10 replies to this topic

[wannafulfill]

I have a simple question that I have been wondering for some time and should already know the answer to.

When we take things like, bacopa, the activities of anti-oxidant systems increase, such as catalase, superoxide dismutase, and glutathione peroxidase. From this we assume we get a benefit. But don't deadly poisons like, say, streptozotocin, do the same thing? Isn't the increase of these systems indicative of a natural defense against things that are pro-oxidative? How do we know that taking bacopa, for example, doesn't cause that upregulation through harmful pro-oxidant effects which the body tries to counter-act?

Thank-you very much!

[LifeMirage]

So far all research on compounds that have this effect increases lifespan. I believe this is the Most Important class of compounds everyone should take if you want to reduce and slow one of the main aging processes.

Your bodies antioxidant enzymes work quite differently from dietary antioxidants like C and E which have no impact lifespan due to free radical production. Part of the reason that the CR diet works is due to its effects on increasing antioxidant enzymes.

[trh001]

These are both nice reviews, if you have access.

Dietary flavonoids: Effects on xenobiotic and carcinogen metabolism.
Toxicol In Vitro. 2006 Mar;20(2):187-210. Epub 2005 Nov 11.
PMID: 16289744 [PubMed - in process]

Biphasic effects of dietary antioxidants on oxidative stress-mediated carcinogenesis.
Mech Ageing Dev. 2006 Mar 4; [Epub ahead of print]
PMID: 16519920 [PubMed - as supplied by publisher]


The abstract for the first is farely good, so...

Dietary flavonoids: Effects on xenobiotic and carcinogen metabolism.

Moon YJ, Wang X, Morris ME.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 517 Hochstetter Hall, Amherst, NY 14260-1200, United States.

Flavonoids are present in fruits, vegetables and beverages derived from plants (tea, red wine), and in many dietary supplements or herbal remedies including Ginkgo Biloba, Soy Isoflavones, and Milk Thistle. Flavonoids have been described as health-promoting, disease-preventing dietary supplements, and have activity as cancer preventive agents. Additionally, they are extremely safe and associated with low toxicity, making them excellent candidates for chemopreventive agents. The cancer protective effects of flavonoids have been attributed to a wide variety of mechanisms, including modulating enzyme activities resulting in the decreased carcinogenicity of xenobiotics. This review focuses on the flavonoid effects on cytochrome P450 (CYP) enzymes involved in the activation of procarcinogens and phase II enzymes, largely responsible for the detoxification of carcinogens. A number of naturally occurring flavonoids have been shown to modulate the CYP450 system, including the induction of specific CYP isozymes, and the activation or inhibition of these enzymes. Some flavonoids alter CYPs through binding to the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, acting as either AhR agonists or antagonists. Inhibition of CYP enzymes, including CYP 1A1, 1A2, 2E1 and 3A4 by competitive or mechanism-based mechanisms also occurs. Flavones (chrysin, baicalein, and galangin), flavanones (naringenin) and isoflavones (genistein, biochanin A) inhibit the activity of aromatase (CYP19), thus decreasing estrogen biosynthesis and producing antiestrogenic effects, important in breast and prostate cancers. Activation of phase II detoxifying enzymes, such as UDP-glucuronyl transferase, glutathione S-transferase, and quinone reductase by flavonoids results in the detoxification of carcinogens and represents one mechanism of their anticarcinogenic effects. A number of flavonoids including fisetin, galangin, quercetin, kaempferol, and genistein represent potent non-competitive inhibitors of sulfotransferase 1A1 (or P-PST); this may represent an important mechanism for the chemoprevention of sulfation-induced carcinogenesis. Importantly, the effects of flavonoids on enzymes are generally dependent on the concentrations of flavonoids present, and the different flavonoids ingested. Due to the low oral bioavailability of many flavonoids, the concentrations achieved in vivo following dietary administration tend to be low, and may not reflect the concentrations tested under in vitro conditions; however, this may not be true following the ingestion of herbal preparations when much higher plasma concentrations may be obtained. Effects will also vary with the tissue distribution of enzymes, and with the species used in testing since differences between species in enzyme activities also can be substantial. Additionally, in humans, marked interindividual variability in drug-metabolizing enzymes occurs as a result of genetic and environmental factors. This variability in xenobiotic metabolizing enzymes and the effect of flavonoid ingestion on enzyme expression and activity can contribute to the varying susceptibility different individuals have to diseases such as cancer. As well, flavonoids may also interact with chemotherapeutic drugs used in cancer treatment through the induction or inhibition of their metabolism.

PMID: 16289744 [PubMed - in process]

http://www.ncbi.nlm....l=pubmed_docsum

[FunkOdyssey]

That doesn't answer wannafulfill's original question, which is a very good one.

[trh001]

Actually, the first is a pretty good roadmap, if you have the paper, to a class (an example) of natural products that alter biochemistry at both the genetic and epigenetic level. The details suggest that the only real way to answer such as question

"How do we know that taking bacopa, for example, doesn't cause that upregulation through harmful pro-oxidant effects which the body tries to counter-act?"

...is by examining each case. Worse, pleiotropic responses, and dose-related pleiotropic response, suggest any global answer wouldn't be an answer at all.

I'm reminded of the paper on Benfotiamine I was reading this AM. While Benfotiamine has a multiplicity of functionality, one being an antioxidant, the authors cite evidence that it depletes thiols and generates ROS...yet it still has net benefit, accoridng to the literature and studies they cited/executed.

[opales]

Actually, the first  is a pretty good roadmap, if you have the paper, to a class (an example) of natural products that alter biochemistry at both the genetic and epigenetic level.  The details suggest that the only real way to answer such as question

"How do we know that taking bacopa, for example, doesn't cause that upregulation through harmful pro-oxidant effects which the body tries to counter-act?"

...is by examining each case.  Worse, pleiotropic responses, and dose-related pleiotropic response, suggest any global answer wouldn't be an answer at all.

I'm reminded of the paper on Benfotiamine I was reading this AM.  While Benfotiamine has a multiplicity of functionality, one being an antioxidant, the authors cite evidence that it depletes thiols and generates ROS...yet it still has net benefit, accoridng to the literature and studies they cited/executed.

The problem is not just possibility of creating more ROS, but the fact that counteracting ROS could be detrimental. ROS are involved in multiple signalling systems essential to life. They are studies where increasing endogenous antioxidants DECREASES lifespan. (nevermind that not a single substance has CONSISTENLY increased lifespan in multiple organisms, making LifeMirage's comment baseless. Resveratrol could be the first if it pans out)

http://www.imminst.o...394

Moreover, seems that non mitochondrial ROS has no effect on aging anyway, so counteracting them seems bit stupid (as they still might be involved in signalling systems).

http://www.imminst.o...t=0

But even counteracting mitoROS could detrimental (from the new Scientist article Plugging the Mitochondrial Leak, by Nick Lane):

http://www.thescient.../2006/3/1/34/1/

Other work suggests that antioxidants targeted to the mitochondria, such as mitoQ, concentrate 1000-fold in the mitochondrial matrix, where they inhibit apoptosis. But antioxidants have the potential to interfere with ROS signaling, which plays a major role in the physiology of the cell. Birds solve the problem by cutting leakage from complex I, not by raising intramitochondrial antioxidant levels.

A quote from Aubrey regarding this whole ROS issue:

Thing is, this is not news -- roles of ROS (and not just nitric oxide) in signalling have been kown for over a decade (check out Sue Goo Rhee in PubMed). I have cited this sort of work quite often in my papers as reasons for focusing on removal of accumulating but initially inert molecules and cells rather than removal or bioactive ones.

As regards benfotiamine, what do you mean by net positive results? Decreased blood sugar levels etc. sure, but consistent increase in lifespan, I don't think we have such results yet?

[opales]

Moreover, seems that non mitochondrial ROS has no effect on aging anyway, so counteracting them seems bit stupid (as they still might be involved in signalling systems).

http://www.imminst.o...t=0

That link does not direct me to the right post, anyway the post I am referring to is the one by Michael on page 4. He also has an additional comment on that thread, on page 5.

http://www.imminst.o...t=0

And here is some additional info in regards this issue, again by Michael

http://www.imminst.o...t=0

This paper by Aubrey is also a recommended read as a primer:

4. de Grey (2000), "The non-correlation between maximum lifespan and antioxidant enzyme levels among homeotherms: implications for retarding human aging." J. Anti-Aging Med. 3(1):25-36.

Edited by opales, 15 March 2006 - 01:33 PM.

[trh001]

As regards benfotiamine, what do you mean by net positive results? Decreased blood sugar levels etc. sure, but consistent increase in lifespan, I don't think we have such results yet?

No, no life span data that I'm aware of, either, for Benfotiamine. Yes, the above was in reference to markers of efficacy wrt one or more of the markers for diabetes. I suspect I'll be posting more as I read through the papers on Benfotiamine.

Re. Intrinsic REDOX and exogenous "antioxidants" (quotes meant to convey the lack of universality of such an assignment, which is heavily influenced by microenvironment where the compound resides), ROS from the former seems to be addressed down stream, metabolically, as part of the repair budget set point for a species or individual. The latter seem to be irrelevant, as antioxidants, but yet are often ultimately found important as xenobiotics that stimulate, say, for example, carcinogen inactivation.

"Antioxidants" have really been a big disappointment, not that that's had much impact on sales and marketing.

I like the quote from DeGrey "focusing on removal of accumulating but initially inert molecules and cells rather than removal of bioactive ones." Approaches that affect repair processes seem *very* tractable. On this note, though, I'm not even sure glycation inhibitors, per se, are what they seem, in this regard.

For example, carnosine has been cited as stimulating proteosomal activity, perhaps by forming an adduct which is (more) amenable to clearance. clearly it also can interfere with formation of glycates. Which is more impotent in vivo? Which process is more amenable to supplemental carnosine? Should one focus on, say, NtBHA for one, and carnosine, for the other, wrt dose, and pharmacokinetics? I was pondering this, and keep meaning to follow up, because it may have influence on how much, and in what dosage format, one takes such molecules.

If heavily carnosinalated molecules are eliminated more effectively/completely, and high levels of carnosine once a day are optimal for tagging to increase proteasome turnover, then should I be eating my gram of carnosine all at once, to get a net, "carnosinase adjusted", dose that is as high as possible even if for a short time?

On the other hand, if 24hr *coverage* of a "glycation inhibitor" is deemed to be more important wrt to this particular molecule, then perhaps divided doses with wider, shallower pharmacokinetics.

Both approaches?

It's difficult to know what's biologically relevant. Hopefully the studies will be run.

I digress.

Anyway, if anyone asks, I don't take "antioxidants", I take ****** (substitute whatever politically correct term you see fit to make me look good).

[FunkOdyssey]

If heavily carnosinalated molecules are eliminated more effectively/completely, and high levels of carnosine once a day are optimal for tagging to increase proteasome turnover, then should I be eating my gram of carnosine all at once, to get a net, "carnosinase adjusted", dose that is as high as possible even if for a short time?

On the other hand, if 24hr *coverage* of a "glycation inhibitor" is deemed to be more important wrt to this particular molecule, then perhaps divided doses with wider, shallower pharmacokinetics.

I don't have much to contribute right now except to say, these are awesome questions, and I hope they get answered.

[trh001]

Funk,

I'll likely start another thread once I get through more of these papers.

I'm truly excited by the prospect of up-regulation of the proteasome. I need to get my bearings, wrt to references, but I've seen at least one or two papers on CR and proteosomal activity and/or glycation rates in various tissues. I'm (perhaps naively, but none the less) optimistic about a combination of reductions in preformed glycates, supplementing with a mixture of glycation inhibitors, and stimulation of proteosomal activity through supplements and mild to moderate caloric restriction. While this *may not* be a formula for increased maximum species life span, it *may* be enough to keep one around long enough to take advantage of each new discovery in the literature.

At your age, btw, you should be *very* excited by the edge you have. You are, if I recall, 25? I'm 45. So, you've got an extra 20 years of non-linear, explosive, geometrically progressive science, which you can "body surf", into advanced age with.

Still, folks my age, have a shot.

Oh, and btw, 45 isn't as bad as some folks might have told you it is. You don't worry about your "image", or dating. You look forward to (early) retirement. You have more money to spend on supplements (assuming you aren't paying for 4 kids at Harvard), and things are pretty cool.

[trh001]

Oh, and added to the above, what I've been reading regarding Benfotiamine/Thiamine is really quite fascinating and complementary to "glycation inhibitors" and "proteosomal activators". There seems to be evidence to support the view that Thiamine/Benfotiamine, can make high sugar levels safer via altering the processing of glucose -- a whole separate mechanism to reduce the impact of glucose.

This aspect of Thiamine/Benfotiamine *may* have more to do with a diabetes, unfortunately, but I'm holding out hope that it may be relevant to blood glucose levels found in non-diabetics. Devil's in the details. More later.

And just to be completely tangential (well, nearly), the control of ALP (advanced lipoxygenase products) and the benefit to cell and organelle membrane integrity, may be a reasonable complementary view. A 2003 review article (on membrane stability/integrity in aging) I found needs follow up with more recent papers, and papers on PLP/P5P need to be reviewed more, but this is an exciting area that's analogous to the concern with structure/function in the proteome. In fact, cell surface receptors and many membrane bound enzymes require rathe exacting lipid microenvironments, so a deranged "liposome" translates into the *same* consequences (arguably) as a deranged proteome.

All very tractable, I'm hoping.