Tuesday, December 18, 2012

Love, Carnivores, Big Brain Evolution, and Mating Systems (NSFW)

Conjure One
'Endless Dream' [click to listen]
Courtesy Youtube.com

"When the body sinks into death, the essence of man is revealed. 
Man is a knot, a web, a mesh into which relationships are tied. 
Only those relationships matter."

~From Antoine de Saint-Exupery

Sex: The Birds and The Bees

Sometimes one has to talk about the euphemistic 'birds and the bee's to young adults in one's hormonally peaked household... but really upon contemplation of evolutionary sexual biology, do we want to talk about the mating systems of the b-i-r-d-s and the b-e-e-s (adjunct to plant s*x), unless one is into hardcore advocation of polyamorous systems of mating?

Dunbar et al has produced a fascinating comparison of 4 mammalian groups and birds, comparing the average residual brain volume (corrected for body size and phylogeny) in pair-bonding members and non-pair-bonding members (polygamous, polygynous, etc). Interestingly among primate species (like us) there is no significant difference between average residual brain volumes and respective mating systems. It appears quite vanilla and equally diversified. However for carnivores, the larger the brain volume residual, the higher the percentage of carnivores in pair-bonding mating systems. For non-pair bonding carnivores, the average brain residual was even slightly negative.

Bird-Brains and Bat-Brains

For bats, this differential is way more pronounced.  Smaller-brained bats breed in groups and rear offspring in commune-like settings (e.g. two dads and two moms per two kids).  I've previously discussed bat s*xxxx (NSFW).  What I find the most fascinating about bats is that these omnivorous mammals are so varied and diverse in the way they look and appear and like humans the more complex the social network, the smarter and the more pair-bonded they are.

Birds (yellow circle) display an even greater relationship between small-residual brain volumes and non-pair bonded mating systems. The biological truth is that most birds mate quite non-selectively every season, and, for many species, several times a season if conditions prevail.

What about bees?  Yes they generously help flowers have flower-sex, to inseminate across space and long distances....spreading and mingling pollen from stamen to stamen. Yet bees mate too but only between the chaste newly hatched queen and a squadron of male drones, bred only to inseminate her. Upon escaping the egg casing, a new virgin queen is reared then goes upon a nuptial flight to be mated with a dozen male drones (or even 100). The sperm is saved and the queen lays fertilized eggs for the next few years for the life of the hive and its entire future population. Diagram PDF (click).


An earlier post discussed a seminal PNAS article which reviewed how ancestral divergence among proteins contributed to the rapid evolution of the primate and hominid brain. Oxytocin is one such protein, a nona-neuropeptide (9 amino acids) which is secreted in nearly every organ system in humans. Tremendous interspecies variation in receptor density and secretion patterns exist. It is quite dangerous to extrapolate animal data to human data. Humans are not voles. Or bees or birds (yellow circle).

Our human hominid oxytocin is different. It goes up with so many of our human deep emotional interactions,  cements the memories we have for positive connections and enables trusted communication in relationships. It helps us to mind-read. To tell the thoughts of our loved ones and others. It helps us to read visual and non-visual environmental cues. It produces perhaps both the hunter's trance and lover's glance....

Carnivores and Iron Deficiency Anemia (Driving Evolutionary Force)

Been reading a lot of Shlain lately, his brilliant and magnificent STP ('Sex Time Power').  He proposes that humans had vast evolutionary changes in our relationships when there was perhaps a bottleneck of female hominids some 150,000 years ago.  Something changed 150,000 years ago and perhaps it was the way that females and males related and hooked up with one another...

Going back to the birds and bees, many things may have changed the last 150,000 years. His theory was that if suddenly there were scarce and only a few female hominids but a relative overpopulation of male hominids (Hss, Hs. neanderthalenesis, H. heidelbergenesis, H. ergaster, H. erectus, etc), something drove a dramatic change in archaic human interconnectedness and relationships. He postulated that maternal mortality was high. Many females may have been suffering and dying from a coalescence of evolutionary events --  bipedalism, narrow hips, early ontogeny and neonatal prematurity, troubled tortuous births and a doubling of neonatal brains (during the first year of life). The demand for iron during maternal gestation, birth and lactation for the maternal hominid was never higher. And still is (except for those genetically adapted with hemachromatosis).

And how could she hunt with babies clinging or fecund bellies? Or leaving predator-triggering, blood-tainted tracks during the period of menstrual blood??

Shlain hypothesizes a lot and I think he is actually right on about the majority.....  from the evolutionary point of view, iron is not only a critical brain nutrient for neurons but it is also crucial for all mitochondrial (e.g. cytochrome structures) and oxygen-related metabolic and circulatory processes. Have you ever drowned? Been anemic? Suffocated? Had CO (carbon monoxide) poisoning?  Seen a subpar-IQ kid with an iron-deficient mom?  Because iron deficiency anemia still plagues humans to this day, I think his point has huge merit and requires consideration.


Need it for life or will die... slowly or dumbly or both.

Origins of Human Pair-Bonding?

I can see from Shlain's point of view (a surgeon's) the importance of iron for blood, metabolism, brain growth and maturation, and IQ. Perhaps with other factors, human relationships required the binding transcendant force of a tight pair-bond that only carnivorous pairing could achieve?  When food resources were scarce and fecund females too fatigued to procure, defend, hunt or fight?

In China, a small sexual revolution is occurring.  Because of the last few decades of China's 'one-child birth policy', many families are faced with a crisis and burgeoning population of male offspring and insufficient brides.  Brides are not only scarce, some marry outside of the Chinese race.  As a result many Chinese local females are in a position to bargain for the best candidates.  The resources brought to the table by the male and their familes are I think higher than normal -- house, job, wealth, health, right province, etc.  Looks, romance, hearts-n-flowers?  I don't actually know but if you watch Chinese dating shows (I don't) apparently the check off list also includes talents like killer singing, wooing, and more vocal display.

Is this any different than Paleo or Pleistocene times?

Perhaps no.

The scavenger/hunter/gatherer/fisherperson of the past 10,000 - 2 million years learned to bring home the bacon (iron)... and provide shelter, warmth, extended family help, and other resources to trade.

Meat/Seafood = Outsourced Nutrition

Nutritional science is fascinating to me.  So many nutrients must be consumed by carnivores and omnivores because they are not produced or synthesized endogenously in any significant amount -- Vitamin B12, Taurine, Vitamin K2 (menaquinones), Retinol/Vitamin A, Vitamin C, etc.   Some require our gut microbiome participation to conjugate or produce these nutrients, but again, outsourcing of these nutrients to the hominid diet was far more nutritionally economical over the millenia as our guts shrunk from transforming from primate frugivores to carnivores and later omnivores.  During gestation, a brain is built from scratch.  In the first year of life, the brain DOUBLES in size. The vehicle which carries our DNA forward, the baby, needs nutrients.

Other nutrients and micronutrients that are 100% or profoundly outsourced:
--methylated B-vitamins, 5-MTHF, formyltetrahydrofolates, choline (all from yolks, meat/seafood, organ meats)
--long-chain omega-3 fatty acids (IQ-increasing)
--other minerals: zinc selenium iodine

Meat and seafood contains all of the above, particularly iron which is the most bioavailable and easily assimiliated form of iron in existence. Regarding folates, be careful of supplementation with folic acid, one of the synthesized vitamins that is not find in food in great abundance (less than 10%). Animal- and plant-sourced food has a broad spectrum of folates and reduced derivatives: folinic acid, 5-MTHF (5-methyltetrahydrofolate; Dr.Tim Gerstmar's post), and formyltetrahydrofolates (meat meat meat).

Synthetic folic acid supplementation and industrial food fortification are associated with higher incidences of many cancers.  More shades of uber f-cked upness....

All the above nutrients affect a newborn's brain growth and subsequent intelligence.

All the above nutrients are not found in great quantities in vegetable sources, if at all.

The Carnivore-Fisherman Genetic Codes: SNPs

As an ancient SNP, Apo E4 confers longevity to those who follow the native diet of their ancestors.  Perhaps humans were hunter-gatherer-fishermen for so long, that outsourced all fat-soluble nutrients and cholesterol to the diet rather than producing on our own.  This makes sense as these are all downregulated in both absorption from the intestines and for endogenous production.  The global gradient for the E4 allele is increasing northward in Euroasia. The distribution for agrarian-adapted allele, apo E2, is the opposite and radiates in higher frequencies toward the fertile crescent where the birth of grain-dependence occurred. Several other adaptations are I believe protective reactions to phytates and grains/lectins (which chelate and reduce iron bioavailability or cause intestinal permeability, respectively) and less animal-sourced foods to secure nutrients for the fetal and postnatal brain growth and maturation -- altered metabolism of folates (MTHFR) and hemachromatosis (HFE),  higher fluffier LDL and HDL and less chronic diseases in long-lived Ashkenazi-Jewish (I405V CETP) and increased and larger fluffier LDL and HDL in intelligent Ashkenazi-Jewish with exceptional longevity (I405V CETP).

Tripling of Brain Size: Australopithecus to Now (0.45 L to present 1.4 L cranial volume)

For most of our existence, I think we have been predators. However, we are unique, different from lions, tigers, hyenas and bears. We are the only line of successful carnivores that descended from primates.   The introduction of meat to the diet may have occured about ~2 million years ago. The cooking of meat and other foods may have occurred gradually since that time.  Each become more consistent and regular over time.  Shlain asserted that humans experienced an increase in the neocortex and tripling of the hominid brain over that period of time. He believed it was related to a combination of forces -- choosy and picky, bipedal, big brained females and a dire iron deficiency syndrome.  Language flourished. Like gorgeous song birds attracting mates, dancing bees or croaking bullfrogs, suddenly men and women were able to communicate their attraction outside of  pheromonal scents. Tasting kisses and tender touch blossomed. Love songs and lyrics exploded. Symphonies swayed heart and minds.  Operatic drama captured dreams and imagination.

Sexual dimorphism retreated to the neocortex (brain, the big phat brain). All overt signs of estrus disappeared.  Humans are the ONLY animal species on the planet that does not enter into estrus -- we are sexually receptive ALL THE TIME. (sorta, except during PMS 'pack my suitcase' for the guys) Males can beready to go at any hour, any minute, any second given appropriate cues (visual, verbal, scent, sex-text, etc). Testicular size moderated. Scents, hair, and apocrine glands downgraded. Harems extinguished. Hominid males lost the flaming red cues that signaled female hominid ovulation (without an app). Hooking up became subtle (or tribal orgies, e.g. clubbing). Human males and females were and are both pair bonded and polygamous (83%, Murdock, 1967).

Language became the main sexual dimorphism.  Shlain points to the evidence that iron started it.  Then as brain size and its subsequent accoutrements (language, art, culture) thrived, so did our thinking and metaphysical cognition.

I think on our march of evolution as beings, we have zigged and zagged -- starting as frugivores then emerging as carnivores and then reverting slightly back to herbivores (some ethnicities more than others). Our brains perhaps have followed the same analogous path. We started as primate groups, then had small tribal coalitions similar to social carnivores, then we have perhaps reverted back to large complex primate social networks. We no longer groom each other for hours and hours on end chewing the cud picking off fleas and varmin, but we gab and gossip.  We share stories and tell tales. We admonish our children and train them with truths.  We holler and heed our mentors' words. We solve problems and support in tears and laughter over coffee or sweating out.

The brain and our language serve dimorphic purposes as well maintenance of tight social/family connections and possibly hierarchy.


Shlain posits that at a vital point in history, humans determined the relationship between death and its finality. Our thoughts transcended the present dimension and envisioned the future. Funeral ceremonies, burial rituals and grave artifacts may have developed around 50,000 years ago at the same time in human history when art, culture and language erupted ('Great Leap').  Securing consistent brain nutrient and micronutrients I believe heralded these adjustments.  Society brought on more regular trade. Trade of goods enabled complex social networks and enhanced stability.


Only carnivores and certain omnivores engage in play... Why? Why do little boys play guns and war? Why take 10 years of piano or violin lessons?  Why compete in speech and debate, chess or tennis matches? Why enjoy the sparring with kickboxing gals in class or watching MMA fights?


'It takes 10 years to grow a tree, but 100 years to grow a human being' (ancient Chinese proverb; thanks W).

(Is it all foreplay? . . . m a y b e)

Transcendance: Brain-F-cking (Merging)

Rapid changes have occurred in our communication in just the last short years. Technology has provided tools that never existed. How is our neocortex is adapting? Do you interact differently? Are we more deeply connected? How potent is virtual oxytocin? Is merging of our cognitive beings transforming our brains?  [Personally I've been in deep DEEP awe of my iPhone 4G since I graduated from the archaic one (no camera, no nothing) in January.  Recently I dropped the beloved (phone) which required the LCD to be repaired. Realized in the few days it was broken how we are affected, dependent, and emotionally reliant on technology and being so-called plugged in.]

Shlain believed that a new human species is evolving. Similar insights have been put forth by other luminary thinkers like Gerald Hüther PhD and Bruce Lipton PhD.  Love, harmony, compassion, oxytocin, empathy, and our complex interconnectedness are leading adaptations and understanding that may be creating evolved beings that transcend the physical, hierarchical, material and other barriers.  'Increasing numbers of us live up to the potential that was encoded into each of our chromosomes at the moment of our conception. There can be little doubt that all these drastic alterations in our environment are collectively functioning as transformative agents fueling the human species' metamorphosis....' (Shlain STP, 2003)

[NSFW] As you are reading my thoughts and we connect, am I finger f-cking your brain?

Thursday, November 8, 2012

Mitochondria: Fuel, Fluxxx and Heat (NSFW)

Buddha Bar (Sex Lounge)
Credit: Youtube.com

Fuel and Fluxxx...

Why do we store fat? Why do we eat?  A scientist who wrote about reproduction, fuel, photoperiods and fecundity wrote the below abstract...[1]

"While there is a relatively direct connection between
circulating levels of metabolic fuels and the GnRH [gonadotropin releasing hormone] pulse generator [in SCN behind the retina], this might not be the only energy-related pathway influencing the secretion of this neuropeptide. The overall control of energy balance is an immensely complex process and a number of pathways involved in it might secondarily influence the activity of GnRH neurons. Peripheral signals influencing energy balance and thus possibly GnRH secretion could come from the liver, pancreas, stomach, duodenum or adipose tissue, and these signals could be sent to the brain via the vagus nerves or by hormones such as leptin, insulin, insulin-like growth factor 1 or ghrelin. These hormones could act directly on the neural circuits controlling the GnRH neurons or they could act by modulating the availability of metabolic fuel. Likewise, the neuropeptides regulating GnRH secretion in the forebrain could also include galanin, orexin, the urocortins and endogenous opioids. Recent interest has focused on kisspeptin, the product of the KISS1 gene. The presence of kisspeptin is necessary for normal reproductive development and it can override the reproductively detrimental effect of mild food restriction."

Obviously how we expend fuel is highly complex and humans are ruled by a big, big, big, hungry, hot brains... Grow or growl? Feast or fast? F-ck or forage? Repair or repast?

HEAT: Cellular Bioenergetics Creates Wildly Explosive, Exothermic Reaction Generating Water


...we are not neat bomb-calorimeters, but open, conserved, networked metabolic and energy systems...

Photos credit: [2].

The Evolution of Body Heat?

When oxidized, the great majority of our food and stored energy goes to the production of HEAT.      What governs this? It is multifactorial but adrenaline, thyroid, cortisol and mitochondria quality are just a few [2]. Active tissues contain more mitochondria. Heat makes us mammals and birds. We have hot bodies, precisely 37C for the great majority.

In the 'Hot Brain:  Survival, Temperature, and the Human Body' the authors theorized that temperature gave us advantages over eukaryotic infections (yeast, fungal origins -- we are eukaryotic) which plagued bird/reptile species which were not armed with high 37C temperatures or fever-inducing capabilities [3].  It is a very interesting theory. Control of thermoregulation (heat loss v. heat gain) is believed to have evolved in the brain of therapsids. Our sinuses are larger. Mammalian brains have a Circle of Willis where 4 arteries (internal carotids and vertebral arteries) provide a complete internal brain circulation with collaterals, such that despite blockage of one or more of the 4 major arteries circulation in the brain and to the body remains intact.  Unfortunately only 25-33% of us have a 'perfect' classic circle of Willis; others have degrees of narrowing or asymetry in certain areas or another. Photos courtesy: Hot Brain, pp. 44, 142.

Recently a microbiologist, Casadevall, from Albert Einstein had the same theory that the rise of mammals can be attributed to 'endothermy and homeothermy [which] are thought to contribute to mammalian resistance to mycosis by creating a thermal exclusionary zone that inhibits most fungal species. The remarkable resistance of mammals to mycotic diseases is probably a combination of a vertebrate immune system, with both innate and adaptive arms, and elevated body temperatures... The currently favored hypothesis for the demise of dinosaurs and end of the age of reptiles is a bolide impact approximately 65 million year ago with the possibility that other events, such as increased volcanism, contributed to disrupting the cretaceous ecosystem. That ecological calamity was accompanied by massive deforestation, an event followed by a fungal bloom, as the earth became a massive compost. Although one cannot know which spores were present at the time, the likelihood that pathogenic fungi existed at the K-T boundary is enhanced by the finding that the potential for pathogenicity probably arose independently several times in evolution...'[3]

'Although we do not know the timeline for the recovery of the planet climate, it is estimated that photosynthesis was shut down for 6 months and climate cooling persisted for at least 9 years, and the occurrence of a fungal bloom sufficient to have left fossil evidence implies that surviving animals were exposed to massive numbers of fungal spores. The darkened skies and cooler temperatures that accompanied the K-T cataclysm would have shielded the sun and reduced the ability of ectothermic creatures such as reptiles to induce fevers by insolation, a necessary activity for protection against fungal diseases. Hence, it is reasonable to posit that ectothermic creatures unable to induce behavioral fevers and in weakened states from environmental stress would have been at a severe disadvantage relative to small mammals with their innate thermal exclusionary zones for fungal growth. Further complicating the situation for reptiles is that eggs can be vulnerable to fungal attack, whereas mammalian progeny would be protected in placentae.'[3]

I think it has merit. We generate a lot of HEAT and it comprises a cr*pload of our total energy losses (as many in NY know without electricity due to Storm Sandy and no heat to fight night time drops to freezing temperatures). As Casadevall reported  'the mammalian lifestyle is energetically costly.'

Mitochondria: Water (H2O) = 286 kJ of P-O-W-E-R

Many obesity researchers appear to forget these multiple evolutionary and hormetic factors in their Big Pharma funded, tenure-track equations. One did not (though partly Joslin funded which is Big Pharma).

In a Nature article, Tseng et al discuss mechanisms to find a drug target to increase cellular bioenergetics and energy expenditure as an anti-obesity strategy [2]. (But... Drug targets are always silly, no?) They discuss PPAR-delta, AMPK and several other pathways with potential promise.  A succinct explanation of how mitochondria produce energy on demand by harnessing the energy from the formation of water in the cellular bioenergetics of mitochondrial metabolism of fuel is provided. They define bioenergetics as the 'Studies the flow of chemical bond energy within organisms. In a living cell, the principal reactions of fuel metabolism take place in the mitochondria, where food energy is released,oxygen is consumed, and water and carbon dioxide are produced.'

All life on earth utilizes the energy formed from water formation to power pathways and metabolism. Remember the Calvin Cycle/Photosynthesis where carbs (glucose) are formed from air (CO2), and energy of the sun? In the mitochondria, the opposite reaction occurs. Energy from the exothermic reaction of water forming from air (O2) and the enzymatic burning of fuel (oxidizable food, glucogen, glucose, fat) result in HEAT and ATP. When one mole of H2O is created from one H2 (hydrogen) and half O2 (oxygen), 286 kJ of power are released (in other words, 68 kcal, which is about one small potato).... FROM FORMATION OF ONLY ONE MOLE OF WATER.

CO2 1/2 O2  =   one mole H2O (~18 grams water = 3.5 teaspoons)  =  286 kJ

Fuel Efficiency of Our Mitochondrial Cellular Respiration

With cellular respiration, instead of an enormous, exothermic explosion (like a hydrogen bomb), the electrons and protons are added step-wise on a gradient known as the electron transport chain (ECT) in plants and animals.  A biological mitochondrial 'battery' is created with the 'anode' on the inner mitochondrial membrane side and the 'cathode' on the other.  Heat is energy released when oxygen is the final proton acceptor and coupled to the enzyme (F1F0-ATPase) that forms ATP, the universal currency of cellular energy in the body. When the protons fall across the proton channel, ATP is formed.  We use ATP as fuel every minute every day for all cellular work, then recycled back to ADP.  In one day, it is estimated that our mitochondria may produce our own weight in ATP [5].

Efficiency of the theoretical transfer of energy from oxidizable fuel to ATP and heat is pretty darn good: 39% ATP and 61% heat [5]. Mitochondria are energy rockstars. Obviously many biolgical factors determine true efficiency: iron status (cytochromes are composed of heme), ubiquinol, oxidative and inflammatory state, thyroid, HPA axis function, hormones, etc.

Plants (chloroplasts) get 3-6% efficiency from transfer of solar energy to the energy bonds of plant starches and fatty acids. Particular C4 plants can get 7-8% (sugarcane) and one super cyanobacteria strain Chlorobaculum tepidum achieves 10%. Various modern fuel efficiencies are approximately -- for coal (~20-30s%) and solar (20%). Photo credit: [5].


1. Climate change and seasonal reproduction in mammals. Bronson FH.Philos Trans R Soc Lond B Biol Sci. 2009 Nov 27;364(1534):3331-40.

2. Cellular bioenergetics as a target for obesity therapy.Tseng YH, Cypess AM, Kahn CR. Nat Rev Drug Discov. 2010 Jun;9(6):465-82. [Free PDF here]

3. The Hot Brain: Survival, Temperature, and the Human BodyCarl V Gisolfi, Francisco Mora Teruel. MIT Press (Bradford Book), 2000. [Free SCRIBD text here]

4. Fungi and the rise of mammals.Casadevall A. PLoS Pathog. 2012 Aug;8(8):e1002808.  [PDF]

5. http://highered.mcgraw-hill.com/sites/dl/free/0073525502/930160/mad25502_ch08.pdf

Monday, November 5, 2012

Phat Fat Mitochondrial Energetics: Mobilization v. Accumulation

Adipose is Alive

In ancestral times, adipose stores may have determined longevity and survival past harsh cold winters. My ancestors moved from northern China 8-10+ generations ago to the mountainous areas of Taiwan (according to my dad several hundred years ago). I suppose those who didn't live past the impoverished seasons where food resources were scarce would not have made it, nor would their genes. I can thank them for my persistent fat stores *haa*. Adipose tissue is an endocrine gland which is know to secrete hormones such as leptin and adiponectin to control hunger, body energy balance and energy expenditure. These hormones are involved directly with mitochondrial biogenesis as well, in other words the production and destruction of the mini powerhouses found in all cells (except perhaps glycolytic-dependent cancer cells, which I think are all of them).

Whole body energy balance are determined by many factors, including most importantly:
1) demand
2) diet
3) d*ng hormones (or lack of)

All Organs Sync For Survival

Our brain coordinates many of the hormones that either mobilize or store adipose, e.g. fat. The brain includes the hypothalamus, pituitary, pineal, forebrain, hindbrain, midbrain and our senses for perception (ears, eyes, nose, taste, temperature, barometric pressure, etc). For example, insulin is triggered cephalically (via the brain): by tasting sweetness whether artificial or real, by smelling food, seeing food or even imagining food. Hearing? Hearing the neighborhood ice cream truck as a kid?

Humans Killed for Fat

Fat may have been the biggest boon for man during evolution (see prior animal pharm: humans as marine-based carnivores). Fat contained omega-3s concentrated up the food chain from green chlorophyll sources (grass, algae, etc) and into the muscle fat, organ meats, brains and fat stores of animals and seafood. The encephalization of ancient man is believed to be highly associated with the intake of dietary omega-3s. Perhaps the current de-encephalization over the last 100 yrs is related to the relative deficiency of dietary omega-3s? Or growing overabundance of omega-6s? THANK YOU VERY MUCH corn-fed cows and Keys.

Fat Yields the Most Energy in Human/Mammalian Energy Systems

Hormones for MOBILIZING fat stores far out number the hormones that ACCUMULATE fat. See diagram, modified from Gary Taubes GCBC from a 1965 table of hormonal regulation. Forgive me I use the term 'hormone' loosely because food is hormonal. Fatty acids bind PPAR receptors. We have ~ 3-4 routes to produce energy (some cells utilize glutamine, but I don't know which... neurons only?). Burning fatty acids yields the highest net energy unit (ATP). Why I've wondered? So many hormones promote the escape of fatty acids from temporary storage -- intramuscular, liver, visceral fat, brown fat and subcutaneous fat. Why do we readily release fatty acid energy? Sex, power, survival/suicide? Heat for 37C?

Taubes quoted Hans Krebs who received the Nobel in Medicine in 1953 'All three major constituents of food supply carbon atoms.. for combustion." GNG= gluconeogenesis (glucose/glycogen from any source -- protein, fat, carbs); ATP lesson (click HERE and UCD Lecture and med biochem):

Low Yield but Mandatory Without Oxygen
--anaerobic glycolytic (glucose/GNG) [Yield: 2 ATP]

High Yield in the Presence of Oxygen
--aerobic glycolytic (glucose/GNG) [Yield: 38 ATP] 
--aerobic beta-oxidation of fatty acids like palmitate [Yield: 129 ATP]
--aerobic beta-oxidation of fatty acids like stearate [Yield: 146 ATP]
--aerobic beta-oxidation of fatty acids like ketones [Yield: 51 ATP]
--aerobic oxidation of alcohol [Yield: 16 ATP]

Carbon lengths:
Glucose: 6-carbon carb
Palmitate: 16-carbon saturated fatty acid
Stearate: 18-carbon saturated fatty acid
Ketones (b-oh-butyrate, Ac-Acetate): 4 carbon fatty acid
Alcohol: 2-carbon 'the fourth food group' *haa* tequila is paleo, no?

Prior animal pharm: Palmitate Utilized Between Meals

Mitochondrial Medicine

Where does all this high energy production occur? Of course. Your mitochondria (the lower-net-energy anaerobic pathway is independent of mitochondria, occurs in the cytoplasma).

So. Don't scr*w up your mitochondria. That's like jacking your ride. Blowing out your carburetor.

...FLUNKING your human SMOG TEST.

Mitochondrial medicine is a new field but old premises still apply. The paleo evolutionary paradigm for which your mitochondria and DNA were perfected and honed over 2.5M years of natural and sexual selection are what we believe optimize health and maximize vitality.

Saturday, November 3, 2012

Phytanic Acid (Red Meat, Dairy, Seafood): Binds PPAR-α and RXR

'...Like all things come from the sun'
referencing all the food at the table,
daughter Natalie
ATB Sunset Girl
Courtesy: Youtube.com

Food, Sunlight and Nuclear Receptors

I've discussed RXR/RAR (carotenoids/ vitamin A receptor), VDR (vitamin D receptor) and PPAR-α (saturated fat/omega-3 receptor). These are a constellation of receptors found in the nucleus of all cells which control growth, maturation, reproduction, proliferation, apoptosis (cell suicide), autophagy (cell re-cycling) and inflammation.  Bioactive components of our food and hormone vitamin D from sunlight exposure (or organ meat consumption) bind and control nuclear receptors.

See prior posts:
PPAR -- Dagger in the Heart of CAD and all Chronic Conditions
Benefits of Grassfed Butter

Phytanic Acid Generates Carnitine

A recent study looked at the level of phytanic acid (PA), a
fatty acid found in red meat, dairy fat, and seafood which has activity on receptors known to control and regulate cancer, inflammation, triglycerides/cholesterol and even energy status in skeletal muscles. It may have several mechanisms for health regulation. One mechanism found is that phytanic acid is an agonist for several nuclear receptors including RXR and PPAR-α. I would not be surprised if it has affinity and binds other receptors as well.

We don't synthesize phytanic acid on our own; we can only source from food (animal based). Phytanic acid and its metabolite pristanic acid contribute to the activation of carnitine in peroxisomes which are later transported to mitochondria for fatty acid oxidation (burning and synthesis of energy, ATP). A lack of carnitine has been shown to lower mitochondrial processes and is significant factor in disease. Like phytanic acid, carnitine can mainly be sourced only from MEAT and seafood, not vegetables. We produce it but not very well. Many factors affect carnitine levels (kidney function, ACTH/cortisol, thyroid and diet. French authors write 'L-carnitine ensures regeneration of coenzyme A and is thus involved in energy metabolism. L-carnitine also ensures elimination of xenobiotic substances. Carnitine deficiencies are common.'  Photo credit: [1].

Do butter and bison do a body good?


Chlorophyll Is Biotransformed into Phytanic Acid by Fish and Mammals

Apparently the chlorophyll content of the meat, seafood or dairy is what determines the amount of this important fatty acid, phytanic acid. 'PA (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid generated by the oxidation of the phytol side chain of chlorophyll in mammals. Because humans cannot release phytol from chlorophyll, PA in the human body comes from dairy products and ruminant fats in the diet' [2]. Shore-based food such as fish, salmon, molluscs, snails and krill have significant levels too since these consume smaller fish which consume chlorophyll from algae and green phytoplankton. Phytanic acid is also found in menhaden oils. There is a vague association with prostate cancer and levels of phytanic acid however the below authors discuss "the available data do not support a general causal link between circulating phytanic acid and prostate cancer risk." Phytanic acid is metabolized in peroxisomes -- little fatty storage droplets where enzymes breakdown and metabolize fatty acids. Many of the metabolic breakdown products then go to the mitochondria to provide energy, intermediaries for the respiratory and energy producing complexes, and/or to absorb and quench ROS (reactive oxygen species, aka POLLUTION generated from energy production). If mitochondria are working awry, I suspect phytanic acid accumulation occurs because it is not being appropriately metabolized which could be genomic or post-genomic (Refsum syndrome).

Evolutionary Medicine: Mitochondrial Dysfunction

Many of our chronic diseases are a result of mitochondrial dysfunction -- our tiny nuclear power plants are on the 'blink'...often preferring glycolytic combustion over superior fatty-acid burning.  Mitochondria provide awesome power but can wreak untold destruction as well.

--compromised controls, directions and regulation for proper nuclear plant functioning (AMPK, cAMP)
--lacking power grid efficiency (leptin, insulin, cortisol, SIRT1, adiponectin, secretin, fertuin-A)
--malfunctioning or missing power plant cogs and parts (minerals, carnitine, AcCoA/pantothenic acid, omega-3)
--deficiency of buffering, recycling and containment of nuclear waste (coenzyme Q10/ ubiquinol)
--lacking managers and communicators (cell membrane stability and communication: omega-3 vitamins A B D E K2 thyroid cortisol estrogen progesterone DHEA pregnenolone testosterone saturated fat etc)
--excessive disruptions (high carb diets, endocrine disruptors, PCBs, heavy metals)

From Bacteria 4.5+ bya To Mitochondria

Other strategies to keep mitochondria free of breakdowns -- lifestyles and diet aligned with our evolutionary past from 4.5+ Billion Years Ago:

--lowish carbish (~150 grams or less net effective carbs I like...varying on goals, gut, adrenals, etc)
--saturated fat (~20% or more -- dietary or butt-sourced)
--low fructose
--low omega-6
--high omega-3
--high phytanic acid *wink*
--organic shore-based and grassfed/pasture-based fat and protein
--organic mineral rich plants, berries, nuts, meat/fish/fowl
--intermittent feast v. fast (seasonality)
--optimal hormesis status
--low pollution (air, water, mind)
--enjoyment of culture, music, arts, spiritual enlightenment
--engaging in community and social networks
--movement: rapid intense and languid continuous (yeah S*X counts)

Prior animal pharm:
You are only as strong as your weakest mitochondria...

Health and Food Connection

When I consume ghee (clarified butter), egg yolks, veggies, adequate starches and adequate grassfed beef, pork and lamb, I notice more and easy weight maintenance and improved muscle composition. Mental and physical performance are pretty excellent too. How do you break down food and its effects on mitochondria? Researchers are trying and it's a good thing....
Phytanic acid--an overlooked bioactive fatty acid in dairy fat?

Hellgren LI.
Ann N Y Acad Sci. 2010 Mar;1190(1):42-9.

Phytanic acid is a multibranched fatty acid with reported retinoid X receptor (RXR) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist activity, which have been suggested to have preventive effects on metabolic dysfunctions. Serum level in man is strongly correlated to the intake of red meat and dairy products and the concentration in these products is strongly correlated to the chlorophyll content in the feed of the cattle. Available data suggest that phytanic acid is a natural agonist for RXR at physiological concentrations, while it is more likely that it is the metabolite pristanic acid, rather than phytanic acid itself, that acts as PPAR-alpha agonist. Animal studies show increased expression of genes involved in fatty acid oxidation, after intake of phytol, the metabolic precursor of phytanic acid, but it is at present not possible to deduce whether phytanic acid is useful in the prevention of ectopic lipid deposition. Phytanic acid is an efficient inducer of the expression of uncoupler protein 1 (UCP1). UCP1 is expressed in human skeletal muscles, were it might be important for the total energy balance. Therefore, phytanic acid may be able to stimulate energy dissipation in skeletal muscles. Phytanic acid levels in serum are associated with an increased risk of developing prostate cancer, but the available data do not support a general causal link between circulating phytanic acid and prostate cancer risk. However, certain individuals, with specific single-nucleotide polymorphisms in the gene for the enzyme alpha-methylacyl-CoA racemase, might be susceptible to raised phytanic acid levels. PMID: 20388135

Phytanic Acid (Cheese, Butter) Human RCT

How does phytanic acid perform as a drug? In a tiny Denmark RCT, this was tested.  The control group however also received phytanic acid therefore the results were substantially diluted out IMHO. Methods: In a double-blind, randomized, 4 wk, parallel intervention study 14 healthy young subjects were given 45 g milk fat/d from test butter and cheese with 0.24 wt% phytanic acid or a control diet with 0.13 wt% phytanic acid. The outcomes were positive and associate with metrics that indicate improved mitochondrial functioning (better insulin sensitivity, more fat oxidation, decreased glycolysis).   The lipoprotein changes were impressive but unfortunately the study was too small for meaningful stats. HDL-cholesterol increased by 10% in only one month.  No drug achieves this... or without killing patients or raising BG and diabetes (particularly Crestor).  Is it all phytanic acid?  I dunno...  The researchers enriched the test dairy products by feeding the cows more green material. Subsequently the omega-3 to omega-6 profile in test butter and cheese also improved. They discussed, 'The test butter with the highest content of phytanic acid, also had the highest content of α-linolenic acid [omega-3] and a lower n-6:n-3 ratio of about 1.8. This is in agreement with the higher proportion of clover and grass in the green feeding regime.'   Notwithstanding the beneficial numbers, butter and cheese have other proven bioactive food components which improve heart health, inflammation, insulin resistance and cancer risks, principally, cholesterol, vitamin A/retinol, saturated fatty acids including butyrate, omega-3, taurine (if raw), stigmasterol (if raw; Wulzen factor), folate (5-MTHF) and vitamin K2 (menaquinones).

(a) HDL increase 10% 
(b) Insulin reduction 15%
(c) TG reduction 22% 


1.Verhoeven NM et al. Phytanic acid and pristanic acid are oxidized by sequential peroxisomal and mitochondrial reactions in cultured fibroblasts. The Journal of Lipid Research, Vol. 39, 66-74, January 1998. [Free PDF here]

2. Cell proliferation inhibition and alterations in retinol esterification induced by phytanic acid and docosahexaenoic acid.
Tang XH, Suh MJ, Li R, Gudas LJ.
J Lipid Res. 2007 Jan;48(1):165-76.

3. Novel branched-chain fatty acids in certain fish oils.
Ratnayake WM, Olsson B, Ackman RG.
Lipids. 1989 Jul;24(7):630-7.

4. Oxidative stress and mitochondrial dysfunction in Fibromyalgia. MINIREVIEW.
Cordero MD, Miguel MD, Carmona-López I, Bonal P, Campa F, Moreno-Fernández AM.
Neuro Endocrinol Lett. 2010 Apr 29;31(2):169-173.

5. Oxidative stress: emerging mitochondrial and cellular themes and variations in neuronal injury.
Higgins GC, Beart PM, Shin YS, Chen MJ, Cheung NS, Nagley P.
J Alzheimers Dis. 2010;20 Suppl 2:453-73.

6. Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients: implications in the pathogenesis of the disease.
Cordero MD, De Miguel M, Moreno Fernández AM, Carmona López IM, Garrido Maraver J, Cotán D, Gómez Izquierdo L, Bonal P, Campa F, Bullon P, Navas P, Sánchez Alcázar JA.
Arthritis Res Ther. 2010;12(1):R17. Free PMC ArticleFree text

7. Connecting the Dots: Molecular and Epigenetic Mechanisms in Type 2 Diabetes.
Goh KP, Sum CF.
Curr Diabetes Rev. 2010 Jun 9.

8. Fetal programming of atherosclerosis: possible role of the mitochondria.
Leduc L, Levy E, Bouity-Voubou M, Delvin E.
Eur J Obstet Gynecol Reprod Biol. 2010 Apr;149(2):127-30.

9. Spinal cord repair in MS: does mitochondrial metabolism play a role?
Ciccarelli O, Altmann DR, McLean MA, Wheeler-Kingshott CA, Wimpey K, Miller DH, Thompson AJ.
Neurology. 2010 Mar 2;74(9):721-7.

10. Antibacterial free fatty acids: activities, mechanisms of action and biotechnological potential.
Desbois AP, Smith VJ.
Appl Microbiol Biotechnol. 2010 Feb;85(6):1629-42.

11. Eating, exercise, and "thrifty" genotypes: connecting the dots toward an evolutionary understanding of modern chronic diseases.
Chakravarthy MV, Booth FW.
J Appl Physiol. 2004 Jan;96(1):3-10. [Free PDF here]

12. Glycolysis: a bioenergetic or a survival pathway?
Bolaños JP, Almeida A, Moncada S.
Trends Biochem Sci. 2010 Mar;35(3):145-9.

13. Type 2 diabetes, cardiovascular disease, and the evolutionary paradox of the polycystic ovary syndrome: a fertility first hypothesis.
Corbett SJ, McMichael AJ, Prentice AM.
Am J Hum Biol. 2009 Sep-Oct;21(5):587-98.

14. Liver fattening during feast and famine: an evolutionary paradox.
van Ginneken VJ.
Med Hypotheses. 2008;70(5):924-8.

15. Biochem pages http://themedicalbiochemistrypage.org/fatty-acid-oxidation.html

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J Inherit Metab Dis. 1998 Oct;21(7):697-728. Review.

19. Phytanic acid--an overlooked bioactive fatty acid in dairy fat?
Hellgren LI.
Ann N Y Acad Sci. 2010 Mar;1190:42-9.

20. Effect of dairy fat on plasma phytanic acid in healthy volunteers - a randomized controlled study.  [Free PDF here.]
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Saturday, October 27, 2012

Cancer: 50 Shades of F-cked Up?

Galena Officinalis (French Lilac or Goat's Rue)
Ancient remedy for polyuria
(sign of diabetes mellitus, frequent urine and sugar in the urine)

Original source of chemical that
was tweaked and patented into diabetes drug known as
metformin, which is emerging as the newest cancer drug
Photo Credit: Agro Semena

Hyperinsulinemia and Insulin Resistance: New Metabolic Markers for Cancer ?

I've talked a lot about insulin as it relates to disease but recently it is being discussed as a marker for cancer [1].  Though elevated blood insulin and insulin resistance (calculated HOMA) are emerging as new correlated factors for cancer and tumour progression, modern conventional medicine still has little solutions for either 'identifying' or 'treating' hyperinsulinemia other than two classes of drugs (PPAR agonists and biguanides/metformin). BTW be aware Crestor (rosuvastatin) and other statins can cause diabetes, higher blood glucoses (BG) and insulin resistance. Photo credit: modified [2].

Hyperinsulinemia? Insulin resistance (IR)?

How to recognize signs of hyperinsulinemia and IR?

Hyperinsulinemia and insulin resistance are associated with the initiation and growth of:

--central abdominal adiposity

--intraorgan adiposity (fatty liver, fatty pancreas, fatty gallbladder, fatty heart, fatty coronary/renal/peripheral arteries, fatty ovaries (e.g. PCOS and ensuing infertility), fatty muscles/sarcopenia)

--fatty liver (on ultrasound or reliable predictor: elevated liver test, ALT)

--skin tags


--acanthosis nigricans (darkening in armpits, behind knees, neck)

--melasma (skin darkening from insulin resistance induced by hormone imbalance by birth control, pregnancy, menopause, hormone replacement therapy)

--benign tumours

--malignant cancers, leukemias and lymphomas

--fatty brain degeneration, Alzheimer's ('Type 3 Diabetes Mellitus')

Pervasive Refined, Pesticide-Coated Monsanto-Grains, the S.A.D. and Other Nonsense

For many decades, like heart disease and stroke, cancer had high rates of association with diabetes and obesity. But recently the stats changed. I can agree with higher rates of insulin-related problems being secondary to macronutrient overnutrition of carbohydrates derived from refined sources (wheat, cereals, sugar, white monospecies potatoes, etc) however with the advent of pesticide technology since the Vietnam War and introduction of GMO crops in the 1990s, I believe that our burden of toxicants and insidious intestinal perturbation from GMO Bt crops are having subtle but immense influences on the growing rates of excessive insulin resistance and hyperinsulinemia.

Prior Animal Pharm: Pesticides Cause Insulin Resistance and Obesity
Photo credit: Oberlin Thesis [3]

This is concerning...Before embolic diseases were #1 and #3 for mortality in the U.S.A. (heart disease, strokes, respectively) however, a few years ago, mortality from cancer eclipsed heart disease death as the #1 killer for the first time. Are Americans smoking more (no)? Is the GMO Bt corn/wheat(gluten) based Food Pyramid more engrained than ever in dietary, medical and public school education (yes YES and yes...)?

What are Americans doing differently compared to 5-10 yrs ago? Are they getting more influenza, swine flu, whooping cough, HPV and other mercury-laden or aluminum-laden vaccines (metals can contribute to insulin resistance and hypothyroidism)...? Is our diet and lifestyles more devoid of nutrients, saturated fat, and vitamins (choline, n-3 pufa, methyl donors like animal sourced-folates, magnesium, zinc, selenium, and animal sourced-retinol, etc)?

Why has the cancer rate suddenly jumped? What other factors are behind the story? Is it toxin related, lifestyle related, stress related, epigenetic related?  I believe all have a factor... and like hypertension, heart disease, obesity, metabolic syndrome, migraines, and autism, I think it's 50 shades of f-cked up... [ref Twilight fan fiction]

* 2.6-fold increase prostate CA at highest insulin quartiles (J Natl Cancer Inst. 2009 Sep 16;101(18):1272-9. Serum insulin, glucose, indices of insulin resistance, and risk of prostate cancer.)

* 2.2-fold increase breast CA at highest waist-to-hip ratio (Cancer Causes Control. 2000 Sep;11(8):721-30. Markers of insulin resistance and sex steroid hormone activity in relation to breast cancer risk: a prospective analysis of abdominal adiposity, sebum production, and hirsutism (Italy).)

* Higher quartiles of insulin were predictive in non-diabetic breast CA women of 'poorer outcomes, consistent with the existence of a prognostic effect of insulin across broad categories of body weight.' Goodwin et al. J Clin Oncol 2001;20:42-51.

Aging, Cancer, IR -- AMPK Downregulated and NFkB/Inflammation Ramped Up

Tumor cells can initiate and grow with neolithic, post-agriculture, high/refined carbohydrate, grain-dominant diets as a result of constant and incessant switching to glucose-burning cell metabolism instead of energy efficient fat-burning fluxes. Environmental and food toxicants, stress, lack of exercise, 'iSolation' (excess electronics, less face-to-face contact), deficiency of micronutrients and vitamins (including choline and methyl donors from liver, organ meats and egg yolks) and broken sun-dark circadian rhythms merely add to these heavy metabolic disturbances.

Photo credit: [4]

Insulin and AMPK

Most cancers may take 10-20 years to initiate, progress and amass to recognizable sizes in the prostate, breast, colon, brain, abdominal or other areas [4]. What triggers oncogenes and mutations to occur? To promote diversity of our genes and accelerated evolution to climactic changes in ecological microniches, it is natural for our genes to accumulate DNA mutations and changes. Just as developing abdominal fat and a 'summer mode' of adiposity is protective short term, humans and other lifeforms are built for these changes. Plasticity of DNA expression gives us the benefit of longevity and reverting to forms more adaptable to diverse conditions, environments and shifting situations. Photo credit: modified [5].

Insulin is an ancient growth hormone and mitogenic; its function is to grow tissue. It's essential for life. Type 1 Diabetes individuals have none and, without insulin, may go into diabetic comas within 24-36 hours. Often Type 1 Diabetes patients have a sarcopenic, low muscle phenotype because adequate and correctly timed insulin spikes with meals are necessary for appropriate muscle growth and maintenance. All animals require low basal amounts of insulin for metabolism and energy however the consequences of high, constant and postprandial (aftermeal) insulin levels are activation of mTOR to grow tissues, inflammation, increased ROS and the inability of the mitochondria to phosphorylate ATP for metabolic energy.

AMPK is among many networked pathways known to regulate whole organism and single cell energetics [2, 4-8]. AMPK is found in all eukaryotes and is considered a highly conserved, master metabolic switch by some to coordinate growth, metabolism, food intake, body weight, autophagy, mitophagy, mitochondrial biogenesis and inflammation. AMPK fluxes on and off depending on fasting v. feeding states and energetic demands.  In mammals, AMPK is turned on under situations of perceived low cellular energy, e.g. low ATP which occur whilst exercise demands increase, periodic starvation and long-term starvation. Feeding, hyperglycemia (high BG), insulin spikes and other situations temporarily shut off AMPK. This makes sense, no? The body is accumulating energy, storing for the future, and replenishing depleted reserves. Under normal situations, the pattern is intermittent.  Unfortunately, AMPK can be shut off chronically instead of following a pattern of periodic flux. This is associated and observed in conditions such as clinical hyperinsulinemia, obesity, metabolic syndrome, aging and cancer [5-8]. Metformin  is an indirect stimulator of AMPK.  It is a diabetes drug, that can improve BG control, insulin resistance and shown to reduce both diabetic microvascular complications and cardiac events (macrovascular). Photo credit [7].

Metformin Appears to Desist Cancer Growth

Apparently in triple-negative breast cancer (TNBC; negative for estrogen, progesterone, and the type II tyrosine kinase (RTK) HER-2 receptor), effects of metformin are showing promise in vitro and human prospective studies are underway.  In a 2012 retrospective chart review, metformin combined with adjuvant chemotherapy in triple negative breast cancer was associated with reduced incidence of distant metastatic disease (p=0.06), however no significant differences in survival rates were observed [10].

Other observational studies show significant 25-62% relative risk reduction of colorectal, liver, pancreatic, breast, endometrial/uterine, and other cancers in metformin users versus non-users in Type 2 Diabetes trials. By the way, research shows that diabetes treatments with insulin and/or sulfonylureas (mechanism: increase endogenous insulin secretion) are associated with 500% and 250% SIGNIFICANTLY MORE CANCER, respectively, over other therapies or metformin in a comprehensive, non-industry funded U of T M.D. Anderson retrospective study that shook up the the Big Pharma world [11]. Really?

Yes. Again, many many many shades of f-cked up...

Hold your breath. More exciting research is coming... since there are no 'textbook' neoplasm solutions (besides hack, irradiate, chemo).  Treatment and therapeutics are lacking IMHO just as prevention and treatment for clinical hypertension, obesity, metabolic syndrome, heart disease and other insulin-related consequences are woefully inadequate [12,13].

Metformin: Drug That Lowers Insulin and Insulin Resistance (But Prevents Exercise-induced Muscle Growth and VO2 Max Benefits)

The effectiveness of metformin goes without fanfare. It is the #1 firstline medication for diabetes and the only diabetic drug that has been shown to lower cardiac mortality.  Other diabetic medications like PPAR-gamma agonists (Actos, Avandia) display marginal reductions in mortality but this is negated or even trumped by the associated increased prevalence of drug-associated sudden death, heart disease, heart failure, peripheral edema and heart failure mortality in the published clinical trials [Why? PPAR-gamma increases insulin sensitivity in the brown and subcutaneous white fat, exactly WHERE WE DO NOT WANT IT i.e. epicardial adipose depots ('fatty heart')].

Until recently the mechanism of action of metformin was unknown. Recent studies suggest that metformin affects LKB1 which activates and increases AMPK activity. We have discussed earlier AMPK as it's role is important in conserving proliferation and growth per demand and for the purpose of energy production. Simply put, AMPK increases fat uptake into peripheral cells, fat burning, and mitochondrial biogenesis in muscles upon energetic demands (e.g. when ATP goes down at the cellular level). When I used to counsel patients on metformin, I added sometimes that metformin is like 'exercise in a pill' -- it results in lower glucoses, lower insulin resistance, reduction in adiposity, lowering of inflammation, and weight loss.  Unlike starvation and exercise, however, metformin generally does not induce eventual hunger (in fact it can induce nausea and anorexia). Metformin apparently has no hypothalamus AMPK effects,  and this is perhaps why hunger does not ensue despite weight loss associated with metformin.  Other notable effects of metformin are -- GI upset, nausea, diarrhea, unpredicted 'explosive' diarrhea (as several patients have complained to me), abdominal cramping, intestinal dysbiosis leading to clinical vitamin B12 deficiency and related cognitive deficits over time. Photo credit: [9].

New research from Braun and his brainiac research group showed that metformin actually does mimic exercise yet when combined with exercise, metformin (2000 mg/day) appears to negate the complete, skeletal muscle benefits of exercise in prediabetic individuals [14,15]. Braun and his lab have done fantastic work on elucidating how our bodies utilize varied macronutrient substrates, handle energy deficits/surpluses and teasing out how metformin fits into the metabolic picture IMHO.  Unlike exercise or periodic starvation which typically leads to muscle gains and growth (e.g. protein synthesis) upon refeeding, when the synthetic drug, metformin, is added to an exercise program, the lean mass growth and increases of expected VO2 max benefits are BLUNTED. The exercise program was 12 weeks, 3 times weekly, of 60-75 cycling (45 min, 70% of pretraining max) and progressive resistance training including chest press, leg press, and latissimus pull-downs. Protein synthesis appeared blocked -- the FFM (fat-free mass, proxy for lean body mass) decreased significantly in the span of the 12-week experiment in both drug groups: metformin alone (M-alone, lost 1.7 kg) and metformin+exercise (EM, lost 0.5 kg), whereas the pure exercise group significantly gained 2.0 kg of lean, fat-free mass.

AMPK activation which may be devoid of natural on-off fluxes appears to be ultimately associated with sacrifice of protein and muscle construction post-exercise stimulus. When AMPK is turned-on, the function is to increase net energy (ATP). The metabolic pathways are shunted toward producing energy for IMMEDIATE demands and shunted toward eliminating short-term energy-sucking processes, like pancreatic insulin secretion, liver gluconeogenesis, and growing nice musculature, physiques and hot bodies. Makes sense, no? Yes, it does improve the metrics of conventional diabetes medicine (BG, HgbA1c), but at what cost? Is 'metabolic flexibility' over-compensated and lost without natural AMPK rhythms [16]?  Exercise obviously improves the balance between dysfunctional carbohydrate oxidation and lipid oxidation, yet synthetically knocking out carbohydrate oxidation via constant AMPK appears to induce sarcopenia and hinder the full insulin-sensitizing, anti-inflammatory benefits of exercise. Actually it is no surprise that exercise trumps metformin drug use in cases where insulin resistance may be reversible, as it seems.

Other negatives of metformin are that higher blood lactate may result (build up from anaerobic or hypoxic glucose/carb metabolism). One risk with metformin use is lactic acidosis from toxic accumulation of lactate which can be ~~50% fatal. The danger for this adverse effect is higher in kidney- and liver-compromised states such as dehydration, binge/chronic alcohol use, kidney disease, liver disease, heart failure, elderly, and co-adminstration with kidney-toxic drugs -- therefore use is contraindicated.

Controlling Insulin and Insulin Resistance With Paleo-Ancestral Eating: Frasetto et al

In PCOS women, metformin has some success at improving fertility. What about diet and exercise? At Crossfit and RobbWolf.com, numerous stories of *cough cough* unintended pregnancies in (previously) infertile couples abound! Exercise +paleo/ancestral eating reverse infertility more effectively than pharmaceuticals and current reproductive technology IMHO as it appears from stories in paleo-land.

Frasetto et al (EJCN 2009) 68% Decrease Insulin and 72% Improvement on Insulin Resistance on Hunter-Gatherer 7-Day Paleolithic Diet

In the 10-day experiment, Frasetto et al demonstrated that basal insulin in overweight men and women age 18 to 50 could be lowered by 68% from 69 mol/L to 21 pmol/L on a grain-free, legume-free, dairy-free (~220 grams carbs/day, Low Glycemic Index) diet that simulated our evolutionary roots. Additionally, HOMA, a measure of insulin resistance, dramatically decreased from 3.2 to 1.0 by 72%. Elevated blood pressure and weight naturally decreased. The study aimed for neutral weight (no change) and required higher caloric intake to offset the weight loss in the Paleo group.

This experiment was indeed short. Most of us in the evo/ancestral/paleo/primal community hear of similar success stories of health reversal on this type of timeline all the time.

Why? Because perhaps the evolutionary-based diet is aligned with older DNA and optimal expression of insulin sensitivity?

Ketones Appear to Desist Cancer Growth

Ketones are generated by either consuming MCT oil/coconut oil or a low or no carbohydrate diet. Ketones are the metabolic currency of the (a)  fasting or starving energetic state and (b) when physical training is fat burning (25-70% max heart rate) and extended.

The brain runs naturally well on ketones (granted the adrenals are healthy; ketone generation requires cortisol and adrenaline). We are built to intermittently fast and run on ketones when required (postnatal, extended chronic aerobic exercise, intermittent or chronic starvation).

Several studies show the surprisingly positive benefits of MCT oil, ketotic diets or infusion of ketones for treating cancer [17,18,19]. Why? Ketones are the opposite of IR-promoting, refined, high-carb, grain-intensive diets.

In our evolutionary fitness and paleo communities, it is popular to practice periodic starvation of 18-36 hours several times during a month (granted healthy adrenals and good deep rest/sleep). The practice elicits many health promoting effects as it increases ketone bodies to utilize as fuel for the brain and muscles, synthesized from visceral and subcutaneous fat stores.

[**  FYI... I rarely do intermittent fasting (IF) now since my adrenal glands are borderline-frail. As an individual experiment to combat body fat increases (15 lbs) due to the Mirena IUD (18 months of synthetic progestin toxicity), I did try frequent IF but found it further deteriorated adrenal function. So I'd caution anyone with  un-compensated, frail or marginal adrenal function to consider the value of avoidance of IF and consider the merit of varied, low glycemic index carbs in adrenal exhaustion protocols (100 - 150 grams daily --nonallergenic starches and whole foods) like Dr. Lam's adrenal optimization protocol. **]

Ketones and Metformin are Epigenetic HDAC-Inhibitors

Bioactive components of our food have epigenetic influence on potentical cancer profiles and insulin/IR signatures. We live now in the post-genomic DNA world. DNA may be the text and chromatin, the words, of our chapters, but epigenetic modifications are the punctuation, paragraphs and grammar that give words life and context. Researchers Shaw and Mihaylova at the Salk Institute in San Diego studied the effects of metformin and AMPK and elucidated one of the core mechanisms of metformin and AMPK's action for reversing chronic insulin resistance defects [8]. AMPK activation stimulates downstream inhibition of an enzyme, histone deacetylase (HDAC), that blocks 'punctuation', or in other words, normal chromatin DNA 'editing.'  HDAC inhibition leads to activation of intracellular antioxidant pathways and resumption of normal DNA chromatin form and function.

It turns out that ketones and metformin have similar epigenetic molecular mechanisms; both are HDAC inhibitors [8,20]. This is believed to be how they may elicit some of their powerful effects in insulin resistant conditions. Many spices, herbs, vegetables, animal products, fermented dairy products (phenylbutyrate), royal jelly (phenylbutyrate) and polyphenol-rich foods contain bioactive components that behave by editing and providing clarity/context to our DNA blueprint via inhibition of HDAC [21]. Photo credit [21].

How About An Evolutionary Medicine Based Approach to Cancer Treatment and Prevention?

Radiation, chemotherapy and treatment of cancer take a toll on pediatric, adult and elderly patients. Some of the long term effects including cardiotoxicity, nerve ending and brain damage and even increased risk for other cancers. Many cancer treatments fail with 5- and 10-year survival rates of 25-50% or less. The monetary costs of cancer treatment can add up and may eventually bankrupt Medicare and current health insurances provided by large and small businesses. Can we afford to continue and ignore the misalignment between government sanctioned dietary advice (whole unprocessed lectins, Rockefeller-wheat-gluten-galore, GMO-corn-soy-everything, low fat, high refined carbs, n-6 pufa overload) and the chronic and acute diseases including cancer? How best for modern conventional medicine to mutate, re-align, evolve and provide healthcare from the perspective of evolution?

I have no answers but would be interested in your thoughts...

Evolutionary Bloggers:

Robb Wolf: Sept 2007 post and his interview with Dr. Seyfried 'Cancer and ketosis' [18]

Dr. Eades: Metabolism and Ketones


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18. Targeting energy metabolism in brain cancer through calorie restriction and the ketogenic diet.
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J Cancer Res Ther. 2009 Sep;5 Suppl 1:S7-15. Review.

19. Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides.
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BMC Cancer. 2008 Apr 30;8:122.

20. From natural products to small molecule ketone histone deacetylase inhibitors: development of new class specific agents.
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21. Epigenetic impact of dietary polyphenols in cancer chemoprevention: lifelong remodeling of our epigenomes.
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[Re-tweaked old Nephropal(eo) post]