March 09, 2007
Bioflavonoids Health Benefits Not As Antioxidants

The role of bioflavonoids as antioxidant quenchers of free radicals has been oversold.

CORVALLIS, Ore. – Flavonoids, a group of compounds found in fruits and vegetables that had been thought to be nutritionally important for their antioxidant activity, actually have little or no value in that role, according to an analysis by scientists in the Linus Pauling Institute at Oregon State University.

However, these same compounds may indeed benefit human health, but for reasons that are quite different – the body sees them as foreign compounds, researchers say, and through different mechanisms, they could play a role in preventing cancer or heart disease.

Bioflavonoids join an existing known list of plant compounds that deliver health benefits because they alter metabolism in ways that reduce damage caused by toxins. For example, cabbage and other cruciferous vegetables contain compounds called isothiocyanates such as sulforaphane and indole-3-carbinol. The liver reacts to these isothiocyanates as if they are toxins and the liver therefore makes more enzymes that break down toxins. As a result any real toxins get broken down more quickly and therefore do less harm to the body.

The body metabolises flavonoids into forms that have little antioxidant activity.

“What we now know is that flavonoids are highly metabolized, which alters their chemical structure and diminishes their ability to function as an antioxidant,” said Balz Frei, professor and director of the Linus Pauling Institute. “The body sees them as foreign compounds and modifies them for rapid excretion in the urine and bile.”

Attempts to turn up big health benefits of antioxidant vitamins have been somewhat of a disappointment. The foods that appear to be associated with longer and healthier lives probably deliver most of their benefit due to compounds in them that alter human metabolism in a large assortment of ways.

Flavonoids alter metabolism in several health-promoting ways.

The large increase in total antioxidant capacity of blood observed after the consumption of flavonoid-rich foods is not caused by the flavonoids themselves, Frei said, but most likely is the result of increased uric acid levels.

But just because flavonoids have been found to be ineffectual as antioxidants in the human body does not mean they are without value, Frei said. They appear to strongly influence cell signaling pathways and gene expression, with relevance to both cancer and heart disease.

“We can now follow the activity of flavonoids in the body, and one thing that is clear is that the body sees them as foreign compounds and is trying to get rid of them,” Frei said. “But this process of gearing up to get rid of unwanted compounds is inducing so-called Phase II enzymes that also help eliminate mutagens and carcinogens, and therefore may be of value in cancer prevention.

“Flavonoids could also induce mechanisms that help kill cancer cells and inhibit tumor invasion,” Frei added.

It also appears that flavonoids increase the activation of existing nitric oxide synthase, which has the effect of keeping blood vessels healthy and relaxed, preventing inflammation, and lowering blood pressure – all key goals in prevention of heart disease.

If we could optimally turn up every enzyme pathway that breaks down toxins we could reduce our rate of aging and delay the onset of cancer and other disorders of old age.

Biogerontologist Aubrey de Grey makes what to my mind is a persuasive argument against the expectation that antioxidants will deliver large health benefits: The metabolic cost of making and retaining antioxidants in the body is pretty low. If antioxidants could deliver benefits as large as some of their advocates claim then natural selection would long ago have selected for mutations that boost body antioxidant levels. So why expect consumed antioxidants to deliver a big benefit?

So (I hear you asking) why wouldn't the body make more detoxifying enzymes even in the absence of foods consumed that up-regulate detoxifying enzymes? My guess is that those enzymes are more metabolically expensive to keep around.

Share |      Randall Parker, 2007 March 09 02:03 PM  Aging Diet Studies


Comments
Lou Pagnucco said at March 11, 2007 12:22 PM:

Another possibility is that certain flavonoids (and their metabolites) reactivate some genes silenced during aging.
See: "Dietary Polyphenols May Affect DNA Methylation" at http://jn.nutrition.org/cgi/content/abstract/137/1/223S
Some of these genes may be cancer suppressors.

In the article "The silence of the genes"
(at http://www.innovations-report.de/html/berichte/medizin_gesundheit/bericht-29773.html)
epigenetic therapy to reverse undesirable DNA methylation, possibly resulting in cancer and aging, is proposed.

Several common flavonoids/polyphenols inhibit DNA methylation in vitro. See:
"Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols" at http://carcin.oxfordjournals.org/cgi/content/abstract/27/2/269, and
"Mechanisms for the Inhibition of DNA Methyltransferases by Tea Catechins and Bioflavonoids" at
http://molpharm.aspetjournals.org/cgi/content/abstract/68/4/1018

It is interesting to note that longevity-increasing methionine-deficient diets also decrease DNA methylation. See:
"Diet, Methyl Donors and DNA Methylation: Interactions between Dietary Folate, Methionine and Choline" at
http://jn.nutrition.org/cgi/content/abstract/132/8/2333S

Possibly also relevant is that caloric restriction strongly reduces expression of the MeCP2 gene which is responsible for methylation and silencing of other genes. See:
"Microarray Profiling of Gene Expression in Aging and Its Alteration by Caloric Restriction in Mice" at
http://jn.nutrition.org/cgi/reprint/131/3/918S.pdf

On the other hand, the literature indicates that several types of cancer are caused by hypomethylation of certain genes. Also high concentrations of flavonoids can cause mutations in vitro. See:
"Low Concentrations of Flavonoids Are Protective in Rat H4IIE Cells Whereas High Concentrations Cause DNA Damage and Apoptosis" at http://jn.nutrition.org/cgi/content/abstract/135/3/525

Randall Parker said at March 11, 2007 12:37 PM:

Lou,

A general increase or decrease in methylation is a big throw of the dice. Turning off a bunch of genes with methylation could turn off both tumor suppressors and tumor promoters. Similarly, turing on a bunch of genes with less methylation could again turn on both tumor suppressors and tumor promoters. What's going to be the net effect in either direction? We'd be guessing if we hazarded an answer.

Also, methylation probably activates certain genes while it deactivates others.

I'm left thinking that we should eat the kinds of diets that correlate with longer lifespan and that we do not know yet how to carefully fine tune diets.

Lou Pagnucco said at March 11, 2007 2:31 PM:

Randall,

You are absolutely correct.

I wonder how deterministically the epigenetic program progresses.
Possibly, the process of methylation is stochastic with lots of variability within the same tissues.
I think the "dysdifferentiation hypothesis" of aging implies this.

Taking measures to up/downregulate genetic methylation is certainly dicey.

Still, I am very intrigued that the gene(s) regulating methylation are very strongly repressed during CR.
After all, tumor cells are hypomethylated - but perhaphs this occurs after tumor promotion.
I wonder what interspecies studies would show.

Jerry Martinson said at March 11, 2007 11:54 PM:

Yet another nail in the simplistic free-radical' theory's coffin. Although I can never claim to be an expert in any of the life sciences and I know I'm not espousing anything new to the many very well-informed and intelligent contributors to this site, I must say I always roll my eyes when I hear some substance touted in otherwise reputable media as an "antioxidant". I don't know when the world of nutritional marketing is every going to give up on this worthless terminology. To me, use of the term antioxidant, seems a litmus test for whether or not the company or person talking about it has jumped into the world of wishful crackpot thinking. The simplistic antioxidant theory of nutrition had at one time held great promise, but the actual utility of the basic concept has been thoroughly destroyed by competent investigators. I wish the rest of the world would forget that the theory had ever been invented as it basically never panned out and is leading people down yet another blind alley of crackpot quack nutrition.

On another note, Randall in his post repeated Aubrey de Grey's argument that if antioxidants were so effective, then "why don't humans make more of them since they are metabolically inexpensive to keep around?". While I agree that antioxidant's are ineffective and I'm sure that y'all know this better than me but just didn't perfectly articulate it this time, don't forget that natural selection won't really select for metabolically inexpensive means to extend life. Rather it will tend to select things that produce healthy and novel genetic offspring when that offspring has a chance to flourish. Perhaps this is why menstrual cycles cease and aging decelerates substantially during caloric deprivation so that animals are tuned to ride out the famines without the stress of progeny so that they can later produce healthy offspring during the fat times.

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