Why Sugar Main Cause of Heart Disease

Everything we thought we knew about nutrition and heart health may be wrong. Experts around the world are now looking at an unexpected culprit as the main cause of heart disease: sugar.
By Rachel Meltzer, RD

We’ve heard it so many times, it comes as naturally as looking both ways before you cross the street: Protecting your heart means cutting down on fatty, salty foods.
It’s a mantra made manifest by the easy-to-understand concept of blobs of fat floating about our bloodstream, and by the vision of heart-unhealthy public figures like Dick Cheney and pre-vegan Bill Clinton, towering symbols of political striation and enthusiastic cheeseburger consumption. But while your cardiologist is unlikely to be passing around gift certificates to the Cheesecake Factory, more and more heart experts are coming to realize that fat and salt are only part of the story. The real danger to our hearts may be sneakier. And sweeter.
For the first time, scientists have linked the amount of sugar in a person’s diet with her risk of dying from heart disease. People who ate between 17 and 21 percent of their calories from added sugar had a 38 percent higher risk of dying from heart disease, compared with people who consumed 8 percent or less of their calories from added sugar, according to a study recently published in the Journal of the American Medical Association.
The case against sugar is so compelling that last year the advisory panel that helps create the U.S. Dietary Guidelines eased up on its hardline stance against fat and cholesterol, recommending instead strong limits on added sugar (the government will release the official guidelines later this year). The group suggested that Americans limit added sugars to no more than 10 percent of daily calories (that’s 12.5 teaspoons for someone with a 2,000-calorie diet). The American Heart Association takes an even tougher position, recommending no more than 100 calories per day from added sugars or 6 teaspoons for women, and 150 calories (9 teaspoons) for men. On average, we now get 22 teaspoons per day.
But what exactly is “added sugar,” and why do experts suddenly believe that it’s a threat to your heart?

Sugar Shakedown

When they talk about sugar, heart experts aren’t talking about the stuff that we consume from eating whole foods. “Added sugars are contributed during the processing or preparation of foods and beverages,” says Rachel K. Johnson, PhD, RD, professor of nutrition at the University of Vermont. So lactose, the sugar naturally found in milk and dairy products, and fructose, the sugar that appears in fruit, don’t count. But ingredients that are used in foods to provide added sweetness and calories, from the much-maligned high-fructose corn syrup to healthier-sounding ones like agave, date syrup, cane sugar, and honey, are all considered added sugars.
But aren’t all sugars created equal? Not really, say experts. Even if added sugars and natural sugars are chemically similar, it’s more about the total package. Fructose, the sugar in fruits, seems to be the most problematic health-wise; however it’s generally considered to be harmful only in high concentrations. “It’s almost impossible to overconsume fructose by eating too much fruit,” says Johnson. Consider this: You’d need to eat five cups of strawberries to get the same amount of fructose as in one can of Coke.
Another major difference—the fiber in fruit helps to fill you up, slow down digestion, and prevent rapid blood sugar spikes. What’s more, fruit is also a rich source of disease-fighting vitamins and antioxidants. Here’s what you do want to limit: Fruit juice, which is devoid of fiber and leaves you with too much sugar and too little satisfaction. It also couldn’t hurt to moderate your portions of dried fruit, which is also easy to overdo—about ¼ cup is considered a serving size.
Bottom line: You don’t need to be afraid of a mango. That pumpkin spice latte is a whole other story.

A Spoonful of Trouble

You already knew the stuff wreaks havoc on your teeth, and isn’t doing anything to help your diabetes risk. Plus, those added calories are only adding to your waistline, without providing any substantial nutritional value in return. But did you know that added sugar:

Increases Your Blood Pressure

Sugar may be worse for your blood pressure than salt, according to a paper published in the journal Open Heart. Just a few weeks on a high-sucrose diet can increase both systolic and diastolic blood pressure. Another study found that for every additional sugar-sweetened beverage, risk of developing hypertension increased 8 percent. Too much sugar leads to higher insulin levels, which in turn activate the sympathetic nervous system and leads to increased blood pressure, according to James J. DiNicolantonio, PharmD, cardiovascular research scientist at Saint Luke’s Mid America Heart Institute in Kansas City, Missouri. “It may also cause sodium to accumulate within the cell, causing calcium to build up within the cell, leading to vasoconstriction and hypertension,” he says.

Messes with Your Cholesterol

Eating a diet high in added sugar can do a number on your blood lipid levels, according to a 2010 study published in the Journal of the American Medical Association. Adults who ate the most added sugar (an average of 46 teaspoons per day!) were more than three times as likely to have low good HDL cholesterol levels compared with people who kept the sweet stuff to a minimum, according to researchers at Emory University who analyzed the blood of more than 6,000 men and women. The scientists also found a link between eating more added sugar and an increased risk of elevated triglycerides.

Strains Your Heart Muscle

“Americans have increased their calorie intake over the past 30 years primarily in the form of carbohydrates and sugars,” says Johnson. And those 256 extra calories per day we consume in the form of added sugar are likely leading to weight gain, which may directly damage the heart, according to new research. Obese adults have elevated levels of an enzyme that indicates injured heart muscle, found researchers at Johns Hopkins University—demonstrating that long before a heart attack may occur, those carrying extra weight are experiencing damage directly to their hearts. And you don’t have to be gravely overweight for the damage to occur—the risk rose incrementally with BMI.

Shake the Sugar

Reducing the amount of added sugar can’t be that hard—can it? Well, certain high-sugar foods are obvious—Dr. Pepper, Twizzlers, and Ben & Jerry’s, natch. But an even bigger problem may be the sneaky sugar lurking where you least expect it. “It’s in everything—even seemingly healthy foods like salad dressing, whole-wheat breads, and tomato sauces,” says Brooke Alpert, RD, owner of B Nutritious and author of The Sugar Detox. What’s more, it’s impossible to find out how much added sugar a food contains by looking at the nutrition facts panel, since labels don’t distinguish between added sugars and naturally occurring ones.
So what can you do to cut the sugar? Here are six steps.

1. Read Labels

“There are more than 70 different names for sugar,” says Alpert. Scour the ingredients list on any packaged food you buy for words like sucrose, barley malt, beet sugar, brown rice syrup, agave, and cane juice.

2. Buy Plain

Flavored foods are often code for “sugar added.” If strawberry flavored Chobani yogurt packs 15 grams of sugars, there’s no way to tell how much is from added sugars and how much is from the naturally occurring lactose. Stick with the plain version, and it will be easy to see that all 4 grams of the sugars are supposed to be there. Add flavor with whole fruit—or really shake up your taste buds with a savory topping instead. “It’s the same idea as ordering dressing on the side. This way, you get to be in control of how much sweetness is added to your food,” says Alpert. (Hear are our 6 Fat-Burning Ways to Eat Yogurt.)

3. Drop Drinkable Sugar

“Almost half of Americans’ added sugars intake comes from drinks,” says Johnson. So for many people, limiting beverages like soda, iced teas, lemonade, and fruit punch is a simple way to cut back big time. And healthy-sounding drinks like kombucha and vitamin waters are no exception. Don’t forget about your Starbucks run, either, says Alpert. “Coffee and tea aren’t supposed to be dessert.” Try one of these 14 Detox Waters instead.

4. Skip Juices and Smoothies

Without fiber to buffer the sugar load, the natural fructose in, say, an orange, is a very different animal. A cup of juice can be equivalent to about four oranges—an amount you’d be pretty unlikely to eat in whole-fruit form. As for smoothies, they’re a step in the right direction since they contain the whole fruit—but research from Purdue University found that liquid calories aren’t as filling as chewable ones. And by blending fruit into a pulp, it’s easy to get more fructose than you’re bargaining for.

5. Cut the Condiments

Add-ons like ketchup, barbecue sauce, flavored vinegars, and some mustards (like honey mustards) can be loaded with sweetener. If you’re going to dress up your meal, read labels to be certain there are no surprises—Dijon mustard, apple cider vinegar, and hot sauce are usually good options. Or use produce: Pineapple salsa, Vidalia onions, and tomatoes are all simple additive-free ways of sweetening a plate.

6. Add Herbs, Spices, and Extracts

They’re flavorful and low-calorie additions to any meal. “Cinnamon, vanilla, ginger, and nutmeg are some of my favorite “sweet” spices,” says Alpert, who recommends adding them to oatmeal, yogurt, or even nuts. “Bonus point—a lot of spices also help regulate your blood sugar levels and can even reduce the amount of AGEs (advanced glycated endproducts) that result from too much sugar in your bloodstream,” she adds

While there is a general agreement that sugar intake is bad for heart health, this was not always the case. In the 1960s, when deaths from heart disease in the United States reached a peak, researchers were divided on the primary dietary contributors to the condition: sugar or fat? For years, studies blamed the latter, but recent research suggests the sugar industry may have played a pivotal role in which way the finger was pointing.

Researchers have uncovered a 50-year-old heart disease study that was funded by the sugar industry to shift the blame from sugar to fat.

Earlier this month, dentist-turned-researcher Dr. Christin Kearns, of the University of California-San Francisco (UCSF), and colleagues reignited the debate over the influence the food industry has over scientific research.
In JAMA Internal Medicine, the team published a report revealing the discovery of a study published in the 1960s that received funding from the Sugar Association - formerly the Sugar Research Foundation (SRF).
The problem? The SRF funding was not disclosed - mandatory conflict of interest disclosure was not introduced until the 1980s - and there is evidence that the researchers of the 50-year-old study were paid to shift the focus away from the harms sugar intake poses for heart health.
The study in question was published in The New England Journal of Medicine on July 27, 1967.
Conducted by three former nutritionists at Harvard Medical School in Boston, MA - Dr. Frederick Stare, Dr. Mark Hegsted, and Dr. Robert B. McGandy, who are now deceased - the research claimed that consumption of dietary fats, rather than sugar, was the primary cause of coronary heart disease (CHD).

The landing of 'Project 226'

In their report, Dr. Kearns and colleagues reveal the discovery of documents in public archives that show Drs. Stare and Hegsted were paid $6,500 - the equivalent of almost $50,000 today - by the SRF to detract attention away from previous studies linking sugar to CHD.
According to the UCSF researchers, the documents show that in 1964, John Hickson - then president of the SRF - penned a memo suggesting the SRF "embark on a major program" in order to redress "negative attitudes towards sugar," and one way he proposed doing so was to fund research to "refute our detractors."
One year later, Hickson commissioned Dr. Hegsted and colleagues to conduct "Project 226" - described by Hickson as "a review article of the several papers which find some special metabolic peril in sucrose."
Hickson provided Dr. Hegsted with a number of papers, and according to Dr. Kearns and team, the Harvard researchers "heavily criticized" studies that identified a link between sucrose - or table sugar - and coronary heart disease, while disregarding the limitations of studies that associated fat with the condition.
The study's conclusion? That lowering intake of fat is the only way to keep cholesterol levels low and prevent CHD. This, therefore, would suggest to the general population and policymakers that a high-sugar diet does not play a major role in CHD.
Commenting on their discovery, Dr. Kearns and co-authors say:

"Together with other recent analyses of sugar industry documents, our findings suggest the industry sponsored a research program in the 1960s and 1970s that successfully cast doubt about the hazards of sucrose while promoting fat as the dietary culprit in CHD."

Speaking to Medical News Today, Dr. Kearns said she was "surprised to learn the SRF began funding heart disease research as early as 1965 - and that their tactics to shift the focus off of sucrose were so sophisticated."
Marion Nestle, a professor of nutrition and food studies at New York University, who wrote an editorial accompanying Dr. Kearns' report, told MNT she was "shocked" by the discovery.
"Everyone knew that Fred Stare collected scads of money from food and drug companies and sounded like he worked for the food industry, but Mark Hegsted was another matter," she said. "I knew him as a scientist committed to finding effective dietary approaches to chronic disease and would never have imagined him working so closely with the sugar industry."

The continued influence of one biased study

The new revelation demonstrates how the sugar industry skewed the results of one study almost 50 years ago, but how is this relevant today?
That single study is likely to have influenced our diets ever since; the results were used in SRF marketing, and they even helped inform recommendations relating to diet and heart disease, many of which remain.

The sugar industry-funded study is likely to have influenced what we have eaten for decades.

Stanton Glantz, co-author of the UCSF research, explains that the industry-funded study was a major review published in an influential journal, so it "helped shift the emphasis of the discussion away from sugar and onto fat."
"By doing that, it delayed the development of a scientific consensus on sugar-heart disease for decades," he adds.
Report co-author Laura Schmidt, of UCSF, notes that saturated fat has been perceived as the main culprit in heart disease for years, but increasingly, light is being shed on the role of sugar.
A study published in the journal Progress in Cardiovascular Diseases earlier this year, for example, presented evidence that added sugar intake might be an even greater contributor to cardiovascular disease than saturated fat.
"After a thorough analysis of the evidence it seems appropriate to recommend dietary guidelines shift focus away from recommendations to reduce saturated fat and towards recommendations to avoid added sugars," said Dr. James J. DiNicolantonio, of Saint Luke's Mid America Heart Institute and co-author of the study.
While evidence of sugar's major role in heart disease is mounting, Schmidt notes that "health policy documents are still inconsistent in citing heart disease risk as a health consequence of added sugars consumption."

Industry-funded studies remain a problem

Today, researchers are required to disclose any conflicts of interest they may have, including any industry relationships and funding they have received - a regulation that was not in place in the 1960s, and a fact that The Sugar Association use in their defense in response to the UCSF discovery.
"We acknowledge that the Sugar Research Foundation should have exercised greater transparency in all of its research activities, however, when the studies in question were published, funding disclosures and transparency standards were not the norm they are today," the organization comments.

In some cases, such as with drug development, industry-funded research is beneficial.

But has the introduction of transparency standards in the 1980s reduced how much influence industries have over scientific research? It seems not.
Take the tobacco industry, for example. In a study published in the journal Circulation in 2007, Glantz and colleagues combed through millions of tobacco industry documents, many of which revealed how the tobacco industry funded studies in the 1990s to play down the harms of secondhand smoke exposure, in an attempt to stave off smoke-free laws.
In relation to the food industry, just last year, the New York Times revealed that Coca-Cola was funding the development of a nonprofit organization called Global Energy Balance Network (GEBN).
While GEBN claimed its aim was to conduct research into the causes of obesity, the organization widely claimed that it is lack of exercise, rather than an unhealthy diet, that causes weight gain.
"Most of the focus in the popular media and in the scientific press is that they're eating too much, eating too much, eating too much, blaming fast food, blaming sugary drinks and so on. And there's really virtually no compelling evidence that that in fact is the cause," Steven N. Blair, a member GEBN's executive committee said in a promotional video.
"Those of us interested in science, public health, medicine, we have to learn how to get the right information out there."
On this occasion, it seems the proposal that an unhealthy diet is not a cause of obesity - a claim backed by a soft drink giant - was shunned by healthcare professionals and the general public alike; in November 2015, GEBN ceased operation.
Still, industry-funded research continues - but why? Can it ever be beneficial?

Industry-funded research should be interpreted with caution

One area of research that does benefit from industry funding is drug development.
While grants from government organizations and charities enable some drug trials to go ahead, in the U.S., the bulk of funding comes from the pharmaceutical industry, with more than $30 billion a year spent on drug development.
Without pharmaceutical industry funding, many of the drugs we use today for common illnesses may not have been discovered. But that is not to say such funding isn't problematic; it can result in bias, with numerous studies showing that trials funded by the pharmaceutical industry are more likely to support the interest of the sponsor.
And according to Nestle, this type of bias is very much present in research funded by the food industry.
"In my casual year-long collection of 168 industry-funded studies, I found 12 with results that did not favor the sponsor's interest. Systematic studies come out with slightly higher percentages of unfavorable studies," Nestle told MNT.

"The science is usually done pretty well; it's the research question and the interpretation that seem most influenced. Research shows that investigators who take industry funding are unaware of the influence and bias their science inadvertently. This makes the problem exceptionally difficult to deal with."

Marion Nestle

Is there anything that can be done to reduce the effects of bias from food industry-funded research?
According to Dr. Kearns and colleagues, their recent discovery suggests policymakers should "consider giving less weight to food industry-funded studies and include mechanistic and animal studies, as well as studies appraising the effect of added sugars on multiple CHD biomarkers and disease development."
In her editorial, Nestle says the results emphasize that caution should be applied when interpreting the results of research funded by the food industry.
"May it serve as a warning not only to policymakers, but also to researchers, clinicians, peer reviewers, journal editors, and journalists of the need to consider the harm to scientific credibility and public health when dealing with studies funded by food companies with vested interests in the results," she adds, "and to find better ways to fund such studies and to prevent, disclose and manage potentially conflicted interests."
It is evident that the recent discovery of the sugar industry's role in heart disease research has left a bitter taste in the mouths of nutritionists, policymakers, and the general public. Whether it has the ability to change approaches to food industry-funded research, however, remains to be seen.

Written by Honor Whiteman

Caffeine May Help Treat Parkinson's Disease

 Caffeine has previously been linked to a lower risk of developing Parkinson's disease, but now new research says the ubiquitous stimulant may also help treat disease symptoms.

In a small study of 61 people with Parkinson's disease, Canadian researchers found that giving the caffeine equivalent of about three cups of coffee per day improved motor symptoms, such as slow movement and stiffness. Interestingly, caffeine didn't significantly improve daytime sleepiness, a common symptom in Parkinson's disease.
"Caffeine treats Parkinson's disease," said the study's lead author, Dr. Ronald Postuma, an associate professor in the department of neurology at McGill University in Montreal.
"There was a modest effect on sleepiness that didn't reach statistical significance, but I think it was clear that it helps patients," he said. "Where we saw the most potential benefit from caffeine was on motor aspects and symptoms. People felt better and were more energetic. You could see on the exam that they were better."
Parkinson's disease is a degenerative disorder that causes shaking, stiffness, slow movements and difficulty with balance. More than one million Americans have Parkinson's disease, and more than 50,000 people are diagnosed with the disease each year, according to the National Parkinson Foundation.
In the current study, published in the Aug. 1 online edition of the journal Neurology, half of the group of Parkinson's patients was randomly assigned to receive caffeine treatment, while the other half received an inactive placebo.
To be included in the study, the volunteers had to consume less than 200 milligrams (mg) of caffeine daily -- about two cups of coffee -- and they couldn't have any heart rhythm problems, uncontrolled high blood pressure, or an active ulcer.
For the first three weeks of the study, those receiving caffeine were given 100 mg of caffeine twice daily -- once when they got up and again at lunchtime.
During the second three weeks, the dose was increased to 200 mg twice daily.
Using a test called the Epworth Sleepiness Scale score, the researchers found that while there was a reduction in this score for those treated with caffeine, indicating less daytime sleepiness, that decrease didn't reach statistical significance. Still, Postuma said he believed that caffeine did help improve the level of daytime sleepiness, and that with a bigger study group, a benefit would likely become clearer.
Motor symptoms were judged using the Unified Parkinson's Disease Rating Scale score. There was a modest overall improvement of 5 points in this score.
In addition, there were improvements in the speed of movement and the amount of stiffness in the treatment group versus the placebo group.
"[This study] is important even though it failed to reveal a benefit for caffeine in improving sleepiness in Parkinson's disease. Interestingly, it did reveal a clinically significant potential motor benefit," said Dr. Michael Okun, national medical director of the National Parkinson Foundation. "It will be interesting to see if these findings hold up, and caffeine becomes a treatment approach in Parkinson disease," he added.
Postuma said the mechanism behind coffee's effect on Parkinson's symptoms isn't yet known, but it's believed to block receptors of a substance called A2A adenosine that may play a role in some Parkinson's symptoms. Two new drugs that block A2A adenosine receptors and work in a very similar manner to caffeine are currently in development, he said.
"Their results are almost the same as what we're getting. They may be making and selling expensive caffeine," Postuma said.
"One interesting aspect about the actions of caffeine in Parkinson's disease is that they are thought to be mediated through blocking the A2A adenosine brain receptor. There are several drugs in Parkinson's trials that have similar mechanisms of action, and it would be interesting to perform head-to-head trials comparing caffeine to these drugs," Okun said.
Postuma would like to conduct larger trials on caffeine to see if the effects of the stimulant wear off over time.
The good news, he said, is that caffeine is "incredibly safe and well-tolerated."
So, "if you've been avoiding caffeine because you think it's bad, you can stop. If you're sleepy during the day, you can try it," Postuma said. People with heart rhythm problems, uncontrolled high blood pressure or active ulcers should talk with their doctors about whether they should have caffeine in their diet, however.
Home-brewed coffee tends to have less caffeine than what you get at a coffee shop, Postuma noted. Most people shouldn't go over 400 mg to 500 mg a day (about four to five cups), he advised. And, if you don't want caffeine to interrupt your sleep, try to have your last cup of coffee with lunch.

A number of studies have suggested caffeine has the potential to slow Parkinson's disease. Now, researchers have built on these findings, creating caffeine-based compounds that could halt the protein clumping associated with Parkinson's development.

Researchers have developed caffeine-based compounds that show promise for slowing the progression of Parkinson's disease.

Parkinson's disease is a progressive neurological disorder estimated to affect almost 1 million people in the United States.
Signs and symptoms of Parkinson's include tremors - particularly in the hand or fingers - slowed movement, muscle rigidity, speech problems, and impaired balance and coordination.
While the precise causes of Parkinson's remain unclear, there is mounting evidence that a protein called alpha-synuclein (a-synuclein) plays a role.
Studies have shown that in the brains of Parkinson's patients, a-synuclein misfolds to form protein clumps called Lewy bodies, which accumulate in and destroy dopamine-producing cells of the substantia nigra - the brain region involved in movement.
The resulting reduction in dopamine - a neurotransmitter that helps regulate movement - leads to the impaired motor control characteristic of Parkinson's.
As such, researchers have been investigating ways to block a-synuclein accumulation as a strategy to prevent Parkinson's or slow its progression.
In the new study, co-author Jeremy Lee, of the University of Saskatchewan College of Medicine in Canada, and colleagues reveal the development of two caffeine-based compounds that they say could stop a-synuclein from clumping.

Two 'bifunctional dimers' stopped a-synuclein clump formation

According to Lee, the majority of drug compounds in development for Parkinson's have focused on increasing dopamine production of surviving nerve cells, "but this is effective only as long as there are still enough cells to do the job," he notes.

Fast facts about Parkinson's

• Around 60,000 Americans are diagnosed with Parkinson's each year
• Men are 1 ½ times more likely to develop Parkinson's than women
• More than 10 million people across the globe are living with Parkinson's.

Learn more about Parkinson's

For their study - published in the journal ACS Chemical Neuroscience - Lee and team took a different approach; they set out to identify ways to protect dopamine-producing cells by halting the misfolding of a-synuclein.
Previous research has identified caffeine - a central nervous system stimulant present in coffee, tea, and cola - as having a protective effect against Parkinson's disease.
With this in mind, the team used a "caffeine scaffold" to create eight new compounds called "bifunctional dimers," which are molecules that connect two different substances that affect dopamine-producing cells.
Alongside caffeine, other compounds tested included nicotine, metformin (a drug used to treat diabetes), and aminoindan (an investigative drug similar to the Parkinson's drug rasagiline).
The team applied the dimers to a yeast model of Parkinson's disease, which is a yeast cell line that expresses a-synuclein-green fluorescent protein (AS-GFP).
From this, the researchers identified two caffeine-based compounds - referred to as C8-6-I and C8-6-N - that bind to a-synuclein and stop the protein misfolding and forming clumps.
At present, there is no cure for Parkinson's, only medications that can help patients manage symptoms of the disease. According to the authors, these new findings could pave the way to much-needed strategies to prevent or slow the disease.

"Our results suggest these novel bifunctional dimers show promise in preventing the progression of Parkinson's disease."

Jeremy Lee

Lee and colleagues now plan to test their novel compounds in mouse models of Parkinson's.
Learn how a new protein test could enable early Parkinson's diagnosis.

Written by Honor Whiteman

 

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting approximately 1% of the population older than 60 years. Classically, PD is considered to be a motor system disease and its diagnosis is based on the presence of a set of cardinal motor signs (rigidity, bradykinesia, rest tremor) that are consequence of a pronounced death of dopaminergic neurons in the substantia nigra pars compacta. Nowadays there is considerable evidence showing that non-dopaminergic degeneration also occurs in other brain areas which seems to be responsible for the deficits in olfactory, emotional and memory functions that precede the classical motor symptoms in PD. The present review attempts to examine results reported in epidemiological, clinical and animal studies to provide a comprehensive picture of the antiparkinsonian potential of caffeine. Convergent epidemiological and pre-clinical data suggest that caffeine may confer neuroprotection against the underlying dopaminergic neuron degeneration, and influence the onset and progression of PD. The available data also suggest that caffeine can improve the motor deficits of PD and that adenosine A2A receptor antagonists such as istradefylline reduces OFF time and dyskinesia associated with standard 'dopamine replacement' treatments. Finally, recent experimental findings have indicated the potential of caffeine in the management of non-motor symptoms of PD, which do not improve with the current dopaminergic drugs. Altogether, the studies reviewed provide strong evidence that caffeine may represent a promising therapeutic tool in PD, thus being the first compound to restore both motor and non-motor early symptoms of PD together with its neuroprotective potential.

 

coffee may reduce risk of dementia

 

A cup of coffee a day may not entirely keep the doctor away, but new research indicates women who drink caffeine may reduce the odds of developing dementia.

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"I hope that it's true because we have a real problem in my family with dementia, so if this is true hopefully I'm ahead of the curve," tea drinker Sister Patricia Rogers said.
VIDEO: Coffee may reduce risk of dementia
The study was done at UW-Milwaukee, where researchers said they can make a direct link between higher consumption of caffeine and lower incidents of dementia.
Among a group of older women, who drank two to three eight-ounce cups of coffee a day, or five to eight cups of black tea or seven to eight 12-ounce cans of cola, reported a 36 percent reduction in the risk of dementia over 10 years.
"I'm excited about it because anything that helps stave off dementia would be an awesome thing," coffee drinker Sister Stella Storch said.
But Sathena Gillespie said her grandmother has been drinking coffee forever, and she's suffering right now.
"She is, she has dementia, and she's actually transitioning into Alzheimer's," Gillespie said.
Still, Gillespie plans to continue serving and drinking coffee.
The researchers at UW-Milwaukee were unavailable for comment.

Today is International Coffee Day, and what better way to celebrate than providing our readers with some positive news about one the nation's favorite hot drinks; a new study suggests that older women who drink two to three cups of coffee daily may be at lower risk of dementia and other forms of cognitive impairment.

Women who consumed the equivalent of two to three cups of coffee daily were found to be at lower risk of dementia and cognitive impairment.

Researchers have long suggested that caffeine - a mild stimulant present in coffee, tea, and cola - has cognitive benefits.
A study published in the journal Nature Neuroscience in 2014, for example, identified a link between coffee intake and improved long-term memory.
The new findings - recently published in The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences - offer further evidence of caffeine's brain benefits, after finding the stimulant may help to stave off cognitive decline in later life.
The results come from an analysis of 6,467 women aged 65 and older who were part of the Women's Health Initiative Memory Study (WHIMS) - a study funded by the National Heart, Lung, and Blood Institute.
"What is unique about this study is that we had an unprecedented opportunity to examine the relationships between caffeine intake and dementia incidence in a large and well-defined, prospectively studied cohort of women," notes lead author Ira Driscoll, Ph.D., a professor of psychiatry at the University of Wisconsin-Milwaukee.

Higher caffeine intake reduced risk of cognitive impairment, dementia

Driscoll and team analyzed the participants' caffeine intake, as determined through self-reported consumption of tea, coffee, and cola.

Fast facts about coffee

• Around 54 percent of American adults drink coffee every day
• Coffee drinkers consume an average of 3.1 cups daily
• The U.S. spends around $40 billion on coffee every year.

Learn more about coffee

During up to 10 years of follow-up, all subjects underwent annual cognitive assessments, which the researchers analyzed to pinpoint a diagnosis of probable dementia or other forms of cognitive impairment. A total of 388 women received such diagnoses.
Compared with women who consumed a low amount of caffeine (defined in the study as less than 64 milligrams daily), those who consumed a higher amount (more than 261 milligrams daily) were found to be at 36 percent reduced risk of a diagnosis of probable dementia or cognitive impairment.
The researchers note that 261 milligrams of caffeine is the equivalent of two to three 8-ounce cups of coffee daily, or five to six 8-ounce cups of black tea.
The team's findings remained even after accounting for a number of possible confounding factors, including age, race, body mass index (BMI), smoking status, alcohol intake, depression, high blood pressure, sleep quality, and history of cardiovascular disease.
The authors say that their study is unable to establish a direct association between caffeine intake and reduced dementia risk, nor are they able to generalize the findings to men.
Still, the researchers believe that their study brings us closer to understanding how caffeine might benefit cognitive health, and it paves the way for future research into this association.
The authors conclude:

"Although more studies are needed to verify the consistency of reports, given that caffeine intake is easily modifiable, it is important to quantify its relationship with cognitive health outcomes not only from preventive standpoint but also to better understand the underlying mechanisms and their involvement in dementia and cognitive impairment.
Given that AD [Alzheimer's disease] prevalence is expected to quadruple by 2050, even a small reduction in age-related cognitive impairment or dementia burden would thereby have significant public health implications."

Why might coffee have cognitive benefits?

Medical News Today asked Driscoll what she believes are the underlying mechanisms that might explain caffeine's potential cognitive benefits.
"The potential protective effect of caffeine is thought to occur primarily through the blockade of adenosine A2A receptors (ARs), whose expression and function become aberrant with both normal aging and age-related pathology," she replied.

"Adenosine acts by facilitating A2A and acting on the inhibitory A1 receptors to integrate dopamine, glutamate, and brain-derived neurotrophic factor signaling, thereby modulating synaptic plasticity in regions relevant to learning and memory and providing the molecular and cellular basis for AR role in modulating cognition," she added.
Additionally, Driscoll said that ARs are being increasingly investigated as a target for reversing cognitive impairment; studies have shown that blocking these receptors can reverse Alzheimer's and other neurodegenerative disorders in animal models.
While the findings may be welcome news for coffee drinkers, Driscoll told MNT that women should not increase their coffee intake based on the results.
"It remains unknown if this holds primarily for caffeine derived from coffee or other dietary sources," she said, "and we are certainly not suggesting that more is better."
Learn how our genes might influence how much coffee we drink.

Written by Honor Whiteman

Coffee Drinking Lowers Risk Of Parkinson’s, Type 2 Diabetes, Five Cancers

 

Harvard University Staff Writer Alvin Powell reports that Harvard scientists have had coffee under the microscope for years, and last year announced the discovery of six new human genes that relate to coffee, reconfirming existence of two others previously identified. The long-running Harvard Nurses Health Study has found that coffee has protective qualities against type 2 diabetes and cardiovascular disease, and investigators are revisiting a 2001 study finding that it can also protect against Parkinson’s disease.
Powell notes that this research at Harvard is just part of an emerging body of evidence that coffee is a potentially powerful biochemical agent against a range of ailments, from cancer to dental caries.
Powell cites Sanjiv Chopra, a professor of medicine at Harvard Medical School and Harvard-affiliated Beth Israel Deaconess Medical Center, saying he has been so impressed by these revelations that he’s become something of a “coffee evangelist.” Dr. Chopra included a chapter on coffee in his 2010 book, Live Better, Live Longer, in which he tells his readers that by drinking coffee “You’re doing your liver a big favor [and] coming from me, a liver specialist, that is high praise indeed.” Dr. Chopra acknowledges that in the past, drinking too much coffee had been supposedly linked to a variety of health problems including heart attacks, birth defects, pancreatic cancer, osteoporosis, and miscarriages, and says we do know coffee can cause insomnia, tremors, raise blood pressure and increase urination. However, he maintains that “more recent evidence indicates that rather than being dangerous, coffee may also offer substantial benefits, including protection against heart disease, Type 2 diabetes, liver cirrhosis, Parkinson’s disease, cavities, colon cancer, prostate cancer, and even suicide. It is known to bring relief for asthma, increase endurance and concentration… and increase the absorption of other medications…. And contrary to conventional wisdom, it appears to lower the risk of being hospitalized for an arrhythmia.”
Powell notes that Dr. Chopra first became aware of the potentially powerful protective effects of coffee when a study revealed that consumption lowers levels of liver enzymes and protects the liver against cancer and cirrhosis. When he began asking students, residents, and colleagues on the liver unit to quiz patients about their coffee habits, they found consistently that none of the patients with liver ailments were coffee drinkers.
Dr. Chopra personally drinks several cups of coffee a day, and encourages others to do likewise, and while other researchers are more conservative in their dietary recommendations, they’re convinced enough to continue investigations into coffee’s health benefits.
Meanwhile, Professor of Epidemiology and Nutrition at the Harvard T.H. Chan School of Public Health and professor of medicine at Harvard Medical School Alberto Ascherio, a has been studying coffee’s potential anti-Parkinson’s effects that were first suggested in the 2001 study’s findings. That study, of which Dr. Ascherio was lead author, showed that drinking four or five cups of coffee daily cut risk of developing Parkinson’s Disease nearly in half compared with little or no caffeine consumption.
The study was published in the journal Annals of Neurology, entitled “Prospective study of caffeine consumption and risk of Parkinson’s disease in men and women” (Ann Neurol. 2001 Jul;50(1):56-63) coauthored by Dr. Ascherio with S.M. Zhang, M.A. Hernn, I. Kawachi, G.A. Colditz, F.E. Speizer, and W.C. Willett, who noted that while results of case-control studies and a prospective investigation suggest that coffee consumption could protect against Parkinson’s disease (PD) risk, the active constituent is unclear, so to address the hypothesis that caffeine is protective against Parkinson’s disease, they examined the relationship of coffee and caffeine consumption to the risk of PD among participants in two ongoing cohorts, the Health Professionals’ Follow-Up Study (HPFS) and the Nurses’ Health Study (NHS). The study population comprised 47,351 Parkinson’s disease free men and 88,565 women who were also free of, stroke, or cancer at baseline. A comprehensive lifestyle and dietary questionnaire was completed by study participants at baseline and updated every two to four years. During the follow-up (10 years in men, 16 years in women), the investigators documented a total of 288 incident cases of Parkinson’s disease. Among men, after adjustment for age and smoking, relative risk of Parkinson’s disease was 0.42 for men in the top one-fifth of caffeine intake compared to those in the bottom one-fifth. An inverse association was also observed with consumption of coffee, caffeine from noncoffee sources , and tea but not for decaffeinated coffee. Among women, the relationship between caffeine or coffee intake and risk of Parkinson’s disease was U-shaped, with lowest risk observed at moderate intakes (1-3 cups of coffee/day, or the third quintile of caffeine consumption) — results that support a possible protective effect of moderate doses of caffeine on Parkinson’s disease risk.
Powell says that currently the Harvard research group’s focus is on identification of causes, risk factors (positive and negative), biomarkers of susceptibility and early diagnosis of multiple sclerosis (MS), Parkinson’s disease, and Amyotrophic Lateral Sclerosis (ALS). Due to of their progressive and disabling nature, these diseases inflict major adverse personal, social, and economic consequences on persons who develop them, with prevention and early detection critical, because there are no cures for any of these neuromuscular disorders and clinical diagnoses typically occur after substantial and often irreversible neuronal loss has been incurred, at which point any neuroprotective interventions applied will probably be too late to be fully effective.
Powell reports that Harvard Professor of Nutrition and Epidemiology and Professor of Medicine Frank Hu, who leads the diabetes section of the long-running Nurses Health Study, has also become interested in whether coffee drinking affects total mortality. “I’m not a huge coffee drinker, two to three cups a day, Hu said. [But] I like it and, thinking about the extra benefits, thats comforting.
In a Harvard video entitled “How Coffee Loves Us Back” Dr. Ascherio says coffee drinkers have an approximately 10 to 15 percent lower mortality rate, which he attributes to the antioxidant and anti-inflammatory chemicals in coffee, such as chlorogenic acid which is one of the richest antioxidants. Dr. Chopra observes that coffee consumption seems to diminish the risk of developing five different types of cancer, and the positive effect is not realized from the caffeine content in tea, so it’s “something about coffee,” and says if you start with half a cup a day and work yourself up to two cups, “you’re all set.”

Powell notes that last year, a team led by then research associate at the Harvard T.H. Chan School of Public Health Marilyn Cornelis, who is currently an assistant professor at Northwestern University’s Feinberg School of Medicine, traced coffee’s relationship to the human genome, discovering the six new genes related to coffee consumption and reconfirming two others found earlier referred to above. The six genes included two related to metabolism, two related to coffee’s psychoactive effects, and two whose exact purpose in coffee consumption is unclear, presenting a possible avenue of investigation, but which are related to lipid and glucose metabolism.
The findings were published last year in the journal Molecular Psychiatry in a paper entitled “Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption” (Molecular Psychiatry 20, 647-656 (May 2015) | doi:10.1038/mp.2014.107). in which The Coffee and Caffeine Genetics Consortium coauthors note that they conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in 30,062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis, and the investigators report that genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.
In another Harvard report, Dr. Cornelis says that while there has been disagreement over coffee’s health effects in the past, evidence of its benefits has been mounting, so much so that she herself, who says she hates the taste of coffee, has been persuaded to try cultivating the habit. You can find out more about Dr. Cornelis’s research on health effects of coffee here.
Daniel Chasman, an associate professor of medicine at Harvard Medical School and an associate geneticist at Harvard-affiliated Brigham and Womens Hospital, who worked with Dr. Cornelis on the study, said caffeine consumption habits are highly heritable and that the genes they found appear to explain about 7 percent of the heritability. Thats a significant amount, he said, considering how strong an influence culture also plays on coffee consumption.
Powell concludes that while the links between coffee and better health are becoming considerably clearer, the exact agent or agents that confer the benefit remain an unanswered question, but caffeine alone does not explain the effects, not least because some of the benefits are seen even with decaf, prompting researchers to focus attention on the many other active bioactive compounds in your morning cup.
Other findings of Harvard research on coffee include a 2005 study that found no link between higher blood pressure and coffee and actually some suggestion that it lowers blood pressure, and a 2011 study that found regular coffee drinking was linked to lower prostate cancer risk. Another
2011 study showed that drinking four or more cups of coffee daily lowered rates of depression among women, while a 2012 study linked three cups a day coffee consumption to a 20 percent lower risk of basal cell carcinoma, and a 2013 Harvard study linked coffee consumption to reduced suicide risk.
A 2013 Harvard meta analysis of 36 studies covering more than a million people found that even heavy coffee consumption did not increase risk of cardiovascular disease and that drinking three to five cups of coffee daily provided the most protection against cardiovascular disease.
Finally, in 2014, Harvard Chan School researchers found that increasing coffee consumption by more than a cup a day over a four-year period reduced type 2 diabetes risk by 11 percent, and that those who decreased their coffee consumption by more than a cup a day increased their type 2 diabetes risk by 17 percent.

Parkinson’s Disease (PD) is a debilitating neurodegenerative disorder. In Europe, almost 1.2 million people are estimated to have PD, with about 75,000 new cases diagnosed every year⁴⁸. The age of onset of PD is usually over 60, but it is estimated that one in ten people are diagnosed before the age of 50, with slightly more men than women affected⁴⁹.
The cardinal features of Parkinson’s disease are the slowing down of motor function, resting tremor, muscular rigidity, gait disturbances, and postural reflex impairment. The underlying pathological lesion is the progressive destruction of dopaminergic neurons in the midbrain. There is currently no available treatment to either prevent or slow down this neuronal loss and the resulting dopamine decrease in the midbrain.
Experimental and epidemiological research has focused on lifestyle, dietary and environmental risk factors, including coffee consumption.
Coffee, caffeine and risk of Parkinson’s disease
A large number of epidemiological studies report an inverse, dose-responsive relationship between coffee/caffeine consumption and the risk of developing PD. Coffee consumption appears to reduce or delay the development of PD and caffeine is most likely the causal factor. In women, however, the interaction between caffeine and hormonal therapy still needs further clarification.
As early as 1968, a study reported a higher percentage of non-coffee consumers in the control compared to the affected group⁵⁰.
Subsequent studies performed in Spain⁵¹, Sweden⁵² and Germany⁵³ found an inverse relationship between coffee consumption and PD, and a lower coffee consumption before disease onset.
The first prospective study on 8,004 Japanese American men living in Hawaii (the Honolulu Heart Program), carried out over a median duration of 27 years, reported an inverse association between PD incidence with a five-fold reduced risk for those drinking more than four cups of coffee per day when compared to non-consumers. The same inverse relationship was shown for caffeine from non-coffee sources⁵⁴.
However, a case control study published in 2014 suggested only a weak inverse association between coffee intake and the risk of PD⁵⁵.
Two meta-analyses, including 20 and 26 studies respectively, reported that the global risk of developing PD decreased by 31% (relative risk 0.69)⁵⁶ and 25% (relative risk 0.75) in coffee drinkers compared to non-coffee drinkers⁵⁷. Some of the individual studies found very strong risk reductions, up to 80% with the consumption of over 4 cups of coffee per day. The second meta-analysis found that the overall risk of developing PD fell by 24-32% per 300 mg increase in caffeine intake (i.e. with every 3 cups of coffee, approximately). These data confirm an inverse association between caffeine intake and the risk of PD which can hardly by explained by bias or uncontrolled confounding^56,57.
In an additional 2013 dose, response meta-analysis showed a linear relationship between risk reduction of PD with tea and caffeine consumption, however, the association with coffee intake reached a maximum at approximately 3 cups of coffee a day⁵⁸.
In women, the data are more equivocal. One study found a U-shaped relation, with moderate consumption of coffee/caffeine being the most protective⁵⁹.
A further study performed on 77,713 women, followed up for 18 years, reported that in those not taking postmenopausal hormones, coffee was as protective against PD as in men. In women taking estrogens, the risk for PD was similar to men in case of low coffee consumption, but significantly increased four-fold in women drinking 6 or more cups of coffee a day when compared to non-coffee drinkers⁶⁰.
A case-control study, part of the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), did not find convincing evidence that variations in the genes coding for caffeine metabolism (CYP1A2 and NAT2) or estrogen receptors (ESR1 and ESR2) could predict the risk of PD linked to hormone replacement therapy use⁶¹.
A randomised control trial published in 2012 evaluated the effects of caffeine intake on the symptoms of PD, including daytime somnolence, motor severity and other non-motor features.  The results showed improved objective motor measures, but only equivocal effects of caffeine on somnolence in PD; further evidence is required⁶².
A review of 304,980 participants in the National Institutes of Health-AARP Diet and Health Study suggested that higher caffeine intake was associated with subsequent lower PD risk in both men and women. The authors conducted a meta-analysis of prospective studies and confirmed that caffeine intake was inversely associated with PD risk in both men and women and suggested that there was no gender difference in the relation between caffeine and PD⁶³.
Additionally, a prospective study published in 2012 confirmed previous findings showing a protective effect of caffeine on PD risk, with an attenuating influence of HRT in women. Consumption of decaffeinated coffee was not associated with a reduced risk of PD⁶⁴.
Mechanism of action
Experimental studies have identified a mechanism of action for caffeine’s preventative role in the development of PD.
Low doses of caffeine antagonize mainly adenosine A2A receptors, which are located with D2 dopaminergic receptors in the striatum, i.e. the cerebral region involved in the control of locomotion and movement and in which dopaminergic neurontransmission is dramatically impaired in patients with PD. In the striatum, the blockade of A2A receptors increases motor activity and improves motor deficits in models of PD, via the stimulation of D2 receptors^{65, 66}.
In animals, caffeine counteracts the symptoms of PD induced in rats and mice and enhances the effects of the classical treatment of PD, the precursor of dopamine, L-DOPA^67,68.
Data obtained from several preclinical studies point to the beneficial effects of chronic A2A receptor antagonists (such as caffeine) on PD motor disability and on motor complications produced by long-term L-DOPA treatment, suggesting that they will be effective in the symptomatic treatment of PD58.
Moreover, the A2A antagonists, including caffeine and D2 agonists, have neuroprotective properties and can attenuate the degeneration of dopaminergic cells in various animal models^{57, 69}.

Breakthrough in mapping nicotine addiction could help researchers improve treatment

 

A scientific blueprint to end tobacco cravings may be on the way after researchers crystallized a protein that holds answers to how nicotine addiction occurs in the brain.

The breakthrough at the Peter O'Donnell Jr. Brain Institute comes after decades of failed attempts to crystallize and determine the 3D structure of a protein that scientists expect will help them develop new treatments by understanding nicotine's molecular effects.
"It's going to require a huge team of people and a pharmaceutical company to study the protein and develop the drugs, but I think this is the first major stepping stone to making that happen," said Dr. Ryan Hibbs, Assistant Professor of Neuroscience and Biophysics with the O'Donnell Brain Institute at UT Southwestern Medical Center, who co-authored the findings published in Nature.
The protein, called the α4β2 (alpha-4-beta-2) nicotinic receptor, sits on nerve cells in the brain. Nicotine binds to the receptor when someone smokes a cigarette or chews tobacco, causing the protein to open a path for ions to enter the cell. The process produces cognitive benefits such as increased memory and focus but is also highly addictive.
Until the new findings were generated, scientists didn't have a way to examine at atomic resolution how nicotine achieves these cognitive and addictive effects.
Who will benefit?
The expectation is that the 3D structures will help researchers understand how nicotine influences the activity of the receptor and lead to a medication that mimics its actions in the brain.
The finding may also have benefits in creating medications for certain types of epilepsy, mental illness, and dementia such as Alzheimer's, which are also associated with the nicotinic receptor. However, Dr. Hibbs cautioned that testing of any ensuing treatment would likely take many years.
Studies have shown smoking cessation drugs have mixed results in treating nicotine addiction, as have other methods such as nicotine patches and chewing gum.
"I just cannot quit smoking," said Tom Loveless of Dallas, who has tried many times to kick his cigarette habit after becoming addicted 40 years ago while in the Air Force.
He found the study's findings encouraging and hopes one day scientists can find a way to beat nicotine addiction. "I hate what it does to me," said Mr. Loveless, a retired 65-year-old grandfather. "I hate the expense. I hate the odor. It upsets my wife. It isn't worth it."
Motivating Factors
Despite widespread education on the dangers of tobacco use, it still causes nearly 6 million deaths per year worldwide, with smoking the leading cause of preventable death, according to the U.S. Centers for Disease Control and Prevention. Cigarettes alone account for 1 in 5 deaths annually in the U.S.
Those statistics are among the motivating factors for Dr. Hibbs, whose laboratory team began researching how to determine the structure of the receptor in 2012.
The receptor is "a critically important therapeutic target" for addiction and various mental and neurological disorders, said Dr. Joseph Takahashi, Chairman of Neuroscience and Investigator for the Howard Hughes Medical Institute.
"This is a major advance and solves a longstanding problem in crystallizing" the nicotinic receptor, said Dr. Takahashi, who holds the Loyd B. Sands Distinguished Chair in Neuroscience.
How they did it
For years scientists around the globe had concentrated efforts on the receptor found in the electric organ of a torpedo ray, a rich source of nicotinic receptors that yielded a wealth of biochemical information and held promise for obtaining a high-resolution atomic map of the protein.
"But they were never able to get the torpedo protein to crystalize," Dr. Hibbs said, explaining that the protein from the ray proved too unstable and couldn't be genetically modified. "Many very good research groups had tried to do this and failed. We took a different approach."
Instead, UT Southwestern researchers developed a method for mass producing nicotinic receptors by viral infection of a human cell line. The team inserted genes encoding the proteins that make the receptor into the virus, and the infected human cells started producing large amounts of the receptor.
They then used detergent and other purification steps to separate the receptor from the cell membrane and wash away all other proteins. Researchers were left with milligrams of the pure receptor that they mixed with chemicals known to promote crystallization.
The team looked at thousands of chemical combinations before eventually being able to grow crystals of the receptor, bound by nicotine and about 0.2 mm long. Lastly, they used X-ray diffraction measurements to obtain a high-resolution structure of the receptor.
The team's next steps involve determining structures in the absence of nicotine, and in the presence of molecules with different functional effects. Comparisons between structures will allow them to understand better what nicotine does, and how its actions are distinct from those of other chemicals, said Dr. Hibbs, Effie Marie Cain Scholar in Medical Research.

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Materials provided by UT Southwestern Medical Center. Note: Content may be edited for style and length.

In a piece of good news for people trying to quit smoking, researchers have crystallized a protein that they hope will show what happens in the brain when a person becomes addicted to nicotine.

Nicotine is a highly addictive drug.

Scientists expect the findings - published in Nature - to eventually lead to new treatments.
In the United States, 1 in 5 deaths are attributed to smoking, and tobacco use is responsible for nearly 6 million deaths globally every year.
Smoking is the number one cause of preventable death in the U.S., according to the Centers for Disease Control and Prevention (CDC).
Existing drugs, nicotine patches, and chewing gum have had mixed success in helping people to quit using nicotine products.
For decades, scientists have been trying to identify the 3-D structure of a protein known as the alpha-4-beta-2 (α4β2) nicotinic receptor.
Until now, there has been no way to study nicotine's effects on the brain, and how it becomes addictive, at the atomic level.
The current breakthrough should lead to a new understanding of the molecular effects of nicotine.
The α4β2 nicotinic receptor is located on nerve cells in the brain. When a person smokes a cigarette or chews tobacco, the nicotine binds to this receptor. This opens a pathway for ions to enter the cell.
There are cognitive benefits, including an enhancement of memory and focus, but it is also very addictive.

Searching for clues in the torpedo ray

For years, teams from around the world have been expecting the torpedo ray to provide the clues they needed to understand how this protein works.
The ray's electric organ is known to be a rich source of nicotinic receptors, and it provided a wealth of key information. However, the close-up view the scientists craved remained elusive.

Fast facts about nicotine

• More people in the U.S. are addicted to nicotine than any other drug
• Nicotine may be as addictive as heroin, cocaine, or alcohol
• Nicotine withdrawal can trigger stress, weight gain, and irritability.

Learn more about nicotine

The protein from the ray was too unstable. It could not be genetically modified, and it would not crystallize.
The present team tried a new strategy; they found a way to produce large numbers of nicotinic receptors by infecting a human cell line with a virus.
They inserted genes into the virus, and these genes encoded the required proteins. The cells that were infected with the virus began to produce large amounts of the receptor.
Using detergent and other methods of purification, the researchers separated the receptor from the cell membrane, and they eliminated all the other proteins. They were left with milligrams of the pure receptor.
Next, they mixed the receptor with chemicals that normally promote crystallization. They looked at thousands of chemical combinations, and they finally succeeded in growing crystals of the receptor.
The crystals were bound by nicotine, and they measured around 0.2 millimeters in length.
To obtain a high-resolution structure of the receptor, the researchers used X-ray diffraction measurements.
The next step will be to look at the structures when there is no nicotine, and when molecules with different functional effects are applied.
Comparing the structures in this way is expected to shed light on how nicotine acts and what it does differently from other chemicals.

Possible future applications

Study co-author Dr. Ryan Hibbs, assistant professor of neuroscience and biophysics with the O'Donnell Brain Institute at the University of Texas Southwestern Medical Center in Dallas, notes that it could take years to develop and test any treatment.

"It's going to require a huge team of people and a pharmaceutical company to study the protein and develop the drugs, but I think this is the first major stepping stone to making that happen."

Dr. Ryan Hibbs

Other conditions linked to the nicotinic receptor include some types of epilepsy, mental illness, and dementia - for example, Alzheimer's disease. These, too, could benefit from the discovery.
Find out how nicotine has been proposed as a possible way to prevent brain aging.

Written by Yvette Brazier

Cigarette smoking remains a leading cause of preventable disease and premature death in the United States and other countries. On average, 435,000 people in the United States die prematurely from smoking-related diseases each year; overall, smoking causes 1 in 5 deaths. The chance that a lifelong smoker will die prematurely from a complication of smoking is approximately 50%.¹

Tobacco use is a major cause of death from cancer, cardiovascular disease, and pulmonary disease. Cigarette smoking is also a risk factor for respiratory tract and other infections, osteoporosis, reproductive disorders, adverse postoperative events and delayed wound healing, duodenal and gastric ulcers, and diabetes. In addition, smoking has a strong association with fire-related and trauma-related injuries. Smoking-caused disease is a consequence of exposure to toxins in tobacco smoke. Although nicotine plays a minor role, if any, in causing smoking-induced diseases, addiction to nicotine is the proximate cause of these diseases.

Currently, about 45 million Americans smoke tobacco. Seventy percent of smokers say they would like to quit, and every year, 40% do quit for at least 1 day.² Some highly addicted smokers make serious attempts to quit but are able to stop only for a few hours.³ Moreover, the 80% who attempt to quit on their own return to smoking within a month, and each year, only 3% of smokers quit successfully. Unfortunately, the rate at which persons — primarily children and adolescents — become daily smokers nearly matches the quit rate, so the prevalence of cigarette smoking has declined only very slowly in recent years.²

This article focuses on nicotine as a determinant of addiction to tobacco and the pharmacologic effects of nicotine that sustain cigarette smoking. Tobacco addiction (like all drug addictions) involves the interplay of pharmacology, learned or conditioned factors, genetics, and social and environmental factors (including tobacco product design and marketing)⁴ (Fig. 1). The pharmacologic reasons for nicotine use are enhancement of mood, either directly or through relief of withdrawal symptoms, and augmentation of mental or physical functions.

Figure 1

The Biology of Nicotine Addiction

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BRAIN MECHANISMS

NICOTINIC ACETYLCHOLINE RECEPTORS

Inhalation of smoke from a cigarette distills nicotine from the tobacco in the cigarette. Smoke particles carry the nicotine into the lungs, where it is rapidly absorbed into the pulmonary venous circulation. The nicotine then enters the arterial circulation and moves quickly from the lungs to the brain, where it binds to nicotinic cholinergic receptors (ligand-gated ion channels that normally bind acetylcholine). The binding of nicotine at the interface between two subunits of the receptor opens the channel, thereby allowing the entry of sodium or calcium.⁵ The entry of these cations into the cell further activates voltage-dependent calcium channels, allowing more calcium to enter. One of the effects of the entry of calcium into a neuron is the release of neurotransmitters.

The nicotinic cholinergic receptor consists of five subunits.⁶ The mammalian brain expresses nine α subunits (α₂ through α₁₀) and three β subunits (β₂ through β₄). The most abundant receptors are α₄β₂, α₃β₄, and α₇, the latter of which are homomeric. The α₄β₂^* receptor (the asterisk indicates that other subunits may be present in this receptor) is the principal mediator of nicotine dependence. In mice, disruption of the β₂ subunit gene eliminates the behavioral effects of nicotine; reinserting the gene into the ventral tegmental area restores behavioral responses to nicotine.^7,8 The α₄ subunit is an important determinant of sensitivity to nicotine. A mutation affecting a single nucleotide in the pore-forming region of the mouse receptor gene makes it hypersensitive to the effects of nicotine.⁹ Other subunits can form functional receptors. The presence of an α₅ subunit combined with α₄β₂ increases calcium conductance seven times; α₅ gene variants also alter nicotine responsiveness in cultured human cells.^10,11 The α₃β₄ subtype probably mediates the cardiovascular effects of nicotine.¹² The α₇ homomeric receptors are involved in rapid synaptic transmission and long-term potentiation to dopaminergic neurons at excitatory inputs and have a role in learning and sensory gating.^13–16

NICOTINE AND NEUROTRANSMITTER RELEASE

Stimulation of nicotinic cholinergic receptors releases a variety of neurotransmitters in the brain.^5,17 One of them, dopamine, signals a pleasurable experience and is critical for the reinforcing effects (effects that promote self-administration) of nicotine and other drugs of abuse, as well as for compelling drives such as eating.¹⁸ Experimentally induced lesions in dopamine-releasing neurons prevent self-administration of nicotine in rats. Nicotine releases dopamine in the mesolimbic area, the corpus striatum, and the frontal cortex (Fig. 2). The dopaminergic neurons in the ventral tegmental area of the midbrain and in the shell of the nucleus accumbens are critical in drug-induced reward (both regions have a role in perceptions of pleasure and reward).^6,18

Figure 2

Role of the Mesolimbic Dopamine System in Nicotine Activity

Nicotine also augments both glutamate release, which facilitates the release of dopamine, and γ-aminobutyric acid (GABA) release, which inhibits dopamine release.^15,16 With long-term exposure to nicotine, some nicotinic cholinergic receptors become desensitized but some do not. As a result, GABA-mediated inhibitory tone diminishes while glutamate-mediated excitation persists, thereby increasing excitation of dopaminergic neurons and enhancing responsiveness to nicotine.

A measure of the function of the reward system in rats is the threshold for electrical self-stimulation in the medial forebrain: a lower threshold indicates increased responsiveness to rewarding stimuli. Nicotine lowers the threshold for reward, an effect that can last for more than 30 days.¹⁹ It also increases activity in the prefrontal cortex, thalamus, and visual system, reflecting activation of corticobasal ganglia–thalamic brain circuits (part of the reward network), and releases dopamine in the striatum.²⁰ Other neurotransmitters that may be involved in nicotine addiction are the hypocretins, neuropeptides produced in the lateral hypothalamus that regulate the stimulatory effects of nicotine on reward centers in the brain and modulate self-administration of nicotine in rodents.²¹

MONAMINE OXIDASE

Constituents of cigarette smoke other than nicotine contribute to nicotine addiction. Monoamine oxidases, enzymes located in catecholaminergic and other neurons, catalyze the metabolism of dopamine, norepinephrine, and serotonin. Condensation products of acetaldehyde in cigarette smoke with biogenic amines inhibit the activity of monoamine oxidase type A and monoamine oxidase type B, and there is evidence that inhibition of monoamine oxidase contributes to the addictiveness of smoking by reducing the metabolism of dopamine.^22,23

NEUROADAPTATION

With repeated exposure to nicotine, neuroadaptation (tolerance) to some of the effects of nicotine develops.²⁴ As neuroadaptation develops, the number of binding sites on the nicotinic cholinergic receptors in the brain increases, probably in response to nicotine-mediated desensitization of receptors.²⁵ Desensitization — ligand-induced closure and unresponsiveness of the receptor — is believed to play a role in tolerance and dependence: the symptoms of craving and withdrawal begin in smokers when desensitized α₄ β₂^* nicotinic cholinergic receptors become responsive during periods of abstinence, such as nighttime sleep.²⁶ Nicotine binding of these receptors during smoking alleviates craving and withdrawal.

Cigarette smoking in amounts that are typical for daily smokers maintains near-complete saturation — and thus desensitization — of the α₄ β₂^* nicotinic cholinergic receptors.²⁷ Thus, smokers are probably attempting to avoid withdrawal symptoms when maintaining a desensitized state. By sustaining sufficient levels of plasma nicotine to prevent withdrawal symptoms, they also derive rewarding effects from the conditioned reinforcements associated with smoking, such as the taste and feel of smoke.²⁸

Nicotine withdrawal causes anxiety and stress, both of which are powerful incentives to take up smoking again.²⁹ The negative affect that typifies the response to nicotine withdrawal probably results in part from a cascade of events involving increased levels of extrahypothalamic corticotropin-releasing factor (CRF) and increased binding of CRF to corticotropin-releasing factor 1 (CRF1) receptors in the brain, thereby activating the CRF–CRF1 receptor system, which mediates responses to stress. In rats, anxiety-like behavior and the release of CRF in the central nucleus of the amygdala occur during nicotine withdrawal.³⁰ CRF causes anxiety, whereas the pharmacologic blockade of CRF1 receptors inhibits the anxiogenic effects of nicotine withdrawal. The blockade of CRF1 receptors also prevents the increase in self-administration of nicotine that occurs during abstinence from forced nicotine administration in rats. Thus, both underactivity of the dopaminergic system and activation of the CRF–CRF1 receptor system contribute to the symptoms of nicotine withdrawal that often precipitate relapse.

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CLINICAL ASPECTS OF NICOTINE ADDICTION

PSYCHOACTIVE EFFECTS OF NICOTINE

Nicotine induces pleasure and reduces stress and anxiety. Smokers use it to modulate levels of arousal and to control mood. Smoking improves concentration, reaction time, and performance of certain tasks. Relief from withdrawal symptoms is probably the primary reason for this enhanced performance and heightened mood.³¹ Cessation of smoking causes the emergence of withdrawal symptoms: irritability, depressed mood, restlessness, and anxiety.³² The intensity of these mood disturbances is similar to that found in psychiatric outpatients.³³ Anhedonia — the feeling that there is little pleasure in life — can also occur with withdrawal from nicotine, and from other drugs of abuse.³⁴

The basis of nicotine addiction is a combination of positive reinforcements, including enhancement of mood and avoidance of withdrawal symptoms (Fig. 3).³⁵ In addition, conditioning has an important role in the development of tobacco addiction.

Figure 3

Molecular and Behavioral Aspects of Nicotine Addiction

CONDITIONED BEHAVIOR

When a person who is addicted to nicotine stops smoking, the urge to resume is recurrent and persists long after withdrawal symptoms dissipate. With regular smoking, the smoker comes to associate specific moods, situations, or environmental factors — smoking-related cues — with the rewarding effects of nicotine. Typically, these cues trigger relapse.

The association between such cues and the anticipated effects of nicotine, and the resulting urge to use nicotine, constitute a form of conditioning. Studies in animals show that nicotine exposure causes changes in the protein expression of brain cells and in their synaptic connections — a process termed neural plasticity — which underlie conditioning.^36,37 Nicotine also enhances behavioral responses to conditioned stimuli, which may contribute to compulsive smoking.³⁸ Furthermore, studies in nicotine-dependent rats show that conditioned stimuli associated with nicotine withdrawal increase the magnitude of withdrawal through an elevation of the brain’s reward threshold.³⁹ Thus, cues associated with nicotine withdrawal can decrease the function of the brain’s reward systems.

The desire to smoke is maintained, in part, by such conditioning. Smokers usually take a cigarette after a meal, with a cup of coffee or an alcoholic drink, or with friends who smoke. When repeated many times, such situations become a powerful cue for the urge to smoke. Aspects of smoking itself — the manipulation of smoking materials, or the taste, smell, or feel of smoke in the throat — also become associated with the pleasurable effects of smoking.^40,41 Even unpleasant moods can become conditioned cues for smoking: a smoker may learn that not having a cigarette provokes irritability and that smoking one provides relief. After repeated experiences like this, a smoker can sense irritability from any source as a cue for smoking. Functional imaging studies have shown that exposure to drug-associated cues activates cortical regions of the brain, including the insula (a structure in the cortex associated with certain basic emotions). Smokers who sustain damage to the insula (e.g., brain trauma) are more likely to quit smoking soon after the injury, and to remain abstinent, and are less likely to have conscious urges to smoke than smokers with brain injury that does not affect the insula.⁴²

THE TOBACCO ADDICTION CYCLE

Smoking is a highly efficient form of drug administration. Inhaled nicotine enters the circulation rapidly through the lungs and moves into the brain within seconds. Rapid rates of absorption and entry into the brain cause a strongly felt “rush” and reinforce the effects of the drug. In animals, rapid administration of nicotine potentiates locomotor sensitization, which is linked to reward, and neuroplastic changes in the brain.⁴³ The smoking process also provides rapid reinforcement and allows for precise dosing, making it possible for a smoker to obtain desired effects without toxicity. Unlike cigarettes, nicotine medications marketed to promote smoking cessation deliver nicotine slowly, and the risk of abuse is low.⁴⁴ In addition to delivering nicotine to the brain quickly, cigarettes have been designed with additives and engineering features to enhance its addictiveness.⁴⁵

There is considerable peak-to-trough oscillation in blood levels of nicotine from cigarette to cigarette. Nevertheless, it accumulates in the body over the course of 6 to 9 hours of regular smoking and results in 24 hours of exposure. Arteriovenous differences in nicotine concentrations during cigarette smoking are substantial, with arterial levels up to 10 times as high as venous levels.⁴⁶ The persistence of nicotine in the brain throughout the day and night changes the structure and function of nicotinic receptors, stimulating intracellular processes of neuroadaptation.

The pharmacologic basis of nicotine addiction is thus a combination of positive reinforcements, such as enhancement of mood and mental or physical functioning, and avoidance of withdrawal symptoms when nicotine is not available. Figure 4 shows a typical daily smoking cycle.⁴⁷

Figure 4

The Tobacco Addiction Cycle

Smokers tend to take in the same amount of nicotine from day to day to achieve the desired effects. They adjust their smoking behavior to compensate for changes in the availability of nicotine (e.g., when switching from regular to low-yield cigarettes) to regulate the body’s level of nicotine.⁴⁸ Light smokers (those who smoke ≤5 cigarettes per day) and occasional smokers smoke primarily for the positive reinforcing effects of nicotine and have minimal or no withdrawal symptoms.⁴⁹ They smoke primarily in association with particular activities (after eating a meal or while drinking alcohol), and are less likely to smoke in response to negative affect. Although withdrawal symptoms may not be prominent, many light and occasional smokers have difficulty quitting. Some of them have a high level of dependence, but with pharmacodynamics that differ from those in heavier smokers.

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GENETICS OF NICOTINE ADDICTION

Studies in twins have shown a high degree of heritability of cigarette smoking (≥50%), including the level of dependence and the number of cigarettes smoked daily.⁵⁰ These studies have also revealed the heritability of the particular symptoms that occur when a smoker stops smoking.⁵¹

Numerous attempts have been made to identify genes underlying nicotine addiction.⁵⁰ Such studies are problematic because multiple genes and environmental factors determine complex behavior, and the many different dependence phenotypes may have different genetic underpinnings. Candidate genes coding for nicotine-receptor subtypes, dopamine receptors and dopamine transporters, GABA receptors, opiate and cannabinoid receptors, and other types of receptors have been associated with different aspects of smoking behavior.⁵² Subsequent research, however, has not replicated many of the initial findings.

Recent genomewide association studies point to several promising genetic determinants of nicotine dependence. Bierut et al. compared the genomes of smokers who became dependent on nicotine with the genomes of smokers who did not.⁵³ Signals from genomewide association studies guided a second-phase candidate-gene association study by Saccone et al. in which several strong genetic associations were uncovered.⁵⁴ Most prominent were genes within the α₅/α₃/β₄ nicotinic cholinergic receptor gene complex on chromosome 15. This and other genomewide association studies of tobacco addiction have also identified genes affecting cell adhesion and extracellular matrix molecules, which are common among various addictions. These findings are consistent with the idea that neural plasticity and learning are key determinants of individual differences in vulnerability to nicotine dependence and other drug addictions.⁵⁵

Variants associated with nicotine dependence in the α₅/α₃/β₄ gene region (chromosome 15, 15q25) also have a significant association with the number of cigarettes smoked per day, plasma levels of cotinine (a biomarker of nicotine intake), urine levels of tobacco-smoke carcinogens, and the risks of smoking-related diseases.^11,56–62 The mechanisms of the associations between these variants and disease are probably related to the level of dependence and therefore the level of intake of tobacco-smoke toxins; however, nicotinic cholinergic receptors also modulate inflammatory responses, angiogenesis, and apoptosis, and thus account for additional mechanisms through which nicotine could affect the risk of disease.⁶³

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VULNERABILITY TO ADDICTION

Tobacco use typically begins in childhood or adolescence — 80% of smokers begin smoking by 18 years of age.⁶⁴ Although two thirds of young people try cigarette smoking, only 20 to 25% of them become dependent daily smokers, usually as adults.^65,66 Risk factors for smoking in childhood or adolescence include peer and parental influences, behavioral problems (e.g., poor school performance), personality characteristics (rebelliousness, risk taking, depression, and anxiety), and genetic influences.⁶⁴

The risk of dependence increases when smoking begins early.⁶⁴ Studies of the developing brain in animals suggest that nicotine can induce permanent changes that lead to addiction. Brain changes in adolescent rats exposed to nicotine are greater than those in exposed adult rats. Adolescent rats that have been exposed to nicotine have higher rates of nicotine self-administration as adults, which is consistent with the idea that early exposure to nicotine increases the severity of dependence.^67,68

Tobacco addiction is highly prevalent among persons with mental illness or substance-abuse disorders.^69,70 The mechanisms of this association are likely to include a shared genetic predisposition, the capacity of nicotine to alleviate some psychiatric symptoms, and the inhibitory effects of tobacco smoke on monoamine oxidase.^23,71,72

Smoking behavior in women is more strongly influenced by conditioned cues and negative affect; men are more likely to smoke in response to pharmacologic cues, regulating their intake of nicotine more precisely than women.⁷³ On average, women metabolize nicotine more quickly than men,⁷⁴ which may contribute to their increased susceptibility to nicotine addiction and may help to explain why, among smokers, it is more difficult for women to quit.⁷⁵

Insofar as smokers regulate their intake of nicotine to maintain particular levels throughout the day, those who metabolize nicotine rapidly take in more cigarette smoke per day than those who metabolize nicotine slowly. Nicotine is metabolized to cotinine primarily by the liver enzyme CYP2A6.⁷⁶ Persons with a genetic basis for slow metabolism (those with variant CYP2A6 genes that are associated with reduced enzyme activity) smoke fewer cigarettes daily than persons with faster metabolism.⁷⁷ The observation that the fraction of smokers with genetically slow metabolism in the population of smokers decreases with the increasing age of the cohort of smokers suggests that those with slow metabolism are more likely to quit than those with faster metabolism. Rapid metabolism of nicotine is associated with more severe withdrawal symptoms and a lower probability of success in quitting during nicotine-patch treatment.^78,79