Saccharin And Sugar Found More Addictive Than Cocaine.


Sugar and artificial sweeteners are so accessible, affordable and socially sanctioned, that few consider their habitual consumption to be a problem on the scale of say, addiction to cocaine.  But if recent research is correct their addictive potential could be even worse.

Sugar and Saccharin More Addictive Than Intravenous Cocaine?

Almost 40 years ago, William Duffy published a book called Sugar Blues which argued that refined sugar is an addictive drug and profoundly damaging to health.  While over 1.6 million copies have been printed since its release in 1975, a common criticism of the book has been that it lacked sufficient scientific support.

Today, William Duffy’s work is finding increasing support in the first-hand, peer-reviewed and published scientific literature itself. Not only is sugar drug-like in effect, but it may be more addictive than cocaine.  Worse, many sugar-free synthetic sweeteners carry with them addictive properties and toxicities that are equal to, or may outweigh those of sugar.

Back in 2007, a revealing study titled, “Intense sweetness surpasses cocaine reward,”  found that when rats were given the option of choosing between water sweetened with saccharin and intravenous cocaine, the large majority of animals (94%) preferred the sweet taste of saccharin.[i] This preference for sweetness was not attributable to its unnatural ability to induce sweetness without calories, because the same preference was found with sucrose; nor was the preference for saccharin overcome by increasing doses of cocaine.

Research: Sugar and Saccharine Found As Addictive As Cocaine

A common argument against the relevance of animal studies like this to human behavior is that rats differ too profoundly from humans. However, even insects like forager bees have been found to respond in a similar way to humans when given cocaine, experiencing an overestimation of the value of the floral resources they collected, with cessation of chronic cocaine treatment causing a withdrawal-like response.[ii]

Researchers believe that intense sweetness activates ancient neuroendocrine pathways within the human body, making obsessive consumption and/or craving inevitable. The authors of the cocaine/saccharin study summarized this connection as follows:

Our findings clearly demonstrate that intense sweetness can surpass cocaine reward, even in drug-sensitized and -addicted individuals. We speculate that the addictive potential of intense sweetness results from an inborn hypersensitivity to sweet tastants. In most mammals, including rats and humans, sweet receptors evolved in ancestral environments poor in sugars and are thus not adapted to high concentrations of sweet tastants. The supranormal stimulation of these receptors by sugar-rich diets, such as those now widely available in modern societies, would generate a supranormal reward signal in the brain, with the potential to override self-control mechanisms and thus to lead to addiction.

In a previous article, “Is Fructose As Addictive As Alcohol?”, we looked at the addictive properties of isolated fructose in greater depth, including over 70 adverse health effects associated with fructose consumption. It appears that not only does fructose activate a dopamine- and opioid-mediated hedonic pathway within the body, but like excessive alcohol consumption, exacts a significant toll on health in exchange for the pleasure it generates.

The drug-like properties of common beverages and foods, have been the subject of a good deal of research over the past few decades. Wheat and related grains, for instance, are a major foodsource of opioid peptides. These pharmacologically active compounds, also found in milk,coffee and even lettuce, may even explain why ancient hunters and gatherers took the agrarian leap over 10,000 years ago.  Likely, the transition from the Paleolithic to Neolithic was motivated by a combination of environmental pressures and the inherently addictive properties made accessible and abundant due to the agrarian/animal husbandry mode of civilization. For more on this, read our essay “The Dark Side of Wheat.”

As far as synthetic sweeteners, an accumulating body of toxicological research indicates they have a wide range of unintended, adverse health effects beyond the aforementioned problem of addiction.

Are Oreos really as addictive as cocaine?


A recent study claims that the biscuits are as addicting as cocaine. But tasty though they are, can Oreos really be that dangerous?

OREO COOKIES

They may be more-ish, but are they really as addictive as cocaine?

No. No, they’re not.

It seems like everything can make us addicted these days. Our iPhones. The internet. Oreos. But just because something is pleasurable and causes a relevant reward area of your brain to light up does not mean that it is addictive.

An addiction is like a compulsion, where you continue performing a behaviour even though it has resulted in negative consequences – like continuing to drink even though it’s lost you your driving licence, your job and even your partner. Addiction also involves complex changes in your brain in areas where you process reward and self-control. These changes can result in feelings of craving and withdrawal, where your body has adapted to rely on the drug to feel normal. In some cases, withdrawal can be so severe that your body may actually shut down and you can die if you don’t have another hit.

No matter how many Oreos you eat, this will not happen to you.

The idea of food addiction is not a new one, but a study released last week takes this claim to a whole other (and unsubstantiated) level, claiming that Oreos – and especially that all-enticing creamy centre – is as addicting as cocaine.

Unfortunately, the researchers from Connecticut College who ran this study, led by Professor Joseph Schroeder, never actually tested this hypothesis. They used a standard conditioned place-preference test, giving rats either an Oreo or a rice cake on one side of a maze or another and then watched to see where the animals later chose to spend their time. This type of task is typically used to measure associations between a stimulus (like cookies or cocaine) and the environment in which it was experienced, with the idea being that the more pleasurable an experience is, the more likely you will want to repeat it, and thus the more time you will spend in the place where you first received it. Stemming from this logic, as might be expected, the rats preferred the side of the maze where they received the Oreo.

Fine, great, we all like Oreos more than rice cakes. No surprise there.

Then the researchers repeated the experiment, but this time they injected rats with a dose of cocaine or morphine on one side and with a neutral saline solution on the other. Once again, as you might anticipate, the rats kept going back to the side where they had received the drugs, hoping for more.

Now here’s where it gets sketchy. The researchers measured the amount of time the rats spent in each half of the chamber and claim that because the two groups of mice spent equal amount of time in the Oreo and in the cocaine area, these two stimuli are equally rewarding, or “addicting”. However, they never actually compared the cocaine with the cookies! These were two completely separate groups of animals that took part in two different experiments – one testing Oreos with rice cakes and another comparing cocaine and saline. Yes the animals showed similar behaviours in response to the drugs and to the high-fat/high-sugar food, but these things cannot be equated if they are not directly compared.

To be fair, the researchers didn’t just rely on behavioural tests, but also measured the amount of chemical activity that was seen in a reward region of the brain, the nucleus accumbens, in response to each of the two vices. Here they report that there was greater evidence of activation in the Oreo-eating rats than in the cocaine-consuming ones. However, again, they haven’t directly compared the amount of activity seen within an animal after receiving cocaine and Oreos.

Many previous studies have directly compared cocaine with food rewards and the results are conflicting. One study measured cell firing in the nucleus accumbens in primates directly after receiving a sip of juice or a dose of cocaine. In these animals, there was significantly greater activity in response to the drugs than the juice.

Now, this isn’t to say that the idea of “food addiction”, particularly to foods high in fat and sugar, is complete nonsense. For over the past 10 years Dr Nicole Avena and others have been conducting elegant experiments where they let rats binge on chocolate pellets and then measure changes in their brain and behaviour. These researchers quite frequently see similar effects in rats that have been gorging on chocolate as those given cocaine. This includes physical changes in the brain (including in that crucial reward centre), as well as behaviours reminiscent of craving and even withdrawal.

The idea that junk foods can create addictive-like tendencies is not new, nor is it wrong. But the claims that this particular study makes are.

As for whether the eating the middle of an Oreo first really is better, well I guess I’ll let that one slide.

Effect of slosh mitigation on histologic markers of traumatic brain injury.


Helmets successfully prevent most cranial fractures and skull traumas, but traumatic brain injury (TBI) and concussions continue to occur with frightening frequency despite the widespread use of helmets on the athletic field and battlefield. Protection against such injury is needed. The object of this study was to determine if slosh mitigation reduces neural degeneration, gliosis, and neuroinflammation.

Methods

Two groups of 10 adult male Sprague-Dawley rats were subjected to impact-acceleration TBI. One group of animals was fitted with a collar inducing internal jugular vein (IJV) compression prior to injury, whereas the second group received no such collar prior to injury. All rats were killed 7 days postinjury, and the brains were fixed and embedded in paraffin. Tissue sections were processed and stained for markers of neural degeneration (Fluoro-Jade B), gliosis (glial fibrillary acidic protein), and neuroinflammation (ionized calcium binding adapter molecule 1).

Results

Compared with the controls, animals that had undergone IJV compression had a 48.7%–59.1% reduction in degenerative neurons, a 36.8%–45.7% decrease in reactive astrocytes, and a 44.1%–65.3% reduction in microglial activation.

Conclusions

The authors concluded that IJV compression, a form of slosh mitigation, markedly reduces markers of neurological injury in a common model of TBI. Based on findings in this and other studies, slosh mitigation may have potential for preventing TBI in the clinical population.

Source: Journal of neurosurgery.

 

 

 

Ultrasound-assisted convection-enhanced delivery to the brain in vivo with a novel transducer cannula assembly.


In convection-enhanced delivery (CED), drugs are infused locally into tissue through a cannula inserted into the brain parenchyma to enhance drug penetration over diffusion strategies. The purpose of this study was to demonstrate the feasibility of ultrasound-assisted CED (UCED) in the rodent brain in vivo using a novel, low-profile transducer cannula assembly (TCA) and portable, pocket-sized ultrasound system.

Methods

Forty Sprague-Dawley rats (350–450 g) were divided into 2 equal groups (Groups 1 and 2). Each group was divided again into 4 subgroups (n = 5 in each). The caudate of each rodent brain was infused with 0.25 wt% Evans blue dye (EBD) in phosphate-buffered saline at 2 different infusion rates of 0.25 μl/minute (Group 1), and 0.5 μl/minute (Group 2). The infusion rates were increased slowly over 10 minutes from 0.05 to 0.25 μl/minute (Group 1) and from 0.1 to 0.5 μl/minute (Group 2). The final flow rate was maintained for 20 minutes. Rodents in the 4 control subgroups were infused using the TCA without ultrasound and without and with microbubbles added to the infusate (CED and CED + MB, respectively). Rodents in the 4 UCED subgroups were infused without and with microbubbles added to the infusate (UCED and UCED + MB) using the TCA with continuous-wave 1.34-MHz low-intensity ultrasound at a total acoustic power of 0.11 ± 0.005 W and peak spatial intensity at the cannula tip of 49.7 mW/cm2. An additional 4 Sprague-Dawley rats (350–450 g) received UCED at 4 different and higher ultrasound intensities at the cannula tip ranging from 62.0 to 155.0 mW/cm2 for 30 minutes. The 3D infusion distribution was reconstructed using MATLAB analysis. Tissue damage and morphological changes to the brain were assessed using H & E.

Results

The application of ultrasound during infusion (UCED and UCED + MB) improved the volumetric distribution of EBD in the brain by a factor of 2.24 to 3.25 when there were no microbubbles in the infusate and by a factor of 1.16 to 1.70 when microbubbles were added to the infusate (p < 0.001). On gross and histological examination, no damage to the brain tissue was found for any acoustic exposure applied to the brain.

Conclusions

The TCA and ultrasound device show promise to improve the distribution of infused compounds during CED. The results suggest further studies are required to optimize infusion and acoustic parameters for small compounds and for larger molecular weight compounds that are representative of promising antitumor agents. In addition, safe levels of ultrasound exposure in chronic experiments must be determined for practical clinical evaluation of UCED. Extension of these experiments to larger animal models is warranted to demonstrate efficacy of this technique.

Source: Journal of neurosurgery.

 

 

 

Studies more firmly tie sugary drinks to obesity.


New research powerfully strengthens the case against soda and other sugary drinks as culprits in the obesity epidemic.

A huge, decades-long study involving more than 33,000 Americans has yielded the first clear proof that drinking sugary beverages interacts with genes that affect weight, amplifying a person’s risk of obesity beyond what it would be from heredity alone.

This means that such drinks are especially harmful to people with genes that predispose them to weight gain. And most of us have at least some of these genes.

In addition, two other major experiments have found that giving children and teens calorie-free alternatives to the sugary drinks they usually consume leads to less weight gain.

Collectively, the results strongly suggest that sugary drinks cause people to pack on the pounds, independent of other unhealthy behavior such as overeating and getting too little exercise, scientists say.

That adds weight to the push for taxes, portion limits like the one just adopted in New York City, and other policies to curb consumption of soda, juice drinks and sports beverages sweetened with sugar.

Soda lovers do get some good news: Sugar-free drinks did not raise the risk of obesity in these studies.

“You may be able to fool the taste” and satisfy a sweet tooth without paying a price in weight, said an obesity researcher with no role in the studies, Rudy Leibel of Columbia University.

The studies were being presented Friday at an obesity conference in San Antonio and were published online by the New England Journal of Medicine.

The gene research in particular fills a major gap in what we know about obesity. It was a huge undertaking, involving three long-running studies that separately and collectively reached the same conclusions. It shows how behavior combines with heredity to affect how fat we become.

Having many of these genes does not guarantee people will become obese, but if they drink a lot of sugary beverages, “they fulfill that fate,” said an expert with no role in the research, Jules Hirsch of Rockefeller University in New York. “The sweet drinking and the fatness are going together, and it’s more evident in the genetic predisposition people.”

Sugary drinks are the single biggest source of calories in the American diet, and they are increasingly blamed for the fact that a third of U.S. children and teens and more than two-thirds of adults are obese or overweight.

Consumption of sugary drinks and obesity rates have risen in tandem — both have more than doubled since the 1970s in the U.S.

But that doesn’t prove that these drinks cause obesity. Genes, inactivity and eating fatty foods or just too much food also play a role. Also, diet research on children is especially tough because kids are growing and naturally gaining weight.

Until now, high-quality experiments have not conclusively shown that reducing sugary beverages would lower weight or body fat, said David Allison, a biostatistician who has done beverage research at the University of Alabama at Birmingham, some of it with industry support.

He said the new studies on children changed his mind and convinced him that limiting sweet drinks can make a difference.

In one study, researchers randomly assigned 224 overweight or obese high schoolers in the Boston area to receive shipments every two weeks of either the sugary drinks they usually consumed or sugar-free alternatives, including bottled water. No efforts were made to change the youngsters’ exercise habits or give nutrition advice, and the kids knew what type of beverages they were getting.

After one year, the sugar-free group weighed more than 4 pounds less on average than those who kept drinking sugary beverages.

“I know of no other single food product whose elimination can produce this degree of weight change,” said the study’s leader, Dr. David Ludwig of Boston Children’s Hospital and the Harvard School of Public Health.

The weight difference between the two groups narrowed to 2 pounds in the second year of the study, when drinks were no longer being provided. That showed at least some lasting beneficial effect on kids’ habits. The study was funded mostly by government grants.

A second study involved 641 normal-weight children ages 4 to 12 in the Netherlands who regularly drank sugar-sweetened beverages. They were randomly assigned to get either a sugary drink or a sugar-free one during morning break at their schools, and were not told what kind they were given.

After 18 months, the sugary-drink group weighed 2 pounds more on average than the other group.

The studies “provide strong impetus” for policies urged by the Institute of Medicine, the American Heart Association and others to limit sugary drink consumption, Dr. Sonia Caprino of the Yale School of Medicine wrote in an editorial in the journal.

The American Beverage Association disagreed.

“Obesity is not uniquely caused by any single food or beverage,” it said in a statement. “Studies and opinion pieces that focus solely on sugar-sweetened beverages, or any other single source of calories, do nothing meaningful to help address this serious issue.”

The genetic research was part of a much larger set of health studies that have gone on for decades across the U.S., led by the Harvard School of Public Health.

Researchers checked for 32 gene variants that have previously been tied to weight. Because we inherit two copies of each gene, everyone has 64 opportunities for these risk genes. The study participants had 29 on average.

Every four years, these people answered detailed surveys about their eating and drinking habits as well as things like smoking and exercise. Researchers analyzed these over several decades.

A clear pattern emerged: The more sugary drinks someone consumed, the greater the impact of the genes on the person’s weight and risk of becoming obese.

For every 10 risk genes someone had, the risk of obesity rose in proportion to how many sweet drinks the person regularly consumed. Overall calorie intake and lifestyle factors such as exercise did not account for the differences researchers saw.

This means that people with genes that predispose them to be obese are more susceptible to the harmful effects of sugary drinks on their weight, said one of the study leaders, Harvard’s Dr. Frank Hu. The opposite also was true — avoiding these drinks can minimize the effect of obesity genes.

“Two bad things can act together and their combined effects are even greater than either effect alone,” Hu said. “The flip side of this is everyone has some genetic risk of obesity, but the genetic effects can be offset by healthier beverage choices. It’s certainly not our destiny” to be fat, even if we carry genes that raise this risk.

The study was funded mostly by federal grants, with support from two drug companies for the genetic analysis.

Source: Yahoo news.

Underground Supermodels.


What can a twentysomething naked mole-rat tell us about fighting pain, cancer, and aging?

Pitch dark, dank, and seething with saber-toothed, sausage-shaped creatures, the world of the African naked mole-rat is a hostile habitat. In the 1980s, scientists made the remarkable discovery that naked mole-rats live like termites with a single, dominant breeding queen and scores of nonbreeding adult helpers that never leave their natal colony. But the bizarreness doesn’t stop there. Naked mole-rats, unlike other mammals, tolerate variable body temperatures, attributed to their lack of an insulatory layer of fur. Their pink skin is hairless except for sparse, whisker-like strands that crisscross the body to form a sensitive sensory array that helps them navigate in the dark. Both the naked mole-rat’s skin and its upper respiratory tract are completely insensitive to chemical irritants such as acids and capsaicin, the spicy ingredient in chili peppers. Most surprisingly, they can survive periods of oxygen deprivation that would cause irreversible brain damage in other mammals, and they are also resistant to a broad spectrum of other stressors, such as the plant toxins and heavy metals found in the soils in which they live. Unlike other mammals, they never get cancer, and this maintenance of genomic integrity, even as elderly mole-rats, most likely contributes to their extraordinarily long life span. In contrast to similar-size mice that only live 2–4 years, naked mole-rats can survive and thrive, maintaining normal function and reproduction, into their 30s.

Brain tissue of naked mole-rats remains functional with no oxygen supply for more than three times as long as brain tissue of laboratory mice.

The current hypotheses for the existence of this suite of unusual features center around the equally unusual lifestyle traits of the naked mole-rat. (See illustration on page 33.) Naked mole-rats live in large family groups in elaborate underground burrows. Although they are protected from large temperature fluctuations as well as from predators and pathogens, they have to contend with low oxygen and high carbon dioxide levels, due to the large number of individuals—usually 100 to 300—living and respiring in close quarters under poorly ventilated conditions. The unusual ecology and social structure of the naked mole-rat make this an exciting system for understanding evolution and specialization, and details of the molecular mechanisms underlying the mole-rat’s unusually good health are providing insights into human disease.

No oxygen? No problem!

Most mammalian brains, including those of humans, start to suffer damage after just 3–4 minutes of oxygen deprivation. This is because brain tissue does not store much energy, and a steady supply of oxygen is needed to generate more. Hence, when the oxygen supply to the brain is reduced or blocked, brain cells run out of energy, and damage quickly ensues. This is a major concern for victims of heart attacks and strokes, in which the blood supply to the brain is interrupted. Brain tissue of naked mole-rats, on the other hand, remains functional with no oxygen supply for more than three times as long as brain tissue of laboratory mice. And when the oxygen level is restored, brain tissue from naked mole-rats frequently recovers fully, even after several minutes of inactivity.1

This remarkable ability no doubt stems from the challenge that all subterranean animals face: low oxygen levels because of poor air exchange with the surface. Oxygen depletion is even more pronounced for naked mole-rats because they live in large groups, with many individuals sharing the same poor air supply, and gas exchange is limited to diffusion or air turbulence caused by animals moving in the tunnels. So how do mole-rats survive in such smothering conditions?

Naked mole-rats display several physiological adaptations for survival in a low-oxygen environment. The hemoglobin in their red blood cells has a higher affinity for oxygen than that of most other mammals, meaning that their blood is better at capturing what little oxygen there is. They also have a greater number of red blood cells per unit volume. In addition, their mass-specific metabolic rate is only about 70 percent that of other rodents, so they use oxygen at a slower rate. But when it comes to the brain, naked mole-rats protect themselves by borrowing a strategy used by the brains of infants.

Infant mammals, including humans, are known to be much more tolerant of oxygen deprivation than older juveniles or adults. It turns out that calcium is a key factor in this tolerance. Normally, calcium ions in our brain cells play vital roles, including helping memories form. But it’s a delicate balance: small amounts of calcium are essential for brain function, but too much calcium makes things go haywire. When nerve cells are starved of oxygen, they no longer have the energy to regulate calcium entry, resulting in an influx of too much calcium, which poisons the cells. This is the primary cause of neuronal death during oxygen deprivation.

In the last decade or so, researchers discovered that adult and infant brains express different calcium channels in their cell membranes. Calcium channels in infants actually close during oxygen deprivation, protecting the brain cells from calcium overdose in the womb, where the baby gets much less oxygen. After the baby is born, however, oxygen is plentiful, and these channels are largely replaced by ones that open in response to oxygen deprivation, often leading to cell death.

Recent studies on naked mole-rats show that this species retains infant-style calcium channels into adulthood.2 Accordingly, calcium-imaging techniques show that oxygen deprivation leads to much less calcium entry into the brain cells of adult naked mole-rats compared to other adult mammals.3 These findings suggest a new strategy that may help human victims of heart attack and stroke: increase the numbers of infant-style calcium channels in the brain. Brain cells of adult humans actually have some of these channels already, just not enough to protect them during oxygen deprivation. If a drug is designed to quickly upregulate production of infant-style channels in the brains of heart attack and stroke victims, it could provide valuable protection during a time when a steady supply of oxygen-rich blood is not reaching the brain.

Digging the Underground Life

Naked mole-rats (Heterocephalus glaber) are rodents found in the hot tropical regions of the Horn of Africa. When he first described a naked mole-rat in 1842, the famous German naturalist Eduard Rüppell suspected he had encountered a diseased specimen—because the animal had no fur and permanently protruding teeth. Only after several more specimens had been collected did it become apparent that their weird appearance, variously described as resembling saber-toothed sausages or miniature walruses, was normal.

Naked mole-rats live in a maze of underground tunnels that may extend more than a mile in length and as deep as 8 feet beneath the soil surface. Their burrows contain both nest chambers, tended by sterile worker animals, and several toilets, which the animals use religiously to avoid contamination of their living space. To locate the roots, tubers, and small onion-like bulbs they eat, mole-rats must dig through the soil, expanding their tunnels using their chisel-like, ever-growing incisor teeth. They occasionally make an opening to the outside world to kick excavated soil to the surface, where it forms small volcano-shaped mounds—the only aboveground signs of the vast colonies below. Given this strictly subterranean existence, it is not surprising that naked mole-rats have evolved a set of characteristics highly suited to life in dark, dank burrows.

Feeling no pain

In addition to dealing with low oxygen levels, living in crowded underground burrows also means naked mole-rats must contend with high carbon dioxide (CO2) concentrations. In contrast to the typical atmospheric concentration of CO2 of about 0.03 percent, CO2 levels in naked mole-rat tunnels are closer to 2 percent, possibly reaching concentrations of 5 percent or more in their nest chambers. High levels of CO2 can be painful to the eyes and nose due to the formation of acid on the surface of those tissues—akin to the feeling of burping through one’s nose after drinking a carbonated beverage—but mole-rats are completely insensitive to this phenomenon. The skin and upper respiratory tract of naked mole-rats are also insensitive to other irritants, including other acids, ammonia, and capsaicin. Behaviorally, the animals show no signs of irritation or discomfort when a capsaicin solution is applied to their nostrils, whereas mice vigorously rub their noses after such exposure. Unlike rats and mice, naked mole-rats also fail to avoid strong ammonia fumes. When placed in an arena with sponges that are saturated with ammonia or water, mole-rats spend as much time in close proximity to the ammonia as they do to the water. The animals also show no response to capsaicin or acidic saline (like lemon juice) injected into the skin of the foot, while the same irritants cause rubbing and scratching at the injection site in humans and vigorous licking in rats and mice.

 

Recent experiments have shown that nerve fibers called C-fibers, which normally respond to high levels of CO2and other chemical irritants, are much less sensitive in naked mole-rats than in other mammals. These fibers are small in diameter, and release neuropeptides—notably Substance P and calcitonin gene-related peptide—onto targets in the central nervous system to convey a stinging or burning sensation. Importantly, the same C-fibers that respond to acid and capsaicin are responsible for the pain people experience minutes, hours, or even days after an injury.

Surprisingly, physiological studies revealed that naked mole-rat C-fibers innervating their eyes, nose, and skin do respond to capsaicin, but that the nerves do not make the neuropeptides usually released because of a defect in gene promoters associated with the pain-relaying nerve cells. While the animals express the neuropeptides in other parts of the body, such as the brain and intestines, lack of these neuropeptides from the C-fibers acts to “disconnect” the fibers from the central nervous system, preventing the feelings of pain and irritation. Sure enough, when researchers introduced one of the missing neuropeptides, Substance P, into the C-fibers of naked mole-rat feet using gene therapy, the animals licked at the injection site similarly to rats and mice.4

Insensitivity to acidic saline appears to be mediated by a different mechanism. In contrast to their response to capsaicin, C-fibers in naked mole-rats are completely unresponsive to acidic saline. A recent study revealed that acid insensitivity involves voltage-gated sodium channels, which are necessary to propagate signals along the nerve fibers.5 In naked mole-rats, these channels have a mutation that make them shut down under acidic conditions.

Naked mole-rat C-fibers also have an unusual pattern of connectivity in the spinal cord. Almost half of the cells in the deep dorsal horn of the spinal cord receive direct connections from C-fibers, whereas in other species, most C-fibers terminate in the superficial dorsal horn, at the outer edge of the spinal cord. The significance of this unusual connection pattern is not clear, but it suggests that whatever signals are conveyed from the C-fibers might not follow the usual pain and irritant pathways once they reach the spinal cord.

Interestingly, naked mole-rats respond normally to pinch and heat; only C fiber-mediated pain has been muted in these animals. A greater understanding of how this type of pain processing is altered in naked mole-rats could have significant implications for the treatment of chronic pain in humans, such as post-surgical, joint and muscle, and inflammatory pain.

Cancer schmancer

Unlike mice, which very commonly develop tumors, naked mole-rats have never been found to naturally have cancer. Moreover, subjecting mole-rats to ionizing radiation does not induce much DNA damage, as seen in other animals, nor does it result in tumors, even 5 years later. Attempts to turn naked mole-rat cells cancerous via injection of oncogenes have also failed, whereas similar methods using human, mouse, and even cattle cells results in conversion to highly aggressive and invasive cancer-forming cells.6 Instead of starting to proliferate in an uncontrolled manner, transformed naked mole-rat cells immediately stop dividing, though they do not die.7 Similarly, naked mole-rat cells treated with a toxin or simply housed under suboptimal conditions immediately stop dividing until conditions improve.

Unlike mice, which very commonly develop tumors, naked mole-rats have never been found to naturally have cancer.

This has led some scientists to suggest that naked mole-rat cells are claustrophobic in culture and stop dividing as soon as they touch other cells, and that this contact inhibition is a mechanism of cancer resistance. However, several different labs have now shown that naked mole-rat cells grow to even higher densities than do mouse cells under optimal conditions, and do not avoid cellular contact under these circumstances. Rather, it has become increasingly clear that naked mole-rat tissues are better able to recognize abnormal cells, neutralize their tumorigenic properties, and repair their DNA. Should that fail, the cells are ushered into programmed cell death pathways.

The recently sequenced genome of the naked mole-rat has afforded a number of novel insights into why naked mole-rats appear to be impervious to cancers.8 Many of the genes involved in the regulation of cell proliferation are positively selected for or have unique sequences that appear to result in the naked mole-rat’s unusual health. Similarly, many gene families in the mole-rat genome are involved in DNA repair and detoxification processes, and the expression of these genes remains unchanged as the animals age. Given that cancer is one of the largest contributors to mortality in elderly humans, sustained genomic maintenance and simultaneous invulnerability to cancer may contribute substantially to the exceptional longevity of naked mole-rats.

Naked mole-rats also have in place several mechanisms to ensure protein quality control and homeostasis. Their proteins appear to be very resistant to unfolding stressors such as high temperatures and urea, and the animals’ cells are particularly efficient at removing damaged proteins and organelles via the ubiquitin-proteasome system and autophagy. Indeed, naked mole-rat proteasomes are both more abundant and show greater efficiency in degrading stress-damaged proteins in liver tissue than do the proteasomes within liver tissues of laboratory mice.9 Similarly, autophagy occurs at a twofold greater rate in naked mole-rat cells than those of the mouse. Collectively, these enhanced intracellular cleaning processes may contribute to the better maintenance of a high-quality proteome and help the naked mole-rat’s cells resist damage in the face of cellular toxins, such as heavy metals or direct DNA-damaging agents. Much higher concentrations of these toxins are needed to kill naked mole-rat cells than are needed to kill mouse cells subjected to the identical experimental treatment.

Forever young

Although naked mole-rats are the size of a mouse, weighing only about 35–65 grams, in captivity these rodents live 9 times longer. With a recorded maximum lifespan of 32 years, they are the longest-lived rodents known.10 And remarkably, they appear able to maintain good health for most of their lives. At an age equivalent to a human age of 92 years, naked mole-rats show unchanged levels of activity and metabolic rate, as well as sustained muscle mass, fat mass, bone density, cardiac health, and neuron number. These clear indications of both attenuated and delayed physiological aging are also accompanied by the maintenance of protein quality and gene expression levels.

Some of the oldest naked mole-rats (>26 years; equivalent to humans >105 years old) do begin to show signs of muscle loss, osteoarthritis, and cardiac dysfunction, demonstrating that mole-rats do, eventually, age like other animals. Somehow they delay the onset of aging and compress the period of decline into a small fraction of their overall lifespan. These findings of sustained good health are surprising given that the naked mole-rat is an exception to many of the current theories of why we age. For example, the widely accepted oxidative stress theory of aging attributes the gradual decline in function to damage caused by the free radicals or reactive oxygen species formed as an inevitable by-product of oxygen respiration. In much the same way that oxygen causes metal to rust when exposed to the elements, cell membranes, proteins, and DNA are damaged by the gas, and this accumulating damage, so goes the theory, causes physiological systems to malfunction. Naked mole-rats in captivity, however, show very high levels of oxidative damage at an early age, yet cellular function is not impaired, and the animals are able to tolerate these high levels of oxidative damage for more than 20 years.

Another aging theory posits that the length of an organism’s telomeres, the repetitive DNA that caps the ends of chromosomes, is a biomarker of aging and will correlate with species’ life span. But compared to the much shorter-lived laboratory mouse, the naked mole-rat has relatively short telomeres—similar in length to those of humans, in fact. Alternatively, cellular levels of telomerase, a reverse transcriptase enzyme that extends telomeres, may correlate with species longevity. But while telomerase activity has been measured in mole-rat skin cells in culture, it is generally very low, and is limited to those tissues that are actively replicating, such as testes, spleen, and skin. Thus, telomere length or maintenance is unlikely to explain the exceptional longevity of the naked mole-rat.

Clearly, studies involving this bizarre-looking but fascinating animal have highlighted many key facets of their unusual biology that are directly relevant to biomedical research. Indeed, these studies have yielded critical information regarding how the brain works, and how animals respond to the lack of oxygen and of light, as well as how we might learn to slow down aging, prevent cancer, and mitigate inflammatory pain and the harmful effects that occur when oxygen delivery is impaired. It will be exciting to be a part of the continued research on these incredible creatures that is likely to reveal novel drug targets for a variety of human ailments.

Thomas Park is a professor of biological sciences and neuroscience at the University of Illinois at Chicago. Rochelle Buffenstein is a professor of physiology at the Barshop Institute for Longevity and Aging Studies and the University of Texas Health Science Center in San Antonio, Texas.

References

  1. J. Larson, T.J. Park, “Extreme hypoxia tolerance of naked mole-rat brain,” NeuroReport, 20:1634-37, 2009.
  2. B.L. Peterson et al., “Adult naked mole-rat brain retains the NMDA receptor subunit GluN2D associated with hypoxia tolerance in neonatal mammals,” Neurosci Lett, 506:342-45, 2012.
  3. B.L. Peterson et al., “Blunted neuronal calcium response to hypoxia in naked mole-rat hippocampus,” PLoS One, 7:e31568, 2012.
  4. T.J. Park et al., “Selective inflammatory pain insensitivity in the African naked mole-rat (Heterocephalus glaber),” PLoS Biol, 6:e13, 2008.
  5. E.S. Smith et al., “The molecular basis of acid insensitivity in the African naked mole-rat,” Science, 334:1557-60, 2011.
  6. S. Liang et al., “Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber),” Aging Cell, 9:626-35, 2010.
  7. K.N. Lewis et al., “Stress resistance in the naked mole-rat: the bare essentials,” Gerontology, in press, doi:10.1159/000335966, 2012.
  8. E.B. Kim et al., “Genome sequencing reveals insights into physiology and longevity of the naked mole rat,” Nature, 479:223-27, 2011.
  9. K.A. Rodriguez et al., “Altered composition of liver proteasome assemblies contributes to enhanced proteasome activity in the exceptionally long-lived naked mole-rat,” PLoS ONE, 7:e35890, 2012.
  10. R. Buffenstein, “Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species,” J Comp Physiol B, 178:439-45, 2008.

Source: the scientist

 

Neuroprotective and neurorestorative effects of thymosin β4 treatment initiated 6 hours after traumatic brain injury in rats.


Thymosin β4 (Tβ4) is a regenerative multifunctional peptide. The aim of this study was to test the hypothesis that Tβ4 treatment initiated 6 hours postinjury reduces brain damage and improves functional recovery in rats subjected to traumatic brain injury (TBI).

Methods

Traumatic brain injury was induced by controlled cortical impact over the left parietal cortex in young adult male Wistar rats. The rats were randomly divided into the following groups: 1) saline group (n = 7); 2) 6 mg/kg Tβ4 group (n = 8); and 3) 30 mg/kg Tβ4 group (n = 8). Thymosin β4 or saline was administered intraperitoneally starting at 6 hours postinjury and again at 24 and 48 hours. An additional group of 6 animals underwent surgery without TBI (sham-injury group). Sensorimotor function and spatial learning were assessed using the modified Neurological Severity Score and the Morris water maze test, respectively. Animals were euthanized 35 days after injury, and brain sections were processed to assess lesion volume, hippocampal cell loss, cell proliferation, and neurogenesis after Tβ4 treatment.

Results

Compared with saline administration, Tβ4 treatment initiated 6 hours postinjury significantly improved sensorimotor functional recovery and spatial learning, reduced cortical lesion volume and hippocampal cell loss, and enhanced cell proliferation and neurogenesis in the injured hippocampus. The high dose of Tβ4 showed better beneficial effects compared with the low-dose treatment.

Conclusions

Thymosin β4 treatment initiated 6 hours postinjury provides both neuroprotection and neurorestoration after TBI, indicating that Tβ4 has promising therapeutic potential in patients with TBI. These data warrant further investigation of the optimal dose and therapeutic window of Tβ4 treatment for TBI and the associated underlying mechanisms.

Source: Journal of Neurosurgery.