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What Do We Know About The Role of Ketones?

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Coronavirus: What Do We Know About The Role of Ketones?ShareFollow us 261.1k

Quick Summary tl;dr

Update: In February 2021, a commentary in the prestigious journal Cell Metabolism by the NIDDK called for a shift in research priorities towards Metabolic Health! Masks Matter. Metabolic Health also Matters.

It's not the COVID-19 virus that kills people, it's the body's response to the virus. When the body is overwhelmed, it overreacts with what is known as a "cytokine storm."

The relationship between ketones and COVID-19 is still within the realm of speculation. Theory suggests that ketogenic diets could help protect against the "cytokine storm" in COVID-19, but research is needed to determine whether theory translates into clinical practice.

It's important — now more than ever — to be conscious of our health choices. Getting enough sleep, stress management and eating a healthy nutrient-dense diet low in processed foods can help you maintain a strong immune system.

Table of Contents

It's March 29th, 2020 and the world is awash in confusion (and hand sanitizer). With the COVID-19 pandemic progressing so quickly and the deluge of advice hitting your news feed, it's hard to know what advice helpful and what advice is not.

Certainly, hoarding toilet paper and chugging gallons of orange juice (in the hopes that it's meagre vitamin C contents will boost immune function and shield you from the virus) isn't going to save lives. In fact, a fair number of people are now experiencing weight gain as a result of being cooped up inside without access to gyms and unrelenting proximity to their fridges and pantries.

We're not criticizing the responsible choice to stay at home and prevent viral spread, but what we are saying is that now, more than ever, it's important to be conscious of our health choices so we don't end up damaging our overall health, exacerbating problems like obesity, diabetes, and heart disease, and impairing our immune systems to boot!

As experts in ketogenic nutrition, we here at KetoDietApp thought we'd share some thoughts on the potential relationship between ketogenic diets and COVID-19.

Could Ketones Have Beneficial Effects?

Ketones could possibly protect against COVID-19 in at least two ways. First, a mouse study, published this past December in Science Immunology, found that a ketogenic diet protects mice against the influenza flu virus, which is like COVID-19's cousin. The mechanism by which the ketogenic diet protected the mice is the same mechanism by which infants are protected against the influenza ( 1). Since we know infants are also protected against COVID-19, although we aren't yet sure why, it's possible that it's the babies' ketones that protect them.

Second, it's important to note that it's not the COVID-19 virus that kills people, it's the body's response to the virus. When the body is overwhelmed (more likely in elderly and immunocompromised people), it overreacts with what is known as a "cytokine storm." This is a fancy way of saying, the body releases tons of inflammatory factors that can lead to "acute respiratory distress syndrome" (ARDS) in COVID-19, the need for ventilator support, and ultimately, death.

Ketones are known to be potent inhibitors of inflammation by increasing levels of an important molecule called NADPH ( 2), inhibiting the NLRP3 inflammasome ( 3), and other mechanisms. Therefore, ketones may protect against the cytokine storm that leads to death in severe cases of COVID-19.

At this time, the relationship between ketones and COVID-19 is still within the realm of speculation although researchers are hard at work to change that. However, it's notable that there have been numerous clinical reports of individuals (including the elderly and those with chronic diseases) who are in ketosis and have presented with mild respiratory symptoms — runny noses, scratchy throats, and mild coughs — as well as other COVID-19-associated symptoms — conjunctivitis ( 4) and diarrhea ( 5) — but who are otherwise fine.

Is it possible that they are infected and that their diets are blunting the impact of the virus? Possibly. In any case, we'd argue that you're better off simply trying to eat healthily than chugging orange juice while hidden inside your fortress made of toilet paper.

It's not the COVID-19 virus that kills people, it's the body's response to the virus. When the body is overwhelmed, more likely in elderly & immunocompromised people, it overreacts with what is known as a "cytokine storm."

February 2021 Update

Earlier this month (February 8, 2021), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) published a perspectives piece in the prestigious journal, Cell Metabolism, highlighting the relationship between COVID-19 and metabolic diseases, including diabetes and obesity. (William T. Cefalu et at, 2021)

The ketogenic diet is a means to achieve metabolic health. In fact, randomized controlled crossover trial in individuals with metabolic syndrome demonstrated that a low-carb diet is better than a low-fat diet for improving metabolic syndrome, even when calories and weight are controlled. Therefore, this piece was relevant to what we do here at KetoDiet.

Personally, I couldn’t be more pleased that a government body and top scientific journal are willing to call out that metabolic health matters when it comes to saving lives from the viral pandemic, and in particular minority lives.

Metabolic Diseases & COVID-19

Diabetes and obesity unequivocally increase COVID-19 severity, including a two-fold increase in mortality. So, how many lives have metabolic diseases contributed to the COVID-19 death toll this past year? Well, as the NIDDK is an American group, we will focus on United States statistics.

Over half-a-million people have been taken by the virus at the time of this writing in March 2021. Given that more than one third of Americans have diabetes or pre-diabetes, 42.4% are obese, and 88% have at least one marker of metabolic syndrome, the number is not one I’m keen to quantify.

Minority Burden

The authors rightly point out that minorities carry a disproportionate burden of metabolic diseases and COVID-19-related deaths. These observations are inseparable. For example, Black Americans have a prevalence of diabetes that two-fold that of white Americans, the highest prevalence of obesity among any minority group, and a corresponding 3.5-fold increase in COVID-19-related mortality as compared to non-Hispanic whites.

The racial disparities in COVID-19-related do not appear to be attributable to differences in genetics or immune disposition, or by a difference in the of certain medication that interact with SARS-CoV-2 virus. Instead, multiple studies referenced in the perspectives article demonstrate that COVID-19-realted mortality was not increased in minorities after adjusting for sociodemographic factors and co-morbidities.

The conclusion is evident — metabolic diseases contribute to COVID-19 severity and mortality — but what about the solution?

Therapeutic Carbohydrate Reduction (TCR) as a Solution

There are obviously tremendous gaps between minorities and white Americans with respect to important environmental factors, including food availability and affordability. We can and should close the gaps, but this will not happen overnight. By contrast, therapeutic carbohydrate reduction (TCR) is a tool we do have at our fingertips to address the epidemic of obesity and diabetes, and thereby save American and minority lives from COVID-19.

TCR is effective at reversing obesity and type II diabetes. ( Athinarayanan et al, 2019) For example, the Virta health trial found that over two-years individuals who practiced TCR lost 30 pounds and 60% were able to come off of insulin. By contrast, the standard of care control group gained weight and most had to increase their medications. In this study, TCR was shown to be 11-times as effective as standard of care at reversing diabetes, based on markers of glycemic control. And, not surprisingly, better glycemic control in diabetes has been associated with lower COVID-19-related mortality. What’s more, a randomized crossover trial including 16 people with metabolic syndrome showed that, even independent of weight loss, TCR was able to reverses metabolic syndrome in 9/16 subjects in just four weeks, as compared to 1/16 subjects on an isocaloric lower fat, higher carb diet. ( Parker N Hyde et al, 2019)

Where Are We Now?

The issue with generating any content on this topic is that the field is rapidly changing. However, when I look back at the principles, I wrote one-year ago at the start of the pandemic in March 2020 (above) I personally feel the principles still apply.

Masks matter but so does metabolic health. Again, personally, I want to do all I can to protect myself and my loved ones and the community at large. That means being a responsibly cautious — not paranoid — citizen. For now, mask up (it keeps your face warm in Boston winters anyway), get your vaccine when you have the opportunity (I know it’s a controversial topic but the bigger gamble is with the virus [you’re even gambling on your brain!]), and eat healthy. Personally, I think a well-formulated ketogenic diet is a fantastic option for metabolic health. But, honestly, so long as you’re eating a whole foods diets that’s low in sugar you’re doing pretty well.

Related video: COVID19, metabolic disease, race

References & COVID-19 Resources

  1. Goldberg EL et al.,  Ketogenic diet activates protective γδ T cell responses against influenza virus infection, Sci Immunol. (2019 Nov 15).
  2. Richard L. Veech et al.,  The "great" controlling nucleotide coenzymes, IUBMB Life. (2019 May).
  3. Youm YH et al.,  The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. (2015 Mar).
  4. CDC, WHO,  Important coronavirus updates for ophthalmologists (Updated March 28, 2020)
  5. Lei Pan, MD, PhD et al.,  Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study (March 18, 2020)
  6. William T. Cefalu et at., COVID-19 and metabolic diseases: a heightened awareness of health inequities and a renewed focus for research priorities, Cell Metabolism (February 8, 2021)
  7. Parker N Hyde et al.,  Dietary carbohydrate restriction improves metabolic syndrome independent of weight loss, JCI Insight (Jun 20, 2019)

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Comments (15)

Dear Nicolas,
I am very impressed with the information you presented on Ketones/COVID19. I have been supportive of this concept for a long time and presented it to my patients on a daily basis during this saga.
I’d like to add that SARS-COV2, as you know, occupies the AC2 receptors, especially in lungs, heart, and GI track. This leads to an increase in angiotensin 2 and a decrease in angiotensin 1,7..which leads to the production of Superoxide and massive oxidative stress...(Inflammation)... which leads to endothelial cells dysfunction and an increase in their VWF secretion ...leading to clotting (DIC). Inflammation and clotting are the two major drivers to the ICU.
A proper ketogenic diet has the potential to protect against these 2 drivers.
As you mentioned, ketones are excellent down regulators of the inflammation cascade that a viral infection may cause. We also know that from observational studies, we noticed that people who have VWF disease tend to bruise a lot more when on ketogenic diet. So It is thought that KETONES decrease platelets  response to the VWF. This will prevent clotting in the setting of a clotting cascade.
In summary,
The Ketogenic diet has the potential to decrease inflammation and clotting in the setting of SARS-COV2 infection- the two drivers to ICU.
Joseph Sleiman, MD, FAAFP

Thank you for your generous feedback Dr. Sleiman. Certainly, all your points are well made and I have little to add, other than some new speculations on interaction between the angiotensin system and NO, given the new data going out on NO. Being someone who has had/has colitis, IBS-C, and thrombocytopenia, I'm especially sensitive to your points. Keep doing what you're doing!

I don't believe that viruses exist to kill mammals. To kill the host is to kill their opportunity to procreate and successfully spread. We are 6-8% viral DNA after all. Ketosis is the 'normal' metabolic state at which people are supposed to function. I think evolutionarily, the virus is meant to be endocytosed by oronasalpharyngeal mucosal cells.   Very little if any symptoms of cough and nasal discharge is created to permit aerosolized transmission for a short period of time. The ketosis/low inflammasome state allows for maybe a local reaction. High autophagic/xenophagic flux prevents extensive/overwhelming viral replication. COVID patients getting myocarditis, pneumonitis and enteritis, exist with a metabolism that is not evolutionarily optimal. Low insulin states promote effective CD8 function which permits active/specific/quick identification of MHC1 virally labeled/infected cells.  Perhaps in good times when mammals/primates had access to abundant fruit/honey in nature, the insulin levels might be a bit higher thus permitting the immune system to allow the host to have more symptoms allowing for more viral spread. This would make sense because more more nutrients would allow more animals to exist allowing the virus to take advantage of the 'good times' and spread itself even more. But never in the time of primate history have we consumed such high density carb food that maintain a constantly high insulin level. This deranges this fine tuned symbiotic process.(symbiotic in the sense that we get viral dna from them and they get access cellular machinery.
BTW, this is my opinion based on the curating and processing of existing information out there.

I've written over 200 online pieces for the general public. This is among the best comment I've ever gotten on any of them.
A digested form so that others can understand your immensely insightful comment:
It doesn't make sense for a viruses to kill its host because then the virus loses its home and dies. It's better for the virus if the host just gets sick enough to spread the virus (in the case of corona, this would be respiratory droplets/coughing). Given this evolutionary logic, one could make a reasonable case that a contributing factor to why so many people are being killed by corona is that our modern diets and lifestyles (which are pro-inflammatory) put us out of tune with our evolution and cause our body to overreact. By at least living a healthier, more evolutionarily sound (and perhaps low-carb) lifestyle, we stand our best chance at not being killed by a immune system overreaction to a little virus that's looking for a (living) home.

This is interesting and I hope that being vlchf for 5-1/2 years really will play a part in not getting sick from this thing. However, I've read in various places that when you have been in ketosis for a long time, you don't have many ketones (or is it that they aren't really discernible?) - something like that - do you have a comment on that?
Also if someone has immune issues or inflammatory conditions, and ketosis has mitigated the symptoms of those issues, I wonder if that puts the person sort of back at square one in terms of having an edge in fighting this. Like, are the ketones (however many) busy fighting the already-existing inflammation and won't be able to mount the "extra" defense against covid19. I'm probably not asking these questions very well but maybe you'll see what I'm getting at. Thanks

With regards to your first concern about having lower blood ketones following a long-term ketogenic diet, this is true but not bad! Think of blood ketones as the storage form of ketones. It doesn’t actually matter how high your blood levels are. What matters more is how much ketones versus glucose you are burning.
I like the analogy of a funnel. Imagine that you’re pouring water into a funnel and that this represents your body’s production of ketones. The amount of water in the funnel at any one moment is like the amount of ketones in your blood. As you can see, two factors determine how much water is in the funnel (ketones in your blood). First, there is the rate at which you are pouring the water (turning fat into ketones) and second there is the width of the funnel’s bottle neck (the rate which your using ketones). As you adapt to ketosis, you get better at burning ketones. This is like the funnel bottle neck expanding. As a result, the levels of water in the funnel (ketones in your blood) will decrease and reach a new, lower, steady state.
This gradual shift is evidence that your body is using ketones better, not that you’re making less. Provided you adhere to the LCHF lifestyle, think of it as a good thing! (Also ask yourself this, why do ketones go down when you work out hard, even if you’re fasted?… The bottle neck is getting wider and you’re using them up!)
As for your second concern about ketones being “distracted” fighting off pre-existing inflammatory conditions, actually the opposite is true. It’s less like the ketones are being used up to fight, say IBD or lupus, and more like that are supporting general anti-inflammatory pathways that universally protect against inflammation and disease. That’s why people who adopt a KD for inflammatory disease X usually experience improvements in a broad range of symptoms (when I started KD for ulcerative colitis, my rosacea and knee swelling disappeared).
I hope this helps and apologize for the sub-par prose and typos. Busy morning but I wanted to make sure to reply to you. Best wishes.

Thanks so much!! I appreciate your time and information. Stay well 😊

Hi Nic, thank you so much for your concise article on this.
“However, it's notable that there have been numerous clinical reports of individuals (including the elderly and those with chronic diseases) who are in ketosis and have presented with mild respiratory symptoms — runny noses, scratchy throats, and mild coughs — as well as other COVID-19-associated symptoms — conjunctivitis (4) and diarrhea (5) — but who are otherwise fine.”
This called my attention because you mention that these people are in ketosis, and I wondered whether they were being tested for it. I went to the source and couldn't find anything.
I can see some detractors of ketosis being fueled by your statement so I just want to make sure I understand the point here.
Are you trying to say you assume these people to be in ketosis, experiencing symptoms, yet not developing a full-blown case of COVID-19?
Or has this been thoroughly tested?
Very interested to read more!

Great (defensive) question. To clarify, I am referring to first person observations my colleagues and I have made of individuals we know to be in ketosis (study participants, patients, etc.), a good number of whom are currently presenting with an unusual array of symptoms. The fact that all these symptoms are related to COVID and that each person is presenting simultaneously and independently could be a coincidence, possibly. However, given that there is mechanistic reason to believe ketosis could be protective against COVID, these observations serve as a sort of cherry-on-top reason for me to feel that it’s at least worth inquiring about a metabolic approach to coronavirus. Unfortunately, testing is currently being reserved for those with obvious stereotypical symptoms (e.g. fever and extreme respiratory symptoms). Furthermore, when respiratory symptoms are mild and swabbing technique is poor, I’m not sure what the false negative rate is of the PCR technology we currently use is. Once an anti-body test is developed, or wider/drive by testing is implemented, we’ll have more information.

I'm following the news every day. What's interesting is that many infected people have high insulin and blood sugar levels. It's a correlation that's worth observing!

FYI, infants are not immune to COVID-19. There's been several deaths under the age of one year from COVID-19 in China and so far, one in the USA. There's several in Italy that have been tested positive and hospitalized, but so far all have recovered.

You are correct. Infants are not "immune." But, in general, they do appear to be somehow "protected." Since COVID is so new, we don't know why. The ketones hypothesis is currently pure speculation. But, if it were true, consider this: breast milk promotes ketosis in newborns over formula. I'm curious whether breast fed newborns with higher BHB levels are also more protected against COVID than formula fed newborns with lower BHB levels. Just a thought. Thank you, Scott, for your cautious comment. You're evidently staying up to date on the literature and presumably being a responsible citizen during this hard time. Cheers.

I think especially at this juncture you need to be EXTREMELY cautious about publishing any OPINION you feel an obligation to temper as being "pure speculation".  It leads people down the road of "what do I have to lose by trying?" and that can cause people (especially those who are higher on the fear driven scale) to make unwise choices.  

I agree that we have to be very very careful and I've seen lots of silly theories BUT I also have to say I can't see how this specifically may lead to unwise choices. Eating healthy, keeping your blood sugar down, washing your hands and being generally cautious are all important.

Dear Jo, I appreciate your cautious perspective and grant you that a possible reaction to this piece is a flippant attitude. Perhaps I’m too overconfident in the intelligence of this readership? Perhaps, but I don’t think so. Rather, I tend to agree with Sam. You’ll note I end on an open question. It’s too early to have all the answers so we can either shelter behind maladaptive hysteria (and toilet paper fortresses) or open informed discussions, ask questions, and try to find a way forward. We all have our piece to do this in. You, and folks liver Trevor Noah, are doing extremely important work by advising caution. I chose to do my part by pursuing research questions (I am one of those “scientists” designing clinical studies) and trying to open dialogue that can help calm people’s nerves and refocus them on more productive practices. For example, as Sam points out, the only advise I imply is to not let the shutdown cause collateral damage to your help by way of poor nutrition and lack of exercise. I hope that all makes sense. Cheers and thanks for your comment.