Tim Ferriss’ personal ketosis biomarkers
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A fan of self-experimentation, Tim Ferriss tracks the effects of his dietary interventions using several biomarkers. In particular, he monitors his ketone levels, both upon waking and following exercise. Tim maintains that not everyone processes ketones to the same extent, and he prefers to tailor his ketone level to allow maximal mental clarity. He also measures fasting glucose and hemoglobin A1c, a three-month average of glucose levels, to ensure that he does not trend toward pre-diabetes. Tim also chooses to measure free testosterone and sex hormone-binding globulin along with numerous other parameters. In this clip, Tim Ferriss outlines the biomarkers that he measures routinely to make sure his health is on-track while following a ketogenic diet
- Rhonda: On the self-experimentation topic, you've been self-experimenting for many years and I was wondering if throughout your years of experimentation if there are three or four biomarkers . . . so, you typically measure blood biomarkers routinely. If there are three or four really important ones that you think are important that you routinely measure and if they have anything to do with performance or mental acuity or perhaps aging.
- Tim: Yeah. There are a few . . . well, there are many blood markers that I look at. I had a fun conversation with Pete Attia on the podcast not too long ago about this. But my markers, the markers that I'm following right now are number one, my millimolar concentration of ketones. So I have a device just on the counter over there, a Precision Xtra device by Abbott Labs that allows me to use both glucose strips and ketone strips. So I can look at my fasting or waking fasting glucose level and then ketone level and monitor that after certain types of, say, exercise when the ketone level can drop and so on and so forth. Because I've identified for myself, part of the reason I have fat in my tea, is I operated best mentally at around 1.1 to 1.7 millimolars and I only figured that out by tracking.
- Rhonda: Very interesting.
- Tim: Some people, for instance, perform much better the higher concentration. The higher the concentration of ketones, the better they feel. I don't fall in that camp. I was having a conversation with a scientist a few days ago about this. He said, "Well, really," and this is not a new observation, "But your blood level of ketones can be gained or increased in many different ways." So you can just eat a meal that's full of medium chain triglycerides or eat a meal that's just full of fat in general and you can spike your ketone level. That's not necessarily indicative of an endogenous production of ketones or you could be fasting and like deep fasting after five or six or seven days. In my particular case, I think you also want to look at--and this is true, a lot of very smart people like Pete Attia, Dom D'Agostino, very, very smart guy, Dominic--would say likely that it also could be some people utilize ketones better than others.
- Rhonda: Yes.
- Tim: So just because you have a high level of ketones, doesn't mean you're necessarily doing a lot with it. So in my case, a high level of ketones, my hypothesis is well maybe past a certain point, my kind of machinery gets very inefficient or gets damaged. So between 1.1 and 1.7, my brain operates functions at a level reminiscent of pre-Lyme. That's a whole separate thing. I kind of knocked out normal cognitive function for nine months due to severe Lyme disease. But when I am focused on at least a nominal amount of ketones, I feel like my old self. So that's one. Other things that I focus on or look at . . . there are some esoteric things that I play with every once in a while. But if you're looking at the routine levels, I'm going to look at obviously the sex hormones, look at free testosterone. I'll look at free testosterone as relative to sex hormone binding globulin, for instance. I'm not convinced that higher sex hormone binding globulin is always a bad thing. That's a whole separate. Because my testosterone in experimenting with high fat, total testosterone has gone from 650 to 950 in a span of nine months. It's a non-trivial increase. Now, sex hormone binding globulin has also increased over time. But I've gained so much lean muscle tissue that I have other ideas. I was talking to Steven Phinney about this--scientist, very well known for looking at the ketogenic diet--and what he was saying is independent of insulin levels, insulin made very anabolic . . . sorry, we're getting into the weeds here. It's possible that my lean mass gains can be account for by decreased degradation of branch chain amino acids. I was like, "That's really interesting." Maybe that explains by fasting plus chemotherapy is very, very effective, for instance. People can recover faster from chemotherapy. So you have the ketones. You have the sex hormones. Hemoglobin A1c, sort of like your running three-month average of glucose levels just as an insurance policy to ensure that I'm not skewing towards pre-diabetic in any way. And then a laundry list of like five or six different pages of stuff.
- Rhonda: So your biomarkers tend to be a lot of performance-related biomarkers.
- Tim: Yeah. And I've done the genetic stuff. So I know, let's just say that I'm a poor methylator, the motherfucker gene, as they say.
- Rhonda: Yes, MTHFR.
- Tim: Yeah. I'm not in an ideal spot. So taking, say, l-methylfolate could be a good option for me and I've experimented with that in the past, looking at how that can lower homocysteine or things like that.
- Rhonda: Have you noticed any differences after experimented with 5-methylfolate, L-5-methylfolate, methylcobalamin?
- Tim: Yeah. I haven't noticed many changes in blood markers and I haven't noticed subjective changes in, say, performance or clarity or anything like that.
- Rhonda: Yeah.
- Tim: It doesn't mean it isn't doing things.
- Rhonda: Yeah. I have an anecdotal story. So I'm very into looking at different gene polymorphisms. 23andMe is a great service that can do that. So my friends, family, etc., I'm telling everyone to do it. So my mother-in-law got genotyped and we found out that she is homozygous for MTHFR, meaning that her MTHFR enzyme only is working at about 10 to 20% efficiency. She's always had really high blood pressure, to the point where doctors were wanting to get her on medicine for it and she's always refused. Nothing she did . . . she's done various diets, lots of exercise, lots of things she's tried, nothing has gotten her into a normal range until we identified she had MTHFR, got her supplementing with 5-methylfolate and methylcobalamin. But she's been taking pretty high doses of it. But now her blood pressure for the first time is in like a normal range. So I was kind of curious if you had ever . . .
- Tim: I have very consistently what you would consider excellent blood pressure. So I haven't looked closely at that. The question that comes to mind for me always because I've noticed . . . so, I'm a big fan of Richard Feynman. Richard Feynman, and I'm not saying this is the case with your, you said mother-in-law?
- Rhonda: Yes.
- Tim: But the importance of not tricking yourself because you're the easiest person to fool, basically, is what he would say. I know that what I have initially thought were sort of causal relationships with high correlative value . . . for instance, I've talked to people who have gone on fill in the blank diet. They're like, "This thing changed. I'm so glad I found this diet." I'm like, "So you haven't changed anything else?" "No, no, no. I started running in the morning. I started doing this. I started doing that." I'm like, "Hell yeah" . . . because like one, it's so hard. That's where the observational data gets so challenging, when you look at, say anything, whether it's the China study or whatever. We don't need to get into that one. That's a sensitive one. But any observational self-reporting and so on, the data is almost always so flawed because humans almost never change just one thing.
- Rhonda: Yeah. I think that's why it's so important when you're looking at epi studies that are associative that are not a clinical, randomizable trial, coupling that data with mechanistic data done on animal models or lower organisms, I think coupling the two is very important because then you go, "Oh, okay. We've noticed this observational data and here we've done X, Y or Z to manipulate it in a worm or in a fly or a mouse."
- Tim: Right. So you have a plausible mechanism.
- Rhonda: Right. So you have a mechanism. That's where I think looking comprehensibly at the whole . . .
- Tim: At the intersection.
- Rhonda: Yeah, scientific is very important.
- Tim: Totally agree.
- Rhonda: It's interesting. You mentioned the ketone thing. I just want to briefly give you my story.
- Tim: Yeah.
- Rhonda: So I've never noticed, really, any extreme mental benefits or mental acuity changing when I consume large amounts of MCT on empty stomach, on whatever. I found out that I have one ApoE4 allele. And of course, at that point, I became terrified of Alzheimer's because it increases the risk for Alzheimer's by two-fold and I'm writing an academic paper on this right now and getting into all the mechanisms--diet, lifestyle, things like that. But what I found really interesting are the studies that they've done where they give, for example, people who have dementia or people in the early stages of Alzheimer's, they give them beta-hydroxybutyrate, which is a ketone body. And there's improvement.
- Tim: I have some synthetic jet fuel in the freezer if you want to try it. We'll probably both vomit on my couch. So let's do it later.
- Rhonda: Yeah. I've heard it's disgusting. So people who were ApoE3 responded very well. So they had improvements in learning and memory.
- Tim: With a supplemental MCT?
- Rhonda: With beta-hydroxybutyrate. They gave them beta-hydroxybutyrate. But what was interesting to me and also very discouraging was that people with ApoE4 allele did not have those benefits. If you look at Alzheimer's, people with Alzheimer's, between 65 and 80% of all people who have Alzheimer's have one allele of ApoE4.
- Tim: Oh, well I bet I have that on both sides of my family, then because I have Alzheimer's on both sides.
A neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes. The pathological hallmarks of Alzheimer's disease include amyloid-beta plaques, tau tangles, and reduced brain glucose uptake. Most cases of Alzheimer's disease do not run in families and are described as "sporadic." The primary risk factor for sporadic Alzheimer's disease is aging, with prevalence roughly doubling every five years after age 65. Roughly one-third of people aged 85 and older have Alzheimer's. The major genetic risk factor for Alzheimer's is a variant in the apolipoprotein E (APOE) gene called APOE4.
One of three common genetic variants of the APOE (apolipoprotein E) gene. The APOE4 allele, which is present in approximately 10-15% of people, increases the risk of developing Alzheimer's disease and lowers the age of onset. Having one copy of E4 increases risk 2- to 3-fold, while having two copies increases risk as much as 15-fold.
A chemical produced in the liver via the breakdown of fatty acids. Beta-hydroxybutyrate is a type of ketone body. It can be used to produce energy inside the mitochondria and acts as a signaling molecule that alters gene expression by inhibiting a class of enzymes known as histone deacetylases.
A measurable substance in an organism that is indicative of some phenomenon such as disease, infection, or environmental exposure.
An amino acid having aliphatic side-chains with a branch (a central carbon atom bound to three or more carbon atoms). Among the proteinogenic amino acids, there are three BCAAs: leucine, isoleucine and valine.
A general term referring to cognitive decline that interferes with normal daily living. Dementia commonly occurs in older age and is characterized by progressive loss of memory, executive function, and reasoning. Approximately 70 percent of all dementia cases are due to Alzheimer’s disease.
Any of a group of complex proteins or conjugated proteins that are produced by living cells and act as catalyst in specific biochemical reactions.
A type of water-soluble B-vitamin, also called vitamin B9. Folate is critical in the metabolism of nucleic acid precursors and several amino acids, as well as in methylation reactions. Severe deficiency in folate can cause megaloblastic anemia, which causes fatigue, weakness, and shortness of breath. Certain genetic variations in folate metabolism, particularly those found in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene influences folate status. Inadequate folate status during early pregnancy increases the risk of certain birth defects called neural tube defects, or NTDs, such as spina bifida, anencephaly, and other similar conditions. Folate deficiency and elevated concentrations of homocysteine in the blood are associated with increased risk of cardiovascular disease. Low folate status and/or high homocysteine concentrations are associated with cognitive dysfunction in aging (from mild impairments to dementia). The synthetic form of folate is called folic acid. Sources of folate include most fruits and vegetables, especially green leafy vegetables.
The genetic constitution of an individual organism. The combination of genotype and environment determine an organism's physical characteristics – known as the phenotype.
A blood test that measures the amount of glycated hemoglobin in a person’s red blood cells. The hemoglobin A1c test is often used to assess long-term blood glucose control in people with diabetes. Glycation is a chemical process in which a sugar molecule bonds to a lipid or protein molecule, such as hemoglobin. As the average amount of plasma glucose increases, the fraction of glycated hemoglobin increases in a predictable way. In diabetes mellitus, higher amounts of glycated hemoglobin, indicating poorer control of blood glucose levels, have been associated with cardiovascular disease, nephropathy, neuropathy, and retinopathy. Also known as HbA1c.
An amino acid present in the blood. Homocysteine is produced during the metabolism of methionine. Abnormalities in methionine metabolism can lead to elevated homocysteine levels, a condition called hyperhomocysteinemia. Elevated homocysteine levels can contribute to arterial plaque formation and increase the risk of clot formation. Some evidence suggests that elevated homocysteine levels double the risk of developing Alzheimer’s disease. Homocysteine levels vary according to dietary intake, with highest levels associated with consumption of animal protein. Variants in the genes that encode for the enzymes that metabolize homocysteine, specifically MTHFR, or methylenetetrahydrofolate reductase, markedly increase the risk of developing a wide array of diseases, including cardiovascular disease, Alzheimer’s disease, and cancer. High intake of dietary folate (present in leafy greens and other fruits and vegetables) can modulate the harmful effects associated with MTHFR.
A peptide hormone secreted by the beta cells of the pancreatic islets cells. Insulin maintains normal blood glucose levels by facilitating the uptake of glucose into cells; regulating carbohydrate, lipid, and protein metabolism; and promoting cell division and growth. Insulin resistance, a characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response, which can lead to high blood glucose levels.
A diet that causes the body to oxidize fat to produce ketones for energy. A ketogenic diet is low in carbohydrates and high in proteins and fats. For many years, the ketogenic diet has been used in the clinical setting to reduce seizures in children. It is currently being investigated for the treatment of traumatic brain injury, Alzheimer's disease, weight loss, and cancer.
Molecules (often simply called “ketones”) produced by the liver during the breakdown of fatty acids. Ketone production occurs during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, or prolonged intense exercise. There are three types of ketone bodies: acetoacetate, beta-hydroxybutyrate, and acetone. Ketone bodies are readily used as energy by a diverse array of cell types, including neurons.
An infectious disease caused by bacteria of the Borrelia type which is spread by ticks. The most common sign of infection is an expanding non-painful area of redness on the skin, fever, headache and feeling tired. Lyme disease is the most common disease spread by ticks in the Northern Hemisphere and is estimated to affect 300,000 people a year in the United States and 65,000 people a year in Europe.
A class of saturated fats. Medium-chain triglycerides are composed of medium-length fatty acid chains (six to 12 carbons long) bound by a glycerol backbone. They occur naturally in coconut oil, palm oil, and butter, but they can also be synthesized in a laboratory or food processing setting. Evidence suggests that MCT therapy improves cognitive function in older adults with Alzheimer's disease.[1] Examples of MCTs include caprylic acid (C8), capric acid (C10), and lauric acid (C12).
- ^ Juby, Angela G.; Blackburn, Toni E.; Mager, Diana R. (2022). Use Of Medium Chain Triglyceride (MCT) Oil In Subjects With Alzheimer's Disease: A Randomized, Double‐Blind, Placebo‐Controlled, Crossover Study, With An Open‐Label Extension Alzheimer's & Dementia: Translational Research & Clinical Interventions 8, 1.
A gene coding for an enzyme that converts homocysteine into methionine; a critical step in the methyl cycle. Natural variation in this gene is common among healthy people, however, some variants have been reported to influence susceptibility to occlusive vascular disease, neural tube defects, Alzheimer’s disease and other forms of dementia, colon cancer, and acute leukemia.
A test in which a person's glucose and sometimes insulin is tested before and at multiple intervals after having consumed a measured dose of glucose. Depending on the protocol, blood may be drawn for up to 6 hours afterward.
A health condition in which blood glucose levels are higher than normal, but not high enough to indicate a diagnosis of type 2 diabetes. Prediabetes can be halted or reversed with dietary and lifestyle modifications, including weight loss, exercise, and stress reduction.
A glycoprotein that binds to sex hormones, and is produced mostly by the liver. Testosterone and estradiol circulate in the bloodstream bound mostly to SHBG. Only around 1-2% is unbound or "free", and thus biological active. The relative binding affinity of various sex steroids for SHBG is dihydrotestosterone (DHT) > testosterone: androstenediol> estradiol> estrone.
A change in one nucleotide DNA sequence in a gene that may or may not alter the function of the gene. SNPs, commonly called "snips," can affect phenotype such as hair and eye color, but they can also affect a person's disease risk, absorption and metabolism of nutrients, and much more. SNPs differ from mutations in terms of their frequency within a population: SNPs are detectable in >1 percent of the population, while mutations are detectable in <1 percent.
The primary male sex hormone. Testosterone is critical to the maintenance of fertility and secondary sexual characteristics in males. Low testosterone levels may increase risk of developing Alzheimer’s disease.
A molecule composed of a glycerol molecule bound to three fatty acids. Triglycerides are the primary component of very-low-density lipoproteins (VLDL). They serve as a source of energy. Triglycerides are metabolized in the intestine, absorbed by intestinal cells, and combined with cholesterol and proteins to form chylomicrons, which are transported in lymph to the bloodstream.
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Ketosis News
- Ketogenic diet raises brain blood flow by 22% and increases brain-derived neurotrophic factor by 47%, highlighting its potential to support cognitive function even in people without cognitive impairment.
- Beta-hydroxybutyrate, a ketone used by the brain during fasting or exercise, may help counteract toxic protein buildup in aging and Alzheimer's disease.
- A ketogenic diet restores long-term potentiation, a crucial mechanism for learning and memory, to healthy levels in mice prone to Alzheimer's-like symptoms, implicating ketone bodies as potential therapeutic agents.
- Long-term nutritional ketosis improves metabolism and reduces inflammatory markers in women.
- Ketone supplements marginally hinder high-intensity cycling performance, echoing earlier research.
