Lipid peroxidation - Wikipedia

Lipid peroxidation - Wikipedia

Lipid peroxidation refers to the oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism. It most often affects polyunsaturated fatty acids, because they contain multiple double bonds in between which lie methylene bridges (-CH₂-) that possess especially reactive hydrogens. As with any radical reaction, the reaction consists of three major steps: initiation, propagation, and termination.

Contents 1 Initiation 2 Propagation 3 Termination 4 Hazards 5 Tests 6 References 7 External links

Initiation

Initiation is the step in which a fatty acid radical is produced. The most notable initiators in living cells are reactive oxygen species (ROS), such as OH· and [[HO₂]], which combines with a hydrogen atom to make water and a fatty acid radical.

Propagation

The fatty acid radical is not a very stable molecule, so it reacts readily with molecular oxygen, thereby creating a peroxyl-fatty acid radical. This radical is also an unstable species that reacts with another free fatty acid, producing a different fatty acid radical and a lipid peroxide, or a cyclic peroxide if it had reacted with itself. This cycle continues, as the new fatty acid radical reacts in the same way.^[1]

Termination

When a radical reacts with a non-radical, it always produces another radical, which is why the process is called a "chain reaction mechanism". The radical reaction stops when two radicals react and produce a non-radical species. This happens only when the concentration of radical species is high enough for there to be a high probability of collision of two radicals. Living organisms have evolved different molecules that speed up termination by catching free radicals and, therefore, protecting the cell membrane. One important such antioxidant is vitamin E. Other anti-oxidants made within the body include the enzymes superoxide dismutase, catalase, and peroxidase.

Hazards

If not terminated fast enough, there will be damage to the cell membrane, which consists mainly of lipids. Phototherapy may cause hemolysis by rupturing red blood cell cell membranes in this way.^[2]
In addition, end-products of lipid peroxidation may be mutagenic and carcinogenic.^[3] For instance, the end-product malondialdehyde reacts with deoxyadenosine and deoxyguanosine in DNA, forming DNA adducts to them, primarily M₁G.^[3]
The toxicity of lipid hydroperoxides to animals is best illustrated by the lethal phenotype of glutathione peroxidase 4 (GPX4) knockout mice. These animals do not survive past embryonic day 8, indicating that the removal of lipid hydroperoxides is essential for mammalian life.^[4]

Tests

Certain diagnostic tests are available for the quantification of the end-products of lipid peroxidation, to be specific, malondialdehyde (MDA).^[3] The most commonly used test is called a TBARS Assay (thiobarbituric acid reactive substances assay). Thiobarbituric acid reacts with malondialdehyde to yield a fluorescent product. However, there are other sources of malondialdehyde, so this test is not completely specific for lipid peroxidation.^[5]

[Saturated fats, on the other hand, fortify the intestinal barrier...]: Saturated fats, unsaturated fats, endotoxin, and implications of the Mani study: Andrew Kim Blog

[Saturated fats, on the other hand, fortify the intestinal barrier...]: Saturated fats, unsaturated fats, endotoxin, and implications of the Mani study: Andrew Kim Blog

[EXTRACT] Saturated fats, on the other hand, fortify the intestinal barrier, and medium-chain saturated fats, in addition to fortifying the intestinal barrier, bypass absorption via the chylomicron system.  Instead, medium chain fats are delivered to the liver, where upon arrival, they are rapidly oxidized to generate energy in the mitochondria.

Over time–on the order of weeks–membrane lipids in certain cells, including the intestinal cells, will reflect the types of fat consumed, near perfectly.  A consequence of these changes concerns the enzymes that function in their proximity.

[Monounsaturated fats and saturated fats (namely, short and medium chain) are ideal]: Lipopolysaccharide, physical attractiveness, and the complex network of aging

Monounsaturated fats and saturated fats (namely, short and medium chain) are ideal]: Lipopolysaccharide, physical attractiveness, and the complex network of aging: Lipopolysaccharide, physical attractiveness, and the complex network of aging - Andrew Kim

Adipose tissue fatty acids, which are stored as triglycerides, reflect an individual’s dietary fat intake near perfectly.  NEFA are mostly derived from adipose tissue triglycerides, so in this sense, the types of dietary fat consumed is an important consideration.  Monounsaturated fats and saturated fats (namely, short and medium chain) are ideal in this respect in that they flow down the ω-9 synthetic pathway, rather than ω-6 or ω-3, resulting in polyunsaturated fatty acids with three or four double bonds, instead of five or six.

A lower saturation index goes along with a greater amount of fatty acid substrates that bend into a U shape for eicosanoid synthesis, e.g., arachidonic acid.  As previously put forth, cycloxoygenase-2 is one of the gene products upregulated by LPS.  The upregulation of cyclooxygenase-2 is associated with breast cancer in mammals (Brodie et al., 2001).

Taken together, maintaining a high muscle-to-fat ratio, as well as a high saturation index, reasonable quantities of fat-soluble antioxidants, low NEFA levels, and avoiding the dietary factors that increase bacterial proliferation and intestinal permeability allows us to deal with stresses, really, of any kind in a timely and innocuous manner, which in turn, preserves our youth and the things that make us physically attractive to others.

[forced fatty acid burning] Lipopolysaccharide, physical attractiveness, and the complex network of aging - Andrew Kim Blog

Lipopolysaccharide, physical attractiveness, and the complex network of aging -Andrew Kim

Possibly a topic for another post, but energy, namely, ATP, serves as the principle cardinal adsorbent in all cells, and allows for cells to “organize” its water and structural elements properly.  In other words, ATP is synonymous with life, and anything that diminishes it, such as forced fatty acid burning/glycolysis, diminishes our life force.

Diabetes, Dangerous Fat, and Protective Sugar - Andrew Kim Blog

Diabetes, Dangerous Fat, and Protective Sugar -

Andrew Kim Blog

So in summary, it’s my contention that the excessive mobilization and oxidation of fatty acids—a signature of sorts of the diabetic metabolism— impairs insulin actions, primarily by way of inhibiting the PDH complex (Koves et al., 2005).  Simply put, when free fatty acid levels are elevated, the metabolism of glucose to carbon dioxide becomes impaired, and glucose is rerouted to lactate instead.  This has important implications for the cardiovascular disease—of which, to recap, diabetics have an increased risk of.

So, in my roundabout way, how does this translate to recommendations that you could start applying now if you are diabetic or trending towards it?  This isn’t my area of expertise and, really, others elsewhere have done a good job in this regard. 

Nonetheless, tentatively, I would recommend, in no particular order, to :

(1) supplement with vitamin B1 (cofactor of the PDH complex) and

(2) magnesium (helps retain ATP in the cell),

(3) eat sugar as in fruit in preference to starches as in grains and tubers,

(3a) reduce excess body fat if you have it, and replace it with muscle, which serve as sinks for free fatty acids,

(4) reduce the fat in the diet and replace them with carbohydrates and protein, keeping calories more or less the same.¹  (I’ve found, and most dieters knows, that the loss of muscle occurs long before the fat stores become depleted, which is why carbohydrates are superior to fat during periods of weight loss, as carbohydrates are strongly anabolic),

(5) opt for small meals over large ones in order to maintain steadier blood glucose levels over the course of a day, and

(6) de-stress as much as possible by, for instance, getting into the habit of creating and writing down plans for how you will get an A on an upcoming exam, cope with a major life change, complete a paper, win an argument, etc.   This can be more powerful than executing the plan itself…it has been for me at least.²

EXTRACTS - Why cells go bad: a new appreciation and understanding of ATP opens up an untapped avenue for fighting diabetes, cancer, aging, etc. - Andrew Kim Blog

EXTRACTS - Why cells go bad: a new appreciation and understanding of ATP opens up an untapped avenue for fighting diabetes, cancer, aging, etc. - Andrew Kim Blog

It’s due to this line of reasoning that carbohydrates, and especially sugar and fructose, have fallen by the wayside of late, driven by an irrational fear, bordering on obsessiveness, that’s evolved to where sugar is now conceived of as a toxic poison and blamed for causing diabetes, cancer, obesity, gout, etc. (Thank you Dr. Lustig).

It’s important to point out that sugar is used by virtually every cell in the body to generate energy, or ATP.  The brain is especially reliant on glucose for optimal functioning: The brain represents only 2 percent of the body’s total weight yet accounts for 15 percent of the body’s total energy expenditure. ¹  Indeed, the brain is a voracious sugar guzzler, and sugar, not ketone bodies, is its preferred fuel source, despite popular discourse to the contrary.  Insulin and sugar make us smarter ² so it stands to reason that ketosis has the opposite effect.

 If we were to accept the theory of Warburg and others, that a high efficiency of energy generation determines structure, and that structure in turn, namely of the protein complexes of the respiratory chain, determines how we produce energy—via respiration or fermentation—then, glucose, oxygen, and insulin are the fundamental factors that make up the provision of support against cancer formation; high fat diets (and diabetes) would tend to promote it. 

Warburg also noted that the availability of blood sugar (in the presence of insulin) had no effect on the growth or survival of tumors, and so restricting sugar in hopes of staving off cancer is as fruitless an endeavor as restricting cholesterol to prevent cardiovascular disease, or restricting calcium to slow the progression of pathological calcification processes in the arteries, and so on.

In reality, sugar, in the form of fruit promotes respiration and, in part through insulin, is protective against diabetes and cancer.  Fruit supplies other nutrients that support respiration, including magnesium, potassium, vitamin B₁, and vitamin c, which also promotes the absorption of iron in the intestines.  Carbohydrates, in general, suppress the liberation of fatty acids and amino acids, and inhibit the production of ketone bodies and glucose in the liver, all of which prevent the oxidative metabolism of glucose via the PDH complex, and interfere with the delicately poised state of the mitochondrial respiratory chain.  Fructose, which is present in fruit but not starches, stimulates the synthesis of cholesterol more than any other single nutrient, and this means that ubiquinone would almost assuredly be produced in the amounts needed by cells.

Insulin, glucose, and oxygen the fundamental factors that make up our resistance to stress and illnesses.  There are issues inherent in the excessive oxidation of fatty acids in preference to glucose, which is beyond the scope of this post. (Though Danny Roddy laid out the differences between the two here.)  Briefly, glucose oxidation, more than fatty acid oxidation, supports a highly energized cellular state, per Dr. Gilbert Ling’s vision of cell physiology, and this in turn establishes a firmer connection between energy generation and structure, allowing cells—and by extension people—to exist at the highest possible state of functioning, refinement, complexity. 

AnotherOneMarch 23, 2013 at 8:05 AM

"...then, glucose, oxygen, and insulin are the fundamental factors that make up the provision of support against cancer formation; high fat diets (and diabetes) would tend to promote it."

"Warburg also noted that the availability of blood sugar (in the presence of insulin) had no effect on the growth or survival of tumors,'''"

Andrew, I think this is your best post so far.

Ironically, last night I watched a documentary called "Cut, Poison, Burn" ( https://www.youtube.com/watch?v=09wFl4VS-RY ) about the futility and dangers of the current standard cancer treatments of surgery, chemo and radiation. It is a shame that science has veered so far off course with regard to cancer and other metabolic diseases such as diabetes.

Fear of cancer was the impetus for my brief stint with Paleo. But I felt so terrible on a low carb diet, I decided that even if sugar did cause cancer and other diseases, I would rather enjoy a shorter life eating food that makes me feel energized than living a longer life feeling fatigued and stressed.

Currently, the ketogenic diet is popular as a cancer treatment. The premise is that cancer cells prefer sugar so they can be starved to death by radically decreasing sugar and protein while eating mostly fat.

If cancer cells cannot be controlled by reducing sugar, then why are some people experiencing success with the ketogenic diet? Is it possible that temporarily decreasing sugar and protein allows the body to more effectively eliminate or repair damaged cells?

Water fasting is an example of a high fat ketogenic diet in which the body burns it's own fat and many people have removed or shrunken tumors and normalized blood sugar with fasting. So maybe the ketogenic diet is a more tolerable form of fasting?

Reply

Replies

Andrew KimMarch 24, 2013 at 11:40 AM
Hey AnotherOne, According to Warburg's theory, a cancer cell couldn't revert back to a normal cell; it would be like trying to unscramble an egg. The idea that cancer cells survive on sugar is true per se, I guess, but cancer cells will also convert other substrates into glucose when the supply of glucose is abruptly cut off. So if a person with cancer were to embark on a ketogenic diet, the cancer cells would increasingly consume the body's proteins, namely glutamate, to make glucose, accelerating cachexia. I don't think complete fasting can be compared to ketogenic dieting, as there are important differences between the two. (I think I'll write a post on this as it seems to engender a lot of confusion.)

  

cancer treatment critique - Cut Poison Burn ( Vimeo)

Cut Poison Burn from Dr. Paul Ling Tai on Vimeo.

Andrew Kim Blog: Body fat comes from carbohydrates?

Andrew Kim Blog: Body fat comes from carbohydrates?

Consumer books tend to not be factually reliable because the authors of them present data in a selective way to support their overarching message.  Because I’m trusting and take what other people write very seriously, I stay clear of consumer books (and I think other should, too, especially those related to diet and weight loss).   Nonetheless, as an exercise in learning only, herein, one of the claims made in a book (that I won’t reveal the title of) will be addressed.  The claim in question:

"body fat is made almost exclusively from the carbohydrates in your diet….If you consume more than 200g, you will get fatter and fatter.”

To address this claim, first, we’ll look at several controlled over-feeding studies, where subjects are fed more than what's required to maintain their weights, because otherwise, conclusions would be less definitive.

In one such study, 6 subjects first ate 50 percent extra calories as carbohydrate for 5 days, and then – after a 2 week washout period – they ate 50 percent extra calories as fat for 5 days again .  De novo synthesized fat from carbohydrate during the first phase of the study was calculated to amount to, on average, less than 10 grams per day (Schwarz, Neese, Turner, Dare, & Hellerstein, 1995). 

The subjects in that study were eating just under 700 grams of carbohydrates and about 4,500 calories per day.  So this means that most of the newly made fats, via de novo synthesis, were being oxidized or circulating in the blood in lipoproteins as triglycerides, which are essentially sinks for carbohydrates after meals.  Unlike blood glucose concentrations, which  fluctuate up and down throughout the day, blood triglyceride concentrations progressively increase (Parks, 2002).  Anyway, of the 5.07 pounds gained by each subject on average, less than 1 percent came from carbohydrates.

Next, in another study of the same ilk, smokers were recruited and assigned to eat excessively – over 4,000 calories per day – of a mixed diet.  In it, the subjects gained, on average, 2.5 grams and 1.1 grams of additional fat from de novo synthesis (calculated via fractional de novo synthesis data) per day during the two phases of the study: the smoking phase (CS phase) and non-smoking phase (non-CS phase), respectively (Neese et al., 1994).

(Neese et al., 1994)

And finally, Horton and colleagues fed 16 men (9 lean and 7 obese) 50 percent extra calories as fat, and after a 4 week washout period, 50% extra calories as carbohydrates.  Measurements were made of their energy expenditures and profiles of nutrient oxidation via indirect calorimetry.

During the carbohydrate overfeeding phase, there was a progressive increase in glucose oxidation and also total energy expenditure, which represents the sum of the resting metabolic rate and diet-induced thermogenesis.  On the other hand, fat overfeeding had minimal effects on total energy expenditure and fat oxidation.  So for the same amount of energy consumed in excess, carbohydrates caused less fatness than fat did (Horton et al., 1995).

(Horton et al., 2005)

Although this study was not set up to measure rates of de novo synthesis of fat from carbohydrates, estimates taken from calorimetric data showed that virtually no net fat was made via this pathway (indirect calorimetry can’t rule out simultaneous de novo synthesis and fat oxidation).

----------

What then is the fate of the carbohydrates eaten in excess? 

First, as mentioned in the study by Horton et al., the oxidation rate of carbohydrate is intensified, but also, the glycogen storage capacity expands greatly, so that additional carbohydrate can be accommodated (Acheson et al., 1988).

Second, when the above routes become saturated, so to speak, de novo synthesis kicks in, where carbohydrates are converted to fatty acids, namely palmitate, and then, palmitoleate, because de novo synthesis and desaturase enzymes are regulated in parallel (Chong et al., 2008).  Thereafter, these newly made fats, via a futile cycle, are subsequently oxidized, so that body fat remains, more or less, unchanged. 

Third, thermogenic mechanisms become activated when rates of glucose oxidation in the cell reaches a threshold level, and also in response to insulin itself.  Fructose in this regard is more effective than glucose.

And fourth, the conversion of thyroid hormone to its active form, T₃, becomes more efficient during these periods of excess carbohydrate intake, and as a result, cells throughout the body see a higher exposure to T₃, whereby enzymes that regulate basal thermogenesis and oxidative energy production become expressed in higher amounts.

After eating a 1,600 kcal high-fat diet, subjects were placed on a hypercaloric high-carbohydrate diet (86 percent carbohydrate), thyroid output increased and the conversion to T₃ did, too (Acheson et al., 1988).

In summary, carbohydrates eaten in excess, itself, contributes negligibly to stored body fat, whereas fat eaten in excess is simply stored near completely.  However, regardless of the source, carbohydrate or fat, overtime, hypercaloric diets will lead to obesity.  The studies herein referenced bear this out.

Although body fat from carbohydrate overfeeding does not, at first, come from de novo synthesis per se, over time – on the order of weeks – de novo synthesized fats contribute more and more to stored body fat.  And in parallel, the fat oxidation rate progressively decreases and insulin secretion rate progressively increases (in order to clear NEFA and intensify carbohydrate oxidation).  But at some point, the storage of de novo synthesized fats surpasses the oxidation of them.  In the obese, these processes are more efficient.

Nonetheless, diets that include upwards of 200 grams of carbohydrate per day, contrary to what the author of the quotation declared,  do not necessarily lead to weight gain, as long as they are not eaten hypercalorically. 

Finally, several mechanisms begin to progressively kick in as more and more carbohydrate is eaten, and culminates in changes in the expression of genes that make the aforementioned processes more efficient.  These mechanisms, in effect, dispose of excessive carbohydrate so that blood glucose concentrations don’t fall out of range too much.

ApoE4 - The Ancestral Allele | For ApoE4 carriers interested in primal diets and science

ApoE4 - The Ancestral Allele

- For ApoE4 carriers interested in primal diets and science

For ApoE4 carriers interested in primal diets and science

Omega-3s, ApoE Genotype and Cognitive Decline (Paper)

with 2 comments

Googling for the rate of APOE4 among Native Americans, I found this paper on omega-3 fats and ApoE4:

The most recent statistics indicate that dietary intake of omega-3 PUFA is insufficient in >95% of Americans. Deficits in omega-3s have been shown to contribute to inflammatory signaling, apoptosis, and neuronal dysfunction in all cause dementia, including Alzheimer’s disease. DHA (22:6[n-3]), specifically, is a critical contributor to cell structure and function in the nervous system, and a recently identified DHA-derived messenger, neuroprotecting D1 (NPD1) has been found to regulate brain cell survival and to promote non-amyloidogenic processing of amyloid precursor protein, thus protecting against Alzheimer’s disease by inhibiting formation of β-amyloid. Studies utilizing omega-3 supplementation to improve cognitive function in elders, however, have had mixed outcomes, an inconsistency which newly published research indicates is related to ApoE genotype. ApoE ε4 carriers have not been able to benefit from omega-3s. This article discusses why and what can be done to enable carriers of the ApoeE ε4 allele to receive the neuroprotective benefits of omega-3s.

The important thing for us is the dietary recommendations.  Some highlights:

ApoE ε4 carriers are the canaries in the mine of the Western way of life. Individuals with this genetic heritage cannot afford the “normal” level of dietary and lifestyle insults typical of life in the modern industrialized world because the ApoE ε4 allele magnifies the risks inherent in the Western diet and lifestyle.
…
Despite the disproportionately high prevalence of ApoE ε4, cardiovascular disease and diabetes among Native Americans, and the Pima Indians, specifically, research examining a Native American rural population in nearby New Mexico clearly shows that carrying the ApoE ε4 allele does not increase the risk for any of these conditions in people eating a low fat diet and following an active lifestyle.

Another important point the paper makes is that while O3s provide many benefits, they are also vulnerable to oxidative damage.  Depending on the body’s redox state, O3s can be neurotrophic (good for the brain) or neurotoxic (not so good).
The paper seems to conflate a low fat diet with a plant-centered, unprocessed one.  While it has some great information on omega-3s, it doesn’t have much to answer other key primal / e4 fat questions like whether saturated fats are good (as in primal) or bad (because of differences in lipid metabolism for e4s).

Written by patrissimo
February 21, 2013 at 7:13 am

Posted in Uncategorized

Food collection, not production

with 5 comments

Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a `thrifty’ allele?
R. M. CORBO and R. SCACCHI Department of Genetics and Molecular Biology, University `La Sapienza, Rome.  CNR Center of Evolutionary Genetics, Rome
Summary begins:

Apolipoprotein E (APOE¯gene, apoE¯protein) plays a central role in plasma lipoprotein metabolism and in lipid transport within tissues. The APOE shows a genetic polymorphism determined by three common alleles, APOE*2, APOE*3, APOE*4 and the product of the three alleles differs in several functional properties. APOE is involved in the development of certain pathological conditions. In particular, the APOE*4 allele is a risk factor for susceptibility to coronary artery disease (CAD) and Alzheimer’s Disease (AD). In the present study we analyzed the APOE allele distribution in the world…

Some key messages:

It appears from our analysis that the APOE*3 allele is the most frequent in all the human populations and that its frequency is always negatively correlated with that of APOE*4, indicating that the ancestral allele was progressively substituted by the new allele carrying the 112arg!cys mutation. The highest APOE*3 frequencies are found in populations with a long-established agricultural economy (Gerdes et al. 1996) such as those of the Mediterranean basin (0.849±0.898) or East Asia (0.82±0.87). It is possible that the metabolic properties of the E3 isoform proved to be particularly advantageous in the transition from food collection to food production. At present, the frequency of APOE*4 within all the major human groups remains higher in those populations…where an economy of foraging still exists, or food supply is now or has until recently been scarce, sporadically available or qualitatively poor. Under these environmental conditions, carrying the APOE*4 could be still useful. For example, most of these populations have lower plasma cholesterol levels than those observed among Western countries. Since APOE*4 is associated with both a higher absorption of cholesterol at intestinal level, and higher plasma cholesterol levels, individuals carrying it would be favoured because this allele could help in rebalancing cholesterol levels which would otherwise be too low (Scacchi et al. 1997)

Hopefully this just means we should eat primal, I totally don’t want to eat a low cholesterol diet.  As we can see below, it’s clearly a gene-environment interaction that leads to high levels of heart disease (CAD) and Alzheimer’s (AD) for APOE4s, because the developing world has more E4s yet far less CAD & AD.  There are two hypothesis for what the environmental aspect of the Western lifestyle is which triggers these problems, one of which is good for us & one is bad.
The first is that it’s the Western diet & low-activity lifestyle, which means by eating primal, we’ll be fine.  The second is that since CAD & AD happen when old, it may just be that longer Western lifespans allow the disadvantages of E4 to develop.  The key data for us, then, is to find some high E4 populations, and see what their lifespans are & whether those individuals who live into their 70s & 80s get CAD & AD.

APOE*4 could be considered a `thrifty’ allele based on certain functional properties it exhibits and on its distribution among human populations. At present it is considered a susceptibility factor for CAD and AD, diseases highly prevalent in Western populations but far less so or completely absent in developing countries, where instead APOE*4 is most frequent. Since both CAD and AD are complex diseases whose occurence depends on gene-environment interactions, exposure of APOE*4 to contemporary environmental conditions may have rendered it a susceptibility allele for CAD and AD. One of the new environmental conditions favouring this change could be the western lifestyle in general, with its diets rich in carbohydrate and fat, but poor in fibre intake, along with reduced physical activity. Longer average lifespans and aging populations count as two more environmental factors particular to the developed countries, since both the diseases occur in adult and advanced age.

Written by patrissimo
December 29, 2011 at 5:03 am

Posted in Uncategorized

Should E4s eat low saturated fat?

with 2 comments

It isn’t very primal, but the Track Your Plaque blog – which generally advocates a fairly primal diet – says that APOE4 fat metabolism responds poorly to saturated fat:

I witness spectacular results restricting carbohydrates, both in the office as well as in my online experiences, such as those in Track Your Plaque. Of course, the diet I advocate is not just low-carb; it starts with elimination of wheat (for a long list of reasons). So the diet is wheat-free in the setting of low-carbohydrate.
But there’s one group of people who can experience unexpected effects with this diet: The 25% of people with apoprotein E4….I hate apo E4. I hate apo E4 because it means I’ve got to dust off the nonsense I used to tell patients about cutting their fat, cutting their saturated fat. But that’s what apo E4 people have to do. But it doesn’t end there.
Apo E4 people also typically have plenty of small LDL particles triggered by carbohydrates. Put fats and carbohydrates together and you get an explosion of small LDL particles. Remove fats, small LDL goes down a little bit, if at all. Remove carbohydrates, small LDL goes down but total LDL (mostly large) goes up. The large LDL in apo E4 does seem to be atherogenic (plaque-causing), though the data are fairly skimpy.
So apo E4 creates a nutritional rock and a hard place: To extract full advantage from diet, people with apo E4 have to 1) go wheat-free, low-carb, then 2) not overdo fats, especially saturated fat.
It still gives me the creeps to tell an apo E4 person that they’ve got to watch their fats, worse than watching Starsky and Hutch reruns.

Information like this will help us narrow in on the optimal diet for our ancestral allele.  I’d like to learn more about what kinds of fat are healthy for E4s, since low-fat, low-carb would mean high-protein, and research suggests that too much protein is hard on the body and not good for life-extension in general.  And too much carbs is not good either (unless perhaps it is root vegetables).  Fat is the best macronutrient – so which fat is best for us?  I posted a comment, we will see if the good doctor responds.

Written by patrissimo
August 1, 2011 at 9:15 pm

Posted in Fat
Tagged with ldl, macronutrients

Better Episodic Memory in Young E4s (Paper)

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One of the things we’ll probably do a lot here is to summarize relevant papers.  For a dose of optimism, let’s start with a paper about the advantages of E4, Better Memory and Neural Efficiency in Young Apolipoprotein E ε4 Carriers.  Researchers are interested in this topic because E4 (the ancestral allele) still sticks around at significant frequencies in all populations – it hasn’t been totally displaced by the more recent E2 and E3.  So unlike a genetic disease caused by a rare mutation, where one really can think of the gene as “a disease gene”, it seems likely that ApoeE4 has some benefits, and there is a hypothesis that it is being maintained by “balancing selection”.
Abstract:

The apolipoprotein E (APOE) ε4 allele is the major genetic risk factor for Alzheimer’s disease, but an APOE effect on memory performance and memory-related neurophysiology in young, healthy subjects is unknown. We found an association of APOE ε4 with better episodic memory compared with APOE ε2 and ε3 in 340 young, healthy persons. Neuroimaging was performed in a subset of 34 memory-matched individuals to study genetic effects on memory-related brain activity independently of differential performance. E4 carriers decreased brain activity over 3 learning runs, whereas ε2 and ε3 carriers increased activity. This smaller neural investment of ε4 carriers into learning reappeared during retrieval: ε4 carriers exhibited reduced retrieval-related activity with equal retrieval performance. APOE isoforms had no differential effects on cognitive measures other than memory, brain volumes, and brain activity related to working memory. We suggest that APOE ε4 is associated with good episodic memory and an economic use of memory-related neural resources in young, healthy humans.

So basically, they watched the brains of people with various APOE alleles while they did some brain tests.  The allele made no difference to overall performance, the big difference came in the efficiency episodic memory (memorizing facts from the recent past, as opposed to working memory, which is based on how much you can hold in your head at any one time).  Specifically, there was an interesting effect where E4s used less energy (less brain activity) each time they learned a repeated fact, whereas E2s and E3s used more energy each time.  They all used the same amount of energy the first time, and they performed equally at remembering the fact, but E4s needed less energy to reinforce the memory each time while E2s and E3s needed more.
The paper has a good summary in the intro of what’s known about ApoE4:

Although the frequency of the APOE4 allele is low in humans (15% in Caucasians), studies in primates suggest that it is the ancestral allele (Finch and Sapolsky 1999). The common (75% in Caucasians) and uniquely human APOE3 allele appeared as a mutation, and its frequency increased during human evolution (Finch and Sapolsky 1999). Because the APOE4 allele has been related to several deleterious biological effects, the question arises why it existed in the first place (Finch and Sapolsky 1999). From an evolutionary point of view, a possible advantageous effect of the APOE4 allele in childhood and early adulthood could explain its existence and further persistence in humans. Support for this notion comes from studies where APOE4 has been associated with higher IQ scores (Yu et al. 2000), a higher educational level (Hubacek et al. 2001), a reduced cardiovascular response to experimentally induced stress (Ravaja et al. 1997), and a protective effect against spontaneous abortion during embryogenesis (Zetterberg et al. 2002) and against perinatal death (Becher et al. 2006). Advantageous effects of the APOE4 allele have also been found for memory-related functions in young animals. Hippocampal long-term potentiation (LTP) was enhanced at a young age in knock-in mice lacking mouseAPOE but instead expressing human APOE4 (Kitamura et al. 2004). This LTP enhancement was age dependent and disappeared in adult knock-in mice. Moreover, APOE4, but not APOE3, stimulated the transcriptional activity of cyclic adenosine 3′,5′-monophosphate response element-binding protein (CREB) by activating the extracellular signal-regulated kinase (ERK) cascade in rat primary hippocampal neurons (Ohkubo et al. 2001).

It’s worth remembering that almost all evolutionary changes involve tradeoffs, because any simple change that’s a pure advantage will quickly get discovered and spread by evolution.  Everything left involves tradeoffs, where the optimal balance shifts as the environment changes.  The novel ApoE alleles E2 & E3 have increased in number over the last tens of thousands of years because of their net benefit – in one theory, the main benefit is the longer lives they allow by reducing heart disease and Alzheimer’s, which became important as grandparents took on an increased role in child-rearing.  Here we see one of their costs: increased energy use in episodic memory storage for the young.

Written by patrissimo
July 23, 2011 at 5:18 pm

Posted in E4 Benefits, Research

Welcome to Primal ApoE4

with 2 comments

Is it an ancestral super-allele or a slow-motion Alzheimer’s death sentence?  It depends what you eat and how you play.
This is a new blog for carriers of the Apolipoprotein allele ε4, as well as researchers and others interested.  Our perspective is:

• Practical – interested in taking action to maximize our health.
• Primal – we believe that selectively emulating aspects of the hunter-gatherer lifestyle, such as diet, is a powerful general strategy for health, and that this is especially true for us ApoE4s, since it’s a pre-agricultural allele.

The blog was started by Patri Friedman, an E4/E4, because there seem to be no good central resources for E4s to share practical information and research.  Guest posts, links, and academic articles are welcome.  I’m especially interested in finding other co-bloggers to help run the site – so if you’re a health-conscious E4 whose going to be researching your condition anyway, consider joining us and writing up your findings to share with others!

Contact patrissimo-at-gmail.com.

Written by patrissimo
July 15, 2011 at 6:07 pm

Posted in About