All about Ketones - science, diet, supplements etc.

[Mezmerric]

There are regular posts and snippets about Ketones and Ketone diets. This is an attempt to provide a more definitive post and reference. I’ve tried to keep it simple and jargon free as much as possible. This attempts to provides information on the following areas.

1. What is a Ketone, how and why is it produced by the body?

2. What does being in a state of 'Ketosis' mean? Do I have to be in Ketosis to benefit?

3. Ketones and the Brain - Part 1. The 'Brian Energy Gap'

4. Ketones and the Brain - Part 2. Reduction in Oxidative Stress.

5. Ketones and enhanced energy metabolism.

6 How do I increase Ketone levels? Ketone diets, Ketone supplements and interventions

8. Some specific details on Ketone Esters and MCT oils.

9. Sources of information

What is a Ketone, how and why is it produced by the body?

Ketone are types of molecules produced by the liver when glucose (the body’s primary energy source) is in short supply. Ketones are produced most during fasting, prolonged exercise, or low-carbohydrate diets (Ketone diet), where the body is being forced to shifts to burning fat for fuel in the absence of glucose (glucose comes from carbs or from eating more protein than the body needs to repair and grow).


The ability to burn fat and create an efficient fuel as Ketones was an evolutionary adaptation that enabled our ancestors, hunter/gatherers, to survive long periods without food.

What is meant by being in ‘Ketosis’ - Do I have to reach Ketosis in order to benefit from Ketones?

Being in a 'state of ketosis' simply means that one is using Ketones as the primary fuel for the body rather than glucose.


It is important to know that you don’t have to be in ‘Ketosis’ to take advantage of Ketones. Even without full ketosis, your body can still utilise Ketones alongside glucose as an energy source. It’s NOT a case of either or - it just a case of degree. Later, I will describe the ways that you can elevate your Ketone levels.

Ketones and the Brain. Part 1. The 'Brian Energy Gap'. The work of Prof Stephen Cunnane

Ketones pass the blood brain barrier and are taken up by the brain more efficiently than glucose, particular as one ages.

As people age the brain becomes more insulin resistant and is less able to take up glucose as effectively. Ketones are transported to the cells using a different mechanism which isn’t dependent on insulin.

In a healthy young adult on a western diet 97% of the brains energy typically comes from glucose and only 3% from Ketones.

The average 65 year brain gets 94% of its energy from glucose due to increasing insulin resistance. If the brain is still only getting 3% from Ketones there is a 'brain energy deficit'. In effect, the brain is being starved of energy and this results in accelerating cognitive decline.

In patients with neurological conditions such as Alzheimer's and Parkinson's and those with higher insulin resistance, this energy gap is usually much more severe

Stephen Cunnane a professor from Sherborne, Canada has published extensively on this subject. His studies show that Ketones not only reverse the deficit but can be also still be used by those parts of the brain that are no longer able to use glucose.

Ketones and the Brain - Part 2. Reduction in Reactive Oxidative Species (ROS)

The cells in our body contain mitochondria, which produce all of our chemical energy in the form of a molecule called ATP (Adenosine Triphosphate). During this process, electrons leak out and combine with oxygen to form ROS which is a form of free radical.

Ketones produce ATP with fewer oxidative byproducts compared to glucose.

Ketones also increase the production of critical enzymes that bolster antioxidant defences, particular increasing protection against SOD and Glutathione peroxidase both of which are particularly damaging free radicals.

Ketones are anti-inflammatory. They reduce the NLRP3 inflammasome, a protein complex that triggers inflammation and future ROS in response to stress

Ketones enhances cellular maintenance known as ‘autophagy’ - the process of removing those damaged mitochondria which are responsible for producing greater amounts of ROS.

So, as well as acting as a ‘fuel’, recent findings reveal that Ketones also function as signalling molecules, impacting diverse cellular pathways to protect the body. This extends not only to the brain but also to also to gut health, kidney function and eye health.

Ketones and enhanced energy metabolism.

Besides brain health Ketones are known to improve energy levels compared to glucose.

- Ketones improve the efficiency of the mitochondria to produce ATP.

- Ketones are more energy dense than glucose, producing more ATP per unit.

- Ketones stimulate the formation of new Mitochondria, giving one a greater capacity to produce ATP.

Ketone supplements are now used by many athletes - particularly in endurance sports and events such as the Tour de France.

How does one increase Ketone levels? Ketone diets, Ketone supplements and interventions.


Ketones levels can be increased by:

a) Low carb diet (High fat and moderate protein). However, like many diets this can be challenging to maintain. In addition, high fat diets can raise LDL cholesterol levels for some and therefore may have other health consequences. Therefore, it is advisable to check LDL cholesterol levels and discuss with you doctor before and during the diet.

b) Periods of fasting. Longer periods of fasting may be problematic for many who have PD, however, intermittent fasting or eating within a smaller time frame (8 hours) per day only, may be feasible.

c) Exercise, particularly endurance efforts when in fasted state. For example, a slow run/walk in the morning before eating.

D) Supplements - possibly the easiest way and most direct way to boost Ketones..

Some specific details on the Supplements Ketone Esters and MCT oils.

Ketone Esters - is the most potent, effective and quick. However, they are expensive. A small 50ml bottle that can last perhaps 5 days, costs around $30 - though prices reduce with volume. Also beware of snake oil! There’s several companies claiming that they make but only two companies manufacturer genuine Ketone esters, which is extremely costly to manufacture. One is the USA and is called KetoneAid and the other out of Oxford University called DeltaG. One other consideration is that some find it tastes like jet fuel!

Medium Chain Triglycerides - known as MCT Oil. There are different types but C8 and C10 are good (the C stands for the number of carbons in each molecule). Coconut Oil is also an MCT but will generate fewer ketones than C8 or a combination of C8/C10. Many people take a tablespoon of MCT or two in their coffee each morning. Increase any dose slowly as it can cause gastric distress - it also acts as a laxative which may be helpful for many with PD.

Ketone Salts - I've never used this. They are much cheaper to buy then esters because they are cheap to produce. They are loaded with salts which can cause other issues - so I've stayed away.

Sources of information


For the ‘Brain Energy Gap’ - look for Prof Stephen Cunnane, from Sherborne, Canada

For detailed in insight into Ketones, I highly recommend the book 'From Warburgs to Krebs to Veech - Ketones the fourth fuel'. This book recounts the history of Ketones and links it with the work of some of the most famous nobel prize winning scientists in the field of energy metabolism. It also goes into detail about how Ketone Esters were created after funding from U.S. Department of Defense (DARPA).

There are several publication available by Prof Richard Veech - which show that Ketones influence hundreds of metabolic pathways in the body. Prof Veech and Prof Keiran Clarke are credited with creating the first Ketone Ester and have published extensive research on the use of exogenous Ketone supplements.

Overview of Ketones as Messengers (published in Nature Metabolism in 2023), provides an in-depth exploration of ketones as signaling molecules. This is a more recent paper about the growing understanding that Ketones don’t just provide energy but play a much broader physiological roles.

DeltaG has a number of scientific papers on their website regarding Ketone Esters.

I hope that some of you find this helpful and useful!

[Babanalover]

don’t doubt its benefits. Tried ketone diet and felt constantly thirsty and lousy. Had to give up. Felt low too. Read it can affect serotonin levels. ….

[Mezmerric in reply to Babanalover]

That was a point of my post - showing that you dont need to follow the diet.

[Babanalover in reply to Mezmerric]

irritated?

[Mezmerric in reply to Babanalover]

Irritated? No not at all and sorry if my response came across that way. I think many struggle with the diet, myself included, so my post is hopefully indicating that there are other alternatives.

[Babanalover in reply to Mezmerric]

fine,I understand, thank you.

[Bracondale in reply to Babanalover]

That can happen in the first few weeks whilst you adapt to running on ketones. Without the insulin response to carbohydrates, sodium is lost and water (and potassium and magnesium) too, and you will feel awful ('so called 'keto flu'). Plus you get 'die-off' of gut bacteria that rely on carbs to add to the general grottiness. BUT as Mezmerric beautifully explains, there is a middle ground where you can have the benefits of ketones whilst not having to stick to a rigid ketogenic diet.

[CaseyInsights]

Quite helpful and incisive overview 📌

[JayPwP]

Thank you 🙏

[00Mark]

Great work thanks, Mezmerric, comprehensive and comprehensible.Minor typo - I think noble scientists might mean Nobel. (Perhaps they are both!)

[Mezmerric in reply to 00Mark]

Many thanks… nobel and noble but Ive made the edit😀

[gregorio]

Excellent. When I was diagnosed 6 years ago I went into YouTube like a crazy person for months and of course picked up on the Keto vids so decided to go with it from day one. There is no way to do it other than commit completely which when having researched properly is not that difficult. As time has passed I now allow myself the odd treat/reward, like a pint of beer from time to time. I am Med free and apart from my tremors, which I cant find an answer to, I am in good shape all things considered. BIG QUESTION. Is me being med free and in reasonable condition down to the Keto diet? I couldn't tell you but I have my suspicions😜

[Mezmerric in reply to gregorio]

Great to hear! I don’t do the keto diet but use a combo of exercise, ketone esters and eating only in the afternoon.

[Bracondale in reply to Mezmerric]

I'm using diet, fasting 12 hours and C8 MCT oil 5ml three times daily...and trying to exercise as much as energy/fatigue permits but always after evening meal. A walk after eating helps to decrease blood glucose/insulin and so will lessen inhibition of fat burning/ketone production I understand.

[Bracondale]

Thank you so much for this excellent piece Mezmerric! Having been on a ketogenic diet, with a few brief breaks, for 'inflammation' (not got PD), which I found beneficial (especially for my brain!) I've now needed to stop for a while (gut issues). However, I'm intrigued by the idea of being metabolically flexible and in the 'keto zone' (to get the benefits of ketosis without the inconvenience of being so mindful of carb/protein intake) which is a state that I'd imagined we'd evolved to be in.....and you have also mentioned.

[Eryl]

But you don't mention the Randle cycle which means that the cells ignore ketones while there's more than the homeostatic level of glucose in the blood and when there is insulin resistance the cells are starved of energy. youtu.be/2zt0zLgqrlE?si=x91...(Not working as expected?)

[Mezmerric in reply to Eryl]

Thanks for the feedback. Perhaps I will add a section on my original post about the Randle Cycle - but I was trying to give an overview without getting too much into the weeds!

The Randle Cycle - Carbs vs Ketones

There's plenty of confusion about how ketones and carbs work or compete with one another. Many people think that if you eat more than about 50-100 grams of carbs, your body will completely reject ketones as a fuel source, but I don't think this is entirely the case. It isn't a case of either/or. The reality is more nuanced.

The Randle Cycle describes how your body chooses between burning glucose (sugar) and fatty acids for energy. When you have a lot of glucose and insulin around, your body tends to slow down fat burning and make fewer ketones because it’s focused on the carbs you just ate.

But one can get around this by taking ketone supplements like ketone esters. These supplements skip the usual fat-burning process and go straight into your bloodstream, so they’re ready to be used as energy without being affected by insulin or glucose levels. So even if you’ve just eaten a bunch of carbs, your body can still have access to these ketones.

What About Glucose preventing the Ketones being used?

It’s true that after eating carbs, under 'normal circumstances', your body usually prioritizes glucose as the main fuel because insulin makes it easy for your cells to grab and use. But ketones aren’t totally sidelined, especially in certain situations:

Different Tissues, Different Needs: Some parts of your body, like the brain and muscles, are actually able to use both glucose and ketones at the same time. The brain is especially good at this, and studies show that it can use ketones even when insulin levels are high.

Insulin Resistance: When I say “normal circumstances,” I mean for a healthy person with good insulin sensitivity. But as we get older, many of us become more insulin resistant, which means our cells don’t use glucose as well. In these cases, ketones become a more important fuel. This is also true for people with conditions like Parkinson’s disease.

A Few Studies:

There’s a study by Stubbs and colleagues (2017) that showed drinking ketone esters after exercise increased ketone levels (up to 3 mM) and boosted energy metabolism without impacting glucose.

There are also studies in Nutrition & Metabolism and the British Journal of Nutrition that show how ketones are used more when insulin resistance is present.

So, I think that the idea that eating carbs completely shuts off ketone use isn’t right. Even when glucose is prioritized, ketones—especially those from supplements—can still fuel your brain and muscles, and sometimes even get prioritized, particularly if you’re insulin resistant.  This is the key point being made by Prof Stephen Cunnane, that I refereed to in my orginal post.

Hope you find this useful.

[Eryl in reply to Mezmerric]

It's important that's people know that it's pointless adding ketones to a high carb diet, they should reduce the carbs over a six week period for the body to use them to full effect.

[Bracondale in reply to Eryl]

Agree, reducing carbs should reverse insulin resistance (and inflammation) and exogenous ketones will have a better anti-inflammatory effect. And taken about an hour before food helps to decrease appetite/increase satiety.

[Mezmerric in reply to Eryl]

i don't think it is pointless. I think that is too black and white - as my response points out, the brain can use both fuels simultaneously and in some instances favour Ketones over glucose even if one is eating a high number of carbs - however, I do agree that the more one reduces carbs and/or fasts for a period, exercises etc the more optimised they are for using Ketones effectively.

[Bracondale in reply to Mezmerric]

More excellent information, thank you. I certainly agree that it's not one or the other fuel. Recently, having been in full ketosis for six months, I swapped to a carbohydrate based diet by adding some carbs and decreasing fat and mostly continuing with the same amounts of protein and veg. Upon testing, ketones have decreased but are still present (which I'm happy about!) possibly just due continuing to take C8 MCT oil 5ml tds.

When I attempted to swap from ketosis to carbs a year ago I felt absolutely awful... unfuelled and hungry soon after eating etc I think due to insulin resistance, so restarted a ketogenic diet after a couple of weeks, and once back in ketosis felt much better. I think that being in ketosis decreased inflammation (and so cortisol), in addition to lowering carbs to get into ketosis, reversed any insulin resistance, resulting in carbs actually fuelling me now.

[Eryl in reply to Bracondale]

Eating carbohydrates (especially refined ones which are absorbed quickly) spikes blood glucose which affects the hormones i.e it increases ghreling to make give you stronger hunger pangs an decreases leptin which gives you the satiated signal when you've had enough.

[Bracondale in reply to Eryl]

Thank you, yes I'm sure they were involved too, as well as my not responding well to more fibre in low GI carbs due to dysbiosis/gut inflammation following antibiotics.

[JayPwP]

For all interested in knowing:

According to Dr. Stephen Cunnane...

The problem for the aging brain is that low glucose supply in the blood is not the same as low brain glucose utilization. When blood glucose decreases, ketogenesis normally occurs rapidly in response to decreased insulin. However, when brain glucose utilization is decreased, plasma insulin does not necessarily decrease; indeed, during aging, plasma insulin and glucose are commonly mildly elevated and there is a state of mild-moderate insulin resistance. Hyperinsulinemia inhibits the normal ketogenic response (Bickerton et al., 2008), thereby putting the aging brain in double jeopardy of being deprived of both its primary fuels. We believe that this problem is at the root of the vicious cycle between deteriorating brain fuel uptake/availability and deteriorating brain function that leads to AD.

pmc.ncbi.nlm.nih.gov/articl...

healthunlocked.com/cure-par...

[Mezmerric in reply to JayPwP]

Yes, I believe that is why he is in a believer in supplementation of Ketones via MCT of equivalent to overcome the blunted ketogenic response.

[Rufous2]

Thank you Mezmerric et al for this interesting discussion. Neither my spouse nor I tolerate a keto diet, and I have serious reservations about the lack of fiber such a diet entails. Plus the keto diet "works" by forcing the body to burn fat (which many with PD can't spare) leading to too much weight loss for some.

I agree though, that combating insulin resistance is crucial, so we follow a no sugar/no refined carbs diet, and have incorporated restricted eating and fasted exercise into our lives. Your suggestion of trying to achieve the brain benefits of ketosis by adding ketone supplements to a low-carb protocol like ours is a good one, so I thought I would mention something I discovered when I dabbled in ketosis a few years ago. 

Ketone esters are probably out of the price range for many, but ketone salts might work for some. The ketone (beta hydroxybutyrate) in ketone salts is attached to a mineral. This mineral can be calcium, magnesium, potassium or sodium. Supplements come in powdered form, flavored or unflavored. You can buy a "single salt" form, like Potassium Beta-Hydroxybutyrate or Magnesium Beta-Hydroxybutyrate, or "mixed salts," which combines the four different forms in different proportions. By shopping around a bit, or even combining products, one can tailor their ketone supplement to their individual needs. A person prone to dehydration/low blood pressure could go for a mix higher in sodium, while one with osteoporosis might want more calcium.

Hope this helps.

[Bracondale in reply to Rufous2]

I agree re weight loss. I was already fairly lean and it was surprising how much fat I needed to eat to maintain weight, as obviously eating more carbs (or even too much extra protein) wasn't an option. I managed to get enough fibre for good gut function, but understand that ketosis can cause a decrease in bifidobacteria, which isn't ideal.

[rebtar]

Is it possible to get too much suplemented ketones? How to know how much to take?

[Mezmerric]

Yes it is possible. But the quantity depends on what else one is doing and what supplements you take. If one is already in ketosis due to a very low carb diet then supplementing with Ketone Esters could be too much. If you are following a more moderate diet then a rough rule of thumb is 1-2 tablespoons of MCT in addition to 10-25ml of Ketone Ester per day. Timing is also important for example you would not want to take supplements close to a high carb meal because it can blunt the impact.

The best thing to do is get a ketone testing finger prick kit . This way you can measure the effect of any supplementation precisely