Friday, March 23, 2018

"What You Need to Know About Ski Mountaineering"

Cool post.

Link via The Ultimate Direction Buzz

Thursday, February 15, 2018

New from Japan: Confessions of Love: A Japanese Valentine’s Day

From Grace Under Pressure

"Confessions of Love: A Japanese Valentine’s Day"

Read the whole thing!

Tuesday, January 30, 2018

"My first podcast interview, over at Break Nutrition"

Great interview, of one of the smarter guys out there, with an amazing story.

Link via The High-fat Hep C Diet

Iron Overload: A Myth in Healthy People?

tl;dr: Oft-mentioned iron overload does not appear to be a problem in healthy humans, only in those with genetic defects. Iron is steadily lost through normal mechanisms and regained through dietary intake. Deficiency is the problem in healthy people.

So sometimes I get curious.

Now many people in the health communities I participate in get very concerned about iron overload—more below—but the basic concern has been that people keep eating iron in red meat, say; and there's no way to get rid of it, so at some point it will hit toxic levels and start to do damage. There are a number of genetic conditions where high iron levels do appear to cause damage, so this could be a reasonable concern. People even proactively give blood to lower their iron stores. But that all depends on the notion that you have no way of getting rid of excess iron.

I poked around half-heartedly, but didn't find anything.

Iron retention per year
Dumping iron

Today I got a little more curious about it, and found "Body iron excretion by healthy men and women" (Hunt 2009), which is an update of the last study done on the topic, in 1968 (Green 1968).
"On the basis of turnover rates, these subjects needed to replace as little as 2% and as much as 95% of their body iron annually!"
They used radioactive iron to measure iron turnover, which was the same method used as Green. Seems a reasonable way to do it.

Oddly, the primary mechanism for the body to shed iron is through shedding skin cells (!), exfoliation in the scientific jargon. There are also losses through bile (feces), urine, and shedding cells in the gut. Iron must be pretty hard to come by, as the body is mainly concerned with keeping it, and getting rid of it seems to be incidental to other body functions.

Hunt notes that shedding iron seems to be a somewhat random process, it's not homeostatically regulated like uptake is. (Although they saw a 40-fold variation in loss, so there may be some regulation process going on, it seems unlikely to me that such an important nutrient would be dumped randomly. But Hunt does not report a mechanism.)

One of the reasons Hunt did his study was because Green hadn't looked at women, so Hunt did. Obviously women (who menstruate) lose more iron than men do, and are more at risk from anemia (iron deficiency), consequently. I should mention that most of the iron in the body is contained in hemoglobin in the red blood cells, and the next biggest functional use of iron is in the mitochondria, in the cytochrome C molecule, which I have discussed before. There are also iron stores in the body.

Based on Hunt and Green, I think it's safe to say that the body is perfectly capable of getting rid of iron.

95% loss per annum would get the job done. 

Iron uptake

The known regulator of iron stores in the body is through uptake during digestion. That's sort of outside the scope of this, basically, but there's also a wide variation in iron uptake, depending on iron need and digestive capability.

The US RDA for iron was based on Green, which was a male-only study:
"Current US dietary recommendations for iron use the body weights and the daily iron losses of the subjects of Green et al (2) to derive an average estimated iron loss of 14 ยตg/kg...."
"This reduction, together with the tendency in the present study for the men to (nonsignificantly) increase their body iron in 3 y may mean that dietary recommendations for men in Western countries may best focus on preventing body iron accumulation rather than iron deficiency."
So that's where what I think the myth comes in. Are men in Western countries really at risk of iron overload?

Iron overload

Hunt noted that Green had measured a pretty wide variation of losses in his study—Green was in South Africa:
"Green et al... measured basal iron losses of 0.95 ± 0.30 mg/d for white men in the United States, 0.90 ± 0.31 mg/d for Mestizo men in Venezuela. and 1.02 ± 0.22 mg/d for Indian men in South Africa. Higher and more variable losses of 2.42 ± 1.09 and 2.01 ± 0.94 mg/d for Bantu men in Johannesburg and Durban, South Africa, respectively, were attributed to greater than normal body iron stores in the Bantu population."
From "Body iron excretion in man" (Green 1968), a rather important paper, as noted above.

So, if you're looking for evidence of iron overload, that seems to be the place to look for it. From Walker, 1953:
"Among the South African Bantu, the intake of iron is often very high—as much as 200 mg. per diem. This high intake is due mainly to the uptake of the element from iron utensils occuring during the preparation of their usual foods (particularly fermented cereal products)."
Dang, that's 100-fold what Green reported them losing per day! They must be like Tetsuo, The Iron Man!

[Don't watch that, it's really weird. Included for referential comprehensiveness.]

However, their high intake and status appears to have little effect:
"...there appears to be no evidence that iron overload per se is detrimental to well-being."
If the Bantu are eating that much iron and seeing no ill effects, then I think we in the West can worry less about it.

Genetic iron management diseases

The Bantu (and other Africans) do get a disease of iron overload, known as siderosis. However that appears to be genetic, and not from diet:
"Researchers originally believed that the popular, iron-rich beer caused cases of African iron overload. However, many individuals that drank the beer did not develop the disorder and some individuals that did not drink the beer did develop it. This led researchers to speculate that a mutation of a gene or genes involved in the transport or breakdown (metabolism) of iron must play a role in the development of African iron overload. Such a gene has not yet been identified."
That's from the Rare Diseases site, 2013. So it's similar to the iron overload disease that most are familiar with, hemochromatosis.

So just to wrap this up, I'm including two more links, from the CDC and from Merck.

CDC: Recommendations to Prevent and Control Iron Deficiency in the United States

Merck Manual: Secondary Iron Overload (Secondary Hemochromatosis)

As noted in those two links, virtually all instances of iron overload appear to be genetically caused. It's even possible to have iron overload (in storage) and be anemic (not enough iron in the blood) at the same time, interestingly as noted in the second link, but again from a genetic problem.


Hunt, again:
"Despite this substantial range in iron excretion, homeostatic control mechanisms were effective at maintaining body iron homeostasis for most subjects, with substantially impaired iron-status indexes in only one menstruating woman... These considerable differences in iron excretion and resulting requirements can generally be appropriately met by physiologic control of iron absorption, provided that dietary iron is accessible and reasonably bioavailahle."
Iron, like most important things, is tightly, homeostatically regulated by the body. As a creature that appears to have evolved on a diet of large amounts of heme-rich ruminant meat, we are unlikely to be susceptible to iron poisoning via that route, that is, via a diet far higher in heme iron than what most humans alive today eat. So unless you have an actual genetic problem, it's not necessary to manually regulate things like air, water, or your body's iron stores.

All that said, as I discuss in the cytochrome C link far above, iron is related to the diseases associated with the metabolic syndrome. But that's because it's a catalyst for the oxidation of omega-6 polyunsaturated fats. But the evidence for that beyond what I've already posted will have to be dealt with in another post.

Sunday, January 28, 2018

Meta-analysis of Oxidative Stress and Alzheimer's

No clear effect, little research. Did not look at focal analysis of specific regions or organelles.

"The field of oxidative stress as it relates to AD is large, with primary data coming from many different systems and supplemented by a large and rapidly growing narrative review literature. While this volume of data indicates intense interest in this topic, its utility is diminished by obfuscating or masking the complete picture of the oxidative changes in the AD brain. The purpose of this analysis was to quantitatively address this problem specifically for oxidative-stress related changes in the human AD brain. The pattern of oxidative changes identified in this analysis suggests that the antioxidant enzyme system in the brain is largely intact in AD and the global accumulation of oxidative damage is less substantial than has generally been reported."

And this:

"While this [brain malondialdehyde (MDA) level] is not the most specific or robust marker of lipid peroxidation, it is the most commonly studied marker of lipid peroxidation in AD brain..."


An excellent, comprehensive meta-analysis, well worth reading just to admire the work.

"Markers of oxidative damage to lipids, nucleic acids and proteins and antioxidant enzymes activities in Alzheimer's disease brain: A meta-analysis in human pathological specimens"

Tuesday, January 23, 2018

"Hello, Can We Have Your Liver?": Understanding a High-PUFA Diet.

tl;dr: A diet high in omega-6 and omega-3 polyunsaturated fatty acids has some positive effects on the body: lower weight gain, better preservation of lean mass, improved blood lipids, and increased brown adipose tissue; but also results in increased oxidative stress, mitochondrial dysfunction, and beginning of progressive liver failure.

This paper's a classic
"Fat Quality Influences the Obesogenic Effect of High Fat Diets [HFD]"
Sounds benign enough, right?  We all like quality fats...
"To investigate whether polyunsaturated fats could attenuate the above deleterious effects of high fat diets, energy balance and body composition were assessed after two weeks in rats fed isocaloric amounts of a high-fat diet (58.2% by energy) rich either in lard or safflower/linseed oil. Hepatic functionality, plasma parameters, and oxidative status were also measured. The results show that feeding on safflower/linseed oil diet attenuates the obesogenic effect of high fat diets and ameliorates the blood lipid profile...."
That's terrific!  So we just need to eat more omega-6 and omega-3 fats, and we'll be thinner with better blood cholesterol!

A nice example of a rat diet study

So these two sets of rats got two remarkably well-constructed diets, with 58.2% of fat from either lard (L) or safflower and linseed oil (S).  Lard is the classic bogeyman of rat diets. "Eat your carbohydrates, children, or Lard will get you!" Nice to see them adding in the omega-3 (n-3) fats from linseed oil—gold star. This accomplishes two things: First, it's well known that sufficient n-3 ameliorates the obesity often induced by high n-6 diets, so they're assuring the outcome. I don't know if they knew this, but I did and noticed it immediately. Second, they get around the n-3/n-6 ratio question, as the S diet actually has a better ratio than the lard diet does: the L diet has an omega-6 (n-6) to n-3 ratio of 12:1, which is pretty bad, and the S diet has a ratio of 4:1, which is pretty good, by lab-rat standards.

Fat 58.20% 58.20%
LA 13.93% 59.13%
% E 8.11% 34.41%
ALA 1.12% 14.47%
% E 0.65% 8.42%

So the L rats got 8.11% of their daily bread (% E) from linoleic acid (LA), and just a smidge from the omega-3 fatty acid alpha-linolenic acid (ALA).  The lucky S rats, fed the healthy, anti-obesigenic, cholesterol-lowering high-PUFA diet got 34% (!) of their calories from LA, and a whopping 8.42% from ALA.

The full diet is in the following two images. By lab-diet standards, this is incredibly well done, as they even give the exact breakdown of the individual fatty acids (FA). They get a bit of a demerit for including "chow" as a line-item, and not breaking that out, but at least both arms are getting the same amount of chow, and both are getting the same 20.7%E from carbohydrates. We can infer this is not a high-sugar diet.

I'll say it again.  This is a lovely diet, they're really doing a neat job of controlling their variables here. Lots of heart-healthy PUFAs, and a big dose of plant-based n-3 fats to balance the somewhat troublesome omega-6 fats.

How to make lab rats fat

Now we know that 8% E of LA is plenty to induce obesity in rodents.  See here:

"Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces obesity."

And sure enough, these rats got fat.  Interestingly, the L rats got fatter than the S rats, despite eating much less LA.
"After two weeks of isocaloric high fat feeding, obesity development was evident both in L and S rats, since their percentage of body lipids about doubled compared to initial value, although the final value was significantly lower in S rats than in L rats (Figure 1A)."
Rats don't do very well on HFDs with LA, as the above paper shows, so it's not surprising that these rats all got fat. It's also been shown that adding n-3 fats helps prevent obesity in rats, so that added linseed oil seems to benefit the rats, although it clearly didn't prevent obesity here.

Benefits of a high-PUFA diet, versus lard

What's worse, the L rats got worse fat than the S rats did; visceral (abdominal) and epididymal (the man parts) fat.
"In addition, the percent of epididymal and visceral white adipose tissue (WAT) increased during dietary treatment, reaching a final value that was significantly lower in S rats than in L rats (Figure 1C,D)."
Not only that, but the L rats lost more lean mass than the S rats did, so they're going to have to go to the gym more often.  
"Therefore, it appears clear that L rats exhibit an impaired metabolic flexibility that exacerbates obesity development."
So far, it appears that lard is an unhealthy fat, and that the safflower/linseed combination is far superior. The higher-PUFA diet is also in line with the dietary recommendations, so that's also a benefit.

Brown Adipose Tissue
There were a number of other benefits to the high-PUFA HFD, including better fuel burning, and increased brown adipose tissue (BAT), which is used to turn fuel into heat to keep the animal warm, and also helps with disposing of excess calories. Cholesterol also went down, and for those who like the current dietary guidelines, that's also a plus

Unfortunately those blood lipids went somewhere...

The Catch

Oh, wait a minute...
"Plasma metabolic characterization evidenced lower cholesterol but higher lipid peroxidation and ALT activity in S rats compared to L rats (Table 3). At variance with plasma lipid profile, livers from S rats had higher lipids, triglycerides, and cholesterol, as well as higher lipid peroxidation..."
"...Conversely, hepatic steatosis and mitochondrial oxidative stress appear to be negatively affected by a diet rich in unsaturated fatty acids."
Oh, darn.  "Negatively affected"? Here's where things go off the rails. One expects a lard-based diet to be bad for rats, who reliably get fat on such diets. But swapping out the MUFA and SFA for PUFA is supposed to make things better, and it has so far in this study.

Until we get to the mitochondria and the liver.

They've come for your liver
TBARS is a test looking for a marker of lipid peroxidation (LPO), which is the oxidation of PUFAs, essentially; see in table 3 in the image above. TBARS are notably higher in the S diet. It's not surprising, I suppose, that the oxidation of PUFAs should be much higher on a higher-PUFA diet. But LPO is not a good thing, as the products of LPO are toxic. TBARS is a marker of malondialdehyde (MDA) one of the worst such LPO products. They should have also tested for 4-hydroxynonenal (HNE), in my opinion, but such is life.

LPO has very negative effects on mitochondria and the liver, and sure enough that's exactly what is seen in these rats. A paler liver indicates a fattier liver, and non-alcoholic liver disease (NAFLD) is a major problem in both rats and humans fed a HFD. Here we see that NAFLD is far worse (the paler colors) in the bottom row of images, from rats fed the supposedly-healthy S diet. What's really notable, and a particularly brilliant part of this paper, is these are rats with a high n-6 diet, but a low n-6/n-3 ratio. Which doesn't seem to have helped their livers at all.

Liver n-6 concentrations change:
"...there was a significant increase in the omega 6 fatty acids linoleic, gamma-linolenic, eicosadienoic, and dihomo-gamma linolenic and in the omega 3 fatty acid docosapentaenoic (Figure 5B), in S rats compared to L rats."
Except the liver mitochondria was altered:
"However, some differences were evident in the content of specific fatty acids, such as the monounsaturated fatty acid oleic acid and the omega 6 fatty acids gamma linolenic, arachidonic, and docosapentaenoic, that were found to be significantly decreased, while the omega 3 fatty acids alpha linolenic, eicosapentaenoic, and docosapantaenoic were found to be significantly higher, in S rats compared to L rats (Figure 5A)."
This might confirm a post of mine:
How To Prevent Oxidative Damage In Your Mitochondria
"These reactive oxygen species readily attack the polyunsaturated fatty acids of the fatty acid membrane, initiating a self-propagating chain reaction."
In that post I discussed how a high n-6 diet affects tissue composition, and how the mitochondria could be damaged by such a concentration. In this study we get to see it in action. Increased TBARS suggests that the n-6 membranes are undergoing the reaction described in the post above, and the n-6 fats have been replaced by non-peroxidizable SFA and MUFA fats. It's the same process described in this study:
"...patients with ARDS decrease their percentage plasma concentrations of total plasma linoleic acid, but increase their percentage concentrations of oleic and palmitoleic acids. As plasma linoleic acid concentrations decreased, there was usually an increase in plasma 4-hydroxy-2-nonenal [HNE] values, one of its specific peroxidation products, suggestive of severe oxidative stress leading to molecular damage to lipids. 
"Plasma fatty acid changes and increased lipid peroxidation in patients with adult respiratory distress syndrome."
I won't go into it here, but these seems to confound much research into negative effects of omega-6 fats: the simple n-6 fat level alone does not tell you about the pathological process, as less can mean it's further along.


This is one of the neater studies I've seen, and it seems to have been created as a refutation of the premise, stated in the paper:
"In fact, some authors have hypothesized that HFDs rich in unsaturated fatty acids are less deleterious for human health than those rich in saturated fat [12–15]...."
They successfully illustrate that higher PUFA in the diet do have the effect they surmise:
"...However, polyunsaturated fatty acids exhibit the highest sensitivity to reactive oxygen species (ROS)-induced damage, their sensitivity to oxidation exponentially increasing as a function of the number of double bonds per fatty acid molecule [16]. As a consequence, if antioxidant defense systems are unchanged, a higher degree of fatty acid unsaturation in cellular membranes may increase their sensitivity to lipid peroxidation and would also expose other molecules to lipoxidation-derived damage."
The effect on the liver alone is enough to demonstrate that this higher PUFA diet is unhealthy. However they also manage to demonstrate, in the process, that some of the often-touted benefits of higher-PUFA diets are in fact parts of the pathological process.

(Title is from one of the more bizarre Monty Python skits.)

Tuesday, January 16, 2018

DNA Heritage Test Results Depend on The Company Used

"How DNA Testing Botched My Family's Heritage, and Probably Yours, Too"

Seems like it's more about entertainment that knowledge at this point...
"Four tests, four very different answers about where my DNA comes from—including some results that contradicted family history I felt confident was fact. What gives?

"There are a few different factors at play here.

"Genetics is inherently a comparative science: Data about your genes is determined by comparing them to the genes of other people..."