Statins and Prostate Cancer - Don't Believe What You Read

Every few years, it seems, there is renewed interest in using statins (hydroxy-methyl-glutaryl CoA reductase inhibitors - drugs that lower cholesterol) to treat (or prevent) prostate cancer. WebMD reported on a 2009 study suggesting an almost 2/3 reduction in death rate with the use of statins:

Statins and Prostate Cancer Death

The new study involved 380 men ages 55 to 79 who died from prostate cancer between 1999 and 2001 and who had living spouses who could verify their medical histories. They were compared to 380 married men in the same age group who were still alive.

A total of 63 men who died from prostate cancer had taken statins, as had 109 of the men who were alive.

After taking into account other risk factors for dying from prostate cancer, men taking statins were 63% less likely to die from the disease than men not taking statins.

Stephen Marcella, MD, assistant professor of epidemiology at the University of Medicine and Dentistry of New Jersey in Piscataway, presented the findings at the 2009 Genitourinary Cancers Symposium.

Further analysis showed that high-potency statins like Lipitor, Zocor, and Crestor were linked to a lower risk of dying from prostate cancer even more than weaker statins like Mevacor, Pravachol, and Lescol.

"The high-potency statins were about 2.5 times more effective at preventing prostate cancer death than the weak statins," Marcella says.

"That makes sense," Klein says. "The more potent the drug, the bigger the biologic effect."

That doesn't mean high-potency statins are better than weaker statins, he stresses. "Their primary purpose is for cholesterol lowering and you typically want to use the least aggressive therapy you can to achieve the desired effect," Klein says.

While the studies were not designed to examine how statins might protect against dying from prostate cancer, Klein notes that they are potent anti-inflammatory drugs. "There's a lot of evidence that inflammation contributes to the development of prostate cancer." Alternately, statins may directly kill cancer cells, Klein says.

The anti-inflammatory model of the reduction of cancer severity in those who use statins may be true for some patients. We don't know. But we do that a diet rich vegetables, antioxidants, fruits (especially berries), and anti-inflammatory herbs (curcumin, olive leaf extract, oregano oil), combined with regular exercise and an avoidance of too much red meat (or, more precisely, flame-cooked meat) and too much sugar and other simple carbs, all work in synergism to reduce inflammation, which is the primary driver of cancer growth.

Why use statins when we can get the same benefit (and may others as well) from a proper diet?

In a 2010 paper (Di Stasi, MacLeod, Winters, and Binder-Macleod¹) on how physical therapists can be useful for those taking statins, the authors outline some of the issues with statins and muscle damage:

Approximately 25 million Americans use statins,¹³ and 5% to 18% of these patients report some form of myalgia.¹⁴ Skeletal muscle side effects that are associated with statin use involve muscle cramping, soreness, fatigue, weakness, and, in rare cases, rapid muscle breakdown that can lead to death (ie, rhabdomyolysis).^15,16 Side effects have been associated with all commonly used statins and are dose dependent.^17,18

Other research has suggested the percentage of people who experience side effects (especially in muscle) is not really so tiny. Parker, Capizzi, Grimaldi, Clarkson, et al. (2013²) found that even non-symptomatic patients express increased average creatine kinase, suggesting that statins produce mild muscle injury even among asymptomatic subjects.

However, this is not the most serious with statins and prostate cancer. 

Earlier this year, the research surfaces again. This is a lengthy article, and I am including all of it - it comes via the Prostate Cancer Foundation.

Statins and Prostate Cancer

As the science comes together, risk of aggressive disease may be abated with use, but little effect on indolent, early prostate cancers

March 4, 2014 -- Statins are a group of widely prescribed drugs used to lower cholesterol levels in the body. Common statin medications include well-known brands such as Zocar, Lipitor, and Crestor. Statins work by inhibiting an enzyme in our bodies (HMG-CoA reductase) that is used to manufacture cholesterol, and the drugs can also help clear already formed cholesterol from the bloodstream. High cholesterol is a known cause of cardiovascular disease, and it’s well-established that statins reduce the rate of death and illness caused by cardiovascular disease. And while statins can help prevent the risk of heart attack or stroke, some studies have also suggested that statins may have an effect on prostate cancer.

Whether the effect would be beneficial or harmful has been the subject of ongoing studies for some time. When statins first became widely available to the public in the 1980s, concerns erupted that these drugs might spur some cancers. Those fears are now widely dispelled, and this past year, a massive meta-analysis of 135 randomized studies that included over a quarter million study participants, found that statin use did not increase the risk of developing cancer.

Statins and Prostate Cancer

However, whether or not statins had a positive impact on cancer risk remained an open question. Research has suggested that statins can slow cancer cell growth in certain cancer types such as breast, colorectal, and skin cancers, and may lower the risk for the latter two. And some research has also suggested that statins might lower the overall risk for prostate cancer, but because of inconsistent findings, it was clear more research was needed. From such ongoing research, what is emerging is that statins may indeed reduce the risk of death from prostate cancer, but likely have little effect on whether or not a man develops prostate cancer in the first place.

Statins and Advanced Prostate Cancer



Dr. Elizabeth A. Platz of the Johns Hopkins Bloomberg School of Public Health and a Prostate Cancer Foundation-funded researcher.
Dr. Platz and colleagues have twice found that individuals with lower levels of cholesterol (within the normal ranges, not the super low ranges) had a lower risk of developing more aggressive disease, as defined by high Gleason scores. This is yet another reason for men to put aside that plate of fried chicken and head for the salad bar, in order to naturally lower their cholesterol levels.

This January, research out of Canada published in the Journal of Clinical Oncology found that men who used statins after a diagnosis of prostate cancer had a 24% decreased risk of death from the disease compared to men who did not take statins. The longer the men took statins, the greater the protective effect. For example, men who took statins for less than one year post-diagnosis had a 1% lower risk of death from prostate cancer compared to non-users. But men who had taken statins for three or more years post-diagnosis lowered their risk of death from their cancer by 39%.

Interestingly, the study also found that statin use prior to a diagnosis of prostate cancer was even more protective to the men, in terms of both mortality specifically from prostate cancer, or from any other cause. Pre-diagnostic statin use reduced the men’s risk of death from prostate cancer by 45%, and conferred a 34% reduced risk of death from any cause, compared to men not taking statins.

All the men in the study had been newly diagnosed with non-metastatic prostate cancer at the time of their enrollment into the study; men who used statins after their diagnosis were 23% less likely to develop distant metastatic cancer spread during the study period.

This study adds to other recent research showing reduced prostate cancer-specific mortality among men who used statins. Dr. Janet Stanford, of the Fred Hutchinson Cancer Research Center in Seattle and a Prostate Cancer Foundation-funded researcher, and colleagues published a study this past summer in The Prostate demonstrating that men who took statins prior to their diagnosis of prostate cancer experienced an 81% reduced risk of prostate cancer-specific mortality compared to men who did not take statins. At 10 years of follow-up, only 1% of statin users had succumbed to prostate cancer, compared to 5% of non-users. However, that study also found that statin use prior to prostate cancer diagnosis did not affect whether or not prostate cancer recurred or progressed. At the time the study was published, Stanford called for confirmation study to validate her findings, and suggested that such research could pave the way for a large, randomized, placebo-controlled study that will yield the most definitive results on whether or not men with prostate cancer should or should not be prescribed statins to lessen their risk of death from the disease.

In response to last month’s study in the Journal of Clinical Oncology (JCO), Drs. Lorelei A. Mucci and Meir J. Stampfer from the Harvard School of Public Health and both Prostate Cancer Foundation-funded researchers, penned an editorial on the subject: Mounting Evidence for Prediagnostic Use of Statins in Reducing Risk of Lethal Prostate Cancer. In this article, Mucci and Stampfer point out that much of the inconsistency among studies on statins and prostate cancer “disappears" when the research distinguishes between risk of overall incidence of prostate cancer and risk of advanced or lethal disease. In reviewing the current “mounting" evidence, Mucci and Stampfer pointed to Stanford and colleagues findings of lower risk of death from prostate cancer in statin users, as well as a Danish study showing lower rates of death for statin users, and a Norwegian study finding that risk of lethal prostate cancer also dropped with statin use.

The authors noted that Prostate Cancer Foundation researchers were the first to focus on risk of lethal disease and statin use in a prospective, observational study published in the Journal of the National Cancer Institute (JNCI) , in 2006. (Men at risk for prostate cancer were observed over the course of several years; their use of statins was recorded, as was their incidence of prostate cancer.) That study, with first author Dr. Elizabeth A. Platz of the Johns Hopkins Bloomberg School of Public Health and a PCF-funded researcher, found that men diagnosed with prostate cancer who used statins halved their risk of developing advanced disease during the study period, and lowered their risk of lethal disease (having metastatic disease at time of diagnosis or succumbing to prostate cancer during the study’s follow up period) by 61 percent. Furthermore, the study found that the risk of developing advanced prostate cancer was lower with longer durations of statin use.

Dr. Mucci says that the Canadian study was a particularly good study for a number of reasons. “It is one of the larger studies to date with the ability to study lethal cancer during the follow-up period," says Mucci, referring to the fact that a large number of men in the study developed lethal disease during the study’s follow-up. Because smaller studies may pick up outcomes that happen just by chance rather than due to the effect of the drug, this study allows far greater confidence in the findings that statin use did have a positive effect on risk of dying from prostate cancer. Also, says Mucci, “A really unique feature of this study is that the researchers looked at statin use both before and after diagnosis." That may be important in helping to determine the mechanism of action statins have on prostate cancer. “One can think about statin use after a diagnosis, and that the drug will probably influence tumor cells after they’ve left the prostate, whereas, statin use before diagnosis could influence the tumor itself," says Mucci.

Knowing when and where statins act on prostate cancer can help determine which patients are most likely to benefit, as well as lead to new drug development specific to prostate cancer once the cellular pathways of action are determined.

Dr. Mucci and colleagues are now working out how statins may affect genes and other molecular pathways for better or worse in prostate cancer patients. They will examine prostate tissue samples taken from men who’ve just undergone radical prostatectomy. “We want to determine if there are differences in gene expression between men who use statins and those who don’t," says Mucci. They examine both tumor tissue samples and normal tissue samples taken from the prostate of each man in their study.

Statins and Overall Risk of Prostate Cancer – unlikely to work as chemopreventive agent

While statin use may have an effect on survivability of prostate cancer in some men, the evidence to date does not point to a protective effect from the drug in terms of overall risk of prostate cancer. In the 2006 JNCI study by Platz and colleagues, while risk of lethal disease was lowered among statin users, there was no risk reduction for the overall occurrence of prostate cancer in men who were taking statins.

On the heels of that study, Platz and colleagues decided to further investigate overall risk of prostate cancer and statin use. “Most of overall prostate cancer is early stage disease, and we did not see an association between statin use and prostate cancer overall" says Platz, “and we were worried maybe we might be missing an association because of a particular study bias—detection bias." Men who regularly seek care through their primary-care doctor are more likely to be screened for both high cholesterol and PSA levels. “If a man has high cholesterol he may well be prescribed a statin to lower his cholesterol levels, and if his PSA levels are elevated, his doctor might recommend a biopsy," says Platz. Regular screening can lead to both a high incidence of statin use and prostate biopsy. And because biopsy if quite sensitive to picking up early prostate cancer, this can create a false association between statin use and prostate cancer, says Platz.

“We wanted to study early prostate cancer in a setting where such detection bias is very unlikely to be operating," said Platz.

To that end, her group studied statin use in a group of men enrolled in the Prostate Cancer Prevention Trial, a study that called for annual PSA screening and digital rectal exams for prostate cancer. This eliminated the variability in screening that likely colored other studies. And, because Platz wanted to focus on early cases of prostate cancer, a setting where all men are screened equally also favored early disease detection that gave the researchers a more homogenous group of diagnosed men, weeding out most cases of late stage disease. In a study just published online in the Journal of Urology, Platz and colleagues again found no association between statin use and early prostate cancer among some 10,000 men enrolled in the Prostate Cancer Prevention Trial who were followed for a period of seven years.

“Overall," says Platz, “if you take all of the literature together, it appears as though statin drugs may be inversely associated with aggressive disease—meaning the cancer progresses to the point of distant metastatic spread, or death of the patient—but not associated with the development of the most common form of prostate cancer in men, which is very early disease."

Why and how might statin use affect development of aggressive prostate cancer?

Clearly this needs to be better understood, but there are several likely avenues of action statins can exert on cancer cells. Pre-clinical research has shown that these cholesterol-lowering drugs can inhibit prostate cancer cell growth, and may encourage cancer cell death and prevent tumor blood vessel growth as well as modulate immune system factors. Additionally, it has been suggested that statins may tamp down the activity of certain oncoproteins. Dr. Mucci’s team, in their work just beginning on tumor tissue samples and statin use, will help suss out such molecular activity and pathways involved.

Dr. Platz and colleagues have now twice found, in two different study groups of men, that individuals with lower levels of cholesterol (within the normal ranges, not the super low ranges) had a lower risk of developing more aggressive disease, as defined by high Gleason scores. (This is yet another reason for men to put aside that plate of fried chicken and head for the salad bar, in order to naturally lower their cholesterol levels.)

Moving forward to better answers

And while the indications are fairly ripe for an interventional randomized clinical study of statins as one agent in the treatment of men with advanced prostate cancer, it is very important to do the groundwork to best determine which subset of men and at what time in their treatment scope, statin use may yield the best results, says Dr. Howard Soule, chief science officer at PCF. Large randomized studies are very costly and if not properly set up, may not bring forth the best information.

From a public health standpoint, it doesn’t make sense to give healthy men, who do not have elevated cholesterol levels, statins for prevention of cancer, says Platz. “Even though these drugs are quite safe, they are not without side effects," she says.

Dr. Jonathan Simons, president and CEO of the Prostate Cancer Foundation, says, “This tantalizing possibility that statins may be used in conjunction with other therapeutics to lower a man’s risk of death from aggressive prostate cancer is well worth further exploration." Simons adds: “Finding that subset of men who might most benefit from statin use in order to hold their cancer in check, or discovering what genes and molecular pathways might be targeted with other new drugs, is a definite goal." And with the recent advent of blood tests that use genetic signatures to help separate out risk of less aggressive from risk of more aggressive disease, and the discovery of constellations of single point mutations—changes in DNA sequence called SNPs—that add up to a higher risk of lethal disease , it may be that evaluating statin use in men who are deemed at higher risk of aggressive disease may be ideal candidates in whom to study statin use as a treatment option. In fact, says Platz, such a research strategy would be feasible because in a high-risk group of men the likelihood of having an event of aggressive prostate cancer is higher, so the study would be more manageable in term of size and duration—fewer men would need to be enrolled and follow up time could be shorter in order to get actionable data.

If you noticed in the article, these studies were conducted on non-metastatic cancer patients, and the studies did not progress far enough to see if any of the patients did suffer from metastasis. Although in one of the studies mentioned, "men who used statins after their diagnosis were 23% less likely to develop distant metastatic cancer spread during the study period." But how long was the study period?

Statins, Metastasis, and Red Blood Cells

One of the emerging theories for the metastasis of prostate cancer is that the cancer stem cells have found a way to "hijack" red blood cells, which allows them to move through the body undetected by the immune system and to eventually hide out in bone morrow, where they are safe from radiation and chemotherapies, and where they also have a steady blood flow to keep them alive.

So the question, then, is how do they get into the red blood cells?

Research (Honda, Yamada, Endo, Ino, Gotoh, et al., 1998³) demonstrates that regulation of the actin cytoskeleton of erythrocytes (red blood cells) likely plays a central role in cell motility and cancer invasion. These authors believe that nonmuscle actinin-1 associates with cell adhesion molecules, such as integrin β1 and α-catenin, and is plays an important role in stabilizing cell adhesion and regulating cell shape and cell motility (Otey et al., 1990, 1993; Glück et al., 1993; Glück and Ben-Ze'ev, 1994; Knudsen et al., 1995).

Their research found that cytoplasmic actinin-4 (a novel isoform of nonmuscle α-actinin) regulates the actin cytoskeleton and increases cellular motility. However, it becomes inactivated when it is transferred to the cell nucleus, which "abolishes the metastatic potential of human cancers." So, in essence, activation of actinin-4 increases cell motility. But how?

It's long been known that inflammatory substances in the immune system can damage erthrocytes, which creates an opening for cancer stem cells to enter. The above study showed that actinin-4 was markedly induced in cells along the edges of a wound to the cytoskeleton.  

Actinin-4 was expressed in a limited population of normal cells, including erythrocytes, endothelial cells, and epithelial cells in various tissues at their border with stromal connective tissue.

So where I am going with all of this?

Simvastatin (Zocor), one of the more common statins, has been shown (Clapp, Ellsworth, Sprague, and Stephenson, 2013⁴) to increase erythrocyte deformability, which means red blood cells are more easily deformed, as in the research above. It is highly likely that other statins produce the same risks.

Deformed erthrocyes, whether from cytokines or statins, increase the risk that cancer cells, including prostate cancer, can invade the damaged blood cells and metastasize throughout the body.

So when you read that statins might be an effective treatment for prostate cancer, please keep this in mind.


References

1. Di Stasi, SL, MacLeod, TD, Winters, JD, and Binder-Macleod, SA. (2010, Oct). Effects of Statins on Skeletal Muscle: A Perspective for Physical Therapists. Physical Therapy; 90(10): 1530–1542.
2. Parker, BA, Capizzi, JA, Grimaldi, AS, Clarkson, PM, Cole, SM, et al. (2013). Effect of Statins on Skeletal Muscle Function. Circulation; 127: 96-103. doi: 10.1161/​CIRCULATIONAHA.112.136101 
3. Honda, K, Yamada, T, Endo, R, Ino, Y, Gotoh, M, Tsuda, H, Yamada, Y, Chiba, H, and Hirohashi, S. (1998, Mar 23). Actinin-4, a novel actin-bundling protein associated with cell motility and cancer invasion. Journal of Cell Biology; 140(6):1383-93.
4. Clapp, KM, Ellsworth, ML, Sprague, RS, and Stephenson, AH. (2013, Mar 1). Simvastatin and GGTI-2133, a geranylgeranyl transferase inhibitor, increase erythrocyte deformability but reduce low O2 tension-induced ATP release. Am J Physiol Heart Circ Physiol.; 304(5): H660–H666.

Shelly Fan - The Fat-Fueled Brain: Unnatural or Advantageous?

The current method of doing a ketogenic diet is not like the popular version in the press, a misrepresentation based on Dr. Atkins' original keto diet in the early 1970s. At that time, the medical establishment thought he was crazy for advocating a diet based primarily on protein (mostly from meat) and fat. The popular image was the steak and bacon diet, with a side of whole cream or a stick of butter.

But he persisted and the evidence and research began to accumulate. As this evidence mounted, Atkins responded to some of the criticisms of his diet by changing the emphasis from high-fat red meat to chicken, fish, and turkey. He also reduced the recommended amounts of saturated fats in the diet.

As of now, many experts suggest that saturated fats should be around 10-15% of all calories from fat, with the remained 85-90% divided between monounsaturated fats (almonds, olive oil) and polyunsaturated fats (omega-3, -6, and -9 from fish, flax seed, pumpkin seeds, walnuts, and other nuts).

By the early 2000s, low-carb diets were the fad, and like all fads, it faded away and Americans continued to get fatter, unhealthier, and more resigned to living that way. But in many circles, various versions of the keto diet live on - as the Paleo Diet of Loren Cordain, Ph.D., or as a general low-carb lifestyle adopted by many fitness enthusiasts and athletes.

The reason we can do a low-carb or even a no carb diet is because, of the four macronutrients (water, protein, fats, and carbohydrates), only three are essential to human life. Can you guess the one that isn't?

You got it - carbohydrates are not an essential macronutrient for human survival.

I have been eating a low-carb diet for the better part of 10 years. In the last 3-5 yrs it has become very low-carb. My energy is better, more level throughout the day, my brain is sharp, my mood is more steady, and despite everything you might read, it has not hurt my workouts. Granted, if I planned to ride my bike for 2-3 hours, I would probably ingest a couple of cans of pumpkin the night before so that I have some reserves of carbohydrate and pop a gell if I feel myself approaching a bonk. But I don't do that. I can ride hard for an hour on an empty stomach (well, on 12 grams of BCAAs) and feel great.

It's not really that hard to do this kind of a diet. Many days, my only carbohydrate source is 2 cups of mixed berries (mostly blueberries, raspberries, blackberries, and black cherries) with my cottage cheese for breakfast. Late morning or noonish I might have a couple of chicken sausages (120 calories each, 15 grams of protein, 5 grams of fat), a couple of sticks of lite string cheese (50 calories each, 7 grams of protein, 2.5 grams of fat) and a handful of walnuts or almonds. A few hours later it might be 6-8 oz. of deli chicken or turkey between two thick slices of part-skim mozzarella, or a chicken breast with some spinach or broccoli. Finally, I often have 2-4 squares of 90% dark chocolate with almond butter or sunflower seed butter. [During the day I might eat 2-5 additional tablespoons of almond butter, sunflower seed butter, or some other type of nut butter, though usually not peanut butter so much anymore.]

My version of this diet is what works for my body (trial and error). I generally eat more protein than the typical keto diet, which can be up to 75-90% fat. And I supplement a lot of my fats with fish oil (8-10 grams a day), pumpkin oil (4-5 grams a day), conjugated linoleic acid (CLA, 4-5 grams a day), and omega-3/6/9 (4-5 grams a day) - for a whopping total of 20-25 grams a day.

Anyway, here is an article from Scientific American Mind looking at the current research on ketogenic diets and the many health benefits we can reap from ditching carbohydrates.

The fat-fueled brain: Unnatural or advantageous?

By Shelly Fan | October 1, 2013

Disclaimer: First things first. Please note that I am in no way endorsing nutritional ketosis as a supplement to, or a replacement for medication. As you’ll see below, data exploring the potential neuroprotective effects of ketosis are still scarce, and we don’t yet know the side effects of a long-term ketogenic diet. This post talks about the SCIENCE behind ketosis, and is not meant in any way as medical advice.


It’s not bacon; it’s therapy! Source: Renée S. Suen on Flickr.
The ketogenic diet is a nutritionist’s nightmare. High in saturated fat and VERY low in carbohydrates, “keto” is adopted by a growing population to paradoxically promote weight loss and mental well-being. Drinking coffee with butter? Eating a block of cream cheese? Little to no fruit? To the uninitiated, keto defies all common sense, inviting skeptics to wave it off as an unnatural “bacon-and-steak” fad diet.

Yet versions of the ketogenic diet have been used to successfully treat drug-resistant epilepsy in children since the 1920s – potentially even back in the biblical ages. Emerging evidence from animal models and clinical trials suggest keto may be therapeutically used in many other neurological disorders, including head ache, neurodegenerative diseases, sleep disorders, bipolar disorder, autism and brain cancer. With no apparent side effects.

Sound too good to be true? I feel ya! Where are these neuroprotective effects coming from? What’s going on in the brain on a ketogenic diet?

Ketosis in a nutshell

In essence, a ketogenic diet mimics starvation, allowing the body to go into a metabolic state called ketosis (key-tow-sis). Normally, human bodies are sugar-driven machines: ingested carbohydrates are broken down into glucose, which is mainly transported and used as energy or stored as glycogen in liver and muscle tissue. When deprived of dietary carbohydrates (usually below 50g/day), the liver becomes the sole provider of glucose to feed your hungry organs – especially the brain, a particularly greedy entity accounting for ~20% of total energy expenditure. The brain cannot DIRECTLY use fat for energy. Once liver glycogen is depleted, without a backup energy source, humanity would’ve long disappeared in the eons of evolution.

The backup is ketone bodies that the liver derives primarily from fatty acids in your diet or body fat. These ketones – β-hydroxybutyrate (BHB), acetoacetate and acetone – are released into the bloodstream, taken up by the brain and other organs, shuttled into the “energy factory” mitochondria and used up as fuel. Excess BHB and acetoacetate are excreted from urine, while acetone, due to its volatile nature, is breathed out (hence the characteristically sweet “keto breath”). Meanwhile, blood glucose remains physiologically normal due to glucose derived from certain amino acids and the breakdown of fatty acids – voila, low blood sugar avoided!


Carbohydrate restriction induces the pancreas to "tell" fat cells to release fatty acids, which get taken up by the liver and converted into ketones and released into blood. Once taken up by the brain, ketones enter the TCA cycle to generate energy. Source: Shelly Fan. (click to see large)

Brain on ketones: Energetics, Oxidation and Inflammation

So the brain is happily deriving energy from ketones – sure, but why would this be protective against such a variety of brain diseases?

One answer may be energy. Despite their superficial differences, many neurological diseases share one major problem – deficient energy production. During metabolic stress, ketones serve as an alternative energy source to maintain normal brain cell metabolism. In fact, BHB (a major ketone) may be an even more efficient fuel than glucose, providing more energy per unit oxygen used. A ketogenic diet also increases the number of mitochondria, so called “energy factories” in brain cells. A recent study found enhanced expression of genes encoding for mitochondrial enzymes and energy metabolism in the hippocampus, a part of the brain important for learning and memory. Hippocampal cells often degenerate in age-related brain diseases, leading to cognitive dysfunction and memory loss. With increased energy reserve, neurons may be able to ward off disease stressors that would usually exhaust and kill the cell.

A ketogenic diet may also DIRECTLY inhibit a major source of neuronal stress, by –well- acting like a blueberry. Reactive oxygen species are unfortunate byproducts of cellular metabolism. Unlike the gas Oxygen, these “oxidants” have a single electron that makes them highly reactive, bombarding into proteins and membranes and wrecking their structure. Increased oxidants are a hallmark of aging, stroke and neurodegeneration.

Ketones directly inhibit the production of these violent molecules, and enhance their breakdown through increasing the activity of glutathione peroxidase, a part of our innate anti-oxidant system. The low intake of carbohydrates also directly reduces glucose oxidation (something called “glycolysis”). Using a glucose-like non-metabolized analogue, one study found that neurons activate stress proteins to lower oxidant levels and stabilize mitochondria.

Due to its high fat nature, keto increases poly-unsaturated fatty acids (PUFAs, such as DHA and EPA, both sold over-the-counter as “brain healthy” supplements), which in turn reduces oxidant production and inflammation. Inflammatory stress is another “root of all evil”, which PUFAs target by inhibiting the expression of genes encoding for pro-inflammatory factors.

Neurons on Ketones: Dampen that enthusiasm!

Excited neurons transmit signals, process information and form the basis of a functioning brain. OVER-excited neurons tend to die.

The brain teeters on a balance between excitation and inhibition through two main neurotransmitters, the excitatory glutamate and the inhibitory GABA. Tilt the scale towards glutamate, which occurs in stroke, seizures and neurodegeneration, and you get excitotoxicity. In other words, hyper-activity is toxic.

Back in the 1930s, researchers found that direct injection of various ketone bodies into rabbits prevented chemically-induced seizures through inhibiting glutamate release, but the precise mechanism was unclear. A recent study in hippocampal neurons showed that ketones directly inhibited the neuron’s ability to “load up” on glutamate – that is, the transmitter can’t be packaged into vesicles and released – and thus decreased excitatory transmission. In a model of epilepsy that used a chemical similar to glutamate to induce damage, the diet protected mice against cell death in the hippocampus by inhibiting pro-death signaling molecules. On the other end of the excitation-inhibition balance, ketones increase GABA in the synapses (where neurotransmitters are released) of rats and in the brains of some (but not all) epileptic humans subjects. This increase in inhibition may confer both anti-seizure effects and neuroprotection, though data is still scant.

Then there are some fringe hypotheses. The acidity of ketones may decrease the pH of certain brain microdomains, which might be the mechanism of keto’s positive effect on Type II Bipolar disorder (lots of mays and mights, I know). As keto affects the whole body, global changes due to calorie restriction and regulation of the satiety hormone Leptin are bound to alter brain function, and play a circumstantial role.

Neuroprotection? Show me the evidence!

All these molecular changes suggest that a ketogenic diet is protective against brain injury. But is there any REAL evidence?

A study with 23 elderly with mild cognitive impairment showed that a ketogenic diet improved verbal memory performance after 6 weeks compared to a standard high carbohydrate diet. In a double-blind, placebo-controlled study, 152 patients with mild- to moderate Alzheimer’s disease were given either a ketogenic agent or a placebo, while maintaining a normal diet. 90 days later, those receiving the drug showed marked cognitive improvement compared to placebo, which was correlated with the level of ketones in the blood.

In a pilot study in 7 patients with Parkinson’s disease, 5 were able to stick to the diet for 28 days and showed marked reduction in their physical symptoms. In an animal model of Amytrophic Lateral Sclerosis (ALS), a ketogenic diet also led to delayed motor neuron death and histological and functional improvements, although it did not increase life span; clinical trials are on the way.

Remarkably, a long-term ketogenic diet does not seem to be associated with significant side effects, although constipation, dehydration and electrolyte and micronutrient deficiencies are common complaints. More serious complications include increased chance of kidney stones, gallbladder problems and bone fractures, especially in children. Menstrual irregularities often occur in women, with potential impact on fertlity. Although ketoacidosis – acidification of the blood due to pathological levels of ketones – was historically proposed as a side effect, nutritional ketosis simply cannot achieve the level of ketones required to induce this life-threatening state. Nevertheless, there are no studies directly monitoring the side effects of ketosis yet, hence it’s too early to conclude that the diet is completely safe for everyone.

Brain [hearts] Bacon

While promising, large-scale placebo-controlled clinical trials in patients with neurological disorders are still lacking. The existing data needs to be interpreted carefully to avoid generating false hope or encourage patients to “ditch drugs for diet”. Nevertheless, the possibility that we can reduce symptoms of untreatable neurological disorders through modifying dietary composition is quite incredible; that a ketogenic diet may benefit physical and cognitive performance in healthy individuals is an even more tantalizing idea.

As the science behind this age-old dietary therapy gradually comes to light, social issues such as low adherence and public prejudice will need to be resolved. In the meantime, to those neuroscientists interested in studying keto: pass the bacon and I VOLUNTEER!

Final note: Before I let you go, I’d like to stress again that keto is NOT something to try out without talking to your doctor first, nor is it a replacement for pharmaceuticals. There’s simply not enough evidence, on either its effectiveness or side effects. Nevertheless, it’s a cool area of research to keep an eye on!

Aggression in Boys May Start Before Birth (McGill University)

This new(ish) study from McGill University looked at the epigenetic genesis of some behavioral issues in boys and discovered that the cause can often be traced back to the pregnancy.

Their study revealed that men who displayed chronic aggressive behavior between the ages of 6 and 15 had lower blood levels of four biomarkers of inflammation (cytokines) than in men who displayed "normal" levels of aggressive behavior in their youth (from the original paper).

Compared to the control group, males on a chronic physical aggression trajectory from childhood to adolescence had consistently lower plasma levels of five cytokines: lower pro-inflammatory interleukins IL-1α (T(28.7) = 3.48, P = 0.002) and IL-6 (T(26.9) = 3.76, P = 0.001), lower anti-inflammatory interleukin IL-4 (T(27.1) = 4.91, P = 0.00004) and IL-10 (T(29.8) = 2.84, P = 0.008) and lower chemokine IL-8 (T(26) = 3.69, P = 0.001).

This allowed researchers to distinguish between men with physically aggressive histories from men without such histories simply on the basis of four cytokines (IL-1α, IL-4, IL-6, and IL-8).

In a follow-up study with the same men with aggressive pasts, "the DNA encoding the cytokines showed methylation patterns different from those of the comparison group."

Methylation is an epigenetic modification of DNA in relation to imprinting by parents or caregivers. Methylation also plays a role in regulating gene expression (turning a gene on or off). 

According to the researchers, the prenatal and early postnatal environment may trigger these epigenetic shifts that cause reduced levels of the four specific cytokines associated with youthful aggression.

The authors speculate in the discussion on the connection between specific cytokines and various brain chemicals, specifically serotonin and cortisol (from the original paper):

First, high cortisol levels were found to be associated with high levels of aggression in adolescent males from the same sample [41]. Cortisol levels are known to regulate immune and inflammatory responses [42]. Second, Vasopressin, a mediator of the HPA axis activity released in the brain enhances arousal and aggression [43]. Brain vasopressin is also involved in stress-induced suppression of immune functions in rats [44], [45]. Third, serotonin, a key player in aggressive behavior, is induced by cytokines, such as IL-6 and IL-1β, in brain and in blood [46]–[48]. Serotonin is also known to be involved in regulating IL-4, IL-8, IL-6, TNF-α and IL-1 expression and secretion through the CREB signaling pathway [49], [50]. Together, these studies suggest a link between known mediators previously shown to be involved in aggression and cytokines.

More importantly, the researchers suggest:

There is good evidence that the parents of children on a high trajectory of physical aggression had similar behavior problems and created early childhood family environments which did not support learning to regulate physically aggressive reactions [4], [10]–[14].

As is often the case, aggression is a family issue and is usually intergenerational. The fundamental question, as always, is causality: "Does chronic aggression during childhood result in lowered cytokine activity or does lowered cytokine activity result in more aggression?"

This is an excellent study and worth the time to read. Below is a summary of the research from Futurity, followed by the abstract of the original study.

Aggression in boys may start before birth

Posted by Cynthia Lee-McGill on September 23, 2013


"If our results show that behavioral problems originate from as far back as pregnancy, it means that we can reduce violence through preventive intervention from as early as pregnancy," says Richard Tremblay. (Credit: Peter Dutton/Flickr)

McGill University -- Original Study (PLoS ONE)

Chronic aggressive behavior exhibited by some boys from disadvantaged families may be due to epigenetic changes during pregnancy and early childhood.

A new study shows that men who displayed chronic aggressive behavior during childhood and adolescence have lower blood levels of four biomarkers of inflammation than in men who exhibited average levels of aggressive behavior in their youth, from 6 to 15 years of age.

“This means that using four specific biomarkers of inflammation, called cytokines, we were able to distinguish men with chronic physical aggression histories from those without,” says Richard Tremblay, professor emeritus at the University of Montreal.

In a second study, in the same men with aggressive pasts, the DNA encoding the cytokines showed methylation patterns different from those of the comparison group.

“Methylation is an epigenetic modification—hence reversible—of DNA, in relation to parental imprinting. It plays a role in regulating gene expression,”says Moshe Szyf, a professor at McGill University.

“The pre- and postnatal environment could cause these differences in biomarkers associated with chronic aggression,” Szyf says.

Various studies conducted with animals show that hostile environments during pregnancy and early childhood have an impact on gene methylation and gene programming leading to problems with brain development, particularly in regard to the control of aggressive behavior.

Begins with mom?

Previous work suggests that men with aggressive pasts have one thing in common: the characteristics of their mothers.

“They are usually young mothers at the birth of their first child, with low education, often suffering from mental health problems, and with substance use problems,” Tremblay says.

The significant difficulties these mothers experienced during pregnancy and the early childhood of their child may have an impact on the expression of genes related to brain development, the immune system, and many other biological systems critical for the development of their child.

For the two studies, published in PLOS ONE, researchers collected blood from 32 participants who took part in either of two longitudinal studies that began nearly 30 years ago. The first study followed young Quebecers from disadvantaged backgrounds, while the second involved a representative sample of children who were in kindergarten in Quebec in 1986-87.

It is important to note that in disadvantaged families, the rate of boys with chronic aggressive behavior represents about 4 percent of the population. This greatly restricts the selection of potential participants.

Disorganized lifestyles

“Once they are adults, they are difficult to find because they have disorganized lifestyles,” Tremblay says. “We are studying the impact of the socioeconomic environment on the third generation, now that these children are grown up and have children.”

While no study has yet been published on the subject, he anticipates “significant intergenerational ties, since we observed an association between parental criminality of the first generation and the behavior of their children.”

Nevertheless, Tremblay, who has conducted his work for decades with a prevention perspective, is optimistic.

“If our results show that behavioral problems originate from as far back as pregnancy, it means that we can reduce violence through preventive intervention from as early as pregnancy. We have already shown that support given to families of aggressive boys in kindergarten prevents school dropout and crime in adulthood.”

* * * * *

Here is the abstract of the original article from PLoS ONE, available as an open access publication and downloadable as a PDF.

Childhood Chronic Physical Aggression Associates with Adult Cytokine Levels in Plasma

Nadine Provençal, Matthew J. Suderman, Frank Vitaro, Moshe Szyf, Richard E. Tremblay 

Abstract

Background

An increasing number of animal and human studies are indicating that inflammation is associated with behavioral disorders including aggression. This study investigates the association between chronic physical aggression during childhood and plasma cytokine levels in early adulthood.

Methodology/Principal Findings

Two longitudinal studies were used to select males on a chronic physical aggression trajectory from childhood to adolescence (n = 7) and a control group from the same background (n = 25). Physical aggression was assessed yearly by teachers from childhood to adolescence and plasma levels of 10 inflammatory cytokines were assessed at age 26 and 28 years. Compared to the control group, males on a chronic physical aggression trajectory from childhood to adolescence had consistently lower plasma levels of five cytokines: lower pro-inflammatory interleukins IL-1α (T(28.7) = 3.48, P = 0.002) and IL-6 (T(26.9) = 3.76, P = 0.001), lower anti-inflammatory interleukin IL-4 (T(27.1) = 4.91, P = 0.00004) and IL-10 (T(29.8) = 2.84, P = 0.008) and lower chemokine IL-8 (T(26) = 3.69, P = 0.001). The plasma levels of four cytokines accurately predicted aggressive and control group membership for all subjects.

Conclusions/Significance

Physical aggression of boys during childhood is a strong predictor of reduced plasma levels of cytokines in early adulthood. The causal and physiological relations underlying this association should be further investigated since animal data suggest that some cytokines such as IL-6 and IL-1β play a causal role in aggression.

Full Citation: 
Provençal N, Suderman MJ, Vitaro F, Szyf M, Tremblay RE. (2013, Jul 26), Childhood Chronic Physical Aggression Associates with Adult Cytokine Levels in Plasma. PLoS ONE 8(7): e69481. doi:10.1371/journal.pone.0069481

This is some seriously bad news for American men, 66% of whom are overweight or obese. One of the most debilitating side effects of obesity is that fats cells create estrogen - the more fat cells, and the bigger the fat cells, the more estrogen in the body. It gets worse, fat cells also support high levels of aromatase, an enzyme that converts testosterone to estrogen. More fat, less testosterone due to the aromatization of testosterone into estrogen .

High fat levels (through increases in estrogen due to aromatase conversion) reduce testosterone, which has its own downside: depression, loss of libido, muscle wasting, bone density loss, heart attacks and other cardiovascular issues, and higher risk of early death.

The evidence has been building for years that many neurodegenerative disorders, such as Alzheimer's Disease and other forms of dementia are linked to neuroinflammation (see this article). More recent evidence is showing that inflammation may play a crucial role in depression, schizophrenia, and bipolar disorder.

A 2012 article (Maintaining Brain Health by Monitoring Inflammatory Processes: a Mechanism to Promote Successful Aging) in Aging and Disease looked at how inflammation contributes to mental decline, as well as structural and metabolic dysfunctions. The article is freely available at the link above.

Abstract 

Maintaining brain health promotes successful aging. The main determinants of brain health are the preservation of cognitive function and remaining free from structural and metabolic abnormalities, including loss of neuronal synapses, atrophy, small vessel disease and focal amyloid deposits visible by neuroimaging. Promising studies indicate that these determinants are to some extent modifiable, even among adults seventy years and older. Converging animal and human evidence further suggests that inflammation is a shared mechanism, contributing to both cognitive decline and abnormalities in brain structure and metabolism. Thus, inflammation may provide a target for intervention. Specifically, circulating inflammatory markers have been associated with declines in cognitive function and worsening of brain structural and metabolic characteristics. Additionally, it has been proposed that older brains are characterized by a sensitization to neuroinflammatory responses, even in the absence of overt disease. This increased propensity to central inflammation may contribute to poor brain health and premature brain aging. Still unknown is whether and how peripheral inflammatory factors directly contribute to decline of brain health. Human research is limited by the challenges of directly measuring neuroinflammation in vivo. This review assesses the role that inflammation may play in the brain changes that often accompany aging, focusing on relationships between peripheral inflammatory markers and brain health among well-functioning, community-dwelling adults seventy years and older. We propose that monitoring and maintaining lower levels of systemic and central inflammation among older adults could help preserve brain health and support successful aging. Hence, we also identify plausible ways and novel experimental study designs of maintaining brain health late in age through interventions that target the immune system.

Full Citation:
Rosano, C, Marsland, AL, and Gianaros, PJ. (2012, Feb). Maintaining Brain Health by Monitoring Inflammatory Processes: a Mechanism to Promote Successful Aging. Aging and Disease; 3(1): 16–33. PMCID: PMC3320802

Two easy ways to control and reduce inflammation are an anti-inflammatory diet and regular exercise. Over at Integral Options Cafe, I posted information this morning on foods and supplements that reduce inflammation.

Here is the press release:

Obesity Leads to Brain Inflammation, and Low Testosterone Makes It Worse

June 17, 2013 — Low testosterone worsens the harmful effects of obesity in the nervous system, a new study in mice finds.

The results will be presented Monday at The Endocrine Society's 95th Annual Meeting in San Francisco.

"Low testosterone and obesity are common in aging men, and each is associated with type 2 diabetes and Alzheimer's disease," said the study's lead investigator, Anusha Jayaraman, PhD, of the University of Southern California in Los Angeles. "Our new findings demonstrate that obesity and low testosterone combine to not only increase the risk of diabetes but also damage the brain."

The study -- which was conducted in the laboratory of Christian J. Pike, PhD, Professor in the Davis School of Gerontology at USC and funded by the National Institutes of Health's National Institute on Aging -- consisted of three groups of male mice that received a high-fat diet (60 percent of calories were from fat) to induce obesity. Each group had eight mice and varied by testosterone status. One group had normal testosterone levels, and the second group underwent surgical removal of the testes so that the mice had low testosterone levels. The third group also underwent castration but then received testosterone treatment through a capsule implanted beneath the skin.

The high-fat diet, Jayaraman reported, resulted in obesity and evidence of diabetes -- abnormally high blood glucose (sugar) levels and poor glucose tolerance, which is the ability to clear glucose from the bloodstream. Compared with the group that had normal testosterone levels, the testosterone-deficient mice had more body fat, higher blood sugar levels and poorer glucose tolerance, she said.

After blood testing, brain tissues from the mice underwent analysis for changes. The brains of obese mice showed substantial inflammation and were less able to support nerve cell growth and survival, according to Jayaraman. These damaging effects of diet-induced obesity were significantly worse in mice with low testosterone, she said, adding that control groups of mice fed a normal diet did not show these changes.

"Our findings suggest that low testosterone and obesity interact to regulate inflammation of the nervous system, which may increase the risk of disorders such as type 2 diabetes and Alzheimer's disease," she said.

Because many of the negative outcomes of the high-fat diet were eased in the group of mice that received testosterone therapy, Jayaraman said that "testosterone treatment may be useful in reducing the harmful effects of obesity and low testosterone on the nervous system."