Swine Flu and Avoiding the Cytokine Storm: What to Eat and What Not to Eat?

Pomegranate juice is an ACE inhibitor. (Photo by JOE M500)

The scary connection between the 1918 flu pandemic (Spanish flu), the avian influenza (bird flu) and the swine influenza (pig flu) is that they all strike hardest those with healthy immune systems.

Usually, when people die of influenza, it's because they're old or their immune systems are compromised in other ways. Not so with the swine flu. As with the other two pandemics, death rates from swine flu have been highest among the 15-40 age group. Healthy young people seem to be in an especially big danger of dying from the influenza.

Swine flu, inflammation and the cytokine storm

The reason behind the deaths seems to be an exaggerated immune response, known as a cytokine storm. Since the body doesn't know what to do with the virus, it triggers an all-out release of inflammatory mediators. The reaction then becomes out of control, and the feedback loop ends up killing the patient (link).

The cytokine storm is the reason why the usual recipe for good health doesn't apply in the case of swine flu. Both inflammatory and anti-inflammatory cytokines have their uses in fighting off infection, and inhibiting inflammation is considered a good way to promote health in general. However, increasing anti-inflammatory cytokines during a cytokine storm is a bad idea.

So how do we shield ourselves from a cytokine storm? No one is really sure at this point. In a cytokine storm from avian influenza, the main cytokines responsible are TNF-alpha, IL-6 and IFN-gamma (link, link), with IP-10 and IFN-beta also being expressed more than usual (link). Reducing the levels of these and other cytokines could, at least in theory, be helpful. There is also some evidence that angiontensin converting enzyme (ACE) inhibitors might help in mediating cytokine storms (link, link, link), though we don't know for certain.

While taking cytokine and ACE inhibitors for swine influenza is currently only a theory, I nevertheless find it an interesting one. Specifically, I think a look into how "health foods" affect cytokines is useful, since conventional wisdom may not apply here due to reasons mentioned earlier. Below, we'll take a look at some natural cytokine and ACE inhibitors and also discuss which health foods may actually be harmful.

ACE inhibitors from natural sources

Procyanidins and flavanols have an inhibitory effect on angiotensin converting enzyme (link). They are found in many plants, such as apples, cocoa, cinnamon, berries and tea. Chokeberries have the highest concentration of procyanidins.

In one study, procyanidins and epigallocatechin were effective while catechin, epicatechin, gallic acid, chlorogenic acid, caffeic acid, quercetin, kaempferol and resveratrol at similar concentrations were ineffective (link). Accordingly, wine, chocolate and tea were all found to inhibit ACE activity, with red wine being more effective than white wine, green tea being more effective than black tea.

A word of caution: cocoa, while inhibiting ACE activity, may increase the secretion of TNF-alpha (link) and IL-1 and IL-4 expression (link), which could be bad news in the case of a cytokine storm. Chocolate may therefore not be a good idea if trying to reduce cytokines.

Quercetin, while ineffective in the study mentioned above, has been shown to have an inhibitory effect on the angiotensin converting enzyme, similarly to captopril (link), while also reducing blood pressure (link) and the angiotensin-induced production of IL-6 (link).

Another study found that both green tea and black tea inhibited ACE activity dose-dependently (link). In addition, all four catechins tested (including epicatechin) were effective. Rooibos tea, however, had no effect.

Pomegranate juice seems to be very effective in inhibiting ACE activity in vitro and in vivo (link). Hypertensive patients given 50 ml of pomegranate juice for two weeks had a 36% decrease in ACE activity and a 5% reduction in systolic blood pressure.

Cytokine inhibitors from natural sources

Epigallocatechin gallate (EGCG) inhibits the production of TNF-alpha, IL-6 and IL-8 (link). The best source of EGCG is green tea. Black tea is not without its merits either, though, as the theaflavins in black tea appear to reduce levels of IL-1 and IL-6 (link).

Several compounds in garlic appear to inhibit cytokines. Ajoene partially inhibits the production of TNF-alpha (link). Allicin inhibits IL-1, IL-8 and IP-10 (link), while alliin increases IL-1 and TNF-alpha (link). Crushing or chopping garlic causes alliin to be converted into allicin, while cooking garlic decreases allicin (link). Therefore, for the purposes of reducing cytokines, it's better to crush garlic and eat it raw.

Chronic garlic administration decreases myocardial TNF-alpha expression in rats (link). One study showed that garlic may increase IL-10 (link), and another one showed it increased IL-4 while reducing IFN-gamma (link). However, in humans, garlic powder extract has been shown to reduce IL-1 and TNF-alpha with no effect on IL-10 (link). The ratio of alliin and allicin may be important here as well.

When mice infected with influenza were fed vitamin E, they had significantly lower levels of IL-1beta, IL-6 and TNF-alpha (link, link). A relatively good natural source of vitamin E is red palm oil, which has been shown to reduce TNF in humans (link).

Fats, depending on their omega-3/omega-6 ratio and whether they're saturated or unsaturated, may play an important part in cytokine production. In rats, fish oil (which is high in omega-3) was shown to reduce levels of IL-1 and IL-6 (link). In humans, 4 weeks administration of flaxseed oil followed by 4 weeks of fish oil was shown to inhibit TNF-alpha and IL-1 in healthy humans, with fish oil being more effective (link).

Not all the data is positive, unfortunately. A long-term study comparing various doses of fish oil in humans concluded that supplementation for 1 year did not affect cytokine production (link). In another study, olive oil, coconut oil and fish oil all reduced IL-1 production in rats during the first 4 weeks of administration (link). However, after 4 weeks, olive oil and fish oil increased IL-6 production, and after 8 weeks, olive oil began to increase IL-1 production as well.

While resveratrol was found in the previously mentioned study to be ineffective for inhibiting ACE activity, it appears to suppress the expression of TNF-alpha, IL-6 and IL-8 (link, link). Resveratrol is found in red wine, red grapes and peanuts. Red wine has been shown to reduce levels of TNF-alpha, IL-6 and IL-8 in diabetics (link), although one study found no effect on cytokines from red wine (link) and another one found an increase in IL-6 (link). While those with peanut allergy should obviously avoid peanuts, it is unclear how peanuts affect cytokine levels in non-allergic people.

Quercetin decreases the expression of TNF-alpha, IL-6 and IL-8 (link, link). Food sources of quercetin include green tea, capers, fennel, onions, cocoa, kale and apples with skins (link, link). Compared to supplements, the quercetin content of foods is quite low, however.

Curcumin appears to reduce levels of TNF-alpha along with IL-6 and IL-8 (link, link, link). The main food source of curcumin is the spice turmeric. While the bioavailability of curcumin is very low, heating (link) and the addition of piperine greatly enhances its absorption (link). Piperine, which is found in black peppers, also inhibits inhibits IL-1, IL-6 and TNF-alpha (link).

One study showed that 2,000 IU of vitamin D3 given for nine months resulted in lower TNF-alpha and higher IL-10 levels than the control group (link). Vitamin D3 seems to increase IL-4 but decrease TNF-alpha, INF-gamma and IL-6 (link, link). On the other hand, a vitamin D deficiency reduced IL-1 levels, halved TNF levels and reduced IL-6 levels five-to-tenfold in mice (link). The Vitamin D Council newsletter covers this topic extensively (link); in short, they seem to advocate either not taking any vitamin D3 or taking at least 5,000 IU. Anything in between is potentially harmful for cytokine storms.

Summary

For the purposes of inhibiting ACE and reducing cytokines, the following foods and compounds seem to be the best choices:

• Green tea (ACE inhibitor, reduces cytokines)
• Black tea (ACE inhibitor, reduces cytokines)
• Quercetin (possible ACE inhibitor, reduces cytokines)
• Pomegranate juice (ACE inhibitor)
• Red wine (ACE inhibitor)
• Turmeric (reduces cytokines)
• Black pepper (reduces cytokines)
• Raw crushed garlic (reduces cytokines)
• Red palm oil (reduces cytokines)
• Vitamin E (reduces cytokines)
  
• Coconut oil (reduces cytokines)

The following foods, while beneficial in many other ways, may not be a good idea in terms of reducing cytokine levels:

• Olive oil (may increase cytokines)
• Fish oil (may increase cytokines)
• Chocolate (ACE inhibitor, increases cytokines)

In addition, it seems that vitamin D3 could be on either list, depending on the dosage. Average blood levels of vitamin D may be worse than very low or high levels.

That's it for this week, I'm off for a holiday (hopefully without swine flu), so no updates for a few weeks. For more information on cytokines and inflammation, see these posts:

Examining Possible Causes for Slower Wound Healing
Green Tea Protects from Arthritis in Rats
Green Tea Protects Cartilage from Arthritis in Vitro
Intermittent Fasting with a Condensed Eating Window – Part III: Fasting Blood Glucose, Cortisol & Conclusion

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Soy Isoflavones Reduce DHT, Increase Testosterone

Soybeans contain the isoflavones genistein and daidzein. (Photo by T. Hagihara)

There's a lot of speculation on how soy intake and hair growth are related, so in a series of posts beginning with this one, we'll be taking a look at what the studies have to say. Hopefully, it will become clear whether soy isoflavones really do anything, how much isoflavones is the optimal intake, and whether oral or topical is the way to go.

In the first study we'll look at, male rats were fed soy isoflavones in various amounts (link). After a week, their testosterone and dihydrotestosterone (DHT) levels were measured. Since reducing DHT levels seems to be an effective way to reduce hair loss, this should be an interesting study for people considering soy isoflavones as a remedy.

Composition of the soy diets

To find out how soy isoflavones and androgen levels are related, the authors conducted two experiments. In the first experiment, rats in the treatment group were given soy flour with their normal chow. In the second experiment, rats in the treatment groups were given either a soy methanol extract or semipurified soy isoflavones.

The isoflavone content of the soy flour was 1.92 mg/g. The isoflavone contents of the soy methanol extract and semipurified soy isoflavones were 3.38 mg/g and 218 mg/g, respectively. In the first experiment, the rats in the treatment group received 442.7 g/kg soy flour in their diet. In the second experiment, they received 20 g/kg of soy extract or 2 g/kg of soy isoflavones in their diets.

Long story short, the according to the authors, the actual soy isoflavone intakes of the rats were as follows: 19 mg/day in the soy flour group, 0.9 mg/day in the soy extract group, and 3.3 mg/day in the soy isoflavone group. The control groups consumed zero soy isoflavones.

Soy isoflavones and DHT

Rats on the soy flour diet had significantly lower DHT levels than rats on the control diet. Similarly, the DHT levels of the rats on the soy isoflavone diet were about 60% lower DHT than in the control group. On soy extract diet DHT levels tended to decrease, but the difference was not statistically significant.


The figure above shows the DHT levels for the soy extract and soy isoflavone diets compared to the control group. The observed decrease in DHT from the soy flour diet (not shown above) was similar to that of the soy extract diet, with the exception that the difference was statistically significant.

Soy isoflavones and testosterone

Rats on the soy flour diet had similar levels of testosterone + dihydrotestosterone (T+DHT) as the control group. Since their DHT levels were lower, however, this means that there was an increase in testosterone from eating the soy flour diet. In the soy isoflavone diet, this effect was even clearer; not only was the reduction in DHT balanced by an increase in testosterone, but the total T+DHT levels were much higher than they were before the diet.



The figure above shows the T+DHT levels of the soy extract and soy isoflavone diets compared to the control group. Testosterone levels tended to increase and DHT levels tended to decrease also on the soy extract diet, but again, the differences were not statistically significant.

The fact that the soy isoflavone showed significant effects and the soy extract is possibly due to the differences in soy isoflavone content of the diets. The rats on the soy extract diet consumed only 0.9 mg/day, while those on the isoflavone diet consumed 3.3 mg/day. The two graphs shown here seem to support the idea that the effect is dose-dependent.

What is confusing, however, is that the soy flour diet showed a less pronounced effect than the soy isoflavone diet even though it had a much higher isoflavone content. Perhaps the dose-response is not linear but a bell curve. Unfortunately, the authors offer no explanation or theory for the results in the paper.

Conclusion

Soy isoflavones significantly reduced DHT levels and increased testosterone levels in male rats. An intake of 3.3 mg of isoflavones per day was the most effective of the three treatments tested. A lower intake showed similar but less pronounced effects, while a higher intake did not appear to further add to the effect.

For more information on hair growth, see these posts:

Tea Tree Oil vs. Korean Red Ginseng – Hair Growth Battle Conclusion
North African Plant Extract (Erica multiflora) Increases Hair Growth
Bioactive Form of Silicon (BioSil) Improves Skin, Hair & Nails in Photoaged Women
2% Nizoral Shampoo Increases Hair Growth More than 2% Minoxidil

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Yerba Mate Inhibits AGE Formation

Yerba mate contains caffeic acid, which inhibits glycation. (Photo by MaPev)

Advanced Glycation End products (AGEs) are formed in two ways: outside the body and inside the body. The former happens when sugars are heated with fats or proteins, the latter through metabolism when eating glycation-prone foods such as fructose.

From an anti-aging point of view, reducing the formation of AGEs is important. One way of doing it is to avoid cooking as much as possible. However, since the idea of never eating a fried steak is less than appealing to many, including me, I'm constantly on the lookout for foods and supplements that may help reduce AGEs.

One natural way to inhibit AGE formation is to drink green tea, which has been shown to reduce AGEs both in vivo and in vitro. However, it seems that there's a better anti-glycation drink available: yerba mate.

Infusions of yerba mate (Ilex paraguariensis) are especially popular in South America, but it's becoming increasingly known in other places as well. I've drank yerba mate on and off for years simply because I like it, but this is the first time I've come across it's effects on AGEs. I assume that as we learn more about its benefits, it will be even more popular among health-conscious people. Now, let's look at the study.

Reducing AGE formation: yerba mate vs. green tea

The authors of the paper (link) compared the AGE-inhibiting effect of yerba mate to that of green tea and aminoguanidine, a known anti-glycation agent. Water extracts of normal strength were used for green tea and yerba mate (5 g and 10 g leaves / 2 dl water, respectively). Bovine serum albumin and methylgloxal were used to generate AGEs on proteins in vitro.

As expected, high doses of aminoguanidine reduced both indicators of glycation (tryptophan fluorescence and AGE fluorescence) by more than 90%. The surprise is that yerba mate dose-dependently and significantly reduced AGE fluorescence, while green tea showed only a non-significant positive trend. At the highest dose (20 mcl/ml), the inhibition from yerba mate reached 40%.

How and why does yerba mate inhibit AGEs?

Glycation is really a process with several steps, which eventually leads to the formation of AGEs. Aminoguanidine prevents the first reaction in glycation and thus all its downstream effects from occurring. Yerba mate, on the other hand, works differently. It inhibits the second phase of glycation: the conversion of Amadori products to AGEs. According to the authors, this is likely due to the antioxidant and free radical quenching capability of yerba mate.

One possible explanation for yerba mate beating green tea is that yerba mate naturally contains more polyphenols than green tea. Also, the infusion of yerba mate in the study was stronger than the green tea infusion. A more convicing explanation is that the bioactive substances between the two are different. While most of the benefits of green tea are due to its catechins, yerba mate contains caffeic acid, chlorogenic acids, saponins and sapogenins.

Another study (link) compared the effects caffeic acid, a chlorogenic acid (5-caffeoylquinic acid) and a sapogenin (oleanolic acid) on AGE formation. Out of the three, caffeic acid was most effective and oleanolic acid was the weakest in inhibiting glycation. Importantly, caffeic acid and chlorogenic acid inhibited glycation even more effectively than aminoguanidine, with caffeic acid inhibiting 95% of AGE formation.

How much yerba mate do I need to drink, then?

The important question, of course, is whether drinking yerba mate can really prevent AGEs in the human body. To get some idea of what the answer might be, let's look at some of the figures.

The yerba mate extract used in the study was not especially strong: 10 grams of leaves per 2 desiliter of water heated to 90 °C. This makes for a stronger infusion than green tea, but since the taste of yerba mate is not as strong, 10 grams is very close to how you would normally drink it. The polyphenol content of the infusion was 2.6%.

According to the authors of the first paper, a significant effect was seen in vitro at a concentration of the extract that corresponds to a 1:100 dilution of the preparations usually drunk, which suggests that a high bioavailability may not be needed. The authors of the second paper note that the concentrations of oleanolic acid may mimic those found in humans.

So, even though we don't have enough data at this point to make more than educated guesses as to much yerba mate consumption really helps with reducing AGEs, drinking a few cups of yerba mate with AGE-containing meals may not be such a bad idea.

Conclusion

Yerba mate reduces glycation in vitro by inhibiting the conversion of Amadori products to AGEs. The most potent substances found in yerba mate were caffeic acid and chlorogenic acid, which were more effective than aminoguanidine (an anti-glycation drug) in inhibiting AGE formation. The amount of yerba mate needed to see anti-AGE benefits in humans is unclear, however, because no studies on humans exist.

For more information on glycation and aging, see these posts:

Green Tea Reduces the Formation of AGEs
Intermittent Fasting Reduces Mitochondrial Damage and Lymphoma Incidence in Aged Mice
Anti-Aging in the Media: 60 Minutes on Resveratrol
How the Accumulation of Minerals Might Cause Aging in Humans

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Nootropic Battle: Acetyl-L-Carnitine vs. Ginkgo Biloba vs. Taurine

Nootropics are popular among students as learning aids. (Photo by xb3)

Recently, I've been writing quite a bit about various supplements marketed as nootropics, a term which encompasses pretty much any substance with claimed cognitive enhancing effects. The ones we've covered so far are carnitine, ginkgo biloba and taurine.

Probably the most promising supplement out of the three is carnitine (as L-carnitine or acetyl-L-carnitine). In aged rodents, carnitine improves learning ability and memory while protecting the brain from aging. Even though the human data is not as conclusive, several studies nonetheless show that carnitine can treat mental decline and depression. In addition to its cognitive effects, carnitine may improve physical fitness in old people and protect from exercise-related oxidative stress.

Less clear is the case for ginkgo biloba. Some people swear by its effect on memory and mood, others think it's a complete waste of money. Perhaps surprisingly, several studies have been done on ginkgo biloba and cognition. While some of them do suggest that ginkgo biloba may be an effective natural treatment for dementia and stress-related cognitive decline, it's difficult to say how it works in healthy people.

Probably the one that has the least science behind it in terms of cognition is taurine, which is often added to energy drinks for its claimed stimulant properties. Even though taurine seems to be effective in protecting from acute neurological damage, the evidence for taurine as a brain booster in healthy people is lacking. A few studies suggest it may protect the brain from some of the effects of aging and improve mood, but it's difficult to draw any significant conclusions as of yet.

To see for myself whether any of these three have an effect on learning, memory, energy levels and mood, I have decided to start an experiment using carnitine (as acetyl-L-carnitine capsules), ginkgo biloba (also as capsules) and taurine (in powder form). I will first try each supplement separately, starting with low doses and increasing the dose if there is no effect, and then in combination with the others.

Success and failure will be measured by my subjective evaluation of how I'm feeling (i.e. do I feel energetic, happy, smart, able to concentrate, etc.) and also by seeing how well I do in the memory game I'm playing for my intelligence experiment after taking each supplement. This won't tell us much about the possible long-term effects, of course, but at least I will know whether any of them are worth the money as nootropics.

Ladies and gentlemen, the three-way cognition battle between carnitine, ginkgo biloba and taurine has begun!

For more information on brains and intelligence, see these posts:

Caloric Restriction Improves Memory in the Elderly
Moderate and Severe Caloric Restriction Alter Behavior Differently in Rats
Intermittent Fasting Reduces Mitochondrial Damage and Lymphoma Incidence in Aged Mice
Anti-Aging in the Media: Rolling Stone on Ray Kurzweil

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Does Taurine Improve Cognitive Performance and Mood?

A can of Red Bull contains 1,000 mg taurine, more than many supplements. (Photo by kamshot)

Taurine is found in most energy drinks right alongside caffeine, but nobody seems to know exactly why. Do the manufacturers of Red Bull and Battery know something we don't, or is taurine added simply out of habit?

Since finding any useful information on taurine as a brain stimulant is difficult, in this post, we'll look at what the studies say on taurine's effect on cognitive function and mood. Specifically, the problem areas we'll be focusing on are aging, depression, brain damage, and alcohol.

Taurine and the aging brain

With age, the neurotransmitter system performs progressively worse, resulting in problems with memory, learning and mood, among other things. A key part of this system is the main inhibitory neurotransmitter GABA, or gamma-Aminobutyric acid. Drugs that increase the amount of available GABA in the brain typically have a relaxing and anti-anxiety effect.

There is some evidence that taurine may increase GABA levels by acting as a GABA receptor antagonist. In one study, aged mice supplemented with taurine showed less decline in memory acquisition and retention, which was associated with increased levels of GABA and glutamate (link). Taurine may also protect from Huntington's disease through its indirect antioxidant effect and by increasing GABA levels (link).

Not all studies have found similar benefits, however. One experiment showed that when old rats were given taurine in their drinking water, brain taurine levels increased, but oxidative stress parameters improved only in the liver (link).

Taurine, depression and anxiety

Since taurine is found in energy drinks, one might expect it to have at least a temporary positive effect on mood, similar to caffeine. Indeed, there is some evidence that this is the case. In mice, intraperitoneally administered taurine was shown to increase social interaction and have an anti-anxiety effect in doses between 14-126 mg/kg (link).

However, one study showed that only supplementary taurine increased increased locomotor activity and anxiety while taurine injections had the opposite effect (link). This is contrast to the previously mentioned study. Similarly, in one study 200 mg/kg given orally had a significant anti-anxiety effect (link), but in another one, taurine had no effect on anxiety or depression and even resulted in a decrease in activity in higher doses (link).

Taken together, the animal studies don't give us a very clear picture of how taurine affects mood, if it does so at all. Unfortunately, human studies are scarce and equally confusing. In a study on Korean college students, taurine intake inversely correlated with stress in female but not in male subjects (link). Unlike the rodent studies, however, the study didn't use taurine supplements and only measured taurine intake from food sources.

Taurine and brain damage

Whereas the studies on taurine's effect on brain aging and mood remain inconclusive, the case for protecting the brain from sudden damage is quite strong. Brain ischemia, a condition where there is insufficient blood flow to the brain, causes neuronal death in part through apoptotic pathways mediated by calpain and caspase-3, caspase-8 and caspase-9; taurine appears to dose-dependently protect the neurons from cell death by blocking the pathways (link, link, link).

Other ways taurine may protect the brain is by improving mitochondrial function (link), and by reducing damage from excessive calcium overloads (link) and cadmium-induced oxidative impairment (link). Tryptophan administration also increases oxidative stress in the brain cortex of rats, but pre-treatment with taurine prevents the increase (link). Based on these studies, taurine may be helpful in protecting from short-term damage to the brain.

Taurine and alcohol

Taurine has been suggested as a possible treatment for alcoholism (link), and acamprosate, a promising drug used to treat alcoholism and alcohol withdrawal, contains a synthetic compound similar to the naturally occuring homotaurine (link). One possible reason for helping with alcohol withdrawal is that taurine increases dopamine levels in the brain similarly to ethanol (link).

In addition to helping with staying away from alcohol, taurine also appears to reduce some of the harmful effects of alcohol in the brain. For example, taurine shields from alcohol-induced damage by reducing programmed cell death through a decrease in the immunoreactivity of caspase-3 (link). Taurine may also reduce the lack of coordination of muscle movements resulting from ethanol (link), which can be a good thing or a bad thing, depending on how you ask.

For those who enjoy the short-term effect of alcohol but are worried about the long-term effects, it's interesting to note that taurine reduces the urinary loss of selenium, chromium and manganese in rats chronically consuming alcohol (link). This suggests taurine might be useful as an anti-hangover supplement.

Conclusion

Taurine is a common ingredient in energy drinks, because it is believed to have a cognition- or mood-boosting function. However, the evidence behind these claims is controversial. While taurine appears to protect from acute neurological damage, including alcohol, its other effects are less clear. Nonetheless, at least a few studies have shown that taurine increases GABA levels in the brain, which may help with memory, learning and anxiety.

For more information on aging and the brain, see these posts:

Does Ginkgo Biloba Improve Cognitive Performance?
L-Carnitine, Acetyl-L-Carnitine and Cognitive Function in Humans
Increasing Intelligence by Playing a Memory Game – Experiment Update
Caloric Restriction Improves Memory in the Elderly

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