Apo ε4: Less UV-Triggered Vitamin D Required... Evolutionary Adaptation

** Hat tips to both Mr. Tyler Simmons of Evolutionary Health Systems Blog and a wise, flexible, strong mentor, Mr. Marc Simonson.


The 'Genetic Landscape': Apo E4 Gradient in Europe, China, India and Japan

Mr. Simonson's insights for the migration of pastoralists across Europe, originating from the fertile crescent first started my thinking (nutritional bricolage) for how the world populations have exhibited endless varieties of phenotypes and infinite genotypes (mtDNA, apo E, HFE, and thyroid/autoimmune disorders). He often says that no two people are alike unless they are IDENTICAL TWINS. Therefore, no two dietary prescriptions can be alike.

I'd strongly concur. The perfect human diet is perhaps the one suited to one's ancestral past, unique genomic profile, neolethal toxicity/damage status and metabolic goals.

The below quote comes from Lars Ulrik Gerdes work on Apo E4. He's a FANTASTIC APO*E freak! His thesis is mindblowing. I don't agree w/all of his thoughts but he has plucked through the data comprehensively and thoroughly. Regarding the ApoE4 gradient in Europe (which has also been observed in other countries and continents) 'there is a conspicuous south-to-north gradient of APOE*4 frequencies in Europe, with the proportion of APOE*4 carriers rising from only 10-15% in the south to 40-50% in the north. In contrast, the proportion of APOE*2 carriers is a little higher in Central Europe than in the south and the north. Many other genetic polymorphisms show similar south-to-north gradients in Europe, and this peculiarity of the 'genetic landscape' on our continent is presumably caused by the demic expansion of agriculture (i.e. migrations of farmers) from the Middle East that began about 10,000 years ago. The farmers first migrated westwards along the north coast of the Mediterranean sea, and later turned towards the north. Thus, the APOE*4 gradient could have arisen as an 'admixture gradient', if the apoE*4 frequency were low in the migrating populations of farmers but high in the original populations of hunters/gatherers in the north.'




Evolutionary Adaptation To Lower UV Radiation at Northern Latitudes?

Gerdes has hypothesized that apo E4 allele carriers have less of a need for UV radiation derived vitamin D due to internal adaptations to preserving vitamin blood levels and maximizing intestinal absorption from dietary sources. One of the earliest indications that this was the case was research from Willnow et al. With vitamin D binding protein and apo E protein binding sites being shared regions at the same receptor in the proximal tubule of the kidneys, Gerdes theorized that E4 may have escaped the normal urinary losses of vitamin D and its metabolites. E4 typically produce higher protein amounts of apolipoprotein E (high carb diets lower apo E protein concentrations). From Gerdes' thesis, I restated, see the below. Lard, other pastured animal fats, foraged grub, and organ meats contain substantial, rich sources of fat soluble vitamins including vitamin D. For the ancestral hunter-scavenger-forager 200,000 years ago, these fatty sources of vitamin D, K and A may have been crucial and critical for growth, maintenance and reproduction.

In migrating northward out of sun-drenched Africa, with smaller guts, less fruit/fiber/fish and subsequent lower fermentation of fiber that resulted in SCFA (short chain fatty acids like the potently anti-inflammatory butyrate), how in the world did ancestral HGs survive and have babies?

Upregulation of receptors in the gut for the fat soluble goodies from food and downregulation of the kidney's capacity to leak these fat soluble hormones, metabolites and low molecular weight proteins out...? SUPER HIGH FERTILITY, DIESEL BRAIN FUEL, AND LIPOPHILIC BULLETPROOF IMMUNITY...?

Apo E4, I believe, apparently have ALL of these amazing survivor traits.

Does APOE*4 protect against vitamin D deficiency? [p. 33 from Gerdes' thesis]

A putative association of APOE with bone metabolism has been ascribed to an impact of APOE polymorphism on the transport of vitamin K (see page 40), but it could also relate to vitamin D metabolism and embrace a very strong selection pressure. Hypovitaminosis D in childhood (rickets) causes bone deformations, which can reduce the probability of surviving to adulthood, and perhaps more importantly, can cause pelvic deformations in girls that later may cause their death during delivery under primitive conditions, and also the death of their offspring. Inadequate endogenous production of vitamin D3 can be due to insufficient dietary supplementation or reduced intestinal uptake of the vitamin, or to low exposure to sunlight (UVB-radiation). The latter can be a particular problem to people with dark skin, because melanin blocks for ultraviolet photons and thus limits the synthesis of previtamin D3 [Vogel and Motulsky, 1986].

Mourant and co-workers showed that the frequency of Gc-2-allele for the gene coding for vitamin-D-binding protein (DBP; previously known as the group-specific component, Gc, of the α2-globulins of human plasma) was high in populations living in areas with low levels of sunlight and vice versa (with some exceptions). They suggested that the distribution could be explained by means of natural selection if the encoded isoform were more efficient in binding vitamin, and so in protecting Gc-2 carriers from rickets [Mourant et al., 1976]. This may be true, although the concept has been weakened by an analysis including more detailed climatic data [Cavalli-Sforza et al., 1994].

Interestingly, a very consistent pattern appears if one correlates the frequency of APOE*4 in aboriginal peoples around the world to their skin pigmentation, while also considering the intensity of solar radiation in their habitats:

• The APOE*4 frequency is generally higher in dark-skinned humans than in humans with less melanin, and the frequency is particularly high (40-50%) for instance in Papuans, Pygmies and Khoisan, who are dark peoples and whose (recent) habitats are tropical forests where the intensity of sunlight is relatively low.

• High APOE*4 frequencies (20-30%) are also found in Saami and Inuit, who are moderately pigmented humans living in regions with low average solar radiation, and in peoples living in South American rain forests.

• Conversely, the lowest frequencies of APOE*4 (5-10%) is found among lightly or moderately pigmented humans living in areas of high insolation, i.e. around the Mediterranean Sea, in East Asia, in the southern parts of North America and in Central America.

• The APOE*4 gradient in Europe (and possible also in Japan) could be interpreted to indicate natural selection for this allele with decreasing solar radiation.

The putative advantage of APOE*4 could be related to better intestinal absorption of vitamin D (see page 30), but could also be related, somehow, to the fact that apoE and DBP both binds to megalin. This receptor plays a central
role in vitamin D metabolism, since it binds and internalizes DBP on the luminal surface in the renal proximal tubuli. The function prevents systemic loss of vitamin D through the urine and is also a step in the conversion of 25-hydroxy- vitamin D3 to the biologically active 1,25-dihydroxy-vitamin D3 [Willnow et al., 1999].

Study: Carriers of apo E4 have higher vitamin D (25OHD) blood levels compared to population controls

411 news flash...New research from last month in FASEB supports an earlier speculaton that carriers of the ApoE4 allele require less vitamin D. Willnow's research and Gerdes' theory have a line of evidence for confirmation. To prevent vitamin D deficiency and subsequent health risks (female pelvic dysplasia, fatal childbirths, growth, maturation, steroidogenesis, rickets, testosterone/progesterone production, etc), an evolutionary adaptation to recycling of vitamin D at the kidney level that raises serum vitamin D in apo E4 carriers may have occurred. The researchers state ' The novel link suggests ε4 as a modulator of vitamin D status.'

(Sorry didn't have time for tracking this PDF but if anyone can toss over would be horribly AWESOME *BIG WINK*)

FASEB J. 2011 Jun 9.
APOE {varepsilon}4 is associated with higher vitamin D levels in targeted replacement mice and humans.
Rimbach et al

Abstract
The allele ε4 of apolipoprotein E (APOE), which is a key regulator of lipid metabolism, represents a risk factor for cardiovascular diseases and Alzheimer's disease. Despite its adverse effects, the allele is common and shows a nonrandom global distribution that is thought to be the result of evolutionary adaptation. One hypothesis proposes that the APOE ε4 allele protects against vitamin D deficiency. Here we present, for the first time, experimental and epidemiological evidence that the APOE ε4 allele is indeed associated with higher serum vitamin D [25(OH)D] levels. In APOE4 targeted replacement mice, significantly higher 25(OH)D levels were found compared with those in APOE2 and APOE3 mice (70.9 vs. 41.8 and 27.8 nM, P<0.05). Furthermore, multivariate adjusted models show a positive association of the APOE ε4 allele with 25(OH)D levels in a small collective of human subjects (n=93; P=0.072) and a general population sample (n=699; P=0.003). The novel link suggests ε4 as a modulator of vitamin D status. Although this result agrees well with evolutionary aspects, it appears contradictory with regard to chronic diseases, especially cardiovascular disease. Large prospective cohort studies are now needed to investigate the potential implications of this finding for chronic disease risks.

Vitamin D Dosing Revisited

For those supplementing vitamin D exogenously, care and caution for adverse effects should be monitored. Sunlight derived vitamin D can be shut off -- we have enzymes and systems that control blood/cellular levels, however for supplementation just as taking a birth control or exogenous hormone medication, what goes in, stays in. Previously I listed contraindications for vitamin d supplementation ((a) hypomagnesemia -- get mag up before supplementation because vitamin D will lower serum Mag; (b) sarcoidosis or other condition associated with elevated 25OHD or 1,25OHD3). Now I would add those with E4 should like monitor closely and avoid supratherapeutic levels which probably need to be addressed on an individual basis. With E4 there may be suggestions that intracellular 1,25OHD3 may be higher and this would not necessarily be reflected in serum levels (just like Mag levels are not, intracellular $$$$$ tests are required to accurately assess). Supratherapeutic needs to be individually defined...

So, what's an optimal, ancestral, nutrigenomically perfect serum vitamin D 25OHD and 1,25OHD3 level? I dunno. Who really knows?


Relevant Citations:

LU Gerdes Thesis HERE

The common polymorphism of apolipoprotein E: geographical aspects and new pathophysiological relations.
Gerdes LU.
Clin Chem Lab Med. 2003 May;41(5):628-31.

APOE {varepsilon}4 is associated with higher vitamin D levels in targeted replacement mice and humans.
Huebbe P, Nebel A, Siegert S, Moehring J, Boesch-Saadatmandi C, Most E, Pallauf J, Egert S, Müller MJ, Schreiber S, Nöthlings U, Rimbach G.
FASEB J. 2011 Jun 9.

Essential role of megalin in renal proximal tubule for vitamin homeostasis. Free PDF.
Christensen EI, Willnow TE.
J Am Soc Nephrol. 1999 Oct;10(10):2224-36.

Lipoprotein receptors: new roles for ancient proteins.
Willnow TE, Nykjaer A, Herz J.
Nat Cell Biol. 1999 Oct;1(6):E157-62.

Expression profiling confirms the role of endocytic receptor megalin in renal vitamin D3 metabolism.
Hilpert J, Wogensen L, Thykjaer T, Wellner M, Schlichting U, Orntoft TF, Bachmann S, Nykjaer A, Willnow TE.
Kidney Int. 2002 Nov;62(5):1672-81.

An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3.
Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE.
Cell. 1999 Feb 19;96(4):507-15.

The uptake of lipoprotein-borne phylloquinone (vitamin K1) by osteoblasts and osteoblast-like cells: role of heparan sulfate proteoglycans and apolipoprotein E. Free PDF.
Newman P, Bonello F, Wierzbicki AS, Lumb P, Savidge GF, Shearer MJ.
J Bone Miner Res. 2002 Mar;17(3):426-33.

Ancestral Allele ApoE4: Super Brain Power, Fertility, Lipophilic Immunity

Ancestral Nutrition: The Imperfect Diet Cleaves Adaptive Genetic Polymorphisms

Hat tip to B. Pottenger for the latest science daily (HERE) on the importance of ancestral, customized nutrition for our health. Chilton et al found desaturase/FADS variants in African Americans which take medium chain n-6 PUFAs (polyunsaturated fatty acids) and convert them into long chain n-6 PUFAs, like arachidonic acid which may increase systemic inflammation. They purport this may explain the inordinate increase in Western diseases observed in African Americans who display a certain FADS genotype variant for fatty acid disposal when they eat the high n-6 PUFA Western diet, including prostate cancer, diabetes, diabetic complication, heart attacks, obesity and dementia/Alzheimers. [I edited the last post -- continental Africans also have a high rate of apoE4 in addition to current hunter-gatherer groups in Africa.]








ApoE4, The Ancestral Allele = Carnivorous and Fatty Acid-Adaptive Allele

It is clear that our ancient hominid predecessors had something special that allowed them to leave Africa ~2 mya and navigate the terrain and uncertain food, energy and climate allotments. Like others I subscribe to the marine hypothesis (Cunnane SC) that certain brain nutrients are essential for IQ and brain function. Both Cunnane and Jonathon CK Wells writes about the 'fattiness' of the human brain and how this factored into our brain evolution and global domination of every potential ecological niche... not withstanding the moon and interplanetary travel as well. Wells' book 'The Evolutionary Biology of Human Body Fatness: Thrift and Control' details the fats that built our history and brains.

A couple evolutionary biologists also assert that the APOE4 allele is our 'meat-adaptive' gene. Well. This makes sense to a finite degree however no research that I could find illustrates apoE increasing proteins into the brain or digestion... On the other hand, the research is highly demonstrative of apoE4 increasing FATTY ACIDS into our brains, mitochondrial metabolism and enhancement of neural efficiency.

My view:
apoE4 -- Infiniti of cars (same Nissan engine), running on super premium fuel (ancestral allele)
apoE3 -- Nissan Maxima (wild type allele), runs both regular and premium fuels
apoE2 -- Nissan Sentra, on regular unleaded (agarian allele??)
apoE combos -- Prius hybrids (phenotype varying by degrees)

One change of the protein structure of apoE at the 61 spot from T to R/arginine may have set the stage for evolution of other nervous system and housekeeping genes that not only grew a superior engine in the brain but also the chassis/architecture of our hard drives. The ancestral apoE4 allels may be one among several genetic variations that sets us vastly apart from our not so distant primate past.







Super Brain Power + Super Brain Fuel

Though in the medical literature is rife with negative associations between apoE4 and a variety of conditions, my observations are that in those who exhibit high LDLs appear to display the most supreme levels of super-healing and extraordinary intelligence. See Hyperlipid (Peter D. for studies where high LDL associated with positive improvements and longevity, HERE J-LITT. Please also review the neurobio series on Alzheimer's by the wonderful Emily D. at Ev Psych and how low cholesterol is associated with lower cognition HERE.

As you can see from Mahley and Rall's 2000 publication, LDL sharply corresponds to apoE status. E4, the highest; E2, the lowest LDL. Do most cardiologists know this as they prescribe cookie-cutter NCEP/ATPIII-aligned statins? Please.

The density of the LDL determines its function. Small dense is damaging. For E4, dietary carbohydrates and dietary deficiencies of saturated fat dramatically shape and create small, dense, harmful LDL particles. The only rare cases of coronary calcification improvement on EBCT at a coronary heart website were the uncommon participant on a lower carb, HIGH SATURATED FAT intake. E4 appear exquisitely more sensitive to diet, exercise, fats/carbs and environmental toxicants.

Mondadori et al used new technology fMRIs to brain scan young chess-playing individuals and compared their the apoE status. The apoE4 showed increased memory, retrieval, neuropsychology and apparently neural efficiency. E4 indeed appear to run their brains on better fuel, e.g. fatty acids, the currency of nervous system cells.

Why is this not observed in E4 carriers in older age in the industrial populations? In the prior post, researchers discussed how the cysteine amino acid is lacking in E4, at the 112 site. E2 has 2 cysteine's per allele; E3, 1 cysteine; E4, N-O-N-E. This protein conformation apparently stupendously reduces the capacity for apoE to shuttle trace metals out of nervous system tissues. Many enzymes regulate and control metals in the brain however having the E4 allele is like a neuronal death sentence in a world that is contaminated by metals, not excluding one's own oral cavity. Sources of neolethal metal: dental amalgams (50% are mercury which gas off), stents, ortho/dental implants, well water, water purification at municipal plants (alum/Al), lead from leaded fuel/diesel, copper piping, fish intake (the EPA advises pregnant women limit fish, shouldn't we non-pregnant as well?), vaccines (Hep B, flu, whooping cough, Td, etc) and broken Hg thermometers.




Super Fertility = (Pre-Industrial) ApoE4 Populate the World

The literature abounds with cases of higher infertility in apoE4 women. FYI All literature needs to be viewed from an evolutionary perspective and in this context the great majority of these studies for me only demonstrate that the Western diet/lifestyle are particularly adverse to the hunter-gatherer types who carry the E4 allele. If a person carries the E4, then consuming an anti-HG diet (e.g. refined, non-ancestral), then the preponderance of small dense, oxidizable LDL and a hyperactive immune system which searches and scars, yes of course, will result in higher rates of infertility, fibroids, ovarian cysts, PCOS and less pregnancies, as countless PubMed articles report.

One study looked at HG super fertility... In African-Ecuadorians and a HG group, Capaya Indians, indeed the # of gestations and pregnancies were astoundingly higher in E4 carrier women. See citation below Corbo et al. They hypothesize that higher rates of sex hormone steroidogenesis can potentially occur with the E4 genotype.

My own family may also be a prime example. On low carb, mod-high sat fat, my LDLs are greater than 130s which is 'high' for the medical establishment, EVEN THOUGH THE HDL-CHOLESTEROL ECLIPSES THE S.A.D. HDL for women at 105 mg/dl. Both my father and stepmother's side each have 12 children (with 1-2 nonsurviving siblings). How is this humanly possible, as a mom, I used to WONDER OUT LOUD IN HORROR. I think Catholic families might relate... I could have a litter kids if I didn't have a brakestop. My parents and step mother are from an ancient nomadic group (Hakka, part of Han) and in all likelihood harbor the E4 allele somewhere, as my LDLs my appear to indicate. Each of my siblings and I (4 total) have had an autoimmune disorder and are somewhat sensitive to modern pollution and toxicants (gluten, dairy/casein, medications, and sulfa-, nickel-, metal-allergies).




Super Immunity

In a seminal article in PNAS, Caleb Finch's 'Evolution of the human lifespan and diseases of aging: Roles of infection, inflammation, and nutrition' talks about how humans evade infections and the role of apoE4. As a carnivorous creature, hominids had access to ingestion of better protein, trace minerals and fats. The apoE system shuttles cholesterol and the contents of LDL and HDL particles into nervous system tissues (iodine, zinc, tocopherols, ubiquinone, vit K2, etc).

By absorbing fats from the intestines quickly, this sequesters fat from parasites, bacteria and other pathogens. It is believed this might be one mechanism of super immunity which is observed in E4 carriers. Finch and Stanford (QJB, 2004) report 'In chronic infections by hepatitis C virus (HCV), apoE4 carriers had milder liver disease (Wozniak et al. 2002). The protection against HCV by apoE4 is consistent with the role of lipoproteins in transmission of HCV and other viruses (Wozniak et al. 2002), and fulfills hypotheses that apoE4 is a resistance factor for lipophilic parasites (Martin 1999) and that apoE4 confers advantages in early life (Charlesworth 1996). ApoE may also influence infections by other viruses and by prions, but the evidence is less clear (Table 3, Note 1d and Appendix).'




Human Migration: Evolution of Machinery to Convert Saturated Fat into Omega-3 PUFAs

How did humans go so far north, such high altitudes where seemingly harsh climate and terrains existed? Many SNP variants have apparently evolved which helped our ancestors thrive and live very full lives in certain microecological niches on earth. One thing that has baffled me to know end is the apparent n-3 pufa sources in northern Europe, Africa or northern China as hominids moved there 200,000 years ago. The FADS gene clusters of polymorphisms definitely explains a lot as to how the delta 5 and 6 desaturases control elongation of fatty acids to the ever important essential brain nutrient n-3 pufa.

Terrestrial Brain nutrient allocation and Adaptation from Sahara marine-sources (hypothesis):
EPA DHA n-3 pufa: ???! from where, ?megafauna and small animal predation
ALA n-3 pufa: wild greens
Iodine: ApoE4, possible iodine-oral cavity cellular conservative adaptations, polymorphs of MT1,2,3
Zinc: ApoE4
Magnesium: ApoE4
Taurine: Raw megafauna hunt successes, small animals, fish/seafood from local rivers/tributaries
UVB induced vitamin D: grubs, lighter eyes, lighter skin, melanin reduction, megafauna livers
Red wine: j/k


In a prospective human intervention trial, Dabadie et al gave myristic acid, a 14 carbon SATURATED FATTY ACID, to humans and showed an increase and significant enrichment of DHA, omega-3 pufa, in tissues. The authors later performed another study, increasing the myristic and giving ALA and found a J- or U-shaped curve where less DHA changes were seen at higher saturated fat intakes.

I think this is the first and only study that I could find where saturated fat can be under the influences of our desaturases to produce and synthesize a necessary and essential brain long-chain omega-3. Lard is 1% myristic, the head oil of sperm whale 15% and dairy fat 10%.






Citations

1. The impact of FADS genetic variants on ω6 polyunsaturated fatty acid metabolism in African Americans. Mathias RA, Sergeant S, Ruczinski I, Torgerson DG, Hugenschmidt CE, Kubala M, Vaidya D, Suktitipat B, Ziegler JT, Ivester P, Case D, Yanek LR, Freedman BI, Rudock ME, Barnes KC, Langefeld CD, Becker LC, Bowden DW, Becker DM, Chilton FH.
BMC Genet. 2011 May 20;12:50.

2. Genetic variants in the metabolism of omega-6 and omega-3 fatty acids: their role in the determination of nutritional requirements and chronic disease risk.
Simopoulos AP.
Exp Biol Med (Maywood). 2010 Jul;235(7):785-95.

3. A 'desaturase hypothesis' for atherosclerosis: Janus-faced enzymes in omega-6 and omega-3 polyunsaturated fatty acid metabolism.
Martinelli N, Consoli L, Olivieri O.
J Nutrigenet Nutrigenomics. 2009;2(3):129-39.

4. Apolipoprotein E polymorphism and fertility: a study in pre-industrial populations.
Corbo RM, Ulizzi L, Scacchi R, Martínez-Labarga C, De Stefano GF. Free PDF.
Mol Hum Reprod. 2004 Aug;10(8):617-20.

5. n-3 Fatty acid erythrocyte membrane content, APOE varepsilon4, and cognitive variation: an observational follow-up study in late adulthood. Free PDF. [This will be discussed later (someday). N-3 is a surrogate for mercury toxicity via fish/seafood consumption esp in apoE4 who hoard/harbor trace metals.]
Whalley LJ, Deary IJ, Starr JM, Wahle KW, Rance KA, Bourne VJ, Fox HC.
Am J Clin Nutr. 2008 Feb;87(2):449-54.

6. Moderate intake of myristic acid [MEDIUM CHAIN SATURATED FAT] in sn-2 position has beneficial lipidic effects and enhances DHA [OMEGA-3 PUFA] of cholesteryl esters in an interventional study [HUMAN].
Dabadie H, Peuchant E, Bernard M, LeRuyet P, Mendy F.
J Nutr Biochem. 2005 Jun;16(6):375-82.

7. Omega-3 fatty acid docosahexaenoic acid increases SorLA/LR11, a sorting protein with reduced expression in sporadic Alzheimer's disease (AD): relevance to AD prevention. Free PDF.
Ma QL, Teter B, Ubeda OJ, Morihara T, Dhoot D, Nyby MD, Tuck ML, Frautschy SA, Cole GM.
J Neurosci. 2007 Dec 26;27(52):14299-307.

8. Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers. Free PDF.
Mondadori CR, de Quervain DJ, Buchmann A, Mustovic H, Wollmer MA, Schmidt CF, Boesiger P, Hock C, Nitsch RM, Papassotiropoulos A, Henke K.
Cereb Cortex. 2007 Aug;17(8):1934-47.

9. Superior performance [CHESS PLAYING/STRATEGIZING] and neural efficiency: the impact of intelligence and expertise.
Grabner RH, Neubauer AC, Stern E.
Brain Res Bull. 2006 Apr 28;69(4):422-39.

10. Evolution in health and medicine Sackler colloquium: Evolution of the human lifespan and diseases of aging: roles of infection, inflammation, and nutrition. Free PDF.
Finch CE.
Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1718-24.

11. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Free PDF.
Dorus S, Vallender EJ, Evans PD, Anderson JR, Gilbert SL, Mahowald M, Wyckoff GJ, Malcom CM, Lahn BT.
Cell. 2004 Dec 29;119(7):1027-40.

12. Apolipoprotein E: far more than a lipid transport protein. Free PDF.
Mahley RW, Rall SC Jr.
Annu Rev Genomics Hum Genet. 2000;1:507-37.

13. Meat-adaptive [URRG fat adaptive] genes and the evolution of slower aging in humans. Free PDF.
Finch CE, Stanford CB.
Q Rev Biol. 2004 Mar;79(1):3-50. Review.

Human DNA Migration and How to Extract DNA From a Banana

Courtesy: Youtube.com
Nelly Furtado Mash-Up

DNA Mash-Ups

Who do you look like?

Genotypically and phenotypically, which relative (or mailman) do you resemble? Like our DNA, we're mash-up expressions of our ancestral pasts... My Taiwanese relatives tell me I physically resemble my maternal grandmother, yet my youngest sister is an uncanny amalgamation of my paternal grandmother and my dad's older sisters.


Cetus Corp

In Advanced Bio in high school, our prof taught us how to extract DNA using high tech equipment from Cetus (bought out by Chiron, later bought out by Roche) and protocols from Cold Spring Harbor. Funny how technology merges or gets hijacked. My teacher was Mr. D and was the coolest because he gave us the key to the lab (and yes, we goofed around like all seniors).

Science can make indelible impressions, no?




How to Extract DNA 101

Here is a low tech home science project which is incrediblyfun and easy to do. DNA is the language of life -- 4 letters (A T G C) in a pair linked helix translate proteins to organs to life. Extract it from anything (bananas, beans, etc) with a little clear soap (EDTA -- an organic molecule which chelates and sequesters trace and heavy metals). The end step involves swirling the DNA 'snot' onto a glass rod or q-tip.


o Learn Genetics (Univ of Utah) How to Extract DNA From Anything Living
o PBS Nova Extract DNA From a BANANA Recipe (example HERE)
o Scientific American: Find DNA in a BANANA (see picture)

[Great U of Utah resources here: Evolution starts with DNA and Ingredients for evolution: variation, selection and time]












DNA Flow = Gene Flow (e.g. s*xxx)

In 99% of flora and fauna on earth, gene flow is carried forward via the confluence of events known as fertilization by the combination of an egg and sperm. Rare exceptions include slime molds, asexual fungi and 'immaculate conception'.

Researchers can now trace the ancestral carriage of certain genes by examining the frequence of polymorphisms in expressed proteins like ACE, APOE and APOB. APOE (apolipoprotein E) has been particularly interesting to me because of its role in immunity, neurobiology, and lipoprotein/fat/cholesterol metabolism. Modern medicine ignores the role of Apo E and its impact on lab metrics. Many in the paleosphere appear to *LOVE* calculating their LDL using the Iranian formula, however like Friedewald this metric is highly flawed. Not only is the premise for the LDL-heart hypothesis inherently incorrect, humans and other mammalian species do not conform to uniform cookie-cutter lipoprotein patterns.

See prior nephropal: Apo E4, Highest LDL Expression
























Human DNA Migration (mtDNA)
Let's return briefly to Douglas Wallace, one of the originators of the mitochondrial medicine model (Wallace DC. Am J Hum Genet. 57:201-223, 1995. Free PDF). The above diagram traces the path of mtDNA following human migration since leaving Africa over 100,000 years ago. I think it will be quite neat later when they can include mtDNA data from the skeletal remains of neanderthals, H. heidelbergensis and H. erectus, our other ancestors.







Apo E4 = Ancestral Allele

(above diagram, see Luduc et al) Apo E4 not only is associated with higher Triglycerides (TG) and LDL cholesterol, but also aboriginal and ancestral hunter-gatherer societies. It is argued but widely accepted that apo E4 is the ancestral allele associated with the far past tightly evolved from our 200,000 YBP (years before present) to 4 million YBP hominid ancestors. Apo E3 showed up and evolved at least 300,000 year ago (found also in Neanderthals, Luduc et al), however apo E2 has only appeared recently according to scientific estimates. Rarely does any Amerindian culture exhibits apoE2 without obvious agrarian European gene flow.



Climate: Hot and Cold Extremes Selected ApoE4

The recipe for evolution and the excelling domination of a certain characteristic (phenotype/genotype) are: variation, time and selection. An increasing frequency of apoE4 has been witnessed along a south-to-north gradient in Europe (e.g.increasing with cold and fatty acid requirements for thermogenesis BAT). For equatorial cultures, on the other hand, a north-to-south contrasting pattern has been fully elucidated (increasing with heat and salt/mineral requirements with losses in sweat). Eisenberg et al (see below diagrams) hypothesizes that extreme climates which require higher cholesterol requirements and temperature regulation contributed to the higher apoE4 incidence. Agrarian practices appear to have initiated the latest allele appearance, apo E2, which is associated with less carbohydrate toxicity/sensitivities and an apparent buffer to modern SAD chronic conditions (mental, metabolic, autoimmunity).








Apo E4 Global Distribution

Carriers of apoE4 are 'survivors' since the dawn of time. In the medical literature, apo E4 has had a lot of attention because of its association with Alzheimer's, dementia, autoimmune disorders, Western SAD chronic conditions and obesity/metabolic syndrome/T2DM.

Highest allele frequency observed in:
--Africans
--northern Europe (e.g. my hypothesis, Neanderthal clades)
--northern China (Mongolia, ancestral Han)
--southern India (equatorial)
--Amerindians
--Aboriginal/hunter-gatherer subpopulations



Purpose and Role of ApoE4

Apo E has been associated with protection from infectious disease (diarrhea, viral, bacterial) and perhaps survival in select climate extremes (cold/harsh and hot/equatorial). E4 carriers (2/4, 3/4 or 4/4) exhibit heightened absorption of fat-soluble nutrients and cholesterol from the gut. Singh et al describes apoE4 'has also been proved to be a useful marker for evaluation of biological carriers are more responsive to dietary fats and this could be an advantage when food supplies are scarce or irregular. It is associated with better intestinal absorption of lipids including the fat-soluble vitamins A, D, E and K. This may be the reason that APOE E4 appears to be more common in hunters–gatherers than the long-established agricultural communities, e.g. southern Europe, Southeast Asia and Central America (Gerdes et al. 1996a; Corbo and Scacchi 1999) (Singh et al. Annals of Human Biology, 2006).' ApoE4 guards against cholesterol loss and maintains cholesterol homeostasis and cholinergic integrity in the central nervous system (e.g. brain).
In New Zealand, researchers found a correlation between apoE4, heavy metal toxicity and chronic diseases (chronic fatigue, western diseases, heart disease). After chelation of metals, chronic disease status improved. In the ApoE4 protein structure at position 112 (see Luduc diagram above), arginine occupies the site. In E3 and E2 however cysteine has evolved to occupy position 112. Cysteine has advantages in metal dominant environments.

Godfrey et al explain the variance on heavy metal accumulation by the influence of apoE4 v. E3 v. E2, below.

Isomer ε2 has two cysteine
amino-acids in its structure, ε3 has one cysteine and
one arginine, and ε 4 has two arginine amino-acids and
no cysteine [6]. Cysteine, with its sulphydryl (-SH)
bonds, is potentially able to bind to, and remove metals
(e.g., mercury and lead) from tissues, whereas arginine,
lacking the -SH bonds, would be unable to do this.
Apo-E genotyping therefore becomes relevant once it
is acknowledged that prolonged exposure to mercury
has been associated with neurotoxicity, including the
pathological histology unique to Alzheimer’s senile
dementia, namely, fibrillary tangles, amyloid plaques and
increased phosphorylation of tau protein [12,27,28,32].

Conceivably, IMHO, the ancestral allele allowed hominids and mammals to evolve away from rich marine-mineral sources to northern latitudes and above-sea-level altitudes which were physical terrains and landscapes devoid of and lacking brain/body nutrients: minerals (iodine, mag/calcium, zinc), omega-3 and UVB radiation for skin-synthesized vitamin D3. Our DNA mash-ups and heterogeneity explain not only our current health status but can illuminate the path to physiological recovery of neolethal damage and full health optimization.

See prior nephropal: Survival of the PHAT-est





Citations

1. Influence of apolipoprotein E genotype on the reliability of the Friedewald formula in the estimation of low-density lipoprotein cholesterol concentrations.
Tremblay AJ, Bergeron J, Gagné JM, Gagné C, Couture P.
Metabolism. 2005 Aug;54(8):1014-9.

** Iranian (for apoE2, inherently low TGs) v. Friedwald (for wildtype apoE3). See resource. **

2. The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations. Free PDF.
Hallman DM, Boerwinkle E, Saha N, Sandholzer C, Menzel HJ, Csázár A, Utermann G.
Am J Hum Genet. 1991 Aug;49(2):338-49.

3. The effect of apoE genotype and sex on ApoE plasma concentration is determined by dietary fat in healthy subjects. (Email me for PDF)
Moreno JA, Pérez-Jiménez F, Moreno-Luna R, Pérez-Martínez P, Fuentes-Jiménez F, Marín C, Portugal H, Lairon D, López-Miranda J.
Br J Nutr. 2009 Jun;101(12):1745-52.

4. Apolipoprotein E isoform phenotype and LDL subclass response to a reduced-fat diet. Free PDF. [Higher LDL-IVb 'death band' with 'low fat diet']
Dreon DM, Fernstrom HA, Miller B, Krauss RM.
Arterioscler Thromb Vasc Biol. 1995 Jan;15(1):105-11.

5. Carbohydrate intake, serum lipids and apolipoprotein E phenotype show association in children.
Ruottinen S, Rönnemaa T, Niinikoski H, Lagström H, Saarinen M, Pahkala K, Kaitosaari T, Viikari J, Simell O.
Acta Paediatr. 2009 Oct;98(10):1667-73.

6. Apolipoprotein E genotyping as a potential biomarker for mercury neurotoxicity. Free PDF.
Godfrey ME, Wojcik DP, Krone CA.
J Alzheimers Dis. 2003 Jun;5(3):189-95.

7. Function and Comorbidities of Apolipoprotein E in Alzheimer's Disease. Free PDF
Valérie Leduc, Dorothée Domenger, Louis De Beaumont, Daphnée Lalonde, Stéphanie Bélanger-Jasmin, and Judes Poirier
Int J Alzheimers Dis. 2011; 2011: 974361.

8. Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history. (Email me for PDF)
Eisenberg DT, Kuzawa CW, Hayes MG.
Am J Phys Anthropol. 2010 Sep;143(1):100-11.

Thor: BIG, Bulging, Strong... Cardio+Xfit

Thor/Chris Hemsworth
(Picture at Celebitchy.com)

Today I'll be presenting deep thoughts.

Mhhhhmmm.... Mighty God of Thunder and weather... Thor (played by haaawwwt and humble aussie Chris Hemsworth) and his *haa ah!* mitochondria...


SUMMER FLICKS ARE HERE LADIES!

Watch 'em (and try to stop drooling). It was a toss up between Thor and the FF/XXX franchise (2 hotties) which was a t-o-u-g-h-i-e. [Celebitchy Thor and his mighty abdominal muscles rule the box office was a factor.]

Mr.Hemsworth [and his mitochondria] talk about his workout HERE. Bulking out excessively on heavy lifting made him 'blocky' and unable to move lithely, but provided the beef. However, switching it up to 'cardio and crossfit-style' workouts gave him the final movie form (listen at 1:33), fit that fancy Nordic warrior outfit and save Asgard and the world.

Eat My Biscuits. Sausage Biscuits *wink*

My sister 'M' is a masterful mastermind in the hearth of her house, the kitchen. Her sweet goodies and salty savories are the kibble for my soul and sanctuary. (And sometimes growing adipose cells! )

Each ingredient in her recipe is a SUPER FOOD by all comparisons.

Coconut flour is awesome stuff. Apparently it has great minerals, medium chain fatty acids and fiber. Fiber is good especially when it is lectin and phytic acid free (unlike legumes, raw nuts/seeds and wholebodydiseasegrains).

Red VPO (virgin palm oil) is one of the most popular oils in the world -- rich in deep orange carotenoids, antioxidant tocotrienols, coenzyme Q10, stigmasterol/plant sterols (anti-rheumatic Wulzen factor) and both oleic acid and palmitic acid (yes you need both -- read Peter Hyperlipid THE HORROR NEVER ENDS).

Onions, low carb, high protein -- these food factors make for great health and snacking. Onions and green onions are rich in sulfur and quercetin (if you don't have SIBO and can tolerate FODMAPs) which aid glutathione proteins to detox and keep toxins at bay.

Excessive carbs glycosylate and sugar-coat organs -- the tomatoes are fantastic long-acting carbs without impacting BGs.

High protein -- sustains growth, repair and regeneration.

Sausage biscuits are one of the easiest to make vehicles for coconut flour and the other super foods. These keep for a while and are simply convenient to snack on and easily transportable (though somewhat crumbly if smashed). Coconut flour absorbs a lot of water from the air -- the eggs from the protein seal the moisture in but you may have to adjust the liquid in the recipe depending on your house humidity and other factors.

These make great paleo bisonburger 'buns' when split apart in half...




Sausage Biscuit Recipe
(modified, courtesy of my sister 'M' YOU ROCK GRRRL!!)

4 eggs
1/4 c. virgin palm oil (or lard or ghee or coconut oil)
1/4 tsp. Utah salt
1/4 tsp. onion powder or grated onion, opt.
1/8 - 1/4 c. minced scallions (or shallots or white onions)
1/2 c. coconut flour, sifted
1/4 tsp. baking soda (Aluminum free)
1/2 c. organic sundried tomatoes
4 to 8 oz. sausage or ground beef/bison sauteed with sundried tomatoes and some tomato or fave spaghetti sauce until semi-dry but mildly moist (I like Mario Batali's sauces)


Blend together eggs, oil, salt and onion. Combine coconut flour with baking soda and whisk into batter until there are no lumps. Fold in minced sundried tomatoes and sausage. Let the batter rest for 4-5 min to thicken. Drop batter by the spoonful onto greased cookie sheet (or use parchment paper), 2 in. apart. Bake at 400 degrees for 15 min.

Makes 8 biscuits.




Related References:

Stephan Guyenet PhD: Palm oil -- one study 69% reduction in oxLDL. Palm oil contains Coenzyme Q10, tocotrienols (family of vitamin E's).
http://wholehealthsource.blogspot.com/2010/07/tropical-plant-fats-palm-oil.html

Expert Researcher Barry Tan PhD on carotenoids and tocotrienols in palm oil, interview and research articles.
http://www.drpasswater.com/nutrition_library/tan_1.html
http://americanrivernutrition.com/research/research-articles

History of Palm Oil and production
http://www.cambridge.org/us/books/kiple/palmoil.htm

More history: Introduction: nutritional aspects of palm oil.
Cottrell RC.
Am J Clin Nutr. 1991 Apr;53(4 Suppl):989S-1009S. Review. (free PDF)

Vitamin E tocotrienols improve insulin sensitivity through activating peroxisome proliferator-activated receptors.
Fang F, Kang Z, Wong C.
Mol Nutr Food Res. 2010 Mar;54(3):345-52.
PMID: 19866471

Comparative effects of dietary corn oil, safflower oil, fish oil and palm oil on metabolism of ethanol and carnitine in the rat. [PO improves carnitine status]
Sachan DS, Yatim AM, Daily JW.
J Am Coll Nutr. 2002 Jun;21(3):233-8.
PMID: 12074250 (free PDF)

Heated palm oil [FIVE-TEN TIMES] causes rise in blood pressure and cardiac changes in heart muscle in experimental rats. [unheated palm oil was associated with wt loss compared with control rats]
Leong XF, Aishah A, Nor Aini U, Das S, Jaarin K.
Arch Med Res. 2008 Aug;39(6):567-72.

The effect of dietary red palm oil on the functional recovery of the ischaemic/reperfused isolated rat heart: the involvement of the PI3-kinase signaling pathway.
Engelbrecht AM, Odendaal L, Du Toit EF, Kupai K, Csont T, Ferdinandy P, van Rooyen J.
Lipids Health Dis. 2009 May 29;8:18.

Cardioprotection with palm oil tocotrienols: comparision of different isomers.
Das S, Lekli I, Das M, Szabo G, Varadi J, Juhasz B, Bak I, Nesaretam K, Tosaki A, Powell SR, Das DK.
Am J Physiol Heart Circ Physiol. 2008 Feb;294(2):H970-8.
PMID: 18083895 (free pdf)

Dietary red palm oil supplementation reduces myocardial infarct size in an isolated perfused rat heart model.
Bester DJ, Kupai K, Csont T, Szucs G, Csonka C, Esterhuyse AJ, Ferdinandy P, Van Rooyen J.
Lipids Health Dis. 2010 Jun 18;9:64.
PMID: 20565865 (free pdf)

Replacement of dietary fat with palm oil: effect on human serum lipids, lipoproteins and apolipoproteins. [11% increase in human subjects of HDL2b, the cardio- and disease-protective HDL fraction with palm oil]
Sundram K, Hornstra G, von Houwelingen AC, Kester AD.
Br J Nutr. 1992 Nov;68(3):677-92.

Effect of dietary palm oil on lipoprotein lipases: lipoprotein levels and tissue lipids in rat. [higher HDL, lower TG compared with control diet arms]
Pereira TA, Sinniah R, Das NP.
Biochem Med Metab Biol. 1990 Dec;44(3):207-17.

Palm and partially hydrogenated soybean oils adversely alter lipoprotein profiles compared with soybean and canola oils in moderately hyperlipidemic subjects. [Palm Oil Increases in HDL, increases in apoA1 and both are disease/longevity-protective -- Table--in only 35 days, with palm oil, increased HDL, apoA1, and lowered TG, Lp(a) compared with canola, soy and hydrogenated soy; I ignored authors' conclusions]
Vega-López S, Ausman LM, Jalbert SM, Erkkilä AT, Lichtenstein AH.
Am J Clin Nutr. 2006 Jul;84(1):54-62. (free PDF)

Palm oil and health: a case of manipulated perception and misuse of science.
McNamara DJ.
J Am Coll Nutr. 2010 Jun;29(3 Suppl):240S-244S.

Fermented Asian Food and Gut Dysbiosis 101

Flexibility = Adaptability

This gentleman was kind enough to let me take his photo by the West Lake in Huangzhou. His pose lasted longer than the time we had to hang out! I especially loved his timeless smile and ageless grace.









Fermented Foods of China









Quest for Fermented Food

In our first leg of our vacation in China, my husband and I had dinner with fellow blogger and fermentation fan Seth Roberts at his choice, a Yunnan restaurant which specialized in regional dishes. Wasn't difficult to track down dishes with fermented condiments or fermented flavors. Most traditional ethnicities incorporate fermented foods in daily meals from dawn to twilight no matter where you are on planet earth. (everywhere except the land of McDonalds, Velveeta doesn't count!)

From top to bottom:
-- roasted duck with fermented bean paste (I think, I can't recall now!)
--deep fried insects (grub have microbiota which ferment but *ugggh* the veggie oils)
--fish with fermented black bean sauce
--yak milk yogurt, fermented sweeten rice wine dessert w/tapioca balls, tea with milk (tea leaves fermented)
--(not shown) B-E-E-R, fermented grains (it aint that bad, no?)


YUM!




Exploring the Benefits of Fermentation

Our gut microbiome is primarily responsible for fermenting our undigested food. Under pathologic circumstances, fermentation happens where it is not supposed to, e.g. the stomach, small bowel or in our blood stream.

Below Jiménez describes the benefits and distinct role our gut microbiome plays in our health, longevity and maintenance. Some experts even propose that our gut microbiome fucntions as an neuro-endocrine organ. I would strongly concur. It is transplantable like any other organ and is so indisposable that we cannot live without it. When it goes awry in function, like any other organ, a host of chronic illnesses and disorders ensue -- obesity, autoimmune diseases, cancer, mental conditions/crankiness, infertility, heart disease, etc.




Table IV Primary Functions of Intestinal Microflora (per Jiménez) (free PDF)
I. Planktonic microflora --> METABOLIC

(a) To ferment indigestible substrates (fiber, extruded cells and endogenous mucus)

(b) To favor the growth of beneficial intestinal microflora
----(i) Improves lactose digestion----(ii) Modulates intsetinal gas production
----(iii) Increases genesis of short-chain fatty acids --> intraluminal acidication --> increases intestinal transit
----(iv) Increases the absorption of Ca, Fe, and Mg----(v) Synthesizes vitamins: K, folic acid, biotin, B12

II. Mucosa-associated microbiota (MAM)

(a) Protective
----(i) Barrier effect + bacteriocin synthesis --> prevention of invasion by exogenous pathogens
----(ii) Maintenance of intestinal permeability --> prevents bacterial translocation and systemic infection (e.g. PREVENTION OF POOP IN THE BLOOD STREAM)

(b) Trophic
----(i) Controls epithelial cell proliferation and differentiation of intestinal mucosa
----(ii) Maintains new cell growth in intestinal epithelial crypts
----(iii) Of the intestinal immune system: cells and serum (immunoglobulins)




Sources

Rev Esp Enferm Dig. 2009 Aug;101(8):553-64.
Treatment of irritable bowel syndrome with probiotics. An etiopathogenic approach at last?
Bixquert Jiménez M.
Abstract
Irritable bowel syndrome (IBS) is the most common functional digestive disorder, and may affect 11-20% of the adult population in industrialized countries. In accordance with Rome III criteria (2006) IBS involves abdominal pain and bowel habit disturbance, which are not explained by structural or biochemical abnormalities. Several hypotheses attempt to account for the pathophysiology of IBS, but the etiology still remains uncertain or obscure, perhaps multifactorial. Abnormalities in colonic microflora have recently been suggested in such patients, as has abnormal small-intestine bacterial overgrowth (SIBO), or in particular a significant reduction in the amount of intraluminal Bifidobacteria or Lactobacilli, with consequences like the production of colonic gas, and motility or sensitivity disturbances of the intestinal tract. The disorder is difficult to treat, and the wide spectrum of non-drug and drug treatments shows our ignorance about the cause of the condition. Newer drugs, both pro- and anti-serotonin, have failed to show long-term efficacy or have been withdrawn due to concerns about harmful effects. Recent research has provided increasing support for the idea that disturbances of intestinal microbiota occur in patients with IBS, and that such abnormalities may contribute to IBS symptoms. Studies in Scandinavian countries in the last ten years emphasize the role of probiotics in the modulation of intestinal microbiota, and as a consequence in the regulation of the motility and hypersensitivity of the digestive tract. Although results between studies are difficult to compare because of differences in study design, probiotic dose, strain, and duration of therapy, some studies show symptom improvement. Lactobacilli are found among the normal bacterial flora of the gastrointestinal tract, and Lactobacillus plantarum (Lp) is one of the species frequently isolated from the human mucosa, which is capable of surviving the low pH of the stomach and duodenum, resisting the effect of bile acids in the upper small intestine when ingested, and temporarily colonizing the gastrointestinal tract by binding to the intestinal and colonic mucosa. Concurrent with colonization by Lp there is a decrease in bacterial groups with gas-producing ability, such as Veillonella spp. and Clostridia spp. Evidence has now accumulated to suggest the efficacy of certain probiotics like Lp299v, which may be capable of bringing about a significant reduction in pain, abdominal distension and flatulence, while increasing health-related quality of life in IBS.




Int J Mol Sci. 2009 Aug 27;10(9):3755-75. Free PDFThe improvement of hypertension by probiotics: effects on cholesterol, diabetes, renin, and phytoestrogens.
Lye HS, Kuan CY, Ewe JA, Fung WY, Liong MT.
Abstract
Probiotics are live organisms that are primarily used to improve gastrointestinal disorders such as diarrhea, irritable bowel syndrome, constipation, lactose intolerance, and to inhibit the excessive proliferation of pathogenic intestinal bacteria. However, recent studies have suggested that probiotics could have beneficial effects beyond gastrointestinal health, as they were found to improve certain metabolic disorders such as hypertension. Hypertension is caused by various factors and the predominant causes include an increase in cholesterol levels, incidence of diabetes, inconsistent modulation of renin and imbalanced sexual hormones. This review discusses the antihypertensive roles of probiotics via the improvement and/or treatment of lipid profiles, modulation of insulin resistance and sensitivity, the modulation of renin levels and also the conversion of bioactive phytoestrogens as an alternative replacement of sexual hormones such as estrogen and progesterone.

Outs*de of the Main... R-evolutionary docs, Integrative Medicine, Mitochondrial Medicine/Chi

'Western medicine is in crisis. Continually increasing resources are being expended to combat the age-related diseases that include diabetes and metabolic syndrome, Alzheimer's disease, Parkinson's disease, cardiovascular disease, and cancer. Yet the causes of these diseases remain a mystery, while their incidence and morbidity either remain constant or are increasing.'

Douglas C. Wallace, PhD
Center for Molecular and Mitochondrial Medicine and Genetics, Departments of Ecology and Evolutionary Biology, Biological Chemistry, and Pediatrics
University of California, Irvine, California
'Mitochondria as Chi'

Eric Turner and Tinie Tempah
'Written in the Stars'
Courtesy Youtube.com

Evolutionary Medicine

Dr. Tourgeman, Mr. Billy E (from Nephro-paleo) and many others subscribe to an evolutionary (revolutionary) approach for the delivery and science of medicine and reversal of neoLETHAL diseases. The failures of pharmaceutical treatments (ACCORD--diabetes treatment, STATINS S*CK AND DEBILITATE MITOCHONDRIA, etc), out of control incidence of dia-besity and exponential increases in autism, autoimmune disorders and cancer never cease to astound. Modern medicine illustrates too well where we are going wrong with a false foundation of non-functional exercise prescriptions (lack of intensity and weight bearing), high carb grain-based diets and ignorance for ancestrally cemented diurnal/circadian hormesis patterns.



Busy With Blog- and BOOKLUST *ha aaaaahh!*

I've been reading, reading, reading and absorbing... Yeah... it's awful... multitasking my reading b/c I cannot choose and they are all awfully EXCELLENT. Evolutionary medicine, horticulture/PHARMING, hormones and integrative medicine have the been the topics of keen interest the last few months.

• Hofmekler--The Anti-Estrogenic Diet (of warrior diet fame)
• Gedgaudas--Primal Body, Primal Mind (evolutionary integrative practitioner who understands our primordial past and neolithic strategies/testing to reverse neoLETHAL damage to the gut, mind and metabolism; 'paleo' is not enough)
• Young--The pH Miracle
• Hotze--Hormones, Health and Happiness (former ER doc and allergist turned anti-grain integrative physician)
• Turner--The Hormone Diet (fixed her thyroid, hot ND hormone s*xxxxpert)
• Somers--S*xxxy Forever (she's FINALLY addressing gluten and focusing on environmental toxins with consults from Crinnion and Blaylock; online resources: HERE incl integrative paleo Dr. LePine MD)
• Kimball--The Dirty Life: On FARMING, Food and LOVE (NPR interview)
• Peter Ballerstedt--Grass-based Health Blog (my fave post: LARD)
• Rosensweet--Menopause and Natural Hormones
• Stephenson--Awakening Athena (interview)
• Werner--Why You Are Fat (gluten-free, hawwwt, hormone queen, trainer who fixed her low progesterone)
• Taubes--Why We Get Fat (sublime, drool-inducing physicist)
• Lepine--revolutionary integrative Dartmouth-trained physician and educator
• Teta brothers--The ME Diet (Metabolic Edge) -- paleo ND physicians and trainers
• Kurzweil--Transcend (paleo high-tech)
• Fossel et al--The Immortality Edge (paleo, HIIT telomere science)
• Sara Godfried--organic gynecologist blog (giggle-worthy, ginormously gifted Harvard-trained integrative physician)
• Rich Stagliano MD--Blog, former ER doc now blog-astic integrative MD
• [Pending, Energy and Life: The Promise of Evolutionary Medicine and the Vital Role of Mitochondria by Douglas C. Wallace, Robert Cooke]

Integrative Medicine

Lately I've had the pleasure and oportunity to meet many other integrative practitioners. For one, last year I have had more time after going part-time working 2/days per week at a new position at an integrative medicine/BHRT compounding pharmacy. With chances to talk to integrative practitioners and patients who are ahead of the curve happening all day long, knowledge gaps are being filled in. Sometimes tales do morph to reality. Integrative medicine is where the rubber meets the road -- an interface between high and low tech; between science and folklore. We know paleo works but does it meet modern metrics? Yes naturally of course. You knew that. Is an evolutionary diet and lifestyle enough? Why not, if not?




Wallace: Evolutionary Medicine

Below are a couple of abstracts from Wallace a scientist with a bend toward evolutionary medicine and special emphasis on mitochondrial medicine. Many of us including Tourgeman and I are enormous fans of mitochondria (read the seminal Nick Lane's Power, S*x, Suicide), our endocytosed bacteria what we host and cater to. Both plants and animals have mitochondria, yet only the ascent of man may be attributed to mitochondria and the efficient mitochondrial fatty oxidation of our adipose and ketones. The returns for optimal mitochondrial health are huge -- disease free longevity, happiness and efficient energy production to name just a few. The complexity of mitochondria involve physics, energy, systems biology, maternal genetics, epigenomes, membrane potentials, control of pollution (ROS), bioelectricity, ATP and the explosive, exothermic energy extraction of H2O synthesis.





Chi = Energy = Mitochondria

Wallace describes chi (ancient Chinese philosphy of energy and its flow) as mitochondria. For a Western conventionally-trained scientist, I find that to be mind-numbing and immense.


(Energetics, epigenetics, mitochondrial genetics. Wallace DC, Fan W. Mitochondrion. 2010 Jan;10(1):12-31.)



Our Uniqueness, Based on Bad*ss Factors like Mitochondrial Haplotypes and Migration

If we are all from Africa, then what separates us genetically? Why do some fail on 'paleo' or 'panu' or 'OD' or 'plant avoidance' or ketosis' or 'zone' or whatever? First of all, the dynamics of hormones, toxicity, and extent of neoLETHAL damage on endocrine/GI/brains cannot be overemphasized. Outside of these obvious factors, I conjecture the remainder of genetic variations that were selected for thriving and reproduction depended on our ancestors' local microenvironmental niches, climate changes and resultant food supply.



Omni-wh*res and Recent (3 - 16 kya) Evolution

Unlike guinea pigs or lions, humans are OMNI-WH*RES... *ha* We eat anything and everything edible... EVEN HYDROGENATED TWINKIES.

In Asians, once rice fermentation and alcoholic beverages evolved, so did the gene to process alcohol without toxicity (alcohol dehydrogenase, ADH1B). NY Times: Adventures in Very Recent Evolution.





Mitochondrial mtDNA Variants

Mitochondrial, Y Haplotypes and other DNA variants may indeed describe our bioenergetic differences on the most basic level. Mitochondria utilize for energy production and regulation of genes/growth/reproduction many co-factors: B-vitamins, coenzyme Q10, carnitine, lipoic acid, thyroid hormone (selenium, iodine, tyrosine), etc... Some inviduals have higher B vitamin and methylation requirements whereas others are fine with virtually none? Vitamin C requirements I hypothesize might actually vary by equatorial latitude perhaps in the same fashion perhaps as vitamin D and UV B photons. Where did your ancestors and mtDNA originate from?





Other references:

[edit] THANK YOU GENTLEREADER, TYLER (Blog at Evolutionary Health Systems)!!

Annu Rev Biochem. 2007;76:781-821.
Why do we still have a maternally inherited mitochondrial DNA? Insights from evolutionary medicine.

Abstract
The human cell is a symbiosis of two life forms, the nucleus-cytosol and the mitochondrion. The nucleus-cytosol emphasizes structure and its genes are Mendelian, whereas the mitochondrion specializes in energy and its mitochondrial DNA (mtDNA) genes are maternal. Mitochondria oxidize calories via oxidative phosphorylation (OXPHOS) to generate a mitochondrial inner membrane proton gradient (DeltaP). DeltaP then acts as a source of potential energy to produce ATP, generate heat, regulate reactive oxygen species (ROS), and control apoptosis, etc. Interspecific comparisons of mtDNAs have revealed that the mtDNA retains a core set of electron and proton carrier genes for the proton-translocating OXPHOS complexes I, III, IV, and V. Human mtDNA analysis has revealed these genes frequently contain region-specific adaptive polymorphisms. Therefore, the mtDNA with its energy controlling genes may have been retained to permit rapid adaptation to new environments.



Dev Disabil Res Rev. 2010 Jun;16(2):114-9.
Bioenergetics and the epigenome: interface between the environment and genes in common diseases.

Abstract
Extensive efforts have been directed at using genome-wide association studies (GWAS) to identify the genes responsible for common metabolic and degenerative diseases, cancer, and aging, but with limited success. While environmental factors have been evoked to explain this conundrum, the nature of these environmental factors remains unexplained. The availability of and demands for energy constitute one of the most important aspects of the environment. The flow of energy through the cell is primarily mediated by the mitochondrion, which oxidizes reducing equivalents from hydrocarbons via acetyl-CoA, NADH + H(+), and FADH(2) to generate ATP through oxidative phosphorylation (OXPHOS). The mitochondrial genome encompasses hundreds of nuclear DNA (nDNA)-encoded genes plus 37 mitochondrial DNA (mtDNA)-encoded genes. Although the mtDNA has a high mutation rate, only milder, potentially adaptive mutations are introduced into the population through female oocytes. In contrast, nDNA-encoded bioenergetic genes have a low mutation rate. However, their expression is modulated by histone phosphorylation and acetylation using mitochondrially-generated ATP and acetyl-CoA, which permits increased gene expression, growth, and reproduction when calories are abundant. Phosphorylation, acetylaton, and cellular redox state also regulate most signal transduction pathways and activities of multiple transcription factors. Thus, mtDNA mutations provide heritable and stable adaptation to regional differences while mitochondrially-mediated changes in the epigenome permit reversible modulation of gene expression in response to fluctuations in the energy environment. The most common genomic changes that interface with the environment and cause complex disease must, therefore, be mitochondrial and epigenomic in origin.


Annu Rev Pathol. 2010;5:297-348.
Mitochondrial energetics and therapeutics.

Abstract
Mitochondrial dysfunction has been linked to a wide range of degenerative and metabolic diseases, cancer, and aging. All these clinical manifestations arise from the central role of bioenergetics in cell biology. Although genetic therapies are maturing as the rules of bioenergetic genetics are clarified, metabolic therapies have been ineffectual. This failure results from our limited appreciation of the role of bioenergetics as the interface between the environment and the cell. A systems approach, which, ironically, was first successfully applied over 80 years ago with the introduction of the ketogenic diet, is required. Analysis of the many ways that a shift from carbohydrate glycolytic metabolism to fatty acid and ketone oxidative metabolism may modulate metabolism, signal transduction pathways, and the epigenome gives us an appreciation of the ketogenic diet and the potential for bioenergetic therapeutics.