finding offers hope that rapamycin could be used early in patients that have tested to be at risk for developing HD in order to delay the onset of symptoms even further. (For more information on genetic testing, click here.)

How promising is the use of rapamycin to treat HD?

A slightly modified form of rapamycin, called CCI-779, has better properties as a drug and has been shown to have only mild and treatable side effects in humans. In a clinical study of CCI-779 in cancer patients, the most common side effects were usually treatable acne-like rashes or lesions, and no significant suppression of the immune system was seen even at the highest dose tested. There is also evidence that mTOR is highly involved in learning and memory, but so far researchers have not seen any harmful effects of rapamycin on these processes. However, neither form of rapamycin has yet been tested for efficacy in people with HD. More testing needs to be done to determine whether rapamycin would be safe for the kind of long-term use necessary should the drug be used to delay symptoms starting from the early stages of the disease.

Research on rapamycin and HD

Ravikumar, et al. (2002) investigated whether proteins with expanded sections of the amino acid glutamine (like the altered huntingtin protein) and the amino acid alanine (which causes other diseases) could be degraded by cells using the process of autophagy. They compared autophagy with the ubiquitin-proteasome process, which was originally thought to be the only process by which these harmful proteins are degraded. The researchers used cells that expressed these proteins and tagged them with green fluorescent protein (GFP) in order to visualize their fate within the cells. The use of GFP allows researchers to see the amount of a specific protein present in the cell because it fluoresces, or glows, when viewed under a special microscope. To study how huntingtin aggregates are broken down by the cell, they used cells that expressed the part of the HD allele that contained either 55 or 74 CAG repeats, and thus produced proteins with stretches of 55 or 74 glutamines. (To read more about the huntingtin protein, click here.)

To determine whether autophagy is indeed a key process in the clearance of huntingtin aggregates, the researchers first used two different compounds to inhibit autophagy at different points of the process and observed the effect on aggregate formation. The first compound they used inhibits autophagy by preventing a membrane from surrounding the cell contents that are about to be degraded; if the autophagosome can’t form, the contents cannot be delivered to the lysosome to be broken down. The second compound they used prevents the autophagosome from fusing with the lysosome and releasing its contents, which also prevents autophagy from occurring. Treatment with these compounds resulted in visibly higher levels of huntingtin aggregates in cell cultures, which showed that autophagy does play a role in the breakdown of aggregates. Along with the increase in aggregates, the researchers also saw increased cell death when the cells were treated with autophagy-inhibiting compounds.

The researchers then tested the effects of rapamycin on aggregate formation in the cells. It had no effect on the degree of aggregation in cells that had been producing the altered huntingtin protein for 48 hours. They repeated the experiment with cells that had only been producing the protein for 24 hours, and in this case they found that rapamycin did reduce aggregate formation and cell death. This finding showed that rapamycin may only be effective when the degree of huntingtin aggregation is still low. They also noted that rapamycin promotes autophagy by inhibiting mTOR, but that the exact nature of this interaction is unknown.

Finally, the researchers tested the role of the ubiquitin-proteasome system in reducing protein aggregation in the same cell cultures. Most previous experiments have used a certain compound to inhibit the proteasome that can apparently inhibit the function of the lysosome as well. Because they wanted to test the role of the proteasome only, the researchers used a different compound that inhibits the proteasome and has no effect on lysosomes. They found that inhibiting the proteasome increased aggregate formation in one cell line but not in another. While these results are somewhat inconclusive, they may suggest that the ubiquitin-proteasome process is not the main mechanism by which cells get rid of the altered huntingtin protein. More research needs to be done about the role of autophagy in degrading mutant huntingtin.

Ravikumar, et al. (2004) took these studies further by testing the effects of rapamycin in fly and mouse models of HD. Before testing the drug in animals, the researchers set out to show how mTOR interacts with huntingtin protein aggregates. After showing that mTOR is indeed sequestered by huntingtin aggregates in cell cultures, they went on to show that mTOR does not function properly in cells that have huntingtin aggregates. To set off different cellular processes, mTOR signals to other molecules in the cell by working as a kinase, which is a molecule that adds a phosphate group onto another molecule (or “phosphorylates” it) in order to turn that molecule on or off. The researchers showed that certain molecules phosphorylated by mTOR, were phosphorylated less often in cells that contained huntingtin aggregates. This finding indicates that the interaction between mTOR and the aggregates prevents mTOR from performing its usual functions. By phosphorylating these molecules, mTOR is supposed to stimulate the synthesis of certain proteins. The experiment also showed that in cells with huntingtin aggregates, these proteins were produced at lower levels, probably because mTOR was inactivated. The researchers also found that increasing mTOR activity, which would prevent autophagy, increased aggregate levels and cell death.

The first model the researchers used were flies that expressed the altered huntingtin protein in their photoreceptors, which are specialized cells that receive light in the eyes. The researchers found that treatment with rapamycin decreased degeneration of these cells. The next experiment tested CCI-779, a more water-soluble form of rapamycin, in a mouse model of HD. The researchers used a mouse model that mimics the late onset of disease symptoms that occurs in humans so that they would have time to administer rapamycin treatment before severe symptoms appeared. Throughout the study, the mice treated with CCI-779 performed better on four different motor tasks than did mice treated with a placebo. Afterwards, the researchers found that there were also fewer aggregates in the brains of mice treated with CCI-779 than in the brains of control mice. These findings show that rapamycin plays a role in helping nerve cells get rid of huntingtin aggregates and that it may have promise as a therapeutic agent for HD. However, more research needs to be done on the safety and efficacy of rapamycin humans.

Source: Stanford University Medical School

The New York Times, by Nicholas Wade  —  A new star has appeared in the field of drugs that delay aging in laboratory animals, and are therefore candidates for doing the same in people.

The drug is an antibiotic, rapamycin, already in use for suppressing the immune system in transplant patients and for treating certain cancers.


Rapamycin treatment had the remarkable effect of extending life even though it was not started in the right dose until the mice had lived 600 days – equivalent to a person at age 60. Most interventions that prolong life in mice, including a very low-calorie diet, need to be started early in life to show any effect.


Experts warn that this should not be tried at home. No one knows yet if rapamycin slows aging in people or at what dose it might be effective. And any drug that suppresses the immune system is not to be trifled with.


The finding has been reported in Nature by researchers at three institutions working in parallel. The teams were led by David E. Harrison of the Jackson Laboratory, a mouse-breeding powerhouse in Bar Harbor, Me.; Richard A. Miller of the University of Michigan; and Randy Strong of the University of Texas Health Science Center.


The researchers do not know how rapamycin secures its anti-aging effect. It could be just halting tumors rather than delaying the aging process in general.

The three teams were sponsored by the National Institute on Aging as part of a program to test possible anti-aging drugs much more rigorously.


“One of the nasty secrets of the field is that most mouse longevity experiments are done only once in one lab on one genetic background,” said Steven Austad, an expert on aging at the University of Texas Health Science Center, who was not involved in the research.


The National Institute on Aging program includes a test of two doses of resveratrol, the ingredient of red wine that is thought to mimic the effects of caloric restriction on longevity. The results have not been published, but Christoph Westphal, chief executive of Sirtris, a company exploring the health effects of resveratrol and similar chemicals, said the tests “are seeing quite modest effects of resveratrol.”


The effectiveness of rapamycin in extending the life of elderly mice was discovered by accident. The researchers found that the mice fed rapamycin were not getting the proper dose in their bloodstream. They reformulated the drug in the form of capsules that fed slow doses to the intestine, but by that time the mice were elderly. Nonetheless, life span increased by 14 percent in the females and 9 percent in the males.

“It’s no longer irresponsible to say that following these up could lead to medicines that increase human life span by 10, 20 or 30 percent,” Dr. Miller said.


It will be at least 10 years before matters are sorted out, he said, but, as of right now, “I don’t think there’s any evidence for people that there’s any drug that can slow aging down.”

December 22, 2009, by Gabe Mirkin MD  —  Changes in diet should be the first strategy for anyone with high blood pressure, but most people will need to make drastic changes in their eating habits to succeed. Scientists at the National Institutes of Health have shown why the DASH diet lowers high blood pressure to normal in more than 80 percent of people with high blood pressure. On the DASH diet you eat lots of leafy green vegetables that are rich sources of nitrites, common salts that your bloodstream, can be converted to nitric oxide which opens blood vessels.

This means that nitrites could be a new treatment for high blood pressure, heart attacks, sickle cell disease, and blocked arteries leading the heart, brain and legs. Hemoglobin is the red pigment in red blood cells that carries oxygen in your bloodstream. When hemoglobin releases oxygen, it converts nitrites to nitric oxide, to widen blood vessels. Blood nitrite levels are low in patients with high blood pressure.

However, at high concentrations nitrites are toxic, so you must take limited amounts. Leafy greens are rich sources of safe amounts of nitrites. The nitrites go into the bloodstream, where exposure to oxygen converts nitrites to nitrous oxide which dilates arteries and lowers high blood pressure. Hypertensives should also eat lots of other plants for the same reason and cut back on meat and chicken, that are rich sources of sodium that can raise high blood pressure.

Answer From Andrew Weil, M.D.  —  Fish oil – or, more precisely, omega-3 fatty acids – offers so many health benefits, including reduction of risk of heart disease, that most experts recommend that everyone eat more coldwater, oily fish, (such as salmon, sardines, herring, and black cod). Fish provide both of the omega-3s: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) our bodies need. Another omega-3 precursor, alpha-linolenic acid (ALA), occurs in nuts (especially walnuts), leafy vegetables, flaxseed and some animal fat, especially from grass-fed animals. The body must convert ALA into EPA and DHA, an inefficient process.

Omega-3s are so important to heart health that my longstanding recommendation has been to consume two to three servings of fish per week or to take a fish oil supplement if you don’t like fish. The American Heart Association recommends eating at least two fish meals a week. I eat fish often and also take 2-3 grams of supplemental fish oil a day.

We know that populations that eat fish regularly live longer and have less chronic disease than populations that do not. This may be partly because fish displaces meat in their diets. Certainly, fish provides high-quality protein without the saturated fat present in meat and poultry. In addition, the benefits of supplemental fish oil for people with heart disease are well established: reduction of serum triglycerides by 25 to 30 percent, slowing of the buildup of atherosclerotic plaques that can clog coronary arteries, slight lowering of blood pressure, decreased clotting tendency of the blood, and reduced risk of death, heart attack, dangerous abnormal heart rhythms, and strokes. Fish oil also may benefit people who have diabetes, PMS, breast cancer, memory loss, depression, insulin resistance, rheumatoid arthritis, and other inflammatory conditions.

One widely cited study did find that fish oil tends to raise (“bad”) LDL cholesterol by five to 10 percent while raising (“good”) HDL by one to three percent. But that’s not the whole story, which is rather complicated. I discussed your question with integrative cardiologist Stephen DeVries, M.D. of Northwestern University’s Center for Integrative Medicine and Division of Cardiology in Chicago. He explained that the risk of heart attacks is more dependent on the number of LDL particles than on the amount of cholesterol they contain. Fish oil can slightly increase the amount of cholesterol in LDL, but it also significantly lowers the number of LDL particles. The end result is beneficial. There’s no reason to worry that taking fish oil will sabotage your cholesterol control and every reason to believe that it will benefit your heart and general health.

Andrew Weil, M.D


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