Why does the liver produce ketone bodies instead of exporting acetyl-CoA from beta-oxidation for use elsewhere?

Why does the liver produce ketone bodies instead of exporting acetyl-CoA from beta-oxidation for use elsewhere?

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Under conditions of low oxaloacetate in the liver, acetyl-CoA that cannot be oxidised in the TCA cycle is converted to ketone bodies, which can then be exported for use as fuel in non-gluconeogenetic tissues (e.g. heart, brain).

To avoid this pathway, and the additional enzymes it requires, as well as the enzymes in the receptive tissues which are needed to reverse the pathway and re-produce acetyl-CoA, why does the liver not just export acetyl-CoA directly?

One consideration is an inability to transport acetyl-CoA across membranes, but fatty acyl-CoAs deal with this using a carnitine shuttle across the mitochondrial membrane. Would developing a transport system not, evolutionarily, be a more efficient solution?

This is simplified version of a complex situation, but in summary:

  • A key role of liver is to control the distribution of metabolic fuel for the other tissues (it always has enough for its own requirements).
  • The way it behaves differs in the fed and fasted states (because of control by hormones and the concentration of metabolites).
  • In the fed state (after storing some sugars as glycogen) the liver will synthesize triglycerides and export them as lipoproteins to the adipose tissue, which will take them up and store them. (Other tissues in the fed state will be able to obtain glucose or fatty acids from the blood.)
  • In fasting and starvation the triglycerides in the adipose tissue will be broken down to fatty acids and glycerol, much of which will be used by tissues such as muscle.
  • The priority of the liver in starvation is to provide fuel for the brain and nervous tissues in the form of glucose, by gluconeogenesis. The substrates for net gluconeogenesis under these conditions include glycerol and some amino acids derived from breakdown of protein.
  • Other amino acids, produced in protein breakdown lead to acetyl CoA, which cannot serve as a precursor for gluconeogenesis. However it can be converted to ketone bodies (acetoacetate and β-hydroxybutyrate) that the brain can use to replace some of its glucose requirement.

With this in mind, it can be seen that the reason for producing ketone bodies is not to generate a molecule that can cross the cell membrane into the blood, but to generate a molecule with special properties, lacking in fatty acids or acetyl CoA, that allows its use by the brain in life-threatening circumstances.

Of less importance, but worth mentioning, is the fact that citrate is used as an export form of acetyl CoA (when there is sufficient oxaloacetate available), a surrogate role it plays in any case in the transfer of acetyl CoA across the mitochondrial membrane for fatty acid synthesis. So it is not necessary to export acetyl CoA, and perhaps preferable to it keep intracellular.

A more detailed account of this is available at NCBI bookshelf online in Berg et al. sections 30.2 and 30.3

The P479L gene for CPT-1a and fatty acid oxidation

In order to work out what is happening with a given child having an episode of hypoglycaemia as a result of having the P479L version of CPT-1a, we need some information.

My thanks to Mike Eades for the full text of the paper on the Canadian Inuit, which does include a certain amount of useful clinical data.

Here is the snippet about a young girl having a hypoglycaemic episode while hospitalised:

“Plasma free fatty acid was 3.8 mmol/L and plasma 3-hydroxybutyrate was 0.5 mmol/L”

Blood glucose was 1.9 mmol/l at the time. An FFA level of 3,800 micromol/l is impressively high. She was generating a small amount of ketones.

No one would argue with intravenous glucose at this point, the question is about how she got here.

So. The problem here does not (as I'd initially thought) appear to insulin induced suppression of FFAs to a level at which beta oxidation fails to support metabolism. FFAs are very high, even for an P479L person after a short fast. With ketones starting to be produced (and low blood glucose) I feel it is reasonable to assume that her liver glycogen is depleted and, while some fatty acids are entering the hepatocytes, not enough of them are being oxidised to support ketogenesis. Glycogen is being depleted to keep liver cells functional. Gluconeogenesis from protein is unable to meet the hepatic (and whole body) demand for glucose calories in the situation of limited access to FFA calories.

However much glycogen derived glucose you consider that the ancestral diet contained I feel it is very, very unlikely to be greater than the glucose and fructose of a modern diet. I feel that getting enough glycogen in to the liver to fully fuel its metabolism in the absence of adequate fatty acid oxidation is a non starter. The P479L mutation was not "permitted" by high oral carb loading, it was permitted by conditions which facilitated fatty acid oxidation. You don't have to agree.

What starts to look much more interesting is what controls CPT-1a activity and how this might vary from the ancestral diet to the modern diet.

The paper makes the point that omega 3 fatty acids appear to up regulate fatty acid oxidation (in rats at least) by the liver. If this is true in humans then a high level of omega 3 fatty acids from marine fats might up regulate fatty acid oxidation to a level which no longer necessitates the depletion of hepatic glycogen derived form oral glucose intake or protein catabolism.

In support of this is that the distribution of P479L within Alaska is not uniform, it's significantly commoner in the coastal regions compared to the inland areas.

"The allele frequency and rate of homozygosity for the CPT-1a P479L variant were high in Inuit and Inuvialuit who reside in northern coastal regions. The variant is present at a low frequency in First Nations populations, who reside in areas less coastal than the Inuit or Inuvialuit in the two western territories"

I'm open to other explanations, there are papers suggesting that the mutation helps to preferentially dispose of omega 6 PUFA, with omega 3 fatty acids as the facilitator.

In summary: Maintaining adequate FFA oxidation to avoid glycogen depletion looks to be the core need in P479L. A high fat diet with a large proportion of omega 3 fats might be a plausible way of maintaining adequate hepatic fatty acid oxidation. Hyperglycaemia (via Crabtree effect) looks to be anathema. Glycogen loading with a normal starch/sugar based modern diet is clearly ineffective to prevent hypoglycaemia for some individuals. Resistant starch as a reliable nightly adjunct to infant feeding seems very unlikely in the ancestral diet. Repeated periods of fasting were probably routine when hunting was poor and does not appear to have selected against P479L in weaned children. Unweaned children are unlikely to be exposed to fasting, provided milk was available from lactation.

Well, there are some more thoughts on the biochemistry.

People clearly have very differing ideas of what the Inuit did or did not eat as an ancestral diet. The P479L gene eliminates the need for source of dietary glucose to explain very limited levels of ketosis recorded in the Inuit. While it is perfectly possible to invoke a high protein diet to explain a lack of ketosis in the fed state this goes nowhere towards explaining the limited ketosis of fasting. P479L fits perfectly well as an explanation.

I have some level of discomfort with using the Inuit as poster people for a ketogenic diet. That's fine. They may well have eaten what would be a ketogenic diet for many of us, but they certainly did not develop high levels of ketones when they carried the P479L gene.

However. Over the months Wooo and I seem to have come to some sort of conclusion that, while systemic ketones are a useful adjunct, a ketogenic diet is essentially a fatty acid based diet with minimal glucose excursions and maximal beta oxidation. Exactly how important the ketones themselves are is not quite so clear cut. From the Hyperlipid and Protons perspective I would be looking to maximise input to the electron transport chain as FADH2 at electron-transferring-flavoprotein dehydrogenase and minimise NADH input at complex I. Ketones do not do this. Ketones input at complex II, much as beta oxidation inputs at ETFdh, but ketones also generate large amounts of NADH in the process of turning the TCA from acetyl-CoA to get to complex II, which ETFdh does not. I'm not a great lover of increasing the ratio of NADH to NAD+. These are my biases.

Confirming that the Inuit are not poster boys for ketosis is a "so what?" moment for me. Using their P479L mutation to argue against ketogenic diets is more of a problem. It's a massive dis-service to any one of the many, many people out there who are eating their way in to metabolic syndrome to suggest that a ketogenic diet is a Bad Thing because no one has lived in ketosis before. Even the Inuit didn't! My own feeling is that everyone comes from stock who occasionally practiced and survived intermittent fasting so we are should be adapted to this. I'd guess that if you are of Siberian, Inuit or First Nations extraction you might benefit from Jay Wortman's oolichan oil as part of a ketogenic diet.

I'm always amazed by the concept that a ketogenic diet might be temporarily therapeutic but must be discontinued because it eventually becomes Bad For You. It reminds me so much of the converse concept that low fat diets, which might worsen every marker of health which people may care to look at, will deliver major benefits at some mythical future date.

Ultimately, point scoring on the internet about what the Inuit did or didn't eat shouldn't destroy people's chances of health. Destroying a circular argument about Inuit diets may may the destructor feel good. Destroying the feet, eyes and kidneys of a person with type 2 diabetes, who need a ketogenic diet, as a spin off from that victory must be difficult to live with. I don't know how anyone can do this.




Over 50% of adult males and females over 50 years old have bone loss. Osteoporosis (OP) is responsible for millions of fractures annually, mostly involving the lumbar vertebrae, hips, and wrists. Fragility fractures of the ribs are also common in men. Although more women than men (80% vs. 20%) suffer with osteoporosis, men are more likely to die from OP related fractures. OP related fractures can result in painful loss of mobility and can be life threatening: if people are bedridden as a result of their injuries, there is increased risks of pneumonia and thrombophlebitis (blood clots) and associated pulmonary embolisms. Hip fractures are responsible for the most serious consequences of OP. Hip fractures usually require surgery. The six-month mortality rate for people age 50 and above following a hip fracture is about 14%. The incidence of hip fractures increases each decade from the sixth through the ninth for both women and men for all populations. Vertebral fractures, while having a smaller impact on mortality, can lead to severe, chronic neuropathic pain as well as kyphosis (hunchback) deformities which can impair ventilation. OP is also associated with atherosclerosis, dementias, depression and cancers. OP fractures are associated with a reduced quality of life.


Bones are living tissue and not solid and static structures. Bones constantly change in response to environmental stresses. Bones grow stronger or weaker as a function of movement, exercise and body weight changes. Bones perform four vital roles: 1) structural support, 2) organ protection, 3) production of blood cells, and 4) storage of minerals for on-demand use by other parts of the body. Blood levels of calcium are tightly regulated, perhaps one of the most strictly controlled processes in the body. The two processes of absorption (depositing calcium) and resorption (withdrawing calcium) are constantly changing the structure of the bone in a cycle called bone remodeling.

The underlying mechanism in all cases of OP is an imbalance between bone resorption and bone formation. Like a bank account, bones have counter-balancing cells that make deposits (osteoblasts) or withdrawals (osteoclasts). Osteoblasts produce an organic matrix which contains Type 1 collagen. Bone matrix is the mortar that captures and incorporates calcium and multiple other minerals into the network of interconnected collagen fibers to make the final product of hard bone tissue. In health, the process is kept in balance. With aging, especially because of a lack of supportive sex hormones, withdrawals exceed deposits resulting in reduced bone-mineral density, which results in osteoporosis and increased risks for fractures. The sex hormones estrogen and testosterone are critical for maintaining a healthy balance: they inhibit osteoclast activity (bone breakdown) and promote osteoblast activity (new bone formation).

Another major cause of osteoporosis is focal scurvy of the bones. Quite simply, scurvy (severe vitamin C deficiency), whether general or localized can be prevented, cured and reversed with appropriate dosing of vitamin C and other important nutrients. Vitamin C maintains a healthy osteoblast—osteoclast balance. In the absence of vitamin C, bone-making osteoblasts fail to form. At the same time, there is an unchecked increase in bone-dissolving osteoclasts, resulting in focal scurvy inside the bones, thus initiating the imbalance that results in a detrimental breakdown of the bone integrity, along with calcium loss. Also, a deficiency of vitamin C directly increases oxidative stressin the bones which attacks cellular structure causing damage and even death of the cells. And, vitamin C is essential for the synthesis of collagen and for creating the fibrous interconnecting collagen cross-linking strands required to optimize the physical strength and resilience of the cones. A vitamin C deficiency results in weaker bones.

Bone remodeling is constant: up to 10% of all bone mass may be undergoing remodeling at any point in time. Cortical bone is the hard outer shell of bones and the middle of long bones. Trabecular bone is the sponge-like bone in the ends of long bones and vertebrae where the marrow is located. Trabecular bone is more active with osteoblasts and osteoclasts, and more subject to remodeling. In OP, not only is bone density decreased, but the naturally weaker spicules of trabecular bone may break with stress and are replaced with an even weaker, disrupted bone micro-architecture. The most common areas of OP fractures have a relatively high trabecular to cortical bone ratio. With aging, women may lose as much as 50% of trabecular bone because of a reduction in their alpha-estrogen receptor activity, while men lose about 30%.


1) ***The PRIMARY RISK FACTOR for OP is age related SEX HORMONE DEFICIENCY.*** Consequently, the PRIMARYTREATMENT for osteoporosis is Bio-identical Hormone Replacement Therapy (BHRT). For men, Testosterone therapy is needed. For women, both Estrogen and Testosterone are the KEYS to optimizing therapy. Estrogen and testosterone treatments also help to prevent periodontitis and tooth loss. If there are no contraindications, If there are no contraindications, it is never too late to start Estrogen and Testosterone therapy. However, it is important to consider the appropriate type of Estrogen to use and the route of administration. <REMEMBER: always think of using Estrogen and Progesterone together as a single entity for, Progesterone (but not a progestin like “Provera”) is always required to modulate the adverse effects of unopposed Estrogen stimulation and to enhance receptor functions. However, Progesterone therapy by itself doesn’t help OP.>

2) Vitamin C Deficiency (Because It Prevents Bone Loss and Fractures): Vitamin C creates bone-building osteoblasts suppresses bone-dissolving osteoclasts prevents bone-destroying oxidative stress helps to synthesize collagen and, helps in the formation of bone-strengthening collagen cross-links. In the Framingham Osteoporosis study, the subjects with the highest intake of vitamin C had significantly fewer hip and non-vertebral fractures compared to those with the lowest intake. Intake of vitamin C limited to dietary sources alone had no statistically significant reduction of fractures vitamin C supplementation was required to realize a decrease in risk. Supplementation with vitamin C is non-toxic and safe. Take at least 6 gm daily.

3) An independent risk factorfor both osteoporosis and vascular disease is elevated homocysteine levels.Women with a homocysteine level over 15 compared to women with a level less than 9 had 2.42 increased risk of hip fractures. Effective treatments for elevated homocysteine include: vitamin B12 (1000 IU injections of methylcobalamin or sublingual therapy), vitamin B6 (50 mg daily), folic acid (800 mcg daily), and methylsulfonylmethane (MSM—1 gm twice daily). Even more effective are BETAINE AND CHOLINE– RECOMMENDED DOSES: Betaine: 500 mg/d up to 2,000 mg tid and, Choline: 500-1,000 mg/d.

4) Latitude: Areas of higher latitude, such as Northern Europe, receive less Vitamin D through sunlight compared to regions closer to the equator, and, consequently, have higher fracture rates.

5) Genetics: : White European and Asian ancestry predisposes to OP. Those with a family history of fractures or OP have an increased risk of OP ranging between 25% to 80% increased risk, depending upon the study. At least 30 genes are associated with the development of OP. A small stature is another non-modifiable risk factor for OP.

6) Modifiable risk factors include: excessive intake of alcohol Vitamin D deficiency tobacco smoking malnutrition physical inactivity heavy metal toxicity, especially to cadmium and lead medications, especially proton pump inhibitors and, carbonated beverages.

7) MEDICAL DISORDERS: Our bodies regulate calcium balance with two pathways: one is signaled to turn on when blood calcium levels drop below normal, pulling calcium from bone reservoirs, and one is the pathway that is signaled when blood calcium levels are elevated. Many diseases and disorders influence one or both pathways, disturbing the calcium balance. THUS, it is imperative to have an accurate diagnosis for appropriate interventions. 1) Immobilization: there is truth to the dictum– “use it or lose it.” Athletes with a high bone turn-over may experience localized osteoporosis after prolonged immobilization of a casted fractured limb. Also, people who are bedridden or who use wheelchairs may suffer similarly. 2) Hypogonadal states: such as various genetic disorders including Turner syndrome, Klinefelter syndrome, and Kallman syndrome. Other conditions such as anorexia nervosa, hyperprolactinemia, and hypothalamic amenorrhea affect the endocrine system and can also cause OP. Surgical bilateral oophorectomy and spontaneous premature ovarian failure cause deficient estrogen production. Surgical removal of the testes and andropause cause testosterone deficiency. 3) Endocrine disorders: Adrenal diseases such as Cushing’s syndrome (too much cortisol) and Addison’s disease (too little cortisol) thyroid diseases such as hyperthyroidism (too much thyroid hormone) and hypothyroidism (too little thyroid hormone) both Type 1 and Type 2 Diabetes Pituitary gland diseases such as acromegaly and, hyperparathyroidism. 4) Hematologic and Renal diseases can result in OP.: for example, renal insufficiency, sickle cell disease, hemophilia, thalassemia, multiple myeloma, lymphomas and leukemias. 5) Malabsorption and malnutrition: inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis surgeries including gastrectomy, intestinal bypass surgery, and, bowel resection and, gluten enteropathy, lactose intolerance and milk allergy, bulimia, and cystic fibrosis. 6) Rheumatological disorders: (either as a part of the disease or frequent use of corticosteroids) include rheumatoid arthritis, systemic lupus, ankylosing spondylitis. 7) Systemic disorders: such as sarcoidosis, amyloidosis, vitamin D, vitamin K and vitamin B12 deficiencies. Chronic Obstructive Pulmonary Disease (COPD) can also cause OP. 8) Neurological conditions such as Parkinson’s disease and complex regional pain syndrome.


1) FOR WOMEN: Both oral and topical Estradiol improve OP. While Estriol can be especially helpful with vaginal dryness and hot flashes, it has no significant usefulness for OP nor Coronary Artery Disease (CAD). If a woman has been menopausal for >10 years and is not on BHRT, it is wise to only consider using a topical Estradiol, particularly if she has any CAD risk factors, in order to avoid vascular plaque rupture and blood clot formation. I will typically a use a compounded Estrogen cream: 2 mg to 3 mg of estrogen daily, , or an Estrogen patch (such as Climara patches 0.0375 mg up to 0.1 mg once per week or Vivelle dots twice per week), or an Estrogen gel (such as Elestrin 0.06% 𔂿 pump daily). NOTE: Estradiol needs to be used along with oral Progesterone: 100 mg to 600 mg daily.

Testosterone cream also benefits OP. The standard dose is 20 mg/gm (2%) of a compounded cream: applying ¼ gm daily to the skin or to the vulvar mucous membranes. Women over 60 years old typically require a higher dose: a 40 mg/gm (4%) cream: applying ¼ gm daily to the skin or vulvar mucous membranes. The total and free Testosterone levels are monitored. A vanishing cream will be used if the cream is to be applied to the vulva, and a lipoderm cream is used if it is to be applied to the thighs and buttocks skin.

2) FOR MEN: I use of a topical Testosterone cream or gel, or intramuscular injections of Testosterone is the treatment of choice.

3) In addition to Estrogen/Progesterone and Testosterone helping to prevent and treat OP, BHRT has a direct effect upon the brain. Particularly for elders, who have an increased OP risk for death and disability from falls with consequent hip and spinal fractures, BHRT helps to improve their stability and coordination, as well as helping with their memory and with their cognitive impairment.

4) Be aware that treatment with Human Growth Hormone (HGH)can also be very beneficial. However, it is very expensive, requires nightly injections, and it is typically restricted in its use by State Medical Boards. Thus, I don’t use recombinant HGH. However, I may prescribe an amino acid non-peptide secretagogue, called “Secretropin”, which is used as a sub-lingual spray, if indicated, to help release one’s own HGH.

5) Don’t be concerned about using Thyroid Hormones when they are monitored and used in balance with Estrogen, Progesterone and Testosterone. Inappropriate use of Thyroid Hormones, eg. for weight loss, may cause OP because it accelerates bone turnover. In both hyperthyroidism and hypothyroidism the risk of fractures is significantly increased. Treatment with thyroid hormone is best when thyroid stimulating hormone (TSH) is not overly suppressed because TSH has a direct bone-protecting effect, and, very low levels of TSH are associated with increased cardiovascular risk.

6) BISPHOSPHONATES: ***I generally choose NOT to prescribe Bisphosphonates because they poison osteoclasts (that remodel old, brittle bone) so that they can’t function. Bisphosphonates are the most popular treatment for OP. They can be useful in decreasing the risk of fractures in people who have already sustained a fracture from OP. Fracture risk reduction is between 25 and 70%, depending on the bone involved. HOWEVER, be very cautious if you are considering using them. Using them may make you think that you have stronger bones. Simply by preventing the necessary removal of the old brittle bone matrix, your DXA scan will look better. Although these medications will delay or stop bone loss, they don’t facilitate bone growth! The bone appears denser, but the “life has been snuffed out”. Consequently, Bisphosphonates are associated with osteonecrosis of the mandible (bone death of the jaw), spontaneous mid-shaft femur fractures, and an increased risk of esophageal inflammation and cancers. Also, there is often poor patient compliance because of the painful side-effects of esophagitis and stomach upset. Similar medications such as Raloxifene (Evista), and Calcitonin are also available, however, each have a very high side-effect profile and also a high cost. limit treatment with bisphosphonates to 5 years. Women who used bisphosphonates for 10 to 13 years had a higher risk of clinical fractures than women who used them for 2 years.> For people with OP but who have not had a fracture, evidence does not support a fracture risk reduction by using bisphosphonates.

7) I am intrigued by the medication Terparatide (Forteo), because it stimulates osteoblasts, thus, increasing the bone matrix along with producing a heterogeneous mineral content consistent with a younger bone age. However, it can stimulate a rare bone cancer called osteosarcoma. In addition to its expensive cost, it has risks for lightheadedness—dizziness and hypotension, nausea, leg cramps, arthralgias and pains. It is administered as a 20 mcg subcutaneously injected dose once daily, with a 2 year maximum total lifetime treatment.


I monitor effective therapy by measuring serum Estrogen, Progesterone, and Testosterone levels, and by measuring a urine N-telopeptide/creatinine ratio (NTX), which helps to evaluates bone mineral metabolism. An NTX evaluates present bone metabolism. NTX measures cross linked N-telopeptides of Type 1 collagen and is an indicator of bone resporption by osteoclasts. I prefer to measure the 2 nd or later morning urine sample, to avoid over-night concentration. The LOWER the level, the better. The goal is to effect a change in the NTX so that it is less than or equal to 35. The urine can be monitored every 3 to 6 months until stable, and then yearly. Levels higher than 35 indicate ongoing bone loss.

The U.S. Preventive Services Task Force recommend that all women 65 years of age or older be screened by bone mineral densitometry. They recommend screening younger women with risk factors. The International Society for Clinical Densitometry suggest bone mineral densitometry for men 70 years old. While bone mineral density X-ray scans (“DXA”, formerly called a “DEXA” scan) evaluate the results of past bone metabolism, it takes 2 to 4 years to see a change on the scan. (That’s why Medicare will only pay for a DXA scan every 2 years.) A DXA scan may look good, however, if the NTX is elevated, then bone loss is certain, and future DXA scans will become abnormal. Bone loss accelerates after menopause with the drop of Estrogen and Testosterone.

A DXA scan is reported as a T-score. 85% of young women have a normal T-score expressed as greater than or equal to -1.0. Osteopenia, or bone thinning, is defined as a T-score between -1.0 and -2.5, and affects about 14% of young women. Osteoporosis is defined by a T-score less than -2.5. Severe OP is defined by a T-score <-2.5 plus a fragility fracture.


At the time of Columbus, it was self-evident that the world was flat. Modern Medicine isn’t immune to a similar simplistic and wrong thinking. Regarding OP, since bones are brittle and largely made up of calcium, it is self-evident that calcium should be supplemented. However, this idea is very wrong! “Osteoporosis involves a lack of calcium in the bones. It does not mean that there is a lack of calcium in the body or in the diet. Osteoporotic individuals have toxic excesses of calcium outside the bounds of bone tissue. The typical American menu is laden with calcium-saturated foods. A legitimate body-wide deficiency of calcium is virtually non-existent, but too much calcium is very common and highly toxic, and it reliably leads to great suffering and premature death. The real problem in osteoporosis is that the body is unable to synthesize a new structural bone matrix and to integrate calcium into it. Simply increasing the quantity of calcium in the body does not even begin to remedy this problem. The calcium simply deposits elsewhere in the body where there are no bone proteins. Excess calcium is a killer.

It is this excess of ingested calcium along with calcium chronically released from osteoporotic bone that poses the most dangerous threat to health and life as it moves in and around all of the cells of the body, promoting disease wherever it accumulates. This notably includes heart disease, hight blood pressure, strokes, and cancer. It fuels and accelerates all chronic degenerative diseases.

When a body-wide state of excess calcium already exists, any added calcium is too much as it promotes abnormal cellular, glandular, and bodily functions. That is why supplemental calcium needs to be stopped, excess dietary calcium needs to be curtailed, and all calcium-rich, vitamin D-fortified foods need to be avoided.

The excess calcium in non-bone tissues has been shown to increase mortality from all causes. You are 30% more likely to have a heart attack and 20% more likely to have a stroke if you take an extra 500 mg of calcium per day. Over one-third of Americans over the age of 45 have evidence of arterial calcification. This percentage rises drastically with greater age, literally skyrocketing in postmenopausal women as well as in testosterone-deficient men. The degree of calcium deficiency in osteoporotic bone is actually an indicator of the amount of excess calcium that has taken up residence in non-bone tissue. Not only does increasing calcium intake fail to improve bone strength, it fuels calcium excess everywhere in the body. Calcium supplementation does not prevent bone fractures. However, adequately dosed vitamin D supplementation does decrease fracture risk.

Until you address your toxin exposures and your hormone deficiencies, you will not prevent or resolve osteoporosis regardless of whether you are ingesting appropriate or even elevated amounts of dietary calcium. Calcium migration from the bone is not the cause of osteoporosis, but rather a symptom of it. Giving large amounts of calcium will eventually result in a small amount of it filling in pores in osteoporotic bones. However, it cannot be emphasized strongly enough that this approach is simply cosmetic. It will make the bones look somewhat better on a bone density test, but it does no more to improve bone strength than blowing finely ground chalk into the cracks of an earthquake-damaged building will to restore its structural integrity, or putting a fresh coat of paint on rotting wood.”


Note: much of the positive impact of these anti-osteoporosis agents results from the increased anti-oxidant impact they ultimately have in the bones and the rest of the body.

  1. a) ***Vitamin D3: 2,000 IU up to 10,000 IU daily. Monitor a 25-OH-Vitamin D level to keep the level 60- 100 ng/ml.
  2. b) ***Vitamin K (for those not on Coumadin)–– up to 1 mg daily. Vitamin K inhibits abnormal calcification outside of the bones helps dissolve pre-existing abnormal calcifications K2 lessens susceptibility to coronary artery disease K1 may increase bone density and definitely decreases fracture risk K2 as MK-4 prevents fractures, sustains bone density, and improves bone quality via increased collagen content and collagen cross-linking when administered in pharmacological doses K2 as MK-4 can compensate for bone weakening induced by magnesium deficiency, can prevent and/or treat some forms of cancer, and,can augment positive bone effects of bisphosphonates and, K2 decreases cardiac mortality as well as all-cause mortality.
  3. c) ***Boron: supplementation reduces urinary loss of calcium and magnesium and improves levels of Estradiol and Testosterone. Foods high in boron include (in descending order): raisins, almonds, hazel nuts, dried apricots, avocado, peanut butter, Brazil nuts, red kidney beans, cashews and dates. Or, supplement with 3 mg of boron daily.
  4. d) ***Magnesiumis nature’s calcium channel blocker. Magnesium and calcium can largely be characterized as biological antagonists. Magnesium levels are strongly associated with the anabolic hormones testosterone and human growth hormone. Magnesium dissolves calcium deposits and keeps them in solution decreases intracellular oxidative stress by decreasing elevated intracellular calcium levels regulates active calcium transport and, increases bone density and decreases fracture incidence. Magnesium is at the center of every chlorophyll molecule, thus, eating green leafy vegetables is a good dietary source for magnesium. Magnesium is also found in nuts, legumes, whole grains, fruits and fish. However, you cannot reliably expect to obtain consistent and sufficient amounts of magnesium by ingesting these foods. Magnesium content is vegetables has seen a huge decline since pre-1950 levels because of soil depletion. Additionally, many soils have too much potassium which competes for absorption of magnesium into the plant. Also, typical grain refining processes for bread and pasta removes 80%-95% of total magnesium. Start supplementing slowly and back off if diarrhea ensues. The mineral form, Magnesium Oxide 400 mg to 800 mg daily, is the least expensive and works just fine if it is absorbed and if it doesn’t cause you diarrhea. However, some people don’t absorb the mineral form of magnesium well. A chelated form of magnesium is usually much better absorbed. The best gut tolerated form is magnesium glycinate 400 mg-500 mg or magnesium asporatate 400 mg to 500 mg daily. Magnesium L-Threonate 1,000 to 2,000 mg taken at bedtime can be very helpful with sleep management and for neurological conditions. This form of magnesium most easily crosses the blood-brain barrier with comprehensive benefits for sleep, anxiety, cognitive function, and migraines.
  5. e) ***Lactoferrin 300 mg daily is a potent anabolic agent that stimulates bone growth and bone repair and can help to prevent osteoporosis. Additionally, it has well-documented anti-infective, immune strengthening, antioxidant, anti-inflammatory and anti-cancer effects. It can also benefit weight management.
  6. f) ***Vitamin C 6,000 mg daily can help to prevent bone loss and fractures.
  7. g) Strontium: 1 gm/day increased to 1 gm twice daily in 1 to 2 month: caution– it may cause diarrhea. Strontium accelerates the action of bone-building osteoblasts and slows the action of bone destroying osteoclasts, with a net positive result for bones.
  8. h)Ipriflavone: is a synthetic flavonoid derived from the soy isoflavone called daidzein. It promotes the incorporation of calcium into bone and inhibits bone breakdown, thus preventing and reversing osteoporosis. It works by slowing down the action of the osteoclasts, thus, allowing the osteoblasts to build up bone mass. A typical dose is 600 mg daily
  9. i) A proprietary product called “Ostinol” ( contains bone morphogenic proteins (BMPs) that stimulate osteoblasts to grow new bone and cartilage. There are no negative side effects. For people with normal bone density, it is recommended to use 150 mg daily. For osteopenia, the recommended dose is 350 mg once or twice daily. If there is associated arthritis, the dose recommendation is 2, 350 mg caps twice daily. For osteoporosis, the recommended dose is 450 mg daily. If the bone loss is rapid or if there is associated arthritis, the dose is 450 mg twice daily.
  10. j) Omega-3 Fatty Acids: help to combat calcium toxicity and to create stronger bones and decreased fracture risk. They increase osteoblast activity and reduce inflammation. Men with the top 20% of DHA concentrations have protection from loss of bone mineral density compared to all the other subject. Higher levels of DHA and EPA in the red blood cells was associated with less OP and greater bone mass. An upper dose is 0.3 g/kg body weight, meaning a 150-pound person can take 21 g daily (having a content of about 13 g EPA and DHA). Most people do well taking 1 to 3 gm daily.


1) FALL PREVENTION: The increased risk of falling associated with aging leads to fractures. The risk of falling is increased by impaired eyesight (eg. Glaucoma, macular degeneration), balance disorders (eg. Vertigo), movement disorders (eg. Parkinson’s Disease), sarcopenia (muscle weakness), dementias (eg. Alzheimer’s Disease), cardiac dysrrhythmias, vasovagal syncope, postural (orthostatic) hypotension, and seizures. People with gait or balance disorders and who have had previous falls are most at risk. It is important to remove obstacles and loose carpets in the living areas. Using a cane or walker may also help.

2) Regular weight bearing ENDURANCE EXERCISING is strongly encouraged. Also, aerobics and muscle resistance exercises help to maintain cognition and increase bone mineral density.

3) AVOID SOFT DRINKS. The high phosphorus level, required for dissolving the sugar and for contributing to the taste, causes calcium to be pulled from bone storage in order to for the phosphorus level to be biologically balanced.

4) Consider ALKALINIZING your dietary intake by eating a predominantly vegan vegetarian diet. BE AWARE: Meat, fish, dairy products, refined sugars and alcohol, coffee, tea and sodas all produce acidity in the body. I encourage quitting smoking cigarettes, eliminating or minimizing alcohol and coffee intake, limiting a diet high in animal protein and milk products, reducing salt intake, and increasing the eating of fresh fruits, vegetables and whole grains. Calcium rich foods are necessary on a daily basis. Good sources of calcium include: green leafy vegetables (such as collards and spinach), Soy products such as Tofu, almonds, sesame seeds, poppy seeds, black-eyed peas, blackstrap molasses, figs, bok choy, broccoli and sardines.

5) ***Olive oil increases serum concentrations of osteocalcin (for bone building) and procollagen type 1 N-terminal propeptide (P1NP) which has protective effects against osteoporosis by increasing bone collagen synthesis and bone formation rates. Black Olives, especially a variety called Lucques olives, have a high quantity of “oleuropein”, which nudges mesenchymal stem cells (MSCs) to turn into bone cells instead of fat cells. It also increases osteoblast formation. A proprietary product called “Osteokol Plus” from combines oleuropein along with vitamin K2, magnesium, manganese and zinc. The recommended dose is 2 tabs twice per day with food.


  1. a) Regular weight-bearing exercise helps to strengthen bones.
  2. b)Avoid smoking cigarettes.
  3. c) Limit drinking alcohol.
  4. d) Avoid drinking sodas in order to limit phosphorus intake.
  5. e)Eat a balanced diet with fresh fruits and vegetables, and calcium rich foods such as dark leafy vegetables, legumes, and whole grains. Use milk products (if at all) in moderation.
  6. f) Strongly consider BHRT from mid-life onward under medical supervision.
  7. g)Avoid Calcium Supplementation. But, be sure to have an optimal vitamin D3 level.
  8. h) TESTING: Get a DXA scan to evaluate your bone-mineral density. A quantitative computerized tomogram or QCT scan is a better study, however, it is not widely available. Since it takes about 2 years to notice any changes on these studies, following a urine N-telopeptide/creatinine ratio: NTX Is the best way to evaluate potential bone loss.


  1. a) Chemotherapeutics for fighting cancers can suppress the sex hormones. Anti-androgens, which suppress testosterone levels, and aromatase inhibitors which reduce estrogen activity contribute to bone loss and fractures.
  2. b) Corticosteroids (such as hydrocortisone, prednisone and dexamethasone) are associated with bone loss and increased risk of fractures.
  3. c) Anti-coagulants eg. Warfarin(coumadin) inhibits calcium incorporation into bone and increases calcium deposition in arterial walls.
  4. d) Proton Pump Inhibitors (PPIs) such as Nexium, Prilosec and Prevacid) suppress stomach acid and slow calcium absorption from the stomach. (Also, aluminum antacids can bind phosphate and interfere with calcium metabolism.)
  5. e) Anti-epileptics such as barbiturates and phenytoin (Dilantin) accelerate the metabolism of vitamin D.
  6. f) Anti-Depressants,especially Selective Serotonin Re-uptake Inhibitors (SSRIs) decrease bone mineral density and increase fracture risk.


The more advanced the OP, the more calcium has been released from the bones over time. Calcium goes from the bone to be deposited in the arterial walls. Calcium can also occur in cardiac heart valves leading to a decreased blood flow, cardiomegaly and CHF, and angina pectoris. There is a 5x increased risk of CAD in people who have OP. Also, women with CAD have a 73% increased risk of OP. Vitamin K2 helps to facilitate eliminating calcium from the arteries and depositing it appropriately in the bones.

Arterial stiffening creates a vicious cycle of degeneration and decline. Consequences include: hypertension, myocardial infarctions, strokes, cognitive decline, Alzheimer’s dementia, Parkinson’s disease, kidney failure, non-alcoholic fatty liver disease (NAFLD), and type 2 diabetes. A main contributor of arterial stiffness is calcification. Increased arterial stiffness is a death risk predictor.

Vitamin K2 activates matrix Gla-protein, which inhibits calcium from depositing in arteries. Vitamin K1 (phylloquinone) is found in plants. Some is converted to K2. Vitamin K2 (MK-4) is found in meat, eggs and dairy and is rapidly absorbed and metabolized. It helps to preserve bone health. Vitamin K2 (MK-7) is found in fermented soy beans and fermented cheeses. It remains active for >24 hours. This is significant, because in the absence of vitamin K2, matrix Gla-proteins are quickly inactivated. Processed foods are nearly devoid of vitamin K. Supplementing with vitamin K helps to prevent and reduce arterial stiffness. Arterial elasticity dampens pulse pressure waves, thus, allowing blood to flow smoothly through capillaries without big pressure fluctuations. Arterial stiffening creates pressure induced capillary damage. Thus, hypertension becomes a vicious cycle resulting in end-organ damage.

Sarcopenia is a decline in muscle mass that begins in the 4 th decade of life. Age related sarcopenia increases the risk for falls, fractures, loss of independence, and, consequently, loss of life. As muscle mass falls, the risk of disability, hospitalization rates and nursing home placements greatly increases. There is an estimated 8% loss of muscle mass per decade after age 40, which increases to 15% per decade after age 70. A vicious cycle is triggered: decreased muscle mass and strength leads to decreased physical activity which leads to further muscle loss.

1) Resistance training EXERCISE is an important component to help maintain adequate muscle strength.

2) Another useful component is Beta-hydroxy beta-methylbutyrate or HMB which is a metabolic product of the amino acid leucine. As with bone health, there is a balance between muscle breakdown (catabolism) and muscle build-up or restoration (anabolism). HMB helps to maintain this balance. With aging, HMB declines with a consequent drop in lean muscle mass. Supplementation with HMB helps to preserve and to enhance lean body mass, and promotes improved muscle function. HMB helps to build up muscle and also to prevent its breakdown. HMB also promotes the growth of new nerve branches, and helps to maintain functional connections between nerves and muscles. A typical dose is 1.5 gm twice per day. J Nutr 131(7):2049-52, and Sanz-Paris, A, et. al. , 2018, J Nutr Health Aging 22(6):664-75.> A proprietary product called “Muscle Strength & Restore Formula” is available from containing HMG and Vitamin D3.

3) VITAMIN D3 can complement this by enhancing muscle contractile strength and performance, and one’s balance and coordination. Vitamin D3 also improves mitochondrial dysfunction, and has potent immunomodulatory properties linked to improvement in inflammatory markers. Dosage is guided by serum 25-hydroxy Vitamin D3 levels to achieve an optimal serum level 60 to 100 ng/ml. J Clin Endocrinol Metab 99(11):4336-45 Cangussu LM, et. al., 2015, Osteoporos Int 26(10):2413-21 Gama ZA, et. al., 2008, Rev Saude Publica 42(5):946-56 and, Girgis Cm, et. al., 2013, Endocr Rev 34(1):33-83.>

4) OMEGA-3 FATTY ACIDS contribute to brain health and neuromuscular function. Higher levels are associated with improved muscle size and strength. A typical dose is 6 to 8 gm daily. Am J Clin Nutr 95(2):428-36 Smith GI, et. al., 2015, Am J Clin Nutr 102(1):115-22.>

5) The amino acid derivative CREATINE helps with mitochondrial cellular energy by recycling ATP, and benefits both the nervous system and the muscles. Supplementation with creatine helps to prevent muscle loss and to improve strength and endurance. A typical dose is 5 gm daily. Nutr Res 53:1-14.>

Cooper exam 2

Membrane fluidity is influenced by temperature.
As temperature cools, the membrane switches from a fluid state to a solid state as the phospholipids pack more closely.
The Na/K channel will shut down. Water will rush in.

Membranes rich in unsaturated fatty acids are more fluid than those with saturated fatty acids.
- the unsaturated fatty acid chain introduces a kink in the molecule because of the double bond.
- this prevents the fatty acids from packing closely together.

cholesterol helps separate the phospholipids so that the fatty acid chains can't come together and cyrstallize.

the plasma membrane stabilizes proteins via lipids rafts. A lipid raft contains high concentrations of cholesterol and sphingolipids-- a type of phospholipid-- containing longer and more saturated fatty acid tails.

It organizes the cell's structures and activities, anchoring many organelles

Tubulin is a dimer of alpha tubulin and beta tubulin

composition = One of several different proteins of the keratin family

There must be a signal to the control center and then a signal to an effector that will mediate the response.

the hypothalmus is the control center and will monitor changes in the ECF osmolality

When deviations occur, neural and hormonal signals are sent (effectors)

It is an effective osmole and will drive the osmosis of fluid from the brain tissue.

The fluid in the brain tissue could have been built up due to neurosurgical procedures and cerebrovascular accidents --> causes edema and swelling of neurons.

J = - PA (C1 - C2 )
J = flux (flow) (mmol/sec)
P = permeability (cm/sec)
A = area (cm2)
C1 = concentration1 (mmol/L)
C2 = concentration2 (mmol/L)

The minus sign allows the equation to predict the direction of diffusion

decrease of the radius of the solute will increase the permeability

k = boltzmann's constant
T = the absolute temp
r = the radius of the molecule
n = the viscosity of the medium

If r or n goes up then the diffusion coefficient will go down.

measurement of D can be used to approximate the radius of the molecule.

If protein A is 8 times more massive than protein B then A will diffuse one half as rapidly as B.

This lead to the Einstein equation -

The time required increases with the square of the distance.

To diffuse 10 times farther that means the molcule has to take 100 times longer.

Diffusion is fast only when the distance scale is microscopic.

The way we calculate a substances solubility in water is looking at the oil/water partition coefficient.

You want it closer to one to be very soluble in nonpolar materials.

NO. diffusion of different substances do not interfere with each other. (no competition)

net flux is the amount of movement and it is proportional to to the concentration difference and the permeability of any barrier

This law states that osmotic pressure depends on the concentration of osmotically active particles. The concentration of particles is converted to pressure using ideal gas law

I = number of ions the into which the solute dissociates (ex: NaCl = 2 where as CaCl2 is 3.
C is concentration (mol/L)

To correct for non ideality of solutes we add in the osmotic coefficient which will depend on the nature of the solute.

RBC want to be in 154mM NaCl. and will be isotonic if the solution has the same osmolality.

When the solution is >154mM NaCl the solution is hypertonic to the cell and the cell will shrink. (solution has high osmotic pressure_

This is important for capillary flow rate.

A difference in either hydrostatic or in osmotic pressure across a membrane will cause water to flow.

flow of water = hydraulic conductivity x change in volume flow/pressure

If the number is closer to zero then the solute becomes more and more permeable.

reflection coefficient approaches zero as the soulte becomes more and more permeable.

they need specific protein mechanisms.

Channels will show
1. stereospecificity
- both stereochemical and chemical
2. No Saturation
3. Competition inhibition
Non competitive inhibition
- ligand will bind in a site that will cause a conformational change that will make it harder for the real ligand to bind to the actual site.

1. Non gated channel (pore)
- always open

glucose binds to external site and then the transporter goes through conformational change. Then glucose is pushed through and let into the cell.

2. Secondary active transport.
Energy can be provided by the gradient of another substance that is begin actively transported.
- eg the Na, glucose symporter
- or the antiporter Na/H exchange

How are these gradients established?
The Na and K ions are pumping all the time.

How are these gradients established?
The Na and K ions are pumping all the time.

A single ATPase can drive the secondary active transport of other soultes. By moving Na across the membrane against its concentration gradient, the pump stores energy.
A substance that was pumped out can do work as it leaks back in.
As Na moves back into the cel lin the channel, other substances are dragged along
- they are cotransported into cells lining the small intestine
- Glucose transported this way in intestine.

Antiport - It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by allowing Na+ to flow down its gradient across the plasma membrane in exchange for the countertransport of calcium ions (Ca2+).

As the title implies there is a lot to cover. For now, I wanted to post that paper from the previous post.

Everybody loves a little click bait. And this is click bait. As part of my ongoing “Unifying biology” series I had planned to do a post on essential fatty acids. It was one of the first things I planned on covering. Initially, as you can see below I have a good start. But then I got side tracked by other things I wanted to cover and because the more I read about EFA’s and the history of their research and their relationship with B vitamins the more I realized this particular topic was not going to be easy to neatly fold and place in the drawer. The truth is while I have been silent on the necessity of the classical essential fatty acids, I have been quite adamant of my position on polyunsaturated fats. Essential fatty acids have always been a sort of moot point for me, my assumption was always that if you are eating animal products you are going to get some depending on your favorite animal. That is true. But it turns out there is a story to be told. Stay tuned for the next post in my “Unifying biology” series.

The Ketogenic Diet for Health

I recently had the honour to speak at Low Carb Breckenridge 2018.
The video will be released publicly in the coming weeks, and when it does I will link to it here.
In the meantime, I’m posting my slides, notes and references.

On a high carb diet, you might need to fast to attain an enlightened brain state.
On a ketogenic diet, as a human, that doesn’t appear to be necessary.

The only disclosure I have to declare is that I have some generous supporters on Patreon for my writing.
Thank you!
The supported content is free, so these are donations.

The foundation of our biochemical understanding of ketosis came from experiments in fasted humans and other animals.
For example the groundbreaking work of George Cahill.
I recommend his publication Fuel Metabolism in Starvation ([Cah2006]) which reviews many of his findings.
We continue to learn about mechanisms for how ketosis may increase health in a variety of ways.
However, these origins carry with them an implicit cautionary note, since starvation is generally not recommended, for obvious reasons.
It’s not sustainable indefinitely. It’s stressful to the body. And it can do real harm, sometimes with lasting detrimental consequences.
Even fasting for short periods is surrounded by controversy among experts at this very conference,
because of its potential to do damage to lean mass, and all the potential problems of protein and calorie malnutrition.
If ketosis is like fasting, we had better use it carefully, judiciously, and sparingly.

Many researchers conceptualise metabolism as operating in two complementary phases.
The act of eating or not eating sets off a cascade of hormonal and molecular signals that result in one phase or the other,
Sometimes called the fed and fasting states.
In this paper [Mat2018] they are called the glucose and ketone phases.
Important things happen in both phases.
The fed state is attributed with generating and synthesising things like tissue, mitochondria, and neurons,
But the fasted state is attributed with
clearing broken structures for renewal and repair, and
providing the stimuli to direct the synthesis phase.
Ketosis is normally indicative of the fasting state

Many believe that staying in either phase prolongedly leads to disease.
And so you will hear people talk about metabolic switching, metabolic flexibility, insulin pulsatility, and so on.
Ketosis is normally an indication and a signal of the fasting state, so reason tells us that chronic long-term ketosis is unhealthy.
[Graphic from a blog post on the role of bitter in enhancing the starvation signal.]

Further, it’s been shown in longevity research that many animals use signals of fed and fasting state to
determine whether to reproduce, because it’s a time of plenty,
or to slow aging and shut down reproductive ability until more favorable conditions arise.
So again, the comparison leads us to fear that ketosis may have benefits, but that it comes with a severe cost.
[Graphic from: Insulin Signaling in the Central Nervous System. Daniel Porte, Denis G. Baskin, Michael W. Schwartz. Diabetes May 2005, 54 (5)]

But hold on.
It turns out that starvation is not the only condition where ketosis naturally arises.
Fetuses use ketones in the womb [Sha1985], [Ada1975], [Cun2016].
The placenta is full of BOHB [Mun2016].
Some mammals, humans included, have “ketosis of suckling”. Breastfed infants are in mild ketosis [Per1966], [Kra1974], [Bou1986].
In fact humans of all ages easily attain ketosis without protein or calorie deprivation, so long as they aren’t eating carbohydrates.

This graph shows how quickly the concentration of BOBH goes up in humans when they stop eating.
It’s inversely related to age,
One of the stunning things about it is the orders of magnitude involved.
Look for example at the 6-8 year old children.
If the 4-hour mark is about 0.1 – 0.2,
Then in a day, it’s increased by a factor of 20 or 40.
Newborns, who typically aren’t yet eating cereal, of course, don’t start that low.
Also notice that children don’t even need to miss a day of food to get above the 0.5 mmol level of ketosis
which has been considered the threshold of nutritional ketosis by Phinney and others.
In his presentation here, he has even said that benefits likely begin even below that level.

But they don’t have to abstain from eating for ketosis to happen.
For example, we have results in epileptic children.
The previous standard had been a tightly protein restricted ketogenic diet.
We now know that most children don’t need that for seizure control.
Eating a modified Atkins diet,
which mostly just means they stay in the induction phase instead of adding back carbs,
typically they are in ketosis,
Even though they eat ad libitum [Kos2013].
these are growing children and adolescents.
Unlike with the protein restricted versions of ketogenic diets for epilepsy,
which in some cases have impacted growth,
when protein isn’t restricted, neither is growth [Nat2014].

Even adults have this ability.
To know whether adults are able to stay in ketosis when protein needs are exceeded,
we have to know what our protein needs are.
It depends who you ask.
[Please see also How much protein is enough? ]

I don’t know of a study with the express purpose to find the upper bound of protein for ketosis,
but we can look at studies that recorded it.
Notice that
The figures in this chart are using current weight, not ideal weight,
and many of them are studies in overweight people,
so the g/kg estimates look lower than they would be if using ideal weight.
I’d love to see this question approached systematically, but the survey does at least suggest that
protein levels above our minimum needs based on positive nitrogen balance
still support ketosis.
[Graphic from: ]

When you compare adult humans with other species instead of with children,
It’s even more impressive.
Dogs are in many ways similar to humans.
Our digestive anatomy and physiology is very similar.
Dogs can reach ketosis from fasting, but it takes longer, and never attains the same level [Cra1941].
With adequate protein in the diet, it doesn’t happen to any significant degree at all [Rom1981], [Kro1973], [San2015].
I have spoken with staff at KetoPet Sanctuary, who treat cancerous dogs with ketosis.
They tell me that it is challenging to keep dogs in ketosis.
They have to use a combination of protein restriction, calorie restriction, and MCT oils.
It takes constant monitoring and adjustment.

Rodents are often used in experimental conditions, and I do think they are very useful models,
but it takes more protein or calorie restriction to achieve an appropriate degree of ketosis than it would with humans.
The line between adequate protein and too much for ketosis is almost vanishingly small [Stephen Phinney Q&A Low Carb Cruise 2017],
and the levels they achieve are again much less spectacular [Benjamin Bikman, personal communication].
Similarly, almost any level of dietary carbohydrates is enough to shut down ketosis [Richard David Feinman, personal communication].
Some researchers believe this has to do with their relative lack of brains,
Since ketosis has been thought of as a way to spare glucose for the brain.
But ketosis isn’t the only solution for that.

Obligate carnivores are always on very low carb diets,
so you might think they are always in ketosis,
but that’s not at all the case.
In fact they are specialised at gluconeogenesis,
that is, getting all their energy needs met by converting protein into glucose.
Protein needs tend to be high.
Cats have much higher protein needs than omnivores
and surprisingly, they don’t adapt well to reduced protein or fasting [Cen2002].
They don’t seem to have good mechanisms to compensate for the various amino acid and vitamin deficiencies that develop,
so they suffer from ammonia toxicity, methylation problems, and oxidative stress.
They do produce ketones fasted, but they don’t seem to use them in a productive way.
and they actually accumulate fatty acids in the liver when fasted
the opposite of what humans do,
Because they are still producing glucose,
they become like human type two diabetics.
Dolphins are particularly interesting because they have really large brains,
and they eat a diet that would be expected to be ketogenic if fed to humans.
However, they don’t seem to even generate ketone at all, not even when fasting.
Instead, they ramp up gluconeogenesis [Rid2013].
They keep their bodies and their brains going by increased glucose.

When faced with this observation that humans use ketosis even when they don’t have to for glucose production,
one obviously wonders how this happens from a mechanistic standpoint.
I have never seen the question raised in the literature, let alone answered.
If I were to take a guess, I’d say it probably happens somewhere in this process.
CPT1A is a kind of gatekeeper, transporting fatty acids into the mitochondria for oxidation.
This is normally a necessary step in the creation of ketone bodies.
The coenzyme malonyl-CoA inhibits CPT1A [Fos2004].
The functional reason it does that is because malonyl-CoA is a direct result of glucose oxidation
and is on the path to de novo lipogenesis.
It could be inefficient to be both generating fat and oxidizing it.
So this is a convenient signal to slow entry of fat into the mitochondria.
However, its action is not stictly linear.
It uses hysteresis.
Hysteresis is a way of preventing thrashing back and forth between two states at the threshold of their switch.
For example, if you set your thermostat to 20°C,
you would not want the heater to be turned on when the temperature drops to 19.999
and turned off again at 20.
This would result in constant switching.
Instead, a thermostat waits until the temperature drops a little lower
before activating the heater, and heats it a little more than required before deactivating it.
Hysteresis is implemented in CPT1A by its becoming insensitive to malonyl-CoA when levels of it are low [Ont1980], [Bre1981], [Gra1988], [Gre2009], [Akk2009].
That means that once CPT1A becomes very active in transporting fatty acids,
it takes time before the presence of malonyl-CoA will inhibit CPT1A at full strength again.
That means that fluxuations in glucose oxidation,
or small, transient increases in glucose oxidation
don’t disturb the burning of fatty acids or the production of ketones.
It could be the case that humans develop more insensitivity to malonyl-CoA under ketosis than other species do,
allowing them to metabolise more protein without disturbing ketosis.
Among humans, this is case in populations such as some Inuit with the Artic variant of CPT1A.
That mutation slows down CPT1A activity immensely.
This was permitted by their diet which was very high in
polyunsaturated fats from sea mammals.
Polyunsaturated fats upregulate fatty acid oxidation by a large proportion compared to saturated fats [Cun2002], [Fra2003], [Fue2004],
so this mutation would not necessarily have been disruptive of ketosis in that population when eating their natural diet [Lem2012].
But a second effect of the same gene further decreases the sensitivity of CPT1A to inhibition by malonyl-CoA.
That means they are less likely to be knocked out of ketosis by high protein intake.
I will go into this in much greater detail in my upcoming talk at AHS18.

The second question that comes to mind is what does this difference imply about our evolutionary environment?
I would suggest that for humans to have developed the ability to stay in ketosis even with more than sufficient protein intake,
we must have at least have spent frequent long periods in a condition of very low carbohydrate, high fat access, either exogenously or endogenously,
and more than adequate protein as a dietary norm.

Finally why?
Why do we stay in ketosis even when we have enough protein to
feed the brain glucose without compromising lean mass.
Or to put it another way:
Other animals continue to burn through lean mass with or without ketosis
until they have enough protein to fuel everything with glucose.
I suspect it has something to do with our brains.
I’ll suggest a few hypotheses along these lines.

The next few slides summarise topics I’ve spoken and written about before. Please see
Optimal Weaning from an Evolutionary Perspective
for more details and links about brain growth and our acquired reliance on meat during evolution.

Our brains are big.
Primates are already big brained for mammals,
and from that starting point our brains tripled in size over the course of a couple million years.

Brains take a lot of energy to run,
To accommodate that we made a trade.
Herbivores get most of their energy from fibre by fermenting it in the gut.
But this isn’t very efficient, because intestines also take a lot of energy.
So we transferred to a strategy of eating fat directly
Giving up colon size for brain size.
To get enough fat directly, we had to eat meat.
[Graphic from: Milton, Katharine. “Nutritional Characteristics of Wild Primate Foods: Do the Diets of Our Closest Living Relatives Have Lessons for Us?” Nutrition 15, no. 6 (June 1999): 488–98.
version enhanced with colour by ]

Energy is one reason we might want to stay in ketosis.
Human brains use an extraordinary amount of energy, at least 20% in adults
Some 40g/day of that has to come from glucose,
because it houses some of the few types of cells that are glucose bound.
But the rest can be met by ketones.
Our brains use ketones preferentially when they are available.
Though in the modern context, that’s not very often.

If adult brains weren’t large and expensive to run enough,
Consider how much bigger the brain of a child is relative to the body.
[Graphic from:,-and-sidways,-and-around).aspx ]

This may explain why human babies are so fat.
These graphs are from a paper exploring different hypotheses about baby fat [Kuz1998],
one of them being to supply the brain energy in the form of ketones.
The one on the left shows % body fat at birth in different species.
Newborn humans come in at 15% fat.
That actually gets higher in the first several months of life,
Peaking at about 25%.
The only other primate in that graph is the baboon infant at 4%.
The one on the right is what percent of oxygen metabolised by the whole body is going to the brain:
Humans at birth 60%, human adults 20%,… the adult chimpanzee comes in at about 9%.

Another consideration is building materials,
since our brains are made mostly of fat and cholesterol and we know that ketones are used to synthesize those in situ.
The diagram here [Cot2013] shows pathways of how ketones can be generated, oxidized, or used to make fat and cholesterol.
Fetuses and newborns use ketone bodies extensively,
as I mentioned previously.
But the point here is that it’s not just because they’re using it for fuel.
It’s also a source of structural components.
In light of that,
It seems like a reasonable hypothesis that ketogenic capacity in humans is so pronounced in childhood because the brain is developing,
And ketones are for some reason the preferred material.

Other species tend to wean at the time when brain growth stops.
That means that for them ketogenesis stops at the same time brain growth stops.
In humans brain growth doesn’t stop at weaning [Ken2005], [Mar1982], [Dob1973], [Dek1978].
Even after it reaches about full size in adolescence, it continues to change structurally well into adulthood.
However, quantitatively, this structural cost is very small compared to energy considerations [Kuz1998],
And so that hypothesis seems relatively weak on its own.

Another set of ideas comes from the metabolic effects we see in the lab and clinic.
Some of the strongest, most consistent effects we’ve seen therapeutically from ketogenic diets take place in the brain,
These are just a few metabolic changes relative to a high carb diet.
Each can have profound effects on the workings of the brain.
I do want to draw attention to the last one about availability of arachadonic acid and DHA.
These are important for the brain as they make up the phospholipids,
and they are subject to a lot of turnover.
Each of these effects has been proposed as a solution to the mystery of why a ketogenic diet treats epilepsy so effectively [Bou2007], [Nyl2009], [Mas2012], [deL2014].

But it’s not just epilepsy that ketosis is good for.
Epilepsy is just the condition with the most research, and the widest acknowledgment.
Other conditions for which at least some evidence supports improvement via a ketogenic diet
include neurological disabilities in cognition and motor control [Sta2012]
the benefit here may have to do with the proper maintenance of brain structures such as myelination
(Recall phases: tear down damage, rebuild)
Survival after brain damage, the hypoxia of stroke or blows to the head is improved in animal models [Sta2012].
There is even animal evidence that brain damage due to nerve gas is largely mitigated by being in a state of ketosis during the insult [Lan2011].
Again, this suggests a structural support and resilience provided by a ketogenic metabolism.
Resilience comes in part from not being as susceptible to damage in the first place,
and that could be from reduced oxidative stress when using ketones for fuel.
Ketogenic diets as a treatment for cancer are controversial, but some of the best evidence in support of it comes from glioblastomas.
See e.g. [Zuc2010], [Sch2012].
This could be due mostly to the hypoglycemia stalling the rate of tumour development.
And to venture into an area less well studied, but of critical importance given the epidemic that would be more apparent were it less taboo,
there is preliminary evidence in the form of case studies that ketogenic diets may be promising treatments for many psychiatric illnesses too, for example, [Kra2009], [Phe2012].
Given that anticonvulsants are also used to treat bipolar, and the solid results of ketogenic diets on epilepsy, this may not be surprising.
Additionally, the enhanced availability of AA and DHA may play a crucial role
Because these fatty acids are critical for the brain, and dysregulation in their flux has been associated with bipolar disorder and schizophrenia.
See e.g. [McN2008] and [Pee1996].

I would almost like to call a ketogenic diet a brain-growth mimicking diet.
The question of how and why humans are so ketosis prone may lead to interesting new insights about us as a species.
We seem to avoid giving up ketosis as long as possible.
only halting it when we take in so much glucose exogenously that we have to store it.
It seems likely that it facilitated the evolution of our brains,
that organ that makes us so different from other animals that we sometimes forget we are animals.

Returning to the importance of metabolic switching between glucose and ketone mode,
there seems to be a false dichotomy.
There is a stage that doesn’t usually come up in discussions of fed and fasted, and that’s the “postabsorptive” phase.
The absorptive phase on a high carb diet lasts about 4 hours.
That’s how long it takes to clear away the exogenous glucose.
Only after that can you start the postabsorptive phase,
Marked by using glycogen as your source of blood sugar.
Other than overnight, SAD dieters typically don’t go more than 4 hours without eating, and so we don’t get very far.
But if you are on a protein and calorie sufficient very low carb diet, then even after eating, your glycogen stores don’t get that full in the first place.
I don’t know how long it takes to get from the meal to maximum glycogen storage,
But essentially, we should expect to get to a SAD dieter’s postabsorptive almost immediately after a meal, and easily into the ketogenic zone every day.
You can accentuate this by demanding more energy between meals (exercise)
or eating less frequently, for example only once or twice a day.
Interestingly, this often naturally happens to ketogenic dieters.
( Graphic from [Cah2006] )

On a high carb diet, you might need to fast to attain an enlightened brain state.
On a ketogenic diet, as a human, that doesn’t appear to be necessary.


In the interest of time, I did not do my usual practice of end-to-end citations.
I will probably return to fix that later!