Vitamin C, Guinea Pigs, Limeys and Gut Worms

Scurvy and the Need for Vitamin C

Old timey sailors got the symptoms of scurvy, defective collagen and connective tissue, presumably because they stopped eating leafy greens that contained the needed vitamin C, aka ascorbic acid.  Primates/humans and guinea pigs are among the few animals that lack the ability to make their own ascorbic acid and therefore must eat a diet with a minimum amount of the vitamin to avoid a deficiency disease.  This is the conventional wisdom partially based on observation and experiment, but also founded on conjecture.

Parasitic Gut Worms Were the Natural Source of Vitamin C

I don't believe that vitamins are essential ingredients of a healthy diet, but rather I contend that all of the necessary nutritional chemicals are produced by the microorganisms of the gut.  I have previously discussed the gut flora (bacteria and fungi) as the source of most vitamins.  I wish to expand vitamin production to include gut fauna (animals).  I think that it is likely that intestinal worms are the historically natural source of human vitamin C.

Gut Bacteria Control the Development of the Immune System

The human gut actively communicates with the biofilms of bacteria and fungi that form a lining for the healthy gut.  The aggressive cells of the immune system that attack invading pathogens, develop in response to chemical signals from filamentous gut bacteria, and the suppressive cells of the other half of the immune system, which prevents attack on innocuous food antigens (to avoid allergies) or the human body itself (autoimmunity), develop in response to Clostridium ssp.  Thus, the immune system can be highly compromised, if the gut flora bacteria are damaged, e.g. by antibiotics.

Vitamins are Signaling Chemicals of Gut Biofilms

The communities of bacteria in gut biofilms are self-regulating by exchanging chemicals called quorum sensing signaling molecules.  Different species of bacteria and fungi in the biofilms produce and detect different chemical signals.  Since the biofilms are in intimate contact with the cells that line the gut and absorb dietary nutrients, it is not surprising that the biofilm signaling molecules are also absorbed by intestine cells.  Many of these biofilm signal molecules are vitamins, e.g. the B vitamins.  Gut bacteria are the natural source of most vitamins and healthy gut flora eliminates the need for eating vitamins in food or supplements.  Vitamin deficiencies are a symptom of a damaged gut flora.  Antibiotics and vitamin supplements can damage healthy gut biofilms.

Dietary Soluble Fiber Feeds Gut Flora

The human gut flora consists of a couple of hundred different species of bacteria in each person.  Those bacteria in aggregate can produce about a hundred thousand different proteins that focus on the digestion of food molecules that the upper gut cannot digest and absorb.  Since the upper gut can only digest proteins, fats and starch/sugars, that means that the gut flora eat the rest, undigested plant/animal polysaccharides.  Soluble fiber is the plant polysaccharides, e.g. inulin and pectin, that are digested and feed the gut flora.  The undigested polysaccharides include cellulose.  Lignin and some other plant polymers also pass through the gut and are eliminated.  The undigested stuff is called insoluble fiber and it also has bound phytate, which drags some metals such as zinc out with it.  That is why insoluble fiber, such as wheat bran, is not nutritious or healthy.  Insoluble fiber is also a minor contributor to the bulk of stools, which are made up predominately of the gut bacteria that have grown on soluble fiber.

Sea Voyages Damage Gut Organisms

The hundred of different species of bacteria in the gut change in proportions to adapt to different foods in each meal.  If the diet is fairly constant, then the diversity of the population gradually increases, just as the diversity of species in a tropical rain forest is greater than in a temperate forest.  This also explains why gut flora diversity is far less in the USA than in other parts of the world.  Americans are encouraged to eat diverse diets in the search for vitamins and superfoods.  Each dramatic change in diet makes it hard for the gut flora to adapt and the remaining bacteria are those that are generalists.  It might also be expected that early sailors who changed their diets dramatically when they went to sea, ended up with a highly compromised ship-board gut flora (and fauna.)

The Perils of Hygiene

I have a fascination for stories involving the potential of rampaging tigers.  Images of a tiger attempting to drag a hunter from his seat on an elephant or the need of a colleague to employ an armed bodyguard when capturing crabs from Malaysian Mangrove roots at night, linger in my imagination.  I still think about the report of Wallace guarding his derrière while collecting beetles in Bukit Timah, Singapore, in “The Malay Archipelago.”  Humans tend to be incompatible with lions and tigers and bears, and we wipe them out.  We do the same with bacteria, fungi and worms.  We wash our hands, flush the toilet, use hand sanitizers, kill weeds, spray pesticides, grow meticulous lawns/crops, dose ourselves with antibiotics and cleanse.  We are free of the threat of tigers, but we failed to see what else was lost during their extermination.

Probiotics Don’t Fix the Damage of Antibiotics

Antibiotics ravage gut flora.  It is no surprise that a course of antibiotics frequently leads to diarrhea or constipation, since normal stools require normal gut flora.  What is surprising is that physicians, e.g. Dr. Oz, seem to think that antibiotic decimated gut flora can be fixed with probiotics.  Sure, probiotics can provide a temporary bandaid, since Lactobacilli that would normally live on milk in the gut of newborns, are able to provide most of the functions of an adult gut flora.  But probiotics don’t survive in the adult gut and probiotics to not repair damaged gut flora.

Changes to Gut Flora are Permanent, Unless....

Gut bacteria are like wolves in Idaho.  If you don’t bring in new wolves and stop hunting them, you never again have wolves in the wilderness.  If you don’t bring in new bacteria and feed them, damaged gut flora does not repair.  Antibiotic treatment that wipes out the bacteria needed for development of the suppressive immune system will lead to autoimmune disease.  However, repairing the gut flora by flushing in new bacteria (fecal transplant) or gradually reintroducing new diverse bacteria with fermented foods, can also reverse autoimmune diseases as the immune system is repaired.

Parasitic Worms Were Lost at Sea

We think that vitamin C is only provided by plants that we eat, because we didn’t notice what was lost when we cleaned out the worms that typically inhabit the human gut.  Who would have thought that those inconvenient creatures were there for our own good?  We unknowingly compensated for the lost vitamin C production of the worms by incorporating foods rich in vitamin C in our diets.  Shipboard diets that eliminated bowel worms were augmented with limes rich in ascorbic acid.

Guinea Pigs Also Need Worms

It is interesting to note that the experimental animal used to replicate human nutritional requirements for vitamin C is the guinea pig, which is one of the few animals (in addition to bats and primates) that doesn’t make its own.  It is also interesting that guinea pigs (and bats?) commonly have intestinal worms that have to be purged from their bowels before they are used in the lab. 

Gut Flora and Fauna Provide Vitamins

My bottom line is that a normal, healthy gut contains all of the bacteria, fungi and worms to supply all of the needed vitamins.  I do, however, think that dietary vitamin C is a good replacement for one function of intestinal worms, even though I will be watching for other benefits ( Helminth therapy?) that were lost with the removal of these parasites.

Some points:

•   Many vitamins are signal molecules for gut biofilm quorum sensing.
•   Intestinal worms are the typical source for human vitamin C.
•   Vitamin D is a hormone produced in the skin in response to sunlight.
•   Vitamin supplements are unnecessary (problem?), if gut flora and fauna are healthy.
•   Modern diets and hygiene eliminate gut parasites, so food needs to supply vitamin C.
•   Chronic inflammation consumes vitamin C and eliminates production of vitamin D.

Baldness Cure: Low Dose Naltrexone?

Naltrexone can be used to block opioids and provide the basis for treatment for drug abuse, but in low doses (LDN) it provides a paradoxical increase in natural endorphins that reverses inflammation and provides an effective treatment for autoimmune diseases, e.g. MS.

Receptors
A recent anonymous post brought the role of cannabinoid and opioid receptors in baldness to my attention. The relationship between these receptors, inflammation and autoimmunity is very complex. The heat and cold sensors, which also bind capsaicin and menthol, appear to be mediated by endorphins. Acupuncture also seems to function by similar mechanisms and is inhibited by high dose Naltrexone.

Low Dose Naltrexone
A side effect of high dose Naltrexone (e.g. 50 mg/d) is hair loss. Low dose Naltrexone (e.g. 1 mg/day, taken at night) appears to stimulate hair production and it may reverse the effects of Finasteride, since LDN improves libido.

Endorphin-Suppressed Inflammation
I would expect hair loss to be prevented/reversed by topical treatments that block inflammation and autoimmune attack on hair follicles. Curcumin, from turmeric, blocks NFkB and appears to help hair loss. Capsaicin can block inflammation via endorphin production and also helps hair loss. I would also expect that topical menthol and castor oil would reduce hair loss.

Anti-Inflammatory Diet
The anti-inflammatory diet that I recommend, may not be sufficient to block hair loss, but it may provide a good foundation for other anti-inflammatory treatments. In fact, other topical treatments may not be effective unless chronic, diet-based inflammation is eliminated. It may also be important to reduce oxidative stress by optimizing glutathione and vitamin C.

I would appreciate comments by others who may have experience with LDN and balding.

Medical Advice Is Just Wrong

Medical advise says to avoid sun, fats and red meat, but to drink lots of water, eat polyunsaturated vegetable oils and focus on the grain-rich bottom of the food pyramid. The medical advice is simply wrong and is not supported by the biomedical literature. A recent article in a major medical journal claims that about 90% of medical advice is not based on clinical research studies, but rather represents the opinions of experts who are supported by the health industry. Most research is conducted to support products. Unfortunately the advice that comes from medical societies is not healthy.

Here I will provide a few examples to illustrate that medical advice is frequently, if not usually, wrong about diet, nutrition, cause of disease, appropriate drug use and whether to spend a few unprotected moments basking in sunshine.

The Sun Is Not the Enemy, but Sun Blockers Can Increase Skin Cancer

Medicine is supposed to provide instructions on how to handle dangerous chemicals and procedures safely and to enhance health. Solar radiation is dangerous and will cause skin cancer if used inappropriately, but solar radiation is also needed to produce vitamin D in skin. The public response to the medical mandate to limit solar exposure to reduce radiation-based skin cancer resulted in increased use of solar-blocking lotions. Unfortunately, the result was that some people spent more time in the sun, assuming that avoiding sun burns meant that they were avoiding skin cancer. Unknowingly they had shifted their skin exposure down from doses sufficient to kill cells and cause inflammation, to levels sufficient to just cause solar mutagenesis -- the lower exposures were optimal for skin cancer production.

Spare the Sun and Spoil the Child

Babies and children are the most sensitive to solar radiation induced skin cancer and need protection from over exposure, but the public response to medical advice has been to avoid prudent exposure to the sun. Now kids in the U.S. are showing symptoms of rickets, a vitamin D deficiency disease common during early industrialization, in which air pollution, urban poverty and factory work limited solar exposure. Babies in strollers are completely covered. One frightening consequence of this over-reaction could be a resurgence of poor bone growth that in the 1920’s resulted in the development of the now-trendy Cesarean section procedure to accommodate women with malformed pelvises due to rickets.

Rickets Is Rampant

Ubiquitous vitamin D deficiencies due to inadequate sun exposure is compounded by inadequate sources of dietary vitamin D and inappropriate medical interventions. Most vitamin D deficiencies go unnoticed, because the typical symptoms of deficiency mimic other forms of inflammation. When serum levels of vitamin D are actually measured and found to be inadequate, supplements of 600-1000 iu/day of vitamin D3 are prescribed. Unfortunately, there is seldom followup testing and a recent study indicates that most treatment for vitamin D deficiencies is inadequate -- much higher doses, ca. 2-5000 iu/day are required to reach optimum levels. Most people are and remain vitamin D deficient.

Scourge of Scurvy

Vitamin C deficiencies are also a problem. Most people get enough vitamin C to avoid losing their teeth (vitamin C is needed for collagen production), but subclinical deficiencies still produce chronic inflammation. The major cellular anti-oxidant is glutathione, but vitamin C is another major defense against reactive oxygen species (ROS). An increase in ROS triggers oxygen stress and inflammation. Deficiency of vitamin C indicates that more vitamin C is being used up than is being replenished in the diet. Numerous metabolic disturbances associated with other deficiencies or infections can result in vitamin C depletion and chronic inflammation. Most people are vitamin C deficient.

Vegetable Oils Are the Problem, Not the Cure

Medical advice to avoid saturated fats in meats and shift to omega-6-rich vegetable oils is a major contributor to chronic inflammation and modern degenerative diseases. The original claimed association between saturated fat consumption and cardiovascular disease was tenuous, but produced a glacial shift in diet toward consumption of omega-6 fatty acids, e.g. corn and soy oils. The medical dependence on measurements and treatments of LDL, has outweighed the actual data in the biomedical literature -- LDL levels are not important in cardiovascular disease. Drugs that lower LDL, serum cholesterol, are only effective in reducing heart disease, if they lower LDL by lowering inflammation. The risk factor is the inflammation, not the LDL level. Agricultural practices that use grain over grass further reduce the omega-3 fatty acid content of meat and increase the inflammatory omega-6 fatty acid level.

Statins Are a Problem, Not the Cure

Statins are broad spectrum disrupters of the function of many different enzymes and proteins. They were originally isolated from fungi based on their ability to poison bacteria, i.e. they are antibiotics. They disrupt fat metabolism and thereby lower LDL levels, but they also cause many undesirable and potentially dangerous side-effects. One of these actions is to block inflammation triggered by activation of the inflammation transcription factor, NFkB. By blocking NFkB activation, some statins lower inflammation and thereby decrease cardiovascular disease. This activity is similar to aspirin, which acts on COX-2 as well as directly on NFkB. Both statins and aspirin (NSAIDs) have multiple activities on numerous areas of cellular metabolism. The activities of both include reduction in inflammation, but they also produce other undesirable side effects. Chronic inflammation is better treated by diet, exercise and traditional herbs and spices, rather than more dangerous statins.

Water Is Miraculous, but just Satisfy Your Thirst

If you are thirsty drink tap water. There is no improvement in health by drinking some extra amount of water each day. Drinking water in plastic bottles from magical sources provides no improvement in health. Much of the “spring water” with designer labels is only locally bottled tap water. The plastic bottles are an ecological disaster and the “purified” water in the bottles is contaminated with compounds leaching from the bottles. If you want a constant source of water, bottle your own tap water. If you want to avoid the minor contaminants added to avoid bacterial contamination of municipal water supplies, use a simple point-of-use filter.

Starch Is the Problem

Starch is rapidly converted into blood glucose and that spike in blood sugar causes major problems. The foundation of the old food pyramid, grains, is no different than table sugar in being hyperglycemic, i.e. rapidly raising blood sugar. A large muscle mass and high physical activity can minimize the rise in blood sugar, by using up the sugar for muscle energy as it enters the blood. Unfortunately, most people do not have enough muscle and are not physically active enough to be protected from the starch and sugars in their diets. The result is chronic inflammation in the form of metabolic syndrome and degenerative diseases, e.g. diabetes, allergies, depression, acne, infertility, cardiovascular disease, autoimmune diseases and cancers.

One slice of white bread with a meal may be too much starch for some people. The maximum for most people is: one half of a ripe banana or one half cup of a starchy entree such as pasta, potato, rice, or one of the two buns on a burger. The starch needs to be spread over several meals. Eating too much starch with a meal produces intense hunger, as the blood sugar rapidly rises, triggers insulin release and a subsequent crash in blood sugar. Don’t believe any of the diets that recommend starches to replace fats. Many “lite” diet foods are more unhealthy than the higher fat originals that they replace. Replacing saturated fats with saturated starch is dangerous. The temporary high blood sugar level produces the increased health risks routinely associated with diabetes.

Insufficient Food Is the Problem -- Insufficient Minerals

It takes only 2-3000 Calories per day to energize most people. That means that most people can eat their day’s worth of calories with the sandwich plate at a fast food restaurant. That meal will provide an overdose of starch and sugar, but will be deficient in vitamins and minerals. A major dilemma is that it takes so little food to provide adequate energy for a low activity lifestyle, that the choice must be made between obesity and vitamin/mineral deficiencies. Eating just enough to satisfy energy needs results in deficiencies, but eating more to avoid vitamin/mineral deficiencies, results in obesity. The only solutions are to eat supplements to supply needed vitamins, minerals, antioxidants, etc. or increase physical activity and body muscle mass, so that more can be eaten without producing obesity. For most people the solution is a combination of increased physical activity and supplements. That combination is also found to reduce inflammation and the associated risk of degenerative diseases.

It’s the Stupid Diet

The obsession of medicine with drugs and invasive procedures provides additional health risks for patients. Many researchers complain in the biomedical literature that there is insufficient focus on the cause of disease and too much emphasis on the study of the impact of specific drugs on disease symptoms. The result is that in most cases the symptoms are treated and the disease becomes chronic. Of course this also means that the patient is a permanent consumer of health care.

The foundation of all healthcare should be to improve the lifestyle of the patient. Diseases don’t just happen. The biggest contributions of immediate family to disease of an individual are not defective genes, but rather defective diet and lifestyle habits. Our healthcare system is too no fault. People are sick because there is something wrong with how they live. They eat too much or they eat the wrong foods. They don’t get enough exercise to develop a healthy muscle system to support their joints. Most importantly, bad diet and lifestyle choices produce chronic inflammation. Drugs can reduce chronic inflammation, but will also produce additional side effects that will also require interventions. It makes more sense to attack the original causes of inflammation.

Every treatment program should address the pervasive contribution of chronic inflammation by including a diet and lifestyle inventory and an assessment of the cause of the disease that is being treated. An appropriate anti-inflammatory diet and a path toward a more active lifestyle should be the foundation of every treatment plan.

A Paleolithic Perspective on Biomedical Literature

Homo sapiens seems to be inflammation prone, based on its assortment of biochemical deficiencies. All of the following lead to inflammation: hyperglycemia, vitamin C deficiency, fish deficiency, vitamin D deficiency, grilling meat. Is this an adaptation to agriculture and high population/communicable disease risk?

I was just visiting Diet Rosso and his article on the paleolithic diet flashed me back to some thoughts that I had on the evolutionary benefits of inflammation. So, Rosso made me think about this.

Inflammation is a big health problem in the US. All of the major diseases are inflammatory and all are exacerbated by the inflammatory US diet. But why is the fast food diet so inflammatory? Why is our corn/soy agricultural economy so hazardous to our health?

Corn and soybeans provide a good balance between carbohydrates, fats and protein. The amino acid composition of the combo is also fairly good, and corn and soy oils are high is unsaturated fats. So why does a corn/soy diet lead to degenerative and autoimmune diseases?

I think that the answer is that inflammation is getting a bad rap; as long as our immune system produces effective local responses to pathogens, we are pleased, but when the immune system cranks it up in response to a deluge of disease, we complain. I argue that our current inflammatory response to fast food is just a slight embellishment of the first dietary-based increase in inflammation that provided adaptive protection against the dangers of agriculture.

As I see it, agriculture had a series of dramatic impacts on the evolution of plants, animals and humans, in particular. Taming of plants and animals altered the human diet. Agriculture also institutionalized grilling and grouling, which meant bringing together carbs and protein at high temperatures. The result was an increase in dietary starch, seed/grain oils and advanced glycation endproducts (AGEs). There was also a decrease in fish, leafy vegetables and complex carbohydrates/fiber. Agriculture also led to a dramatic increase in population density.

I imagine that the first villages or very large family groups that resulted from sustained planting of harvestable crops resulted in plagues. Lots of people in close proximity with minimal hygiene is a prescription for infectious disease. Agricultural development required an immunological adaptation to higher loads of communicable diseases. That adaptation was inflammation triggered by agriculturally-associated diets high in starch and low in browsed veggies.

Hunting/gathering, especially along coasts, provided dietary vitamin C, as well as a high ratio of omega-3 to omega-6 fatty acids. Early humans defective in the ability to synthesize vitamin C or omega-3 fatty acids, would not suffer if they ate plenty of leaf veggies. Wild fish and game, as well as leafy veggies, have a high ratio omega-3 to omega-6 fatty acids, so these people would be safe from inflammation-based disease and infertility.

Agriculture focused on seed harvest results in a dramatic shift in diet and disease. Communicable disease was not a problem for hunter/gatherers, because of the necessarily widely distributed small population groups. Agriculture concentrates populations around the crop lands and increases the benefits of physiological energy expenditures on heightened immune activity to provide consistent protection against pathogens. Agriculture required chronic inflammation for disease protection.

Inflammation triggered by cues in the agricultural diet would have a high selective advantage. Individuals who increased their chronic level of inflammation in response to high blood sugar, compounds produced during cooking, i.e. AGE, vitamin C deficiency, vitamin D deficiency (low exposure to sun) and/or omega-3 oil deficiency, would have survival advantage in high population densities associated with agriculture.

The fast food diet is nothing more than an exaggeration of the agricultural diet and it produces and an exaggeration in the human adaptation to agriculture, high chronic inflammation and a suite of inflammatory diseases. Metabolic syndrome is another name for high chronic inflammation. Obesity is inflammatory. A sedentary lifestyle is inflammatory and aging is a suite of symptoms associated with inflammation. Hunter/gatherers didn’t show the same signs of aging as modern humans, and probably had comparable longevity (although there were many other risks.)

Lastly, I want to ponder the modern decline in fertility. Fertilization and implantation requires suppression of inflammation in the female reproductive system. Semen is uniquely rich in omega-3 oils and women who have a high frequency of unprotected coitus with a man with a high level of omega-3 in his semen, are much more likely to become pregnant and carry a pregnancy full term. The fetus requires high levels of omega-3 fatty acids for brain development and can rapidly deplete the omega-3 fatty acid a mother with a deficient diet. Omega-3 deficiency is associated with preeclampsia.

Early males and females with an inflammatory agricultural diet would tend to be infertile, because of omega-3 oil deficiencies and chronic elevated inflammation. Periodic exposure to an abundance of omega-3 fatty acids, such as feasting on migrating salmon, would synchronize fertility and subsequent births. It is humbling that a current research program in land-locked regions of South America uses cans of anchovies to remedy the same pregnancy problems that plague North America and its inflammatory fast food diets.

Oxygen Starved

Hypoxia is the low oxygen environment of tissue lacking blood vessels. Oxygen is needed as the final, low energy electron acceptor of the aerobic metabolism of mitochondria, but it is also needed to make hydroxyproline, the special amino acid of collagen. Expression of genes in response to the oxygen available is controlled by a transcription factor, HIF.

The oxygen that we breathe is used as a place to dump the low energy electrons produced by mitochondria as ATP is using energy from high energy electrons of carbon and hydrogen present initially in glucose. In the absence of oxygen, fermentation can use glycolysis and dispose of the low energy electrons in the form of products such as lactic acid or ethanol. Aerobic metabolism, in the presence of oxygen, is much more efficient (more ATP per glucose), so fermentation is only used when oxygen is depleted, as in the case of exhausted muscles.

Low oxygen, hypoxia, is also encountered in tissues isolated from the oxygen-distributing vascular system. Cells that constantly secrete new cartilage, chondrocytes, are prevented from ready access to oxygen, because the tensile strength of cartilage would be sacrificed by mechanically weak blood vessels. This is paradoxical, because cartilage also contains large amounts of reinforcing collagen fibers, that require oxygen. Consumption of oxygen by aerobic metabolism must be restricted in chondrocytes to reserve diffusing oxygen for collagen synthesis. This also predicts that energy metabolism in chondrocytes exposed to ample oxygen, as in developing bone or wounds, must be drastically different from metabolism in mature chondrocytes that may be centimeters away from the nearest blood vessel.

Oxygen is used in collagen production to produce the hydroxyproline of the repeated triplets of amino acids that form the spiral threads of collagen. Every third amino acid is glycine and prolines that precede a glycine are converted to hydroxyproline by an enzyme that uses vitamin C. Thus, scurvy, a vitamin C deficiency, is characterized by weakened cartilage, e.g. loose teeth. The high hydroxyproline content of collagen also explains the low nutrition of gelatin, which is denatured collagen.

The trigger for shifting a cell to a low oxygen metabolism, is production of hydroxyproline in the transcription factor called, hypoxia-inducible factor, HIF. If oxygen is abundant, a particular proline in HIF is converted to hydroxyproline, and this modified HIF is quickly degraded in proteosomes. Lack of oxygen prevents modification of hydroxyproline and HIF successfully migrates to the nucleus, binds to the promoter sites of specific genes and changes the pattern of proteins in the cell.

HIF is important in all diseases that result in damage to blood supply. Tumors, for example stop growing when they reach a size that limits the oxygen that can diffuse from surrounding blood vessels to the center of the tumor. Hypoxia in a tumor causes release of angiogenic, blood vessel proliferating, cytokines from the tumor. HIF induces the production of angiogenic molecules. In the opposite direction, damage to cartilage that results in increased oxygen, will turn off HIF and prevent the secretion of mature cartilage by chondrocytes. Chondrocytes also secrete proteins that actively block the formation of blood vessels, e.g. endostatin, the end of one of the collagen.

Several drugs are now being developed to block HIF activity and starve cancers. These drugs will also modify the metabolism of many other cells that use HIF. It is worth noting that mice with the HIF gene knocked out do not survive long after birth.