86 replies to this topic

[bgwithadd]

Too bad I can't donate blood. Maybe I should leech myself? It seems they were onto something with this 'barbaric' practice. Actually that's been proven long since, anyway.

[niner]

I ran across a very interesting review article, with almost 2500(!) references, discussing the central role of free or poorly-liganded iron in combination with ROS in the etiology of a vast array of diseases as well as aging. There is some pretty illuminating discussion of the bad and not-so-bad forms of ROS, the nature of anti- and pro-oxidants, not to mention the place of systems biology now and in the future. Free Full Text is available here.

BMC Med Genomics. 2009; 2: 2.
Published online 2009 January 8. doi: 10.1186/1755-8794-2-2.

Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases
Douglas B Kell corresponding author
School of Chemistry and Manchester Interdisciplinary Biocentre, The University of Manchester, 131 Princess St, Manchester, M1 7DN, UK
Douglas B Kell: dbk@manchester.ac.uk
Received September 2, 2008; Accepted January 8, 2009.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommo...licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular 'reactive oxygen species' (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation.

We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation).
The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible.
This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, since in some circumstances (especially the presence of poorly liganded iron) molecules that are nominally antioxidants can actually act as pro-oxidants. The reduction of redox stress thus requires suitable levels of both antioxidants and effective iron chelators. Some polyphenolic antioxidants may serve both roles.
Understanding the exact speciation and liganding of iron in all its states is thus crucial to separating its various pro- and anti-inflammatory activities. Redox stress, innate immunity and pro- (and some anti-)inflammatory cytokines are linked in particular via signalling pathways involving NF-kappaB and p38, with the oxidative roles of iron here seemingly involved upstream of the IkappaB kinase (IKK) reaction. In a number of cases it is possible to identify mechanisms by which ROSs and poorly liganded iron act synergistically and autocatalytically, leading to 'runaway' reactions that are hard to control unless one tackles multiple sites of action simultaneously. Some molecules such as statins and erythropoietin, not traditionally associated with anti-inflammatory activity, do indeed have 'pleiotropic' anti-inflammatory effects that may be of benefit here.

Overall we argue, by synthesising a widely dispersed literature, that the role of poorly liganded iron has been rather underappreciated in the past, and that in combination with peroxide and superoxide its activity underpins the behaviour of a great many physiological processes that degrade over time. Understanding these requires an integrative, systems-level approach that may lead to novel therapeutic targets.

[StrangeAeons]

EDIT: reread article, recanting views on account of I don't know what I'm talking about.

Edited by StrangeAeons, 08 September 2009 - 07:55 AM.

[JLL]

Interesting stuff... I'm going through the article slowly but surely.

A few questions regarding iron. From what I gather, the body is pretty good at keeping iron levels stable regardless of dietary intake. Intake does not seem to correlate very well with serum levels. Does excess dietary iron accumulate in tissues, however? Or is it more a matter of poor iron metabolism due to other reasons?

I get quite a bit of iron from my diet, and am wondering whether I should start taking IP-6 as a supplement. I did ask for serum ferritin levels in my blood test, but apparently they didn't measure it anyway.

[Blue]

The best measure of iron stores is liver biospy or maybe liver MRI. Ferritin is not bad if you do not have a chronic inflammation:
http://www.sciencedi...337a9689e286f8b

But there have been a lot of studies on the relationship between various measures iron stores and chronic disease. While some find a relationship, others do not. So the evidence is not as simple as the article suggests.

Edited by Blue, 08 September 2009 - 03:09 PM.

[rwac]

Blue, I can't access the article. Does it say that Ferretin level is a *bad* indicator if you have chronic inflammation ?

I'm wondering how accurate my high Ferretin levels are ...

[Blue]

Some epidemiological studies finding no effect:
http://www.ncbi.nlm....pubmed/10027804
http://www.sciencedi...101828ca367d5eb

[Blue]

Blue, I can't access the article. Does it say that Ferretin level is a *bad* indicator if you have chronic inflammation ?

I'm wondering how accurate my high Ferretin levels are ...

Changed to direct lilnk

[rwac]

Oh, ok. That's somewhat better.

Looks like ferritin level is not such a good measure if there is inflammation present. (r<0.66)

Edited by rwac, 08 September 2009 - 03:20 PM.

[tunt01]

the guy from longenivex believes that iron (and i think other metals) are a major component of aging. he has some ~10 min chat explaining his viewpoints. he said it's why women live longer than men, because they have a monthly period which leads to excess iron from the blood being expelled routinely. it is an interesting theory that i've kept in the back of my mind.

i try to avoid dates or certain foods with exceptionally high levels of iron. i will give this paper a read, thanks.

Edited by prophets, 08 September 2009 - 03:24 PM.

[kismet]

I ran across a very interesting review article, with almost 2500(!) references, discussing the central role of free or poorly-liganded iron in combination with ROS in the etiology of a vast array of diseases as well as aging.

Oh, boy someone must have had a lot of (paid) spare time. It already starts in a hilarious way:

The 'balkanisation' of the literature is in part due to the amount of it (some 25,000 journals with presently 2.5 million peer-reviewed papers per year, i.e. ~5 per minute [1]), with a number http://www.nlm.nih.g...nts_yr_pub.html increasing by something approaching 2 per minute at PubMed/Medline alone. In addition, the disconnect between the papers in the literature (usually as pdf files) and the metadata describing them (author, journal, year, pages, etc) is acute and badly needs filling.

I just need to find time to read it. Blue, local vs systemic? Perhaps it's similar to the effect of ROS and the failure of antioxidants (the latter does not mean the former does not play any role).

[Blue]

I also try to avoid limit foods with high iron content. In particular those containing heme iron (meat) since the uptake of this form of iron may be less regulated than the uptake of non-heme iron.

But low iron is not good either. Low iron stores increases cadmium uptake which is already at a borderline dangerous level for the population as a whole. Vegetarians and those eating similar otherwise healthy foods in particular have a high intake.

[Blue]

Blue, local vs systemic? Perhaps it's similar to the effect of ROS and the failure of antioxidants (the latter does not mean the former does not play any role).

Agree that there is a similarity to antioxidants which looks good regarding ROS in theory but is less convincing in practice. (Although they may looked at the wrong antioxidants, better effect may or may not come from increasing the levels of catalase, SOD, glutathione, or possibly related here, heme oxygenase). Not sure what you mean regarding local vs. systematic.

Edited by Blue, 08 September 2009 - 04:01 PM.

[niner]

Oh, boy someone must have had a lot of (paid) spare time. It already starts in a hilarious way:

Yeah, it's quite a collection of refs. I don't think I'd call it hilarious, exactly; more like "novel". I can't help but note that single-author papers seem to have a tendency to go farther afield from the usual straight and narrow... Flashes of brilliance, or weirdness? Sometimes it's a fine line, but I think this guy is pretty sharp. The points he makes about systematic annotation of journal articles to enable machine learning are interesting. I would be surprised if science doesn't ultimately go in that direction.

[kismet]

Oh, I just found the choice of words hilarious and fitting. Blue, I mean that perhaps there are different concentrations of those substances (iron or antixoidants/ROS) in different cellular compartments or places which are not reflected by circulating levels.

Edited by kismet, 08 September 2009 - 04:20 PM.

[JLL]

Has anyone studied whether the Masai suffer from their ridiculously high heme iron intakes?

[Blue]

There are conflicting studies regarding whether heme iron absorption is affected by iron stores:

http://www.ars.usda....q_no_115=193539
http://cat.inist.fr/...&cpsidt=4809229

[Blue]

Oh, I just found the choice of words hilarious and fitting. Blue, I mean that perhaps there are different concentrations of those substances (iron or antixoidants/ROS) in different cellular compartments or places which are not reflected by circulating levels.

Yes, maybe, like in plaques caused by various diseases. But if total iron stores do not affect the creation of these areas, maybe because these areas suck in iron regardless of stores, it may be difficult to remove the iron with chelators.

[StrangeAeons]

This all raises the question for me of how exactly I became so iron deficient, and if it's some sort of bizarre congenital issue like my gastroenterologist surrenders it would have to be. Low ferritin, low serum iron, elevated binding. If the levels trend downward over time then this concept of siderophores and pathogens chelating iron becomes really important; though I'm not familiar with any such infections.

On a less personal note, the tone of the article (at least as much as I've read) is definitely more out there, and while part of me thinks this is silly and unprofessional the other part is drawn to a more assertive style.

[albedo]

I recently found too much blood iron 168 mcg/dL (60-160 ref) while ferritin is within range. I am going to (genetic) test for hemochromatosis. I am also considering donating blood but before that I am trying to remove dietary iron or reduce absorption.

Have you a suggestion? As I am also supplementing: which supplements have you found rising your blood iron? (Removed green supplements. Avoid using Vitamim C with meals, regularly drink tea. Tested for zinc and copper which are normal. Taking supra RDA of riboflavin and niacin which make iron released from storage. Taking several other antioxidants....)

[anagram]

a lot of deep sea animals live to very high ages - no iron in body.

taking asprin will increase life span - it will chelate iron and induce ferritin, so depending on when you take it it might have a pro iron effect or a really anti iron absorption effect.

hydroxyl amines like ntBHA will keep iron in the +3 state where it will not produce hydroxyl radicals via the fenton reaction, they will extend the life span of human fibroblasts.

zinc - will lower absorption of iron, and its an antioxidant.

ip6 is common in rice, possible reason why Japanese food is so good, and Japan has the oldest living people on earth?

Edited by anagram, 22 January 2013 - 11:43 PM.

[renfr]

Iron deficiency can cause undesirable to severe side effects though, anemia, muscle spasms, dopamine transporter downregulation.

[anagram]

Iron deficiency can cause undesirable to severe side effects though, anemia, muscle spasms, dopamine transporter down regulation.

I would rather live longer..
and I have done CR to the point where I think I got mild dopamine transporter problems, mild muscle spasms and shit. I kept doing it and the problems went away but I actually had to much dopamine, it wasn't like I was schizo, but I had sort of salience in terms of my likes/dislikes, it made me hate certain people but like others.

Edited by anagram, 25 January 2013 - 02:54 AM.

[Dorian Grey]

When it comes to iron, I feel Goldilocks analogy may apply... Too little is obviously not good, but there is increasing evidence ignoring elevated ferritin (stored iron) may be unwise. "Just Right" would seem to be the smartest way to go!

Problem is, the upper limits for "normal" ferritin/stored iron are set remarkably high at 200 for women, and 300 or more for men depending upon the lab you visit. When upper limits are set this high, iron will not be "flagged" as high until one is thoroughly loaded to the gills with this mineral. Young adults and menstruating females tend to maintain ferritin levels on the low side (20 to 60) for many years, while middle age men and senior populations of both sexes tend to accumulate remarkably high levels of ferritin, often near or above the sky-high limit set as normal.

I find it interesting how middle age men often run into trouble with heart disease while it is almost unheard of in females until they are well post-menopausal. Some say it's the estrogen/testosterone thing, but hormone replacement doesn't seem to help females from developing heart disease in their senior years like one would think it should.

Interesting also is the cancer/iron profile... Young children are born with high iron and ferritin doesn't hit rock bottom until the teenage growth spurt. Younger children are also more prone to childhood cancers than teenagers and young adults. Females, who menstruate tend to have lower levels of chronic disease compared to adult men, as long as their menstruation lasts; but seniors of both sexes tend towards chronic disease at relatively similar levels. Men do start accumulating excess iron earlier than females though, and they do die earlier. About 4 years earlier on average.

I'm an "iron watcher" and I donate blood and cycle on and off IP6 to keep my ferritin between 30 and 60... Don't know if maintaining youthful iron levels will translate into maintaining youthful health, but my rationale is, there is no downside. As long as ferritin is above 30 or so, you've got plenty of iron floating around to make blood... There simply is no up-side to having triple digit ferritin, but it appears there may be risk.

Here's what the "Iron Disorders Institute" has to say on the matter: http://www.irondisor....org/iron-tests


"Serum ferritin measurements range from about 15–200 ng/ml for women and 20–300 ng/ml for men. Although laboratory ranges vary, most are close to these values. Approximately 95% of the population will fall within “normal” population range simply because ranges are calculated using standard statistical methodology. Except for the lower ends of these ranges, which can predict anemia or iron deficiency anemia, the ranges per se do not define optimal or even healthy iron levels. Optimal SF ranges for men and women are 25 – 75 ng/ml. Individuals with risk factors for diabetes, cardiovascular diseases, stoke, liver diseases and cancer face amplified risks proportional to the amount of stored body iron over and above the optimal range.

Numerous medical research studies have demonstrated that serum ferritin above 100 ng/ml has been associated with decreased cardio vascular fitness and increased incidences of: atherosclerosis, type 2 diabetes, cancer gout and accelerated aging including osteoporosis and sarcopenia (muscle wasting) due to oxidative stress. Fortunately this does not pertain to everyone; ferritin levels and stored iron can remain safely contained, even when ferritin exceeds 150 ng/ml, if the body’s natural antioxidant defenses are working properly (see section on GGT)".

Edited by synesthesia, 25 January 2013 - 03:53 AM.

[renfr]

I agree with this. Excreted iron is no more than 2mg/day and yet the RDA is at least 10mg/day which means a significant amount is stored everyday if one would respect the RDA. Long term this can reach very high iron levels.
IP6 (phytic acid) is a good way to chelate iron but I've found that good old Inositol is just as effective.

Edited by renfr, 25 January 2013 - 11:24 AM.

[renfr]

Interesting Danish study :

Total Mortality by Transferrin Saturation Levels: Two General
Population Studies and a Metaanalysis
Christina Ellervik1,2,3, Anne Tybjærg-Hansen3,4,5,6 and Børge G.
Nordestgaard1,3,4,6,*
Clinical Chemistry 57: 459-466, 2011.
Hematology
First published January 12, 2011; 10.1373/clinchem.2010.156802
1 Department of Clinical Biochemistry, Herlev Hospital, Herlev,
Denmark;
2 Department of Clinical Biochemistry, Næstved Sygehus, Næstved,
Denmark;
3 Copenhagen University Hospitals and Faculty of Health Sciences,
University of Copenhagen, Copenhagen, Denmark;
4 Copenhagen General Population Study, Herlev Hospital, Herlev,
Denmark;
5 Department of Clinical Biochemistry, Rigshospitalet, Copenhagen,
Denmark;
6 Copenhagen City Heart Study, Bispebjerg Hospital, Copenhagen,
Denmark.
* Address correspondence to this author at: Department of Clinical
Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev
Ringvej 75, DK-2730 Herlev, Denmark. Fax +45-4488-3311; e-mail
[url=""%20style="margin:%200px;%20padding:%200px;%20border:%200px;%20vertical-align:%20baseline;%20text-decoration:%20initial;%20color:%20rgb(102,%2017,%20204);%20cursor:%20pointer;%20font-family:%20Arial,%20Helvetica,%20sans-serif;%20font-size:%2013px;"]br...@heh.regionh.dk[/url].
BACKGROUND: There is evidence for increased mortality in patients with
clinically overt hereditary hemochromatosis. Whether increased
transferrin saturation (TS), as a proxy for iron overload is
associated with increased mortality in the general population is
largely unknown.
METHODS: We examined mortality according to baseline TS in 2 Danish
population–based follow-up studies (the Copenhagen General Population
Study and the Copenhagen City Heart Study) comprising a total of 45
159 individuals, of whom 4568 died during up to 18 years of follow-up,
and in a metaanalysis comprising the present studies and an additional
general population study.
RESULTS: In combined studies, the cumulative survival was reduced in
individuals with TS 50% vs <50% (log-rank P < 0.0001).
Multifactorially adjusted hazard ratios for total mortality for TS 50%
vs <50% were 1.4 (95% CI 1.2–1.6; P < 0.001) overall, 1.3 (1.1–1.6; P
= 0.003) in men, and 1.5 (1.1–2.0; P = 0.005) in women. Results were
similar if the 2 studies were considered separately. A stepwise
increased risk of total mortality was observed for stepwise increasing
levels of TS (log-rank P < 0.0001), with the highest risk conferred by
TS 80% vs TS <20% with a hazard ratio of 2.2 (1.4–3.3; P < 0.001). The
population-attributable risk for total mortality in the combined
studies in individuals with TS 50% vs <50% was 0.8%. In metaanalysis,
the odds ratio for total mortality for TS 50% vs <50% was 1.3 (1.2–
1.5; P < 0.001) under the fixed-effects model.
CONCLUSIONS: Individuals in the general population with TS 50% vs <50%
have an increased risk of premature death.
Copyright © 2011 by the American Association for Clinical Chemistry.

[Dorian Grey]

Another problem with iron is, that it is so rarely tested for in routine blood labs...

Not included with basic or comprehensive metabolic panels. Often the only patients tested for ferritin are young females who may be anemic.

Ferritin is a dirt cheap test and no doctor should object to adding it into routine labs. It's available from Life Extension for less than $30, and the Iron Disorders Institute also does direct to public iron labs now.

One can get an idea of iron loading from routine labs by looking at hemoglobin, hematocrit and MCV (mean corpuscular volume). If any are high, or up near the top of the normal range, you've obviously got plenty of iron available... Perhaps too much. The blood bank tests for hemoglobin before every donation. Mine was over 17 until I dumped some iron, and is now in the 15-16 range before most donations.

Stay Healthy My Friends!