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

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

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