How ketogenesis and ketones Treat Inflammation

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Intro

Inflammation is a biological mechanism our bodies use to deal with internal and external events, such as combatting infections, repairing tissues or mitigating the immediate consequences of a fractured bone.

However, it often carries a negative connotation since many diseases provoke symptoms through the process of inflammation.

So although it is absolutely necessary for keeping the human body functioning properly, like so many things in biology, too much or too little is the problem. Inflammation can be managed with and without drugs.

Here we will focus on ketogenesis and ketones with regards to treating inflammation since both drug and drug-free approaches can be discussed.

What is ketogenesis?

Ketogenesis is the process whereby your body produces molecules called ketone bodies, also known as ketones (see What’s a Ketone?). More specifically, ketogenesis is a series of biochemical reactions that builds molecules (ketones) from parts of other ones (like 2 acetyl-CoA molecules).

How ketone bodies are formed?

Fellow nerds can gaze upon the ketogenesis pathway below (1) whilst the non-initiated can simply keep in mind that our liver is ground-zero for ketogenesis. This is where fat is used as the raw material to produce 3 kinds of ketone bodies.

 

Humans are remarkably good at ketogenesis. Just for comparison, dogs too can make ketones but the degree to which they require protein, carbohydrate or caloric restriction to do so is greater (2,3).

Once you’ve produced enough ketones by upregulating ketogenesis, you eventually move into a metabolic state called ketosis. People are in ketosis when they are on a diet low enough in carbohydrates, known as a ketogenic diet, or when eating very very little if any food at all for example.

What a ketogenic diet and fasting have in common is very little to no carbohydrate. Doctor Ted Naiman illustrates the different way calories and macronutrients can be manipulated to be in ketosis (some are advisable but not others)—

Ketogenesis

Consuming very few calories or carbohydrates releases the main metabolic break that was stopping your body from producing ketones unnecessarily. The decision to make ketones or not happens at the metabolic ‘roundabout’ in our body.

This roundabout is called the Krebs cycle, or the TCA cycle, short for tricarboxylic acid cycle. It’s often thought of as the place where things get burned up. However, a great researcher in the field of metabolism called Oliver Owen disagrees [4].

He think it’s best described as a roundabout, saying

The widely held view of the TCA cycle as a “metabolic furnace” needs modification in light of information supporting its role in biosynthesis. The cycle acts more as a traffic circle on a busy highway in which the flow of cars into the circle must be balanced by the flow out or the entire traffic pattern will be interrupted with disastrous consequences

Keeping with this analogy, ketogenesis results from changes in the balance of cars entering and exiting the roundabout. Specifically, when the ratio of the cars Oxaloacetate to Acetyl-CoA drops below 1, more and more fats get turned into ketones.

How are ketones metabolized?

By metabolized we mean used up. Build ketones in the liver (ketogenesis), use them up in other tissues (ketolysis). Ketolysis is the process where ketones are broken down into smaller molecular units that get consumed.

What’s important to understand is that ketones get metabolized by a series of molecular machines (enzymes) that break them down into acetyl-CoA molecules. The fact that they end up as acetyl-CoA is important, because these are the right kind of molecules you want for producing the energy currency of your cells, ATP.

Why? Because they can get fully used up. In other words, ketogenesis contributes to efficient production of energy, in part because ketones are broken down into acetyl-CoA which is handled well by the TCA cycle ‘roundabout’.

What does ketosis do to the body?

This metabolic state is understudied unfortunately, so there’s lots more to learn. What is understood though is that humans require the metabolic state of ketosis to handle long fasts and carbohydrate restriction.

Ketogenesis is an important adaptation our ancestors evolved to help them get through ice-ages that severely limited the availability of starchy plants.

Humans persistence hunted a lot of their food. Not only could we do this because we evolved an ability to bring our temperature down by sweating through our skin [5], we could also store lots of calories and use them efficiently.

As luck would have it, humans store lots of energy as body fat that turned into into energy-efficient molecules [6,7]!

[8]

Ketones aren’t only molecules to fuel our daily living, they’re also signaling molecules. For instance, they play a role in how neurons and other parts of the nervous system manage energy use during periods of fasting [9].

Ketones also happen to affect inflammatory processes and structures, one such example of the latter being the NLRP3 inflammasome.

What’s the NLRP3 inflammasome?

The NLRP3 inflammasome is part of the innate immune system, the defence system we have to react quickly and non-specifically to biological threats, such as a sudden infection from a wound.

Specifically, the NLRP3 inflammasome is a large protein that is made from recruitment of a bunch of smaller ones [10]. Imagine it assembling like Power Rangers or Transformers do.

Interestingly, when an NLRP3 inflammasome forms, there is only 1 per cell. It is the largest within its class of molecules measuring 2 µM (an massive molecular complex!).

Once assembled, it mediates the release of what you can think of as ‘inflammation bullets’ called cytokines, specifically the interleukins called IL-1β and IL-18. This inflammasome can also give the go-ahead for cells to activate caspase-1, a major switch used to decide whether or not to commit suicide.

The NLRP3 inflammasome senses threats which may, for instance, be toxins, too much glucose or too much ATP amongst other things. So it’s a great alarm system to have! Problem is, it’s not made to be chronically activated above a certain level, something that can happen if we’re exposed to too much air pollution or we consume inflammatory foods on a daily basis.

These situations may be mitigated somewhat by spurring ketogenesis or exogenous ketones to help dampen the activity of this inflammasome. Ketogenesis can be engaged by eating a high-fat diet low in carbohydrates and by fasting (intermittently or for longer periods of time.

How does ketogenesis or ketones modulate the NLRP3 inflammasome?

The ketone body β-hydroxybutyrate, BhB for short, has a particularly interesting effect on the NLRP3 inflammasome. It sticks to the big protein complex and stops it from firing the IL-1β and IL-18 bullets causing inflammation. It also stops the inflammasome from activating the caspase-1 switch [11]. .

What diseases or conditions could benefit from dampening NLRP3-mediated inflammation?

Research into inflammasomes is relatively new. The first NLRP inflammasome was discovered in 2002 [12].

Some of what we know comes from experimenting on cells in a flask and some more from experiments on rodents or humans.

Many diseases have an important inflammatory component which may be either cause or consequence.

Metabolic therapies, especially those requiring the activity of ketone bodies, appear to be promising candidates. However their efficacy depends on the particular disease and not all have been adequately tested in humans yet. Nevertheless, there are 3 diseases or conditions worth discussing in this regard.

Late-stage severe obesity

The fat tissue of people with late-stage severe obesity is highly inflamed due to, in large part, the activity of the NLRP3 inflammasome [13].

Consequently, the latter has been designated as a therapeutic target by some researchers [14].

The figure below depicts imbalances in the elements listed on the left-hand side leading to insulin resistance via NLRP3 inflammasome activation, and resulting in the diseases and symptoms listed on the right-hand side [15].

Rheumatoid arthritis

Rheumatoid arthritis is a condition where joints like the knees and wrists are swollen, stiff and painful. It has a major inflammatory component to it. IL-β, the cytokine bullet fired by the NLRP3 inflammasome, destroys cartilage in rheumatoid arthritis.

In rodents and humans, blocking IL-β stops the destruction of cartilage [16]. This makes therapies that can target IL-β, either directly or indirectly, very interesting.

Epilepsy (or other CNS disorders)

Epilepsy can present in many ways but generally it can be described as a strong sensory disturbance leading to convulsions and loss of consciousness.

It is thought to be due to electrical disturbances in the brain since this feature very strongly correlates with seizure activity.

There is evidence suggesting that brain cells with dysregulated production of reactive oxygen species (ROS) or inappropriate K+ efflux activate the NLRP3 inflammasome and trigger epilepsy [17].

The human brain is particularly well suited to using ketone bodies as a major source of energy which makes its therapeutic use for epilepsy all the more intriguing.

fasting or a combination of these interventions could be useful to control NLRP3-mediated inflammation

If appropriate, what kind of ketone-based metabolic therapy should I use?

This is a difficult question to answer.

For instance, it’s not always clear which aspect of, say, a ketogenic diet used to reverse obesity is actually doing the work. Is it the appetite appetite suppressing effects? Is the lowered inflammation in fat tissue normalizing local insulin signaling? Or a combination of both and more? And in epilepsy, is a ketone-based metabolism improving seizure control through normalized ROS signaling? Or is it due to dampened inflammation deriving from NLRP3 inflammasome activity? Whatever the case may be, there are different ketone-based approaches that are available and worth considering.

For a drug-centric approach, exogenous ketones are available, such as ketone esters and ketone salts. These can now be bought [18].

Although not cheap, they are relatively safe and do not currently require a prescription in most countries.

One advantage with exogenous ketones is it is easier and quicker to get a desired level of ketones circulating in the bloodstream than it is through dietary manipulation.

For drug-free approaches, ketogenic diets or some form of fasting can generate levels of ketones that have therapeutic effects on inflammation. On the plus side, fasting or intermittent-fasting is a time-tested intervention in obesity as well as epilepsy.

It is free and human physiology is well-adapted to it. Unfortunately, it is hard to implement in an era where the food industry and medical establishment generally discourage this intervention.

Ketogenic diets have similar advantages since they are cheaper than many expensive medications for epilepsy or immune therapies for rheumatoid arthritis. However, few dietitians or doctors can help their patients implement well-formulated ketogenic diets which reduces the odds of long-term success.

Conclusion

Inflammation is a life-maintaining biological process.

However, it needs to be kept in check and not activated chronically above a certain level. Otherwise, it can lead to symptoms or outright disease.

It can be controlled with certain drug and lifestyle interventions, exogenous ketones and ketogenesis being examples of both sides of the coin.

These interventions are relatively safe and are accumulating data suggesting they they may be useful for controlling inflammation.

Their use should preferably be discussed with medical professionals beforehand, especially when suffering from a medical condition and taking medications.

11 comments On How ketogenesis and ketones Treat Inflammation

  • When I ride my bicycle now, say 50 or 60 miles, I do not eat during the ride or until the next day. This has cut the recovery time in half. I used to feel sore for two to three days. I am in nutritional ketosis most of the time and I suspect that this also reduces inflammation during the ride. This is all speculation, but from a practical point of view, it works.

    The ketosis seems to spare the muscle glycogen because there is no problem sprinting or feeling tired during this duration ride. I have not tried a 100 miles ride in ketosis so the glycogen may be depleted toward the end of that ride.

    I am 70 years old and have been riding all of my life, so I am well adapted to this type of exercise. Maximizing fat metabolism seems to work best for this type of activity.

    • First off, you ride 50-60 miles, at 70!? Wow !

      Second, a lack of (excessive) soreness is something that I often heard reported in people going LCHF/keto who exercise at a high level. I don’t know why though. I think inflammation is a reasonable explanation to explore.

      Do you notice the soreness subside in a particular body part?

    • Hi Samuel,
      Your success story, i.e. regular 50-60 miles bike rides at 70 y.o., is very impressive and a goal for many of us. Could you share other details? How often do you do your 50-60 miles rides? Do you workout on recovery days? How many kCal do you eat? How much carbs if any?
      A lot of smart athletes tried the ketogenic diet but could not make it. They were not having enough kCal to replenish caloric expenditure on keto and had to stop it. Their hormones often went in a distress mode. So, your experience would be much appreciated.
      Thank you!

  • Interesting, my quest to understand inflammation was prompted about 14/15 years ago when an uncle, in his early 70’s,  ended up in icu after a bowls match! He hadn’t played for 3 months at that point. He and I were genetically quiet similar thus my concern. By the age of 56 I’d reached a stage where I could no longer train (resistance) without significant pain and stiffness the following 2/3 days. Would I follow the same path as my uncle?
    Long story short I came upon the ketogenic lifestyle and following strict adherence – no more stiffness and soreness on the subsequent days, none at all. This is so remarkable that I have been able to improve my resistance training workouts to the extent that I put on 5kg of muscle while due to the keto dropping my body fat to 7%. Eg, my incline dumbbell bench was 64 kg max, went up to 80, me weighing 72kg and all from  the age of 62 to 64 at present.
    The only clue that I have is that a high insulin level does increase or result in a chronic inflammatory state and thus the doms.
    I would love to have a more complete understanding of how this works. With so much emphasis (rightly so) on obesity and diabetes very little is made known about low level inflammation, the silent killer, the true cause of heart desease, cancer, althziemers, etc?

    • Hi Chris,

      Your story of reduced inflammation and soreness following a ketogenic diet, especially in your later years, is one that keeps popping up. I’d also really like to know what aspects of your lifestyle were most responsible for the improvements you experienced. Was it simply the presence of more ketones in your blood? or was the absence of refined carbohydrates enough? Was it more the inclusion of good ‘keto’ fats? or was avoidance of high omega-6 vegetables oils enough? or a mix of all of the above and more?

      What we do know though, is that hyperinsulinemia is avoided on a well-formulated ketogenic diet. There’s evidence of hyperinsulinemia’s negative effects on the vasculature of diabetics and the obese, as revealed in the late Dr.Kraft’s thousands of autopsies. Until we know more, I like you am putting my eggs in the ‘avoid hyperinsulinemia’ basket 🙂

      Thanks for your comment Chris!

      • Could this throw more light on the issue? Insulin a culprit – high carb, high insulin spikes …
        https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0033-1336676?device=mobile&innerWidth=360&offsetWidth=360

        • What your paper seems to point to is that insulin secretion is associated with inflammation.

          This isn’t necessarily a problem until what insulin is being stimulated to dispose of in tissues throws a wrench into cross-section of metabolism and inflammation.

          Feeding, for example, triggers an insulin release, and feeding itself is followed by an inflammatory cascade – but this is normal. You’re taking in the outside world (food) into your inside world (body) which requires a some level of immune system activation to handle the incoming pathogen and caloric load. The problem we see is you chronically take in elements that cause a disproportionately high insulin response and/or require a stronger immune system inflammatory response.

  • Dr. Joseph R. Kraft’s credible research proofs have convinced me that Insulin is the “aging hormone” and I now try to severely limit carbohydrates (they are in most protein foods, anyway) and I feel much, much better.

    • Dr.Kraft’s research certainly provides strong evidence that hyperinsulinemia is a major cause of most diseases nowadays, diseases of affluence like diabetes, obesity, heart disease and neurodegeneration.

      Certainly avoid the worst carbohydrates like flours and simple sugars and yes, depending on your individual metabolism, limit your total carbohydrate load too (preferably with data to verify its utility, like that obtained with an 2hr OGTT with insulin &/or a CGM device)

  • Despite being 48 rather than 70, my experience when cycling is similar to Samuel’s. I am an avid amateur cyclist and have been on a LCHF diet for approximately the last 18 months. My transition to keto was not without its challenges, however. I, last year, lost almost the entire cycling season to some version of the “keto flu”. While imbued with more than enough energy to undertake daily activities and moderate exercise, I just couldn’t muster adequate power for cycling and lost all motivation as a consequence. Beginning in the fall, however, I undertook a regime of high cadence, low effort cycling on my trainer several times a week; building up both the duration and power over time. This seems to have done the trick. I’ve not felt this strong on my bike for many years: my legs don’t seem to build lactic acid (or at least the pain often associated with it) during periods of extreme effort, recovery time is noticeably reduced, I’ve had fewer (well, no) cramping episodes and I don’t need feeding while on the bike. I’ve done several 100+ (160+km) mile rides this year, at an average speed of 18-20mph (30-33 kph), having not had breakfast (or very little) and frankly not feeling that hungry when I finish 5 or more hours later. As you might imagine, I’m pleased that I stuck with it through the initial months of adversity. Not only am I feeling better than ever, the freedom from a continual requirement for food as been utterly liberating.

    • Hi Kevin,

      Your story seems to mirror observations made by Dr.D’Agostino, Volek, Phinney,and others. Did you find that properly dosing sodium and other electrolytes was a factor in your better long-term adaptation?

      It’s interesting that your training program seemed to have made the biggest difference though, I don’t hear that as often.

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