Every day, I get links to interesting papers. It’s hard not to when thousands of new studies are published every day and thousands of readers deliver the best ones to my inbox. And while I enjoy thumbing through the links simply for curiosity’s sake, they can also seed new ideas that lead to research rabbit holes and full-fledged posts. It’s probably the favorite part of my day: research and synthesis and the gestation of future blogs. The hard part is collecting, collating, and then transcribing the ideas swirling around inside my brain into readable prose and hopefully getting an article out of it that I can share with you.
Last Sunday, I briefly mentioned a paper concerning a ketone metabolite known as beta-hydroxybutyrate, or BHB, and its ability to block the activity of a set of inflammatory genes. This particular set of genes, known as the NLRP3 inflammasome, has been linked to Alzheimer’s disease, atherosclerosis, metabolic syndrome, and age-related macular degeneration. In other words, it’s in our best interest to avoid its chronic, pathogenic activation, and it looks like going into ketosis can probably help in that respect.
One thing led to another, and this paper got me thinking: once we “go into ketosis,” how long should we stay? If some is good, is more better? Is there a point where the benefits slow and the downsides accrue?
We absolutely know that ketones, particularly BHB, do lots of cool things for us. There’s the NLRP3 inflammasome inhibition, for one. There’s also the effect it has on brain health and function, particularly in the context of neurodegenerative diseases and other brain conditions.
- Whether it’s severe hypoglycemia in a live rat or direct glucose deprivation of cortical cells in a petri dish, the addition of BHB protects against neuronal death, preserves energy levels, and lowers reactive oxygen species.
- In an animal model of Cockayne syndrome, a condition characterized by premature aging, short stature, and early death (about age 10 in most human children with it), increasing BHB through ketosis postpones brain aging.
- Ketogenic diets are classic therapies for epilepsy, with BHB being the most important ketone for preventing seizures. The degree of seizure control tracks almost lockstep with rising BHB levels.
- There’s also evidence that patients with bipolar — a disorder sharing certain neurobiological pathways and effective therapies with epilepsy — can also benefit from ketosis. Recent case studies show complete remission of symptoms in two patients as long as they adhered to their diets (which were fairly Primal-friendly, for what it’s worth).
- Parkinson’s disease patients who adhered to a ketogenic diet saw improvements in their Unified Parkinson’s Disease Rating Scale scores.
- Type 1 diabetics who experience reduced cognitive function because of low blood sugar see those deficits erased by increasing BHB through dietary medium chain triglycerides (the same fats found in coconut oil).
- In memory impaired adults, some with Alzheimer’s, BHB improved cognition. Scores improved in (rough) parallel with rising ketones.
- A ketone-elevating agent (purified medium chain triglycerides) improved cognition in patients with mild to moderate Alzheimer’s.
- A very low-carb diet improved memory in older adults. Again, ketones tracked with improvements.
Mitochondrial levels of the endogenous antioxidant glutathione increase on a ketogenic diet; this is likely a major reason for many of its beneficial effects.
It’s quite clear why constant ketosis is attractive to people who read about (and experience for themselves) the benefits of BHB and ketosis in general: There don’t appear to be many downsides. Improved brain health? Increased antioxidant capacity? Inhibition of an inflammatory set of genes involved in the worst kinds of degenerative diseases? What’s not to love? Why wouldn’t someone remain indefinitely ketogenic?
Ketosis also activates the NRF2 pathway — a set of genes that regulate the body’s detoxification, antioxidant, and stress response systems — by initially increasing systemic oxidative stress. If that sounds a bit like hormesis, you’d be right. Ketosis, at least in the early stages, exerts some of its beneficial effects via hormetic stress. Various other stressors also activate NRF2, like plant polyphenols from foods like blueberries and green tea, potent spices like turmeric, intense exercise, and intermittent fasting. These all improve our health by triggering our stress resistance pathways and making us grow stronger for it, but they can also be taken to an extreme and become negative stressors.
Consider intermittent fasting and exercise. While the most famous way to increase BHB is to go on a ketogenic diet, it’s not the only way. Both fasting and exercise also do the trick:
- A properly-executed fast puts you into full-blown ketosis. In healthy adults, two days of fasting increases brain BHB almost 12-fold (and almost 20-fold after 3 days). Even just an eight hour fast, AKA a good night’s sleep, will put you into ketosis and increase BHB (PDF) if you have strong metabolic health.
- Exercise-mediated increases of BHB are a good barometer for the amount of fat a person will lose during a workout program. The more body fat you carry, the greater the elevation in BHB and the more weight you’ll lose.
What do you notice?
These are both transient states that grow problematic when extended indefinitely.
You can’t fast forever. That’s called starvation. And, eventually, dying.
Instead, you fast for 12, 16, 24, or on the very rare occasion 36 hours, and resume your normal diet after the fasting period has ended. You introduce an acute bout of food deprivation to upregulate your fat burning, trigger cellular autophagy, and generate ketone bodies.
You can’t train every waking hour. That’s called working in a forced labor camp, and it too leads to very poor health.
Instead of training 12 hours a day, you sprint, or lift weights, swing a kettlebell really intensely, or any other type of training two or three times a week. Then, you rest and recover and eat, and grow stronger, more fit, and faster in the interim.
Ketosis isn’t fasting. It’s not starvation. You’re still eating, although your appetite may be reduced (which is why many people lose weight from ketogenic diets). You’re still taking in nutrients, even if glucose isn’t among them. And ketosis isn’t anywhere near as acutely stressful as a strong training session. But I think the principle stands: these are all stressors that exert benefits, at least in part, along the hormetic pathway. And when it comes to hormetic stressors, too much of a good thing usually isn’t very good.
What does this mean for indefinite, long term ketogenic dieting?
If you’ve got a legitimate health condition that responds well to ketosis, all bets are off. There’s evidence that people can thrive on good ketogenic diets for at least five years without incurring any serious side effects. For controlling epilepsy, there’s nothing better than a strict ketogenic diet maintained long term to quell the overexcited brain. For any of the neurodegenerative diseases, like Alzheimer’s or Parkinson’s, ketogenic diets look very promising and are worth trying. It even looks promising for bipolar disorder. If you’ve got a problem that ketosis helps or fixes, go for it. It’s helping you, and there’s no mistaking that.
My personal hunch (and I’ve said this for as long as I can remember) is that indefinite ketosis is unnecessary and perhaps even undesirable for most healthy people, and that occasional, even regular dips into ketosis (through fasting, very low-carb cycles, intense exercise) are preferable and sufficient. That way, you get the benefits of cyclical infusions of BHB and other ketones without running afoul of any potential unforeseen negative effects.
Plus, cycling your ketosis means you can eat berries and stone fruits when in season, and enjoy those otherworldly-delicious purple sweet potatoes without worrying. Personally, I like food too much to go full-on keto. You may not, and that’s okay.
If you’re thriving on a ketogenic diet, and have been for some time, keep it up. No one can take that away from you, and the studies indicate it should be safe.
But if you don’t have to remain in ketosis to resolve or stave off a health condition, if you’re just doing it to do it or for yet-to-be-realized benefits, consider rethinking your stance. And if ketosis doesn’t agree with your health or your personal performance goals, then don’t do it. It’s certainly not necessary for optimal health (if such a thing even exists!).
What about you? If anyone’s been on a long-term ketogenic diet, I’d love to hear how it’s worked for you in the comments below. Thanks for reading!
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