In August of this year, 25-year-old bodybuilding mom Meegan Hefford was found unconscious in her apartment, brought to the hospital where she was declared brain-dead, and died soon after. The cause? “Too much protein before competition,” according to the New York Post. She had recently doubled her gym routine, started dieting, and begun slamming protein shakes in preparation for an upcoming bodybuilding competition. No one knew she had a rare genetic disorder that would make the breakdown of protein acutely toxic for her until after her death.
Does this tragic case carry lessons for the rest of us without rare genetic disorders? In this episode, I make the answer a definitive YES.
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Protein is essential to life and health, but its metabolic byproduct, ammonia, is toxic. Humans dispose of excess nitrogen largely as urea, a nontoxic metabolite of ammonia that can be safely excreted in the urine. Rare genetic defects like Hefford's interfere directly with the production of urea. Other genetic defects that interfere with the use of certain fuels, especially fatty acids and branched-chain amino acids, can indirectly impair the synthesis of urea during metabolic crisis. Impairments of urea synthesis lead to the accumulation of ammonia, with devastating neurological consequences.
Null genes manifest in infancy and are best studied. Partial genetic deficiencies, like Hefford's are often asymptomatic through adulthood until dietary changes (protein supplementation, carbohydrate restriction, fasting) or metabolic demands (intense exercise, illness) force a greater rate of protein catabolism.
There is at least one genetic polymorphism in a urea cycle gene that is COMMON and associated with disease: the A allele of rs5963409 in the OTC gene is present in up to 25-30% of some populations. It impairs ammonia disposal and arginine synthesis and it increases the risk of hypertension and Alzheimer's disease.
Does it impair protein tolerance? It hasn't been directly studied, but it is reasonable to believe that people with this polymorphism may not tolerate protein as well as others, and that arginine supplementation could help.
We need to stop dismissing inborn errors of metabolism as too rare to be relevant and we need to start connecting the dots and learning the lessons they carry for everyone.
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Show Notes for “Are We All Evolved to Eat High Protein?”
00:44 Cliff Notes
09:22 The tragic case of Meegan Hefford
10:55 Proteins and amino acids, which serve many functions in the body, contain nitrogen; nitrogen is liberated as ammonia, which is toxic to the central nervous system
13:12 The urea cycle in the liver disposes of nitrogen as urea
14:32 Jose Antonio has shown in athletic populations that consuming 4-5 times the RDA for protein has no observable harmful effects
19:22 Urea cycle disorders are multifactorial and don't usually manifest unless there are multiple stresses on the urea cycle (high protein intake, fasting, dieting, illness, exercise, carbohydrate restriction)
25:48 The details of the urea cycle
32:11 N-acetylglutamate is an activator of the urea cycle and is stimulated by the amino acid arginine; supplementing arginine is a potential strategy to increase the activity of the urea cycle
36:15 Other genetic defects in energy metabolism or problems of a nutritional or metabolic nature can negatively impact the urea cycle; importance of acetyl CoA, ATP, the raw inputs bicarbonate and aspartate, and arginine
42:13 Understanding inborn errors of metabolism in their most severe states can provide enormous insight that applies generally
44:54 Uses of arginine outside the urea cycle
47:14 Common polymorphism in ornithine transcarbamylase, OTC, is associated with increased risk of hypertension and Alzheimer's disease, plausibly as a result of decreased arginine supply
52:05 Conclusions for researchers, clinicians, consultants, and people just trying to be healthy
How to Know If You Have a Common OTC (Urea Cycle Enzyme) Polymorphism
If you have 23andMe, search your raw data for this SNP:
G (or C) is the normal allele and A (or T) is the risk allele.
Currently, this polymorphism is known to increase the risk of hypertension and Alzheimer's. There is no evidence that this can be treated with diet or supplements, or that it affects protein tolerance. However, it is reasonable, as argued in this podcast, to believe this may increase the risk of lethargy, weakness, or brain fog in response to otherwise healthy amounts of protein or in response to catabolic stress (fasting, dieting, exercise, illness, carbohydrate restriction). If this is true it may show up in plasma amino acids and urinary organic acids as one or more of the following: low arginine, high ornithine, low citrulline, or high orotate. Strategies for improving these situations theoretically include a lower protein diet, avoiding catabolic stress, or arginine supplementation.
Links and Research Related to “Are We All Evolved to Eat High Protein?”
Jose Antonio's research on the safety of high protein diets.
For understanding the urea cycle, this section of Berg, Biochemistry, is free. To purchase a biochemistry textbook for understanding this and other pathways, get Ferrier, Biochemistry if you are a beginner or Berg, Biochemistry if you are intermediate or advanced. The 2002 version of the Berg book, linked to above, is free, but the new edition is more up to date and is much more usable since the free version can be searched but not browsed or read straight through. See my all my textbook recommendations here.