Traumatic brain injury is an energy crisis, and ketones can bypass the broken glucose metabolism
After traumatic brain injury the brain first burns glucose in overdrive, then settles into long-term glucose hypometabolism — and ketones do not depend on that damaged pathway, and also suppress neuroinflammation. This explains why ketone metabolic therapy can act on epilepsy, psychiatric disorders and addiction at the same time.
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Traumatic brain injury first overshoots on glucose, then goes short on it long-term
In the first day or two after injury, the sympathetic nervous system and hormones are activated and the brain actually enters a hyperglycolytic state, with glucose levels high on PET scans. What follows is a prolonged period of glucose hypometabolism, in which the brain's energy metabolism is shut down. This hypometabolic period does not only predict the recovery trajectory; it also predicts the risk of post-traumatic epilepsy, psychiatric disorders and substance abuse. The author places it alongside Alzheimer's disease: Alzheimer's glucose hypometabolism takes decades to appear, whereas the traumatic brain injury version shows up within a week and can last months to years.
— Dominic D'AgostinoWhat ketones bypass is the enzyme that is stuck
The brain needs multiple steps to use glucose, and among them the GLUT3 transporter gets internalised and the function of the rate-limiting enzyme pyruvate dehydrogenase complex is also suppressed — this happens in both traumatic brain injury and Alzheimer's disease. Ketones can bypass this glucose hypometabolism step and restore and preserve brain energy metabolism. More critically, as the brain ages its ability to use glucose declines, but its ability to use ketones does not change noticeably. This constitutes the entire rationale for ketone metabolic therapy.
— Dominic D'AgostinoThe older the person, the better they respond to metabolic therapy
The researcher the author cites does not himself study metabolism, but agrees that ageing reduces metabolic resilience, reduces mitochondrial function and causes oxidative stress, and that after brain injury metabolic resilience drops further still. From this comes a counterintuitive conclusion: older people respond more noticeably to metabolic therapy than younger people, because their baseline is lower and there is more room for improvement. Exercise is also one of the strongest metabolic therapies, and anyone who thinks they are too old to exercise is making a mistake.
— Dominic D'AgostinoA scratch assay instead of giving animals traumatic brain injury
The author's wife uses primary neurons for a scratch assay: she scratches a line through the middle of a culture dish, watches how long it takes neurons to grow back, and simultaneously measures synapsin 1 and beta tubulin 3, two proteins related to neural regeneration. In the control group, axons retract after the scratch and the neurons do not even try to enter the scratched area; after adding 2 millimolar ketones, the neurons start growing into it. 2 millimolar is a level achievable and maintainable with a ketogenic diet or supplements. One motivation for this method is to avoid inflicting traumatic brain injury on animals.
— Dominic D'AgostinoHyperbaric oxygen treats traumatic brain injury from ten years ago
The author originally thought hyperbaric oxygen was only effective in the acute phase, but a recent study published in Frontiers Neurology applied hyperbaric oxygen to subjects who had sustained traumatic brain injury ten years earlier, and cognitive scores improved quite noticeably; the author himself was a reviewer on that paper. The risk he worries about is oxygen-toxic seizures, so he advocates entering a strongly therapeutic ketogenic state before hyperbaric oxygen, which both enhances efficacy and prevents seizures. The University of South Florida is running a state-funded $28 million, five-year double-blind randomised controlled trial with a sham control, and the author is a consultant.
— Dominic D'Agostino1,3-butanediol is not a ketone, it is an alcohol
Many supplements on the market are in fact pure 1,3-butanediol. It is not a ketone; after ingestion it must be metabolised by the liver like alcohol, it makes about 30% to 40% of people dizzy, and it is especially dangerous for older people. The author's team has published a paper on liver outcomes from chronic ketone supplementation, and an independent laboratory reproduced the same results in mice: 1,3-butanediol causes hepatocyte ATP levels to plummet and inflammatory markers to rise. After taking high doses himself for two consecutive weeks, his blood tests also showed changes he considers potentially problematic. He recommends that older people use ketone electrolyte salts and avoid 1,3-butanediol.
— Dominic D'AgostinoKetones above 2 millimolar damage the brain instead
More ketones is not better. Above 2 millimolar, counter-regulatory mechanisms are triggered, the body releases insulin, and two hours later ketones are almost back to zero — but because insulin was released, blood glucose is also very low, so the result is low blood sugar plus high ketones. The author says this gives him a headache and impairs brain energy. He knows people who were hospitalised because of large ketone doses. The practical advice is to titrate the dose, and to combine ketone esters with something that slows gastric absorption, or simply to use ketone salts — which themselves also slightly slow gastric absorption.
— Dominic D'AgostinoEvery 1 millimolar per litre of ketones gives the brain another ten percent of energy
For long-term traumatic brain injury survivors, the two daily habits the author prescribes are exercise and nutrition. Exercise should combine aerobic and resistance work, because muscle contraction releases hormone-like substances that help tissue repair. On nutrition, at minimum a whole-food carbohydrate-restricted diet is needed, to push blood glucose down and keep it stable. He believes only about 10% to 20% of people can maintain nutritional ketosis on a ketogenic diet, so the more realistic path is a healthy low-carb Mediterranean diet plus ketone supplements and MCT, pushing ketones to 1 to 2 millimolar. 1 millimolar is equivalent to giving the brain 10% more available energy; 2 millimolar is 20%.
— Dominic D'AgostinoIn their own words · checked verbatim
traumatic brain injury, the acute phase and also the chronic phase, is really a brain energy crisis, a brain energy metabolism crisis, and an important concept here is that your metabolism is modifiable.
Dominic D'Agostino1:17
So, uh traumatic brain injury is almost like Alzheimer's disease in real time.
Dominic D'Agostino20:34
As we age, our brain's ability to use ketones as an energy source is not significantly altered over time.
Dominic D'Agostino23:36
older individuals are actually more responsive to metabolic therapies than younger individuals because they're at a lower baseline.
Dominic D'Agostino27:40
But higher ketones are not always better.
Dominic D'Agostino53:09
If you elevate your ketone 1 millimolar, that's giving your brain an extra 10% of available energy. 2 millimolars, 20% extra energy is available to the brain.
Dominic D'Agostino56:13
Figures
| Traumatic brain injuries per year in the United States | 2.8 million cases | 7:21 |
| Economic burden of traumatic brain injury | $76 billion | 7:21 |
| Incidence of fall-related traumatic brain injury in people over 65 | 10 to 16 times higher | 9:26 |
| Mortality of people over 75 with a Glasgow Coma Scale score of 13 | 15% to 25% | 12:28 |
| Mortality of people over 85 with a Glasgow Coma Scale score of 13 | about 25% | 12:28 |
| Ketone concentration used in the scratch assay | 2 millimolar | 31:44 |
| Creatine dose used in traumatic brain injury research | 20 to 40 grams per day | 36:51 |
| Funding for the University of South Florida hyperbaric oxygen traumatic brain injury trial | $28 million, five-year double-blind randomised controlled | 45:58 |
| Share of people who get dizzy from 1,3-butanediol | 30% to 40% | 46:58 |
| Share of people who can maintain nutritional ketosis on a ketogenic diet | about 10% to 20% | 55:13 |
Glossary
- ketone metabolic therapy
- Using a ketogenic diet, ketone supplements or fasting to raise ketones to therapeutic concentrations, bypassing damaged glucose metabolism.
- hyperbaric oxygen therapy
- Breathing high-concentration oxygen inside a pressurised chamber; the risk is oxygen-toxic seizures.
- Glasgow Coma Scale
- Scored on eye opening, verbal response and motor response; 3 to 8 is severe, 13 to 15 is mild.
- 1,3-butanediol
- An alcohol often sold as a ketone supplement; it must be metabolised by the liver and lowers hepatocyte ATP.
- glucose hypometabolism
- The state in which the brain cannot effectively use glucose long-term after traumatic brain injury; it predicts recovery and seizure risk.
How to listen
Clinical researchers working on traumatic brain injury, neurodegeneration and metabolic intervention; sports medicine practitioners; and anyone making fall-prevention decisions for an elderly family member.
The opening acknowledgements and disclaimer, and the ABCDE emergency care slides around 13:29, can be skipped.