When Dr. Rhonda Patrick returned to the podcast for a Q&A episode, I figured it would be popular. But I didn’t realize it would quickly become one of the most downloaded episodes of all-time.

As a result, many of you asked for the transcript of our conversation, so here it is. Dig in and enjoy the notes from this fascinating episode with Rhonda Patrick!

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Question (from Tim): “What new areas, experiments, discoveries or hypotheses are you most excited about these days?”

Rhonda Patrick: Thankfully, because I’ve put a certain percentage of my brain out here on the internet… much of what I’m actively interested in these days or have been interested in is actually elucidated a little bit as necessary context for some of the questions I’m going to answer here shortly.

But, Tim’s question does sort of give a nice opportunity for an overview. As a rule, the things that usually get me really revved up are ultimately optimizations that we can make to our lifestyles that might increase our functional healthspan, well-being, and lastly …cognitive and physical performance… usually through deeper understandings of biology. Healthspan, or healthy functional lifespan, is especially of interest to me. I sort of lead with that.

To me, “healthspan” is living for as long as we can while doing our best prevent deterioration from the diseases of aging.

Talking about increasing healthspan is one thing though. Often achieving it is a different thing altogether. The reason this is tricky is that the most reliable way to treat aging is to try to, instead, prevent it. A natural extension of that fact means that the earlier we start, the better shot we have of making a large cumulative effect over the course of our lives.

The specifics of how to best mitigate the damaging effects of aging, specifically, is subject to a little bit of individual variation as a consequence of each of our little genetic idiosyncrasies, the combination of which are unique to each of us. This is an area that I’m especially interested in and that I plan to invest a bit more into intellectually in the coming months, especially the interface between nutrition and genetics, known as nutrigenomics.

The good news is there are certain rule of thumb strategies that are able to have a positive effect on health and possibly even longevity. In some cases, it might mean optimizing our diet around inclusion of specific nutrients. One of the most interesting and exciting of which, to me, right now is a compound known as sulforaphane, spelled s-u-l-f-o-r-a-p-h-a-n-e. But also other related compounds that fall into the same class of compounds broadly known as isothiocyanates, all of which, including sulforaphane, being derived from cruciferous vegetables.

What’s interesting about sulforaphane is that this compound, richly found in broccoli sprouts at 50 to 100-times what’s found in mature broccoli, is that it activates a special genetic pathway in our cells known as Nrf2 and it does so more potently than any other known naturally-occurring dietary compound. This gene, a master regulator, controls over 200 other genes… affecting whether or not they’re activated and doing work. These include genes that affect our own anti-inflammatory processes, antioxidant processes, and even the ability to inactivate potentially harmful compounds we’re exposed to on a daily basis from breathing in carcinogens like benzene from air pollution.

In a sense, we’re talking about an on-switch for some of our native stress responses. Our ability to cope with physiological stress, down to the cellular level, ultimately affects how rapidly we accumulate the damage which we often refer to as aging. But, here’s the interesting thing. The reason Nrf2, a stress-response pathway, is activated by sulforaphane is because the compound itself functions as what is know as a xenohormetic, a compound that by virtue of being actually slightly stressful to cells, elicits a biological stress response that has a cumulative effect that is otherwise a net gain in resilience that creates benefit to the organism as a whole.

This is actually somewhat unintuitive if you really think about that. We sort of have this very natural notion that because excess stress is bad, we should venture to avoid stress at all costs. It turns out though, that, in fact, perhaps as a consequence of having received stressful compounds in our diets for millions of years, things that evolved in plants as insect anti-feedants that help ward off insects, we sometimes function better for having them. They can even induce neurostress responses that boost neurotrophic factors that lead to the growth of new neurons and promote the survival of existing neurons, which may function to help make compounds like sulforaphane potentially a candidate as a mild nootropic. We’ll probably come back to that in a little bit… but the bottom-line is that If we take this same concept that stress can be beneficial, known as hormesis, and apply it to other things like exercise, fasting, heat stress, cold stress, some of the various benefits that may be had from many of these strategies similarly come about as a consequence of sometimes overlapping stress-response pathways.

This idea of hormesis and trying to improve our capacity to be resilient to environmental stress and even the stress generated as a byproduct of normal metabolism and immune function, in particular, is a very useful framework for evaluating the potential of strategies that might have promise in preventing even aging. Okay, all of that said, this is a great opportunity to jump from these sort of big picture ideas back to things of a more practical application variety. Specifically, the next question evaluates a straightforward technique that has caught my interest and also happens to be broadly applicable to almost anyone.

Brandon Beckett: Dr. Rhonda Patrick: You interviewed Dr. Valter Longo, Dr. Satchin Panda, and Dr. Ruth Patterson on time-restricted feeding and fasting. Can you summarize your best practices for “time-restricted” eating and who it might not be a good fit for?

Rhonda Patrick: Okay, this is a fun question, but before we dive right into best practices on time-restricted eating, it probably helps to know what it is for the rest of you that may be listening. Time-restricted eating, as it’s called in humans, or time-restricted feeding as it’s referred to in animal research, is this idea that by constraining our eating within a certain time window during the day ranging from only 8 hours to up to 12 hours per day, usually earlier in the day to align better with our circadian rhythm, we stand to benefit from a variety of different angles.

On the more extreme end of 8 hours you’re engaging in a slightly more extreme type of time-restricted eating which is more well-known in the fitness world in particular as 16:8 intermittent fasting. Simply maintaining a slightly more conservative time window than you usually might has started to show advantages as well, potentially functioning as a lifestyle intervention that may be able to protect people from obesity, metabolic related disease and more at a population level. For example, even an 11-hour eating window has been associated in one study with a reduced risk of breast cancer and potential recurrence by as much as 36% in women. We’ll get back to what the research, both mouse and human, says about the duration of the time windows involved, but first let’s talk a little about this circadian aspect.

When healthy adults eat meals that are identical in terms of both their macronutrient and caloric content at breakfast, lunch, or dinner, the postprandial glucose increase is lowest after breakfast and highest after dinner even though the meals were 100% identical. This is just one example that suggests metabolism changes throughout the day. We also know that in humans metabolic genes are more active during the day and less active at night. The underlying reason for this is because humans are diurnal creatures which means we conduct most of our activities during the day, including feeding, exercising, and working, and then resting at night.

What makes humans diurnal creatures is the presence of an internal clock in the brain referred to as the suprachiasmatic nucleus, or SCN for short. The part of this internal clock that interacts with the external cue of light, the SCN, is also referred to as the master oscillator. But light isn’t actually the only external cue we have, we also have food influencing what are known as peripheral oscillators that occur in peripheral tissues such as the liver and influence metabolism. Whereas light is the major cue for circadian rhythm, timing of food intake regulates circadian rhythm in peripheral tissues as well. This fact sort of helps to explain why time-restricted eating as it’s defined by Dr. Panda’s work and that of others begins with the eating period with the very first bite or drink of ANYTHING non-water, because even compounds that exist in black coffee such as caffeine, can be reasonably expected to produce metabolic effects that influence these peripheral oscillators, including activity in the liver.

Everything from making neurotransmitters, to insulin, to glucose transport inside of cells, to oxidizing fatty acids, to repairing damage is on a 24-hour cycle clock that is influenced by these external cues involving metabolism.

To sort of illustrate the importance of circadian rhythm: these clocks regulate thousands and thousands of genes which is somewhere in the neighborhood of around 10 to 15% of the expressed human genome, which means that our basic metabolic physiology is meant to be tuned to behave differently depending on the time of day that is. Even the bacteria that we harbor in our guts have a circadian rhythm with the species of bacteria changing according to the time of day. Some bacteria dominate during the morning and others during the evening. Unfortunately, with the invention of artificial lighting and varying work schedules it has extended people’s eating times to occur much later in the evening and this can have very negative consequences.

Eating late at night also may “reset” peripheral clocks and result in misalignment of metabolism, which means when you wake up your metabolism is already at end of its cycle. So that’s the logic behind the circadian aspect which gets left out of some of the intermittent fasting philosophies that are popular and explains why time-restricted eating emphasizes an earlier eating window and includes non-caloric xenobiotics as a breaking of the fast, something I’ve learned is a specific point of contention for people.

Okay, but shifting away from the xenobiotics and circadian aspects to talk more about the time window itself: animals that have been limited to a 9-12-hour feeding window in which they can eat but otherwise allowing them to eat the same amount of calories that they normally would, they have shown that they can attain some pretty amazing benefits, including:

decreased fat mass

increased lean muscle mass

improved glucose tolerance

improved lipid profile

reduced inflammation

higher mitochondrial volume

protection from mild-age related fatty liver

protection from obesity

generally favorable improvements in gene expression

Increased production of ketone bodies, which is interesting for another reason we’ll get back to in a minute Time-restricted eating also has a growing body of research in humans.

Recent studies suggest that…

Eating within an 11-hour window was associated with a decreased breast cancer risk and reduction in recurrence by as much as 36%.

Earlier meal timing associates with improved effectiveness of weight-loss therapy in overweight and obese patients.

For each 3-hour increase in nighttime fasting duration was linked to a 20% lower odds of elevated glycated hemoglobin (HbA1C), which is a more long-term marker of blood glucose levels.

For each 10% increase in the proportion of calories consumed after 5pm there was a 3% increase in the inflammatory biomarker c-reactive protein otherwise known as CRP.

Eating one additional meal during the day (instead of the evening) was associated with an 8% decrease in CRP.

Eating within a 12-hour window improved sleep and increased weight loss in normal weight people.

As a rule of thumb, anything that has the potential to mitigate chronic systemic inflammation is something I personally consider worth trying to dial in since suppression of inflammation is thought to be one of the most important predictors of successful longevity that increases in importance with advancing age and also influences risk of cancer and even potentially mental health. So putting aside the potential to have better glucose control or protect myself from obesity without actually changing the composition of my diet, reducing systemic inflammation has a lot of appeal to me.

Now that we are all on the same page in terms of what some of the research shows on the benefits of time-restricted eating, I would like to go back and address Brandon’s question about what my best practices are surrounding time-restricted eating. How you choose to implement some of this information is ultimately going to be dictated by life circumstances that include practical realities surrounding work schedule and probably a million other things. The flexibility of my schedule, however, has made implementing time-restricted eating admittedly a bit easier. Unless I have a social reason that forces me to eat later in the day, I usually start my clocks as soon as I wake up. Thus, I don’t concern myself a whole lot about what counts as breaking the fast and what doesn’t and go by the strictest of definitions: if it’s not water, it breaks the fast… unless it’s just brushing my teeth. I don’t count that.

I wake up at 8 am and have my first sip of coffee at 8:15 then I make a note to myself or I set an alarm on my phone to go off 1.5 hours before the clock ends, which is usually around 6:15 pm since I aim for a 10-hour eating window and and 14-hour night time fasting window. When I’m feeling especially motivated I eat within an 8 or 9-hour time window and fast for 15-16 hours during the night, which means if I have my first sip of coffee at 8:15 am then I stop eating by either 4:15 or 5:15 pm.

I follow the same procedure on days I sleep in, even though some animal research shows that this pattern has benefits even if you cheat on the weekend. Now, the reason why I choose a 10-hour window is because it’s a sufficiently tight window of time to likely confer some of the advantages of time-restricted eating without being unduly burdensome. Personal compliance here being the issue. Stretching for the 9-hour or even 8-hour window, however, can be also interesting and may appeal to some. Some animal research has shown a certain aerobic endurance benefit for time-restricted feeding in this 9-hour range but not for shorter fasts. And, if you think about it, mice that only feed for 9-hour periods are fasting the other 15 hours.

It takes around 10-12 hours for liver glycogen stores to be depleted which is then followed by fatty acids being liberated from adipose tissue…these fatty acids then are transported to the liver where they are converted into ketone bodies like beta-hydroxybutyrate, which are then transported to a wide-variety of tissues such as the muscle and used for energy. So it sort of makes sense that eating within a 9-hour window and fasting for 15 hours overnight may lead to endurance enhancements if we’ve managed to kick off a little more ketone production the evening before a run. Anecdotally I’ve observed that personally I feel an improvement in endurance ranging from slight to pretty significant in my morning runs when I’ve tried a little bit harder to eat strictly within just 8 or 9 hours. As a closing thought, I think there’s still a lot of room for more emerging research in this area to teach us things that may be important. Questions like:

What influence later day endurance or weight training has at mitigating the deleterious effects of other sub-optimal parameters like a later-in-the-day eating window?

How large the effect of xenobiotics like caffeine in black coffee is compared to potentially more important factor like just keeping an otherwise tighter time window with a slightly looser definition of what is considered eating?

If you’d like to see interesting questions answered about time-restricted eating, you can actually participate in a mobile app-powered, distributed clinical trial by heading over to Dr. Satchin Panda’s lab website, which can be found at mycircadianclock.org.

Available for iPhone and Android. Basically, you commit to a baseline and then one of the patterns of time-restricted eating and then proceed to submit timestamped pictures of your food over the course of 12 weeks.

Of course, I’d also be remiss if I didn’t mention a that mutual friend and someone that has repeatedly been on the Tim Ferriss show, Kevin Rose, has developed a cool mobile app to help keep track of intermittent fasting and time-restricted eating windows. You can also check that out if you’re an iPhone user, it’s in the app store under the name “Zero”… as in the number of calories you consume while fasting.

To sort of finish off this question, as for who time-restricted feeding may not be a good fit for, well, I’m not sure! As an intervention I believe it actually is broadly applicable, however, I’m 100% certain that there there is someone somewhere for which a unique medical condition may make time-restricted eating inappropriate… especially if you expand the definition of time-restricted eating to mean long, multi-day fasts which are the subject of Dr. Valter Longo’s research in particular. Definitely check in with a physician, particularly if you’re going to do prolonged fasting or if you’re thinking of trying out time-restricted eating but may have a medical condition that for some reason might somehow make it unsafe. It is far better to be safe than to be sorry.

Jasky Singh: For all those that don’t understand the benefits of fasting. How does doing a fast differ from say eating a diet LCHF that puts you into ketosis? And what key metrics (blood tests etc) should someone look at to know it is benefiting you?

Rhonda Patrick: Very interesting question, because, as implied by the question, there are at least a few similarities between a LCHF diet and fasting, but there are also, obviously, some key differences. Probably the main similarity between the two is that metabolism shifts from using glucose as a major source of energy to primarily oxidation of fatty acids and ketone bodies as energy. When it comes to fasting there are a few things that really differentiate it from a low-carb-high fat diet.

One of the major benefits of fasting, particularly prolonged fasting, which is around 4-5 days in humans that is not found on a low-carb, high-fat diet is a dramatic increase in autophagy and apoptosis followed by a massive boost in stem cell production. Autophagy is a genetic program that is very important: it clears away damaged cells to use for energy, while apoptosis is a genetic program that causes damaged cells to self-destruct. Both of these processes prevent damaged cells from becoming cancer cells. When we clear away damaged cells this also means those cells are less likely to become senescent, which is what can happen when too much damage accumulates. A senescent cell is technically a living cell but it is not functioning in a way that is consistent with maintaining the overall health of an organ, in fact, quite the opposite. Senescent cells can accelerate the aging of nearby cells and promote tumor growth by secreting pro-inflammatory molecules and other factors.

Senescent cells are bad news and as we age they are everywhere from our livers to our hearts to our brains and they accelerate the aging process. It has been shown that mice, when given a compound that increases the clearance of senescent cells, it actually extends their average lifespan by 20 percent! Another way that fasting really shines particularly prolonged fasting is that prolonged fasting has a very robust effect on increasing stem cell numbers.

The regenerative power of tissues and organs declines with age. It is the stem cells that provide this regenerative power and because stem cell numbers decline with age so does organ function which means anything that can counter that is a win! Fasting also causes cells to clear away damaged mitochondria and recycles their defective components for energy, called mitophagy followed by a concomitant generation of new mitochondria (called mitochondrial biogenesis). This is really a great thing because mitochondria accumulate damage with age (just as cells do) and this can accelerate the aging process.

So not only does fasting clear away old, damaged mitochondria, it also generates new young healthy mitochondria to replace the damaged ones. There has been some evidence suggesting a low-carb, high fat diet may modestly increase mitochondrial biogenesis but not mitophagy. Another thing fasting does is it increases the levels of something called nicotinamide adenine dinucleotide (or NAD+ which I will just refer to as NAD). NAD levels always increase during a fasted state and decrease during the fed state (no matter what food type). NAD is a very important cofactor for many metabolic enzymes, which just means you need it for these enzymes to work properly.

Your mitochondria need NAD to produce energy from glucose or fatty acids. Any time there is chronic inflammation or DNA damage occurring, this sucks up the NAD and so the mitochondria suffer. Also, NAD levels decrease in multiple tissues with aging. There are several different compounds which are various forms of vitamin B3 that dramatically increase NAD levels and have been shown to delay aging in multiple tissues in mice. Yet another difference between fasting and a low-carb, high fat diet is that fasting activates many repair processes including repair of damaged DNA, damaged cells, damaged mitochondria, and damaged proteins.

You must be in a fasted state to repair damage which is why most repair processes occur during sleep because that is when most people are in a fasted state. Fasting improves blood sugar, insulin sensitivity, and blood lipids and improves inflammatory markers, including C-reactive protein and tumor necrosis factor-alpha (TNF-α), and improves adiponectin, leptin, and brain-derived neurotrophic factor in humans. A low-carb, high fat diet has also been shown to improve blood glucose and insulin levels and reduce inflammation but not consistently and may be highly variable depending on the individual which is likely due to the fact that the way our bodies respond to food is also complicated by genetics.

We have 8 variations in our genes that make them operate a little differently from similar versions in other members of the human population. These variations are known as genetic polymorphisms. One of the best examples I have seen yet demonstrating the immense variability in how people respond to the same foods was a publication that came out in 2015 in the Journal Cell. The study looked at the blood glucose responses of over 800 different people to various foods including fat. Without getting into all of the details of this study what is important to the topic of this discussion is that while most people had a low glucose response to dietary fat some people had a high glucose response.

There have been a few important gene polymorphisms that have been identified to play a role in a context of a high-fat diet such as FTO, PPAR-alpha, PPAR-gamma and APOE4. PPAR-alpha is one of the most important genes that I’ll mention because it plays a very important role in the process of ketogenesis. Activation of PPAR-alpha promotes uptake, utilization, and catabolism of fatty acids by activating genes involved in fatty acid transport, fatty binding and activation, and fatty acid oxidation. There is a polymorphism in this gene that has been associated with lower PPAR-alpha activity and a 2-fold higher risk of type 2 diabetes, increased levels of triglycerides, increased total cholesterol, increased LDL cholesterol, and especially important, increased small-dense LDL particles in the context of high saturated fat intake and low polyunsaturated fat intake. Obviously measuring these blood biomarkers will help illuminate whether any type of diet works for you.

There are also a variety of resources on the web that can help you take your raw genetic data from services like 23andMe and find out whether you have some of these polymorphisms. I similarly offer some resources for this on my website foundmyfitness.com for this purpose. In terms of biomarkers, things I would monitor, particularly if I were doing a ketogenic diet might include biomarkers for lipid and glucose metabolism, such as LDL cholesterol, small dense LDL particles, total cholesterol, triglycerides, glycated haemoglobin (HbA1c). You can also measure your fasting blood glucose levels and ketone levels at home using something like precision xtra (which I use and find to be mostly reliable).

I also like to be aware of any inflammatory biomarkers I can get my hands on, there’s some common measurements like high sensitivity CRP and also IL-6 and TNF-alpha. For those people experimenting with a strict ketogenic diet for greater than 6 months it may be wise to measure thyroid function by doing a full thyroid panel. There was a recent publication where a ketogenic diet for 9 months caused thyroid dysfunction in children with epilepsy. This may not be something to worry about in everyone but it does not hurt to be cautious.

For autophagy-related and stem cell related biomarkers, there are some used in research that you can’t really get ahold of for self-monitoring purposes. For autophagy, LC3-II and for stem cell renewal lin-CD184+CD45- cells. Okay, one quick closing point to sort of finish this section off. It’s important when we talk about fasting that we make clear distinctions between the various duration of fasts we’re talking about. If we discuss prolonged fasting, as I have done a lot of in answering this question, that means we are talking about water fasting on the order of 4 to 5 days. However, in mouse research, this level of fasting is actually achieved in 2-3 days. This has lead to some confusion, because people often attribute the so-called benefits of prolonged fasting to shorter intervals that are a bit more manageable because they might have ran across this rodent research.

The fact is that we may see some of the same benefits such as autophagy even with shorter fasts, but on an order of magnitude greater with prolonged fasts. Also, with a prolonged fast we see entire organ systems can shrink and then experience renewal during the re-feeding period. So, it should be pretty clear we’re actually talking about a whole different level of cellular clean-up that can occur, which is above and beyond what we get in shorter fasts. There’s still a lot of research going on to better tease out the differences between shorter, let’s say 2 day fasts, and fasts that meet the definition of being a “prolonged fast.”

I’m optimistic that evidence will continue to merge that even shorter duration fasts, are still beneficial. That said, as Tim likes to say, I’m not a medical doctor and don’t play one on the internet. If you’re thinking about giving prolonged fasting a shot, make sure to follow the prudent podcast listener’s rule and run it by an actual physician. There is also an emerging body of literature surrounding a fasting-mimicking diet that lasts 5 days instead of 4 and can be prescribed by a doctor via a packaged meal plan, if having that structure is helpful.

Jeff Norton: Rhonda, can you please share your thoughts on the “minimum effective dose” for sauna benefits: session time, temperature, and frequency. From this “minimum effective dose,” what types of changes/benefits can someone expect?

Rhonda Patrick: I’m going to start with the benefits since, as a point of logical progression, it’s helpful to establish what the science says about benefits before we talk about how to dose it. The good news is, I’ve actually partly done a pretty good job of talking about some potential benefits for sauna use in a guest post that’s featured on Tim’s blog entitled: Are Saunas the Next Big Performance-Enhancing “Drug?”

It’s possible Jeff’s already seen that, but, for the rest of you, make sure to check it out. Since that initial blog post, however, some pretty cool research has come out related to sauna use and it touches on areas that I spend some time thinking about: longevity and also Alzheimer’s disease.With this question I’m going to start with the benefits since, as a point of logical progression, it’s helpful to establish what the science says about benefits before we talk about how to dose it.

So humor me for a minute while we talk about that and then I’ll come back to Jeff’s question surrounding what the minimum effective dose might be with respect to temperature, sauna session time, and frequency to elicit some effects that might be loosely characterized as ergogenic or enhancing physical performance in some respects. A study published in JAMA Internal Medicine in 2015, showed that sauna use was associated with longevity. The study recruited over 2000 middle-aged men in Finland and compared frequency of sauna use with sudden cardiac death, fatal coronary heart disease, fatal cardiovascular disease, and all-cause mortality including cancer over the course of 20 years. Heart disease is the LEADING cause of death in the United States and many other countries as well, so that should be a cue to listen up.

Here’s what the study found: that fatal cardiovascular disease was 27% lower for men who used the sauna 2 to 3 times a week and 50% lower for men who used the sauna 4 to 7 times a week compared with men who just used the sauna once per week. In addition to lowering cardiovascular-related mortality, however, the study also found that sauna use lowered all-cause mortality full stop. Using the sauna 2-3 times per week was associated with 24% lower all-cause mortality and 4-7 times per week lowered all-cause mortality by 40%.

Let’s talk about all-cause mortality… what does it mean? Does it mean using the sauna 4-7 times per week made 40% of people immortal? No, what it means is that for the individuals being studied, they had 40% less mortality than those of a similar age not being subjected to these same conditions and this reduction in mortality wasn’t strictly tied to heart disease, but instead something potentially more general. Keep in mind this study also adjusted for other parameters that may affect the data including body mass, serum cholesterol, blood pressure, smoking, alcohol consumption, type 2 diabetes, physical activity, and socioeconomic status. We’ll come back to talk more about this generalized longevity effect in a minute since it’s interesting to discuss plausible mechanisms that underlie that effect.

The effects on heart disease, however, are a little more straightforward to try to explain: some of the positive benefits of sauna use on heart health may have to do with similar benefits seen with regular physical exercise. Heart rate can increase up to 100 beats per min during moderate sauna bathing sessions and up to 150 beats per min during more intense warm sauna use. 150 beats per minute corresponds to moderate-intensity physical exercise, which as we already know, also has a positive effect on cardiovascular health.

Heat stress from sauna use also increases plasma volume and blood flow to the heart, known as stroke volume. This results in reduced cardiovascular strain so your heart has to do less work for each beat that it does to pump oxygen-rich blood to your tissues and brain. Additionally, long-term sauna use has been shown to generally improve blood pressure, endothelial function, and left ventricular function. But… crossing over from the theory to the more practical: what if improving heart health really just meant having a boost of endurance? In fact, this is exactly what’s been demonstrated.

One study demonstrated that a 30-minute sauna session two times a week for three weeks POST-workout increased the time that it took for study participants to run until exhaustion by 32% compared to baseline. If you start to think of mild adaptation to heat stress as a proxy for some of the benefits of exercise, the generalized longevity effect starts to make sense. But there may be molecular mechanisms for this as well. There’s two pathways in particular I’d like to briefly highlight: heat-shock proteins produced by our cells in response to heat stress and also another pathway known as FOXO3. Sauna use robustly activates a class of stress response proteins known as heat shock proteins, and heat shock proteins have been implicated in aging, where increased expression has been shown mechanistically in lower organisms to confer increased longevity, and, similarly, polymorphisms in human populations that increase heat shock protein production have also been shown to have an association with increased longevity.

To understand why this is the case, it is helpful to know the purpose of heat shock proteins. HSPs help all other proteins maintain their proper 3-dimensional structure in the cell which is important for each protein in order for it to be able to perform its function. If various interactions that can occur disrupt the structure of that protein, denaturing it for example, then this prevents the protein from doing its function and changing the half life of it. As I briefly mentioned earlier, damaging products get created from normal immune system function and metabolism. These damaging molecules, produced at a low level every day even in the best of circumstances but made worse by poor lifestyle choices, damage proteins and disrupt their structure. Moreover, once a protein’s structure is damaged it can then misfold, preventing degradation and can lead to the accumulation of toxic protein aggregates that can themselves damage cells as well.

Protein aggregates, something heat shock proteins specifically help prevent the accumulation of, are associated with neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease and Huntington’s disease. In fact, when you take normal mice that have been engineered to accumulate amyloid-beta plaques characteristic of Alzheimer’s, they do begin to manifest a pathology in the brain that is similar to what we might call Alzheimer’s in 12 humans, but if you engineer these same mice to over-produce one of the more well-known heat shock proteins, HSP70, it reduces the severity of this condition, including reducing the associated loss of neurons and synapses. So, if you think about it, this might suggest something interesting.

We know that heat shock proteins are produced in response to heat stress, and they seem to help prevent symptoms of Alzheimer’s in mice by reducing protein aggregation and by helping keep proteins from losing their structure in the first place. What if, by naturally increasing our heat shock protein expression, we could reduce the risk of Alzheimer’s? The same group that studied over 2000 male sauna goers found a very interesting association from the same cohort that they later published in another paper: they found that men that used the sauna 2-3 times per week had a 22% lower risk of dementia and a 20% lower risk of Alzheimer’s disease compared to men that only used the sauna one time per week. Men that used the sauna 4-7 times per week had a 66% lower risk of dementia and a 65% lower risk of Alzheimer’s disease compared to men that used the sauna once a week. Once again, just as before, this is after adjustment for age, alcohol consumption, body mass index, systolic blood pressure, smoking status, type 2 diabetes, previous myocardial infarction, resting heart rate and serum ldl cholesterol.

Now, whether or not it was the heat shock proteins may be a great idea for future research. But, as a plausible mechanism, heat shock proteins seem like a very good explanation for what’s going on there. Since we’ve also mentioned, briefly, the endurance and cardiovascular benefits of sauna use, particularly in a trial involving run-until-exhaustion aerobic activity it’s also worth mentioning that VO2 max, which is the body’s maximum capacity to transport and use oxygen during exercise, has a strong association with cognitive capability in old age, which may have something to do with brain perfusion and even the ability for blood perfusion to wash away metabolic waste products, including amyloid-beta. The other molecular pathway of interest that may help to explain some of what’s going on with this association between a type of longevity and sauna use mentioned earlier is a pathway known as the FOXO3 pathway.There is some evidence that part of the natural cellular stress response when confronted with heat is an activation of this pathway. FOXO3 is one of the big aging genes for which regular ol’ fashioned genetic variation has shown is involved in longevity: humans with a polymorphism that makes more FOXO3 have up to a 2.7-fold increased chance of living to be a centenarian and in mice, having more of their homologous version of this same gene can extend their lifespan by up to 30 percent!

As a pattern of aging, our FOXO3 activation trends downward… decreasing in expression with age., FOXO3 is a master regulator is involved in: autophagy, DNA repair, metabolism, endogenous antioxidant production, stem cell function and Immune function. Since we’ve already spent so much time navigating the especially relevant waters of HSPs, I’ll leave the discussion of FOXO3 alone for now.

Okay, so we got a little bit distracted talking about mechanism and other various odds and ends surrounding sauna use, but to return to part of the core of the question asked by Jeff, we need to address minimum effective dose. For the minimal benefits of lower cardiovascular disease mortality, lower all-cause mortality, and lower Alzheimer’s disease risk, we have to address the literature that actually observed these effects. In this case, that would be 20 minutes at 174º F (or 79º C) 2-3 times per week. Remember, however, those that used the sauna for 4-7 times a week, had an even more robust effect. This is actually a pretty great guide because we’ve got a range of effects based on dosing and a pretty large trial of 2,000 participants.

If we turn our attention to smaller studies, such as the run-until-exhaustion endurance trial we mentioned earlier, the minimum effective dose for endurance appeared to be 30 minutes in a 194 fahrenheit (90C) sauna twice a week… a dose which, by the way, produced a maximum heart rate of 140 beats per minute. This last point is especially interesting if you consider the fact that maximal heart rate might be an appealing candidate for “quantified-selfers” to track their physiological response to heat stress when other variables may differ.

Take for example the fact that not all saunas get as hot, especially the infrared ones that run cooler. It does seem reasonable to think, however, that turning the nobs on other aspects of the sauna session by making changes to the duration, for example, you can probably still elicit comparable effects. What I have not discussed yet, but mentioned in the guest post on Tim’s blog, certain studies have demonstrated some effects on muscle mass and recovery in animal and human trials. For endocrine effects in the area of growth hormone, for example , multiple studies report ranges of 20-30 minutes and around 176°F (or 80°C ) in the neighborhood of 2-3 times a week. Again, pretty similar to the larger 2000 person mortality and alzheimer’s studies mentioned earlier. Finally, molecular evidence for heat-shock protein induction seems to indicate that healthy young men and women sitting in a 163 F (73 C) sauna for 30 minutes are able to increase their heat shock protein levels including hsp72 by 49% and that the elevation in heat shock protein levels persist for 48 hours after the initial heat stress, suggesting 2-3 times per week is again a good moderate frequency to hit a threshold for some sustained effects.

So it’s pretty clear we have a few options available to us. Some more mild than others. More popular here where I live in the United States are infrared saunas, which don’t get quite as hot, often limited to about 140 degrees fahrenheit or 60 celsius. For reasons of practicality and because I believe that benefits from the sauna are primarily conferred directly by heat, I tend to prefer a hotter sauna. But it seems wholly reasonable that making other adjustments, like preceding the sauna session with light cardio, for example, might help make up for other differences. It’s hard to know for absolute certain, but I’m optimistic.

All of that said, I think it’s a good moment to make a point to give the same warning Tim gives on his blog surrounding sauna use and heat stress in general: try to exercise good judgment, if you have some sort of medical condition all bets are off even if you don’t think you have a medical condition, it’s reasonably worth checking in with a doctor before becoming some kind of mega sauna enthusiast. Heat can be no joke and it’s important that you don’t hurt yourself. Cool? Finally, there’s other so-called benefits that I’ve suggested may exist on Tim’s blog that didn’t get talked about here today. Areas where the science may be promising but maybe not quite as robust or otherwise confer itself well to talking about a minimum effective dose, including:

The possibility that that sauna use could play a role in mood and attention by increasing norepinephrine and affecting our sensitivity to and production of beta-endorphin, giving us a sort of runner’s high… the potential of which was something that initially appealed to me when experimenting with my own personal sauna use.

The possibility that sauna use may reduce muscle atrophy and then muscle regrowth — an effect which, while very interesting, is mostly shown in animal studies that might be hard to try to then apply back to humans So definitely go check out that post. Moving forward we can now talk about the flip side of the coin with our next question from….

Thanatos Mors: I would like to know about the interaction between heat and cold exposure and if they will cancel one another out. Example: If I do a workout and then sauna for 10-20 mins to engage the heat shock proteins to maximize the hormonal response and then proceed to take a cold shower will that cancel the benefit of the sauna and heat exposure? Also will that make the cold exposure less effective?

Rhonda Patrick: For this question, I’m going to choose to focus on discussing the question of a combining heat stress and cold stress in rapid succession rather than a discussion of the combination of either with exercise, which is sort of a different if overlapping discussion which comes up in a different question I’ll get to in a moment. So, to answer this question with our slightly narrowed parameters: I have been trying to find to find empirical evidence in the scientific literature discussing various aspects of combining heat stress and cold stress and have come up pretty dry when it comes to answering a lot of the big questions surrounding the combination of both of these modalities in rapid succession.

Frankly, it’s hard to find good information whether we’re talking about winter swimming, as is done by sauna-goers in Finland… or simply a cold shower… or, far more extreme, alternating between a sauna and an ice bath as described by Rick Rubin and Tim Ferriss during their sauna podcasting experience. One thing we can do a little bit of, however, is turn to the molecular evidence. What may surprise many of you is that both heat stress from the sauna and even cold stress are both able to activate heat shock proteins. This is because heat shock proteins respond to cellular stress in general and not exclusively heat stress. Heat, as a cellular stress, does cause a more robust activation than cold though.

Still, it’s sort of good to know that both types of thermal stress seem to positively affect heat shock protein expression which we’ve sort of established may have something to do with some of the benefits we might ascribe to sauna use. But, it’s sort of important to ask yourself what you’re trying to accomplish with the cold exposure aspect.

One of the main reasons I like to expose myself to the cold are the effects it seems to have on the brain, mood and possibly attention. One of the most likely candidates for eliciting an effect is norepinephrine, which is also the catecholamine that is actually responsible for triggering the browning of fat, making our fat more metabolically active. In fact, in terms of pathways or physiological responses to cold, the release of norepinephrine into the bloodstream, as well as in the locus coeruleus region of the brain, is one of the more profound. Guess what else increases norepinephrine release? Heat as from sauna use. So this is a second way in which both hot and cold, instead of having opposing effects where one cancels out the other, at the molecular level are nudging some of the same pathways in the same direction.

But, to elicit these overlapping stress responses, you actually have to get cold enough for that to happen. Otherwise, you’re actually just taking some of the heat burden you created on your own body and removing it. How cold is cold is the real question we have to ask here. In the case of an ice bath, I suspect the stress is almost certainly additive in nature.

The extremes of going from a 200 fahrenheit sauna to near-freezing water isn’t a walk in the park. In the case of a 30 second cold shower that isn’t sufficient to even trigger momentary discomfort, it is probably not adding stress but in fact simply removing it. This isn’t strictly a bad thing, if that’s what you’re wanting to do. That said, to give you an idea for some of the threshold temperatures involved to elicit the norepinephrine response of cold stress: studies have shown that people that immersed themselves in cold water at 40°F (4.4°C) for 20 seconds increased their norepinephrine 2 to 3-fold (200 to 300%) and this release of norepinephrine didn’t seem to be reduced with habituation to cold. Long durations of cold water exposure under more moderate temperature have a more potent effect on norepinephrine release.

For example, in another study, people that spent 1 hour in 57°F (14°C) water increased norepinephrine in their bloodstreams by 530% over baseline. As anyone who has swam in the pacific ocean knows, this is still quite cold and certainly sufficiently uncomfortable but it’s probably very possible, depending on where you live and the season, to get a shower that is similarly cold or even more cold! Something I’ve personally observed that’s sort of interesting is that after a sufficiently intense sauna session, it can be very hard to stop sweating even potentially hours after you’ve cooled down — unless you’ve had a very borderline painfully cold shower. For social reasons, at least for me personally, it can almost be a requirement.

One last quick note before we move onto our next question which shares some overlap with this one. I mentioned a moment ago that information surrounding going from hot to cold, such as combining ice baths with the sauna or even just doing the sauna and winter swimming combination as done in Finland and elsewhere, is lacking. One of the areas I’d like to see more information on is actually safety. There’s clearly a cultural history in some places of going from a hot sauna right into an icy lake, but there is at least one case study reported in the literature of a heavy smoker having a heart attack, possibly as a result of a plaque rupture caused by coronary artery spasm after doing many, many rounds of contrast immersion over several hours.

I’ve personally done ice baths interspersed with sauna use Rick Rubin style and found it to be very, very enjoyable. It seemed to help me sleep better and I definitely felt like my mood was significantly affected for even the next 24 hours. More so than either alone… so I’m hopeful we’ll see some research come out that proves the case report to be an irrelevant association and somehow demonstrating ultimate safety, but in the meantime I’m hesitant and a little cautious. For the broader audience listening now I will make the same advice I made earlier, please please be careful what you subject yourself to, especially if you have a condition that might warrant such caution. If in doubt, check with a physician before you take up a new polar plunge habit.

Rob Schlicker: Dr. Rhonda Patrick, can you explain your thoughts on how regular hyperthermic conditioning and hypothermic stress relate to muscle hypertrophy and strength training?

Rhonda Patrick: First, for our listeners since Rob is clearly in the know, let me define what hyperthermic conditioning is: hyperthermic conditioning refers to deliberately acclimating yourself to heat, either independent of or in conjunction with exercise. I typically refer to hyperthermic conditioning in the context of using the sauna because this is where the most empirical evidence is. But there are other modalities of heat exposure including hot baths, steam showers, and hot yoga… and they probably create a qualitatively similar type of heat stress that approximates sauna use on some level, depending on intensity.

There are a couple of main mechanisms that hyperthermic conditioning through using the sauna may plausibly affect muscle hypertrophy. First, is through the robust activation of heat shock proteins. I mentioned earlier how heat shock proteins play a role in preventing neurodegenerative diseases such as Alzheimer’s disease by helping proteins maintain their proper 3-dimensional structure. Not only does this have a role in preventing the aggregation of proteins but it may also plays a role in muscle hypertrophy.

Here’s why: muscle hypertrophy is ultimately the delta between protein degradation and new protein synthesis. When we train for muscle hypertrophy we often put a lot of thought into how to increase muscle protein synthesis… but if we reduce protein degradation, which is an effect heat shock proteins have, we are still increasing our net protein synthesis by increasing the difference between the amount of new synthesis of muscle protein versus the amount of degradation that is happening. This type of effect has been shown in rats where it was shown that a 30-minute heat treatment at a temperature of 106°F (41°C ) given every 48 hours over a 7 day period caused a sustained increase in heat shock proteins during that time frame… big surprise… but more importantly, this actually correlated with a whopping 30% more muscle regrowth than a control group during the seven days after immobilization. Not bad, right?

Putting aside heat shock proteins for a moment, the other way that hyperthermic conditioning through using the sauna could plausibly affect hypertrophy is by robustly increasing growth hormone. For example, two 20-minute sauna sessions at 176°F (80°C) separated by a 30-minute cooling period elevated growth hormone levels two-fold over baseline. An even more robust effect was found with men using higher sauna temperatures.

For example, two 15-minute sauna sessions at 212°F (100°C) separated by a 30-minute cooling period resulted in a five-fold increase in growth hormone. The boost in growth hormone levels is transient and only lasts a couple of hours. To understand why this might be useful, it’s helpful to understand a little more about this pathway. Many of the effects of growth hormone are mediated through another hormone known as IGF-1 or insulin-like growth factor-1. IGF-1 activates another pathway in skeletal muscle known as mTOR, which is responsible for new protein synthesis. Muscle cells require amino acids for both growth and repair so if we can also plausibly activate mTOR we’re now sort of completing the circle. With heat shock protein induction we reduce protein degradation and through these endocrine effects, actually increasing protein synthesis… by increasing net protein synthesis, we effectively increase hypertrophy.

In fact, if you sort of reverse engineer the habits of bodybuilders: IGF-1 is actually one of the major pathways most robustly activated by dietary protein intake. So the next time you’re shoveling down protein powder or essential amino acids like leucine… you can be aware that part of what you are doing in the first place is robustly activating the production and release of IGF-1 and thus mTOR. Protein (and specifically essential amino acids) are the major dietary regulators of IGF-1. IGF-1 plays a very important role in muscle growth and repair.

For example, mice that have been engineered to express high levels of IGF-1 in their muscle develop a greater degree and diversity of skeletal muscle hypertrophy. Similar experiments have also shown some promise in combating age-related muscle atrophy, especially the kind found in a mouse model of duchenne muscular dystrophy. I’ve previously talked a little bit about a so-called trade-off when it comes to IGF-1… I’m not going to dive into that yet. We’ll talk about that more in some of the diet-related questions, but suffice to say that I think in the context of sufficient physical activity this so-called trade off may become a bit less important. That said, let’s take a minute to talk about TIMING of sauna use in particular and then we can talk about cold showers or ice baths.

I like to sauna after a workout. First, there’s entirely practical reasons: doing an intense sauna session prior to working out can increase exhaustion a little bit too quickly, making it very hard to finish a workout. Studies have shown that to be the case empirically too, but it’s also intuitively obvious. Adding on top of that, the social aspect of potentially drenching gym equipment with your profuse sweating makes it more sensible to sauna afterward. But, if it were not for those reasons in particular, there’s also just the issue of when we most want a boost of IGF-1. To answer that question, it’s helpful to be aware of a mechanism involved in hypertrophy. One which, in fact, becomes especially relevant when we talk about the effect of cold stress after training in a moment. That mechanism is inflammation.

When we train, as a result of the mechanical work being done we produce metabolic byproducts like reactive oxygen species and we also activate inflammatory cytokines. This is actually necessary to activate genetic pathways that contribute to creating more mitochondria (mitochondrial biogenesis as we talked about) and also plays a role in muscle hypertrophy. In fact, it is inflammation that recruits immune cells such as macrophages to skeletal muscle in order to produce IGF-1 that helps induce acute muscle repair. There has been some experimental evidence that indicates that these specific immune cells are also likely involved in satellite cell migration, which is a type of muscle stem cell that serve as precursors to actual muscle cells and for which the raw number of are actually associated very closely with the amount of actual hypertrophy that occurs as a result of strength training.

As we can see, inflammation seems to play a pretty important role in the benefits of actual training. And this inflammation, as measured by an inflammatory cytokine known as IL-6, actually peaks during training and also right after but then falls by 50% of its initial peak after the first hour. So, in a way, if you’re going to try to pick a time to increase growth hormone or IGF-1 activity, it makes sense to probably do so in close proximity to when it’s actually peaking. In my mind, I interpret this to be pretty much immediately on the tail end of my work out. But this peak of inflammation potentiating IGF-1 synthesis that then goes on to play a role in hypertrophy may become especially relevant if we talk about the mixed research surrounding cold stress, such as ice baths or cryotherapy, especially when used in conjunction with working out.

Whereas the sauna seems to be just fine and maybe even beneficial to do immediately after exercise, cold water immersion and possibly other modalities of cold exposure are a bit more nuanced in the context of strength conditioning. Specifically, studies have shown mixed results when paired with strength training. For example, one 2015 study in the Journal of Physiology showed that a 10 minute cold-water immersion immediately following heavy leg training dramatically decreased hypertrophy by almost 2/3rds at 10-weeks follow-up. The active cold treatment group also had a reduction in muscle strength and showed smaller increases in type II muscle fibers which are required for very short-duration, high-intensity bursts of power and all of this coincided with a reduction in biomarkers that are usually associated with hypertrophy, including the activation of satellite cells. That’s pretty alarming, if you think about it.

But maybe it shouldn’t be too surprising. Let’s unpack this anti-hypertrophy effect of cold a little bit. One of the reasons ice baths became popular in professional sports, for example, is because cold exposure blunts inflammation and, specifically, it’s been shown to dramatically decrease the production of what are known as E2 series prostaglandins, which are one of the factors that have specifically been shown to induce the synthesis of IGF-1 by macrophages, that growth factor mentioned earlier because it’s important for hypertrophy. In addition to this, cold exposure also causes vasoconstriction which may also acutely prevent immune cells from migrating to places like muscle tissue. Knowing how to reduce inflammation when needed is good, but only if we account for the various downstream effects that this may have.

This is not the only study (although it is the best one) that has showed that cold water immersion done immediately after strength training may blunt some hypertrophy. There are others but again all of those studies used cold exposure sometime immediately after strength training. So that leaves us with a few open questions, but the most important one is this: would we still have seen the blunted or reduced hypertrophy effects if cold-water immersion was done at literally any point other than immediately after strength training.

I don’t think that, based on the current literature, that we can state this 100% certainty at this stage, but if we take into account this potentially inflammatory-mediated anabolic window that seems to peak especially in the first hour post exercise, then it might help explain some of the mixed results we see surrounding the use of cold stress with various forms of strength training. Specifically, one 2013 study from the Scandinavian Journal of Medicine & Science in Sports showed the almost exact opposite effect — this study showed that whole body cryotherapy for a couple minutes done 1 hour after squat jumps and leg curls was actually associated with performance enhancements which included improvements in power at the start of the squat jump, and squat jump work-up and improved pain measures up to 72 hours after the cold treatment.

This isn’t the only study showing an enhancement in performance from cold either. We see in a study published in PloS one in 2011 that Elite runners that engaged in whole body cryotherapy 1 hour, 24 hours, or 48 hours after doing some hill sprinting ultimately had a 20% increase in speed and power up to two days later. What’s interesting about the cold is that it may also be conducive to enhancing endurance-related activities in particular. Like fat, whereby cold can increase the number of mitochondria in white adipose tissue in order to transdifferentiate it into brown fat, a form of fat that is metabolically active, protective against obesity, and naturally declines as we age muscle also experiences an increase in mitochondria as a consequence of cold exposure. These mitochondria are the energy producing machinery of our muscle cells. The density or number of them on a per cell basis, affects our aerobic capacity. Mitochondria are what give us the ability to use oxygen in order to produce cellular energy, and if we have more of them, it can be said we may be more adapted to aerobic activity. Mitochondria are what give us the ability to use oxygen in order to produce cellular energy, and if we have more of them, it can be said we may be more adapted to aerobic activity.

OKAY! All of that said… to sort of get to the point and to summarize my thoughts on sauna and cold-water immersion or cryotherapy in the context of exercise, I think that:

sauna use after exercise seems to be a good time to do it, generally

we need more research but cryotherapy or cold-water immersion may be better to hold out on until at least an hour after training

And, finally, the effects of and appropriateness of cold-related activities on performance may be, for a few different reasons, very dependent on the actual activity we are actively training for.

Kevin Noonan-Fick: What are your thoughts on nootropic/cognitive-enhancing supplements and do you take any yourself? Ie. choline, lion’s mane mushroom, etc.

Rhonda Patrick: I do take some things that might qualify as nootropics. I am, however, very cautious in what I choose to experiment with, at least over the long-term. My biggest concern comes down to one simple fact: when we introduce outside compounds that too directly perturb complex biological systems, we open up the possibility of triggering feedback systems that can result in unintended consequences such as receptor down-regulation. What do I mean by that? For example, let’s say we take pharmacological drugs that inhibit transporters that re-uptake and metabolize neurotransmitters. This causes these neurotransmitters to then stay around in the synapse for a longer period of time, exerting more biological effects.

This might be perceived as a good thing. BUT the trade-off is this causes the receptors that bind to these various neurotransmitters, which is how they exert their biological effect to decrease in number. This is what we call downregulation. So what happens when you do not take that same drug for a few days? Your baseline level has changed so that, in the absence of those drugs that inhibit reuptake, your neurotransmitters will not by themselves exert the same effect that they might have before your pharmacological intervention due to changes in receptor density or the number of receptors we have for the neurotransmitter to interact with.

This is one reason why I prefer to, instead, focus primarily in the realm of nutrition since it usually works a little bit more indirectly by providing compounds that are found in and needed by the body, and, in the context of this conversation, the brain.

When compounds are identified in food (such as xenohormetic compounds) we have a better chance of achieving benefit without deleterious effects because of the fact that we’ve likely evolved alongside the presence of that compound. If the compound or compounds don’t have that same history it takes a little bit more scrutiny before we can be sure that there isn’t some sort of significant side effect we just haven’t taken the time to observe yet. Maybe we won’t even know about it for years. For this reason, I tend to stay away from compounds that are inhibitors of enzymes in the brain (which I know are ubiquitously found in many nootropic stacks) even though they likely work in the short term, we don’t have good evidence what if any long-term effects may occur.

With that said there are some nootropics that I have tried. Choline is one of them. Choline can either be used to make acetylcholine (acetylcholine is a neurotransmitter that connects neurons together) or phosphatidylcholine or methyl groups. In humans, choline supplements increase choline plasma levels within 1 hour after ingestion and with brain concentrations peaking around 2 hours until at least up to 3 hours after ingestion. Cholines effects on the cholinergic peripheral system peaks between 1 and 2 hours after ingestion. Choline itself (without forming acetylcholine) acts on a subtype of nicotinic receptors (alpha 7 nicotinic receptor) that is involved in long-term memory. Acetylcholine also acts on all the nicotinic receptors. Choline does not cause desensitization of this receptor like other agonists do (like nicotine). In fact, supplementing with choline increases this receptor subtype.

Certain neurodegenerative disorders like AD are linked to decreased acetylcholine so there has been a lot of interest in investigating whether certain choline supplements and other compounds that affect the cholinergic system can improve cognition and memory in people with cognitive decline, dementia, AD. There are different forms of choline supplements but I think the choline that is complexed to phosphatidylcholine is the best because it is 12 times more bioavailable and gets into the brain faster. There is a decent body of evidence that has looked at the effects of various types of choline on brain function.

L-Alpha glycerylphosphorylcholine (more commonly known as alpha GPC) is a naturally occurring form of choline and is thought to be a form of choline that crosses the BBB quickly. I came across this compound when doing a literature review of various phospholipids and their role in Alzheimer’s disease. The study that put it on the map was an old study published in 2003 that demonstrated 1200 mg/day split up over 3 daily doses was able to enhance cognitive performance and slow cognitive decline in Alzheimer’s patients. The problem is this study was done in Mexico city 13 years ago. Since then, another study in 2011 attempted to repeat this but in addition to alpha-GPC about ten other compounds were given. It improved cognitive function but it’s impossible to pinpoint this effect specifically to alpha-GPC. Finally, there is yet another interesting study that showed that alpha-GPC along with other natural compounds reduced reaction times and prevented mental exhaustion after intense exercise, an effect that is likely due to the replenishment of choline that is actually temporarily reduced in the brain as a consequence of endurance exercise (such as long runs).

I have personally tried alpha-GPC before at a dose of around 600 mg per day… an amount that is half the dose that was given to the demented patients in Mexico city and noticed that it did seem to help improve my focus and attention. You should always leave a little room for the possibility that it may be placebo effect, but since it’s my anecdote… a smaller dose of 300mg didn’t really seem to have as much of an effect. In general, I do not take alpha-GPC everyday. I’ll take it on rare occasions when I’m doing a lot of writing or there’s some sort of event I’m speaking at. There is another popular form of choline called CDP-Choline which is an intermediate produced during the generation of phosphatidylcholine from choline. There are a couple human studies looking at the effects of CDP-choline in the cognitive function of healthy young or middle-aged adults… usually in the range of around 1000 mg per day. The only benefits were seen in young adults that had poor processing speed and verbal memory at baseline. Strangely, those individuals that performed well at baseline actually had impaired performance after supplementation which may have to due with genetic variance in the receptor density, etc. which just sort of goes to show how complicated neurobiology is and how even seemingly straightforward relationships can turn out to not be so straightforward.

I have personally tried CDP-Choline and never really noticed any enhancing effect like I seemed to with alpha GPC. The other nootropic I have tried and use semi-frequently is Yamabushitake extract which is also more commonly known as……. Lion’s mane! The main active compound in lion’s mane is hericenones (found in the fruit body of the mushroom). This compound is capable of activating nerve growth factor (NGF). NGF is essential for the growth of new neurons and survival of existing neurons. NGF acts on cholinergic neurons in the central nervous system. What got me interested in lion’s mane as a nootropic was a Japanese study which was a double blind, placebo controlled trial where elderly men with cognitive decline were given 1 gram doses of 96% Yamabushitake dry powder three times a day for 16 weeks for a total of 3 grams per day. Those individuals given the lion’s manes extract but not placebo had a significant improvement in cognitive function at weeks 8, 12 and 16 of the trial. But the cognitive effect wore off 4 weeks after discontinuing the treatment suggesting that continuous intake was necessary to maintain the effect, at least in cognitively impaired older adults.

Lately, I do use lion’s mane extract pretty regularly from Four Sigmatic. They come in packets and each packet contain 1.5 grams of lion’s mane extract from the fruit body only (which would contain hericenones). Note: I have no affiliation with them. They sent me some free packets a couple of years ago, and I liked them so I continue to buy them. When I use them, which only again — tends to happen during periods of intense writing or creative work, I actually like to use 2 packets, a dose that is around 3 grams of lion’s mane extract and the same dose used in the clinical study I mentioned a moment ago out of Japan.

No discussion of nootropics would be complete if I didn’t at least briefly mention two hobby horses of mine: Vitamin D and omega-3. The effects of both of these are pretty far reaching and extend far, far beyond the realms of just cognition, but even if one were concerned with just cognition they would both still have special relevance. First, let’s talk vitamin D. This one is near and dear to my heart since it was my in silico work that actually identified that Vitamin D affects serotonin production, which I believe has very far reaching implications not just for adults trying to stay healthy and live optimally but also for neurodevelopmental disorders as well, where impaired serotonin production may be particularly important for early brain development when the foetus relies on the mother as its source for vitamin D. A whopping nearly 70% of people in the U.S. can be classified vitamin D insufficient and that includes pregnant women.

Returning to the main topic after that brief digression, Vitamin D is something that should be periodically monitored via blood test in order to titrate to a dose that is appropriate. I personally shoot for 40 to 60 ng/ml since there have been a few all-cause mortality studies that seem to indicate that this may be a so-called sweet spot. Because vitamin D can be toxic in the high upper ranges, doing too much can also be problematic. It’s an absolute fact that what may work for one person, especially in terms of dose, may not for another because of the individual variation involved that can affect how deficient you are, including genetic polymorphisms, weight, age, the latitude you live at, ethnicity, how much time you spend outdoors, whether you wear sunscreen and more.

I’ve personally found that the tolerable upper intake level recommended by the institute of medicine of just 4000 IU, usually taken with a vitamin K2 supplement, is actually the amount that lands me right in the middle of that target range. That said, I’m probably not even in the highest risk category for vitamin D deficiency. Next, a quick mention for omega-3.

Approximately 8% of the brain’s weight is actually omega-3. The number of studies that demonstrate optimizing intake of omega-3 has some effect on cognition or behavior are extremely diverse. Today we’ve talked a little about nerve growth factor… so just by way of example… I literally just ran across an animal study that showed that supplemental omega-3 increases nerve growth factor which increases the enzyme responsible for producing acetylcholine, it increases vascular endothelial growth factor, and brain-derived neurotrophic factor and has generally been shown to improve cognition.

Getting past all of the usual suspects on our list of nootropics here, the other nootropic that I actually take frequently is SULFORAPHANE! It’s not even usually considered a nootropic by most people but I think it has potential to be considered at least a mild nootropic for a variety of reasons. One of the the best reasons to make this argument is the fact that sulforaphane crosses the blood-brain barrier, at least in mice. This is the first criteria that a substance must meet in order for there to be a compelling argument that it somehow exerts effects on the brain — but, in addition to that, it also affects the activities of the immune system which is now known to affect the brain through a series of lymphatic vessels. this new understanding of the immune system’s ability to interact with the brain also helps to explain why manipulating levels of systemic inflammation has, in clinical trials, been shown to affect feelings of depression either inducing depression in the presence of an artificial increase in activity in the immune system by injecting things like interferons into human trial participants or reducing depression caused by this artificial increase in inflammation through the co-administration of a natural anti-inflammatory, such as eicosapentaenoic acid, better known as the omega-3 fatty acid EPA.

In addition to sulforaphane crossing the blood-brain barrier in mice, the compound has been shown in a couple of randomized, double-blinded, placebo-controlled studies in humans to have one sort of effect or another on brain and behavior. For example, treatment with sulforaphane extracted from broccoli sprouts at doses ranging from about 9 mg to about 25 mg, which is an amount that might be found in around 65 grams of fresh broccoli sprouts on the high end, was able to improve autistic behavior checklist scores by 34% and significantly improved social interaction, abnormal behavior, and verbal communication in young men with autism spectrum disorder. Similarly, some measurable effects have been shown in a small trial of people with schizophrenia.

The fact that sulforaphane is exhibiting clear effects on the brain and behavior of people, such as those with autism spectrum disorder, hints that it might continue to show promise in other areas of cognition too. This is because animal studies have really shown a diversity of very interesting effects that are really just waiting to be replicated in humans.

For example: Sulforaphane has been shown to improve spatial working memory and short term memory in mice in the context of conditions that can affect memory in a deleterious way, such as Alzheimer’s Disease. It has been shown to increase neurite outgrowth, which is how damaged neurons and synapses repair themselves after damage from traumatic brain injury. The effect of sulforaphane on a rodent model of Alzheimer’s Disease in some respects is particularly interesting, because, if we go back to our conversation a little bit earlier about the potential choline may have for mitigating some of the negative effects of this disorder, sulforaphane has also been shown to significantly reduce memory impairment that has been experimentally induced by a drug that works specifically by interfering with the effects of acetylcholine in the nervous system, a drug known as scopolamine.

Sulforaphane was, in this animal trial to which I am referring, able to improve the cholinergic system by increasing acetylcholine levels, decreasing acetylcholine esterase activity, and increasing choline acetyltransferase, which is the enzyme responsible for synthesizing acetylcholine in the hippocampus and frontal cortex. This ties in nicely with some of our discussion earlier about the potential importance of the choline system in cognition. Finally, sulforaphane has been shown to have a positive effect on mood and alleviated depressive symptoms and anxiety as effectively as the antidepressant Prozac in a mouse model of depression and I understand that there is at least one trial currently in the beginning stages looking to confirm this effect in humans as well.

If you consider the variety of brain and behavioral effects demonstrated already in humans, I’m optimistically hoping that some of the groups out there working on these questions will have something good to show for it in the future. If you’re looking to supplement sulforaphane there’s a few options available. First of all, the most confusing thing that is necessary to understand when gauging the various supplements for usefulness is that sulforaphane is made from a precursor known as glucoraphanin. Many supplements on the market are actually JUST glucoraphanin. You know this because it either says glucoraphanin or it says sulforaphane glucosinolate on the bottle, which is actually somewhat confusingly just another name for glucoraphanin. Then there are a few supplements on the market that is glucoraphanin and the enzyme needed to convert it into sulforaphane, an enzyme called myrosinase. One example of this combination is a product known as Avmacol.

Finally, there is actual stabilized sulforaphane. This includes a french product that hasn’t been introduced to the U.S. known as prostaphane. These three categories of products that I’ve mentioned have very large differences in terms of bioavailability: around 10% on average for glucoraphanin by itself, 40% for the glucoraphanin and myrosinase combination, and then around 70% for stabilized sulforaphane. The dosage range that strike me as particularly interesting because they have showed up often in clinical trials range between 30 to 60 mg of sulforaphane. These doses, however, actually make most of the supplements out there somewhat costly in my opinion. The good news is that many studies seem to be showing promise even at a lower dose and if you’re doing an n=1 experiment it may be useful to be able to get a reliable product like the ones i just mentioned.

That said, this cost factor has been a big reason for why I’ve simply taken up growing broccoli sprouts at home, which is extremely inexpensive. The main challenge being keeping a clean environment with little possibility of contamination from pathogenic bacteria, which can happen. Some estimates land fresh broccoli sprouts at a concentration of about 1 gram fresh weight to around 0.45mg of sulforaphane, but it depends on the seed quality and genetic background, the age of the sprouts, how you consume the sprouts, whether you froze them and threw them immediately into a blender which is what I do and tends to increase the amount of sulforaphane derived… or if you, instead, just chewed them up fresh, the good ole fashioned way.

The drawback to using sprouts is that the dosing becomes tricky. The fact of the matter is that I’ve found that my personal digestion is probably a more reliable source of feedback than trying to work out the dosage math. That’s kind of embarrassingly imprecise to have to admit… but it just comes down to the fact that there’s a tremendous number of variables that can influence how much sulforaphane in a given dose of broccoli sprouts and on top of that what an appropriate amount of sulforaphane to even supplement is. I’ve been known to consume up to 4 ounces of broccoli sprouts a few times per week and will likely continue for the foreseeable future. That said, there are concerns that isothiocyanates like sulforaphane may reduce iodine uptake by the thyroid gland.

While right now I don’t think the evidence is especially strong that this is a cause for great concern unless a person is iodine deficient, an uncommon deficiency, it may be prudent to exercise some degree of caution. Some of the effects from these compounds present in cruciferous vegetables and broccoli sprouts in particular are persistent for several days so one does not need necessarily take an extreme approach in order to reap some effect. Again, run it by your doctor, etc. etc.

Jez Thierry: Is one able to cold press juice broccoli sprouts and still receive high amounts of sulforaphane from ingesting in this way?

Rhonda Patrick: To answer your question, yes you should be able to also cold press broccoli sprouts and make a juice. The myrosinase enzyme (which again is needed to activate sulforaphane) begins to get activated once you “cold press” the sprouts because by cold pressing you are breaking open the plant cell walls and causing the mixing of glucoraphanin in the plant with the myrosinase enzyme stored away in specialized vacuoles. This mixing then allows sulforaphane to form. Ultimately you would not get the same dietary fiber which is why I prefer to blend things rather than juice them but the sulforaphane would be concentrated and since it may be less aversive, it seems like an interesting option.

William McGrath: Besides a low carb diet (which reduces inflammation), what is the most effective non-pharmaceutical pain reliever for arthritis/sport injury sufferers?

Rhonda Patrick: Okay, William’s question here is an interesting one. The reason for that is because of the fact that many NSAIDs, as in non-steroidal anti-inflammatory drugs, which are often used for mild pain relief are actually not especially safe to take on a daily basis. This is even more true of people that tend to take them in larger than recommended doses and it is why the FDA recently strengthened their warning that non-steroidal anti-inflammatory drugs (known as NSAIDs), with exception to aspirin, significantly increase the risk of heart attack or stroke even with short-term use. What these NSAIDs, including ibuprofen, that cause this increased risk have in common is that they all inhibit COX-2, an enzyme involved in inflammation and pain.

There are a few fundamental mechanisms that increase the risk of heart attack and stroke. First, NSAIDs that inhibit COX-2 inhibit the production of a molecule called prostacyclin which is produced by cox 2 and relaxes blood vessels and sort of “unglues” platelets. Second, they inhibit the production of nitric oxide (which is also regulated by cox 2 to some degree) and needed for proper vascular function. Finally, one more mechanism by which chronic NSAIDs use may increase heart attack risk is through a disruption mitochondrial function in heart cells. Knowing these risks sort of motivated me to put avoiding the use of NSAIDs such as ibuprofen, alieve, and naproxen, just to name a few, at a generally higher priority than it may have been previously for me on a personal level.

As an alternative to the use of NSAIDs, however, I’ve found curcumin is actually very helpful. Curcumin is sort of an interesting compound. It exhibits a pretty diverse array of potentially beneficial properties but as a xenobiotic that the body actively makes an effort to get rid of, its activity can be limited unless care is taken to try to make it more bioavailable. There’s a few different formulations that attempt to do that, but the one I’ve found the most interesting is a formulation known as meriva which has been shown to exhibit certain pain-relieving properties.

Meriva, a form which is available from a few well-known brands, consists of a phospholipid complex with 20% curcumin dispersed throughout the phospholipid. This helps to get the curcumin past the stomach lining and from being cleared by enzymes in the liver too rapidly. A few clinical trials have looked into the effects of meriva on pain and inflammation. For example, runners that were given 1 g of meriva twice a day found that it reduced delayed onset muscle soreness about 2-fold and caused a 60% decrease in markers of muscle damage and inflammation, specifically IL-8 and C Reactive Protein, after running until exhaustion downhill. There have also been a couple of other clinical studies published looking at the efficacy of 1 g of meriva per day in reducing symptoms of osteoarthritis and increasing mobility.

After 3 months of treatment, people with osteoarthritis and joint pain had a 4-fold increase in mobility, CRP (decreased by 67%, and they had a around a 58% reduction in arthritis symptoms including pain. There was a similar study that included a longer follow-up (8 months) and found similar increases in mobility and reductions in inflammation and pain. What’s interesting is that meriva has also been compared directly to common pain relievers in terms of ability to give pain relief in a small clinical study, which found that people taking 2 grams of a Meriva per day experienced a pain relief equivalent to 1 gram of acetaminophen or tylenol… an amount, by the way, which has been associated with liver damage in conjunction with long-term use.

Another study also found that 2 g per day of meriva for 6 weeks was equivalent to around 800 mg per day of ibuprofen for pain relief. The study found that the analgesic effect of curcumin lasted for approximately 4 hours, and a second dose, administered 6–12 hours after the first dose, was necessary for controlling pain. On the whole, curcumin is also a surprisingly safe compound. One study out of Japan published in 2011 in the Journal of Cancer Chemotherapy and Pharmacology showed that curcumin in amounts as high as even 8 grams per day for up to 14 days at a time was safe and tolerable. These were cancer patients and this wasn’t a meriva formulation. However, seeing how well tolerated very high clinical doses are generally… for occasional pain relief I tend to be pretty liberal with popping a few grams of curcumin in the form of meriva throughout the day.

There’s a few popular brands offering meriva or sometimes simply marketed as phytosomal curcumin. Right now the one I’m taking is the product from Thorne. Again, like every other supplement brand I’ve mentioned on this podcast, no affiliation whatsoever. Since I’ve sort of put curcumin and meriva out there specifically as a nice NSAID alternative, I need to address the gorilla in the room. Quite recently a very sensational scientific review was making the rounds claiming that curcumin basically had no health benefits and that, because of a quirk of an investigative method used to look at protein-to-protein interactions that may be subject to some degree of imprecision because of how it can behave in a manner that produces background noise, all curcumin research up until this point should be more or less considered null and void. That was sort of the crux of the argument.

A handful of unsuccessful trials were also cited to support, in my opinion poorly, this argument. The problem is that the specific quirk of the research assay being discussed is rendered absolutely and completely irrelevant in the context of the massive body of clinical curcumin research done in humans that has showed the compound exceedingly versatile.

Moreover, even if we put aside the enormous amount of clinical research, it’s been demonstrated that curcumin works in a manner that, at the cellular level, exhibits broad changes in gene expression. Something that cannot be dismissed simply because one specific assay which does not even measure gene expression exhibits some degree of artifact. If you couldn’t tell, I’m not a big fan of this particular review article published and may even feel a little bit of desire to sort of heep mountains of admonishment on the authors. That said, I will concede that there is a need for more double-blinded placebo controlled studies on curcumin and specifically the meriva phytosomal complex of curcumin which does significantly bypass the bioavailability issues associated with the compound, which has also been the source of some criticism. I am, however, very very optimistic about future research surrounding curcumin in general and meriva in particular.

Finally, one more thing I should bring up in the context of joint health is hydrolyzed collagen powder. What first sparked my interest in this was a study shared with me by a colleague that established the fact that, at least in an animal model, hydrolyzed collagen supplemented in the diet did find its way into the cartilage. Sometimes in nutrition relationships don’t tend to be so straightforward as may seem intuitive on the surface, cholesterol is a great example of this.

We actually create cholesterol and consumption of dietary cholesterol is not necessarily strictly a cause of high cholesterol as we think of it. In the case of hydrolyzed collagen powder, however, the relationship does seem to be straightforward: the study to which I’m referring used radiolabelled collagen which allowed the scientists that were doing the investigation to see what happened after the hydrolyzed collagen was consumed. They saw two things happened: that the collagen ended up being broken down into amino acids, but, more importantly, that some of it was also absorbed intact and shown to accumulate in cartilage long-term, which is pretty cool.

So a little bit about collagen. Collagen is an important component of tendons, ligaments, cartilage, and skin, but also an important component of gums, muscle and the gut. About 33% of collagen is made from proline and glycine, which most dietary protein sources are not especially high in. Proline may also have a special place in wound healing as well. The first 10 days after a wound occurs proline levels at the site of the wound are 50% higher than plasma, which might suggest that proline is actively being transported to the site of the wound and probably a necessary part of the wound healing process.

As an interesting aside, proline can also be used by the mitochondria to produce energy. It is converted to glutamate and alpha-ketoglutarate and used by mitochondria to produce energy. The reason this pathway exists is because during conditions when glucose levels drop, proline is released from connective tissue to be used to make energy. I’ve heard Tim mention great lakes brand hydrolyzed collagen powder, which happens to be the same brand I’ve used for the last few years. It does not have a particularly strong taste, so it can pretty much be added into anything, including a beverage like tea or coffee or pretty much anything else.

Guy Fasciana: What brands can we trust for dietary supplement brands? How can we find trustworthy brands?

Rhonda Patrick: This is a great question and an important question because the FDA does not require dietary supplements to be tested before they are marketed. As a result, products may contain unlisted ingredients and contaminants; some products have even tested positive for prescription drugs not listed on the label. Many supplements do not contain what they are actually supposed to contain and instead may be a combination of fillers like clover leaf.

So there’s a few things you can do…. One thing you can do is make sure the product is certified by NSF International, which stands for the National Sanitary Foundation, which independently tests and certifies dietary supplements and nutritional products and ensures that they do not contain undeclared ingredients or contaminants. To earn NSF Dietary Supplement Certification, products must undergo rigorous testing and inspection. The standard requires label claim testing/verification, a contaminant review and a facility audit.

You can look for products containing the NSF label by searching their dietary supplements online product database found at info.nsf.org/Certified/Dietary I usually will just type in the manufacturer name (for example nordic naturals) or I will type in a specific product that I am looking for like Meriva. The drawback to relying on this particular certification is that their database can be pretty restrictive.

While being in the NSF database is a good sign, not being in it isn’t strictly a deal breaker. So here’s another option: Look for products that are USP-certified. The USP, which stands for The United States Pharmacopeial Convention, is a scientific nonprofit organization that sets standards for the quality, and purity of dietary supplements that are manufactured, distributed and consumed worldwide. In the United States, the FDA relies on standards the USP has developed. So you can just go to their website, which is USP.ORG and click “Verified Supplements” to see a list of brands and products within brands that the USP verifies.

In addition to the USP and the NSF, there are independent companies that also test supplements and then rank those products and provide reports to customers, sometimes for a cost. However, I’ve found these to be either misleading or sometimes coming to conclusions that gives me pause. Doing the type of validation necessary may require technical skills that might be executed poorly or sometimes just plain weird ranking criteria may be at play. For that reason, I don’t trust these independent ranking companies as much, but absent other information it may still be better than just blindly grabbing something off a supermarket shelf.

James Enright: Rhonda, what are your core supplements and core foods for health or brain and daily/weekly health routine?

Rhonda Patrick: Okay, first: my perspective on food. I think it’s helpful to understand what I’m about to say because it, to a great degree, informs other opinions I may have about different approaches on diet. Food is, in a big way, a vehicle to deliver micronutrients, or compounds that are beneficial to health but not just micronutrients other compounds such as polyphenols and other xenohormetic compounds as well. Approximately 22% of all the genes that encode for enzymes require micronutrients as cofactors, which means that the machinery doing work inside your cells actually needs micronutrients to function properly. These are enzymes that are involved in metabolism, neurotransmitter production, repairing damage, basically everything that you want to be working optimally needs more than just energy. It needs micronutrients. It needs minerals, like magnesium, which we find particularly abundant in green leafy vegetables because it is at the center of the chlorophyll molecule.

Micronutrients are about 30 to 40 essential vitamins and minerals that we must get from our diet because they are essential for life. That means without them you die. Recommended daily intakes of these vitamins and minerals have been set to ensure we get adequate amounts of them but we really do not know how much of these micronutrients we need to stave off aging as best we can. If the proteins in your body start operating more poorly, let’s say they stop repairing DNA damage quite as well, or they aren’t cleaning up amyloid-beta as well or any of an almost infinite number of other potentially affected processes, you might not notice this as a disease, instead, we might just call it aging.

It’s important therefore to keep in mind that preventing aging is not the goal of RDA — it is to prevent easily observable, obvious diseases of deficiency… and figuring out what those optimal levels are for this more subtle and widespread thing we call aging is a bit more challenging. Adding some complication to this is the fact that this optimal level is probably not the same for everyone. Perhaps as a function of the agricultural practices or constraints placed by foods dictated partly by the geographic area our ancestors resided in, there is a great degree of genetic influence in how we absorb, metabolize, and use micronutrients. Understanding just some of these interactions between genetic polymorphisms and food is an area of study known as nutrigenomics. It is fascinatingly complex and there is a great opportunity for understandings in this area to improve the human condition. As an extension of this fact, I think the specifics of diet will eventually be better understood to NOT BE a one-size-fits-all.

That said, I’ve found some things that have worked for me personally and some of them are probably still relatively generalizable enough as to be useful for others. Here they are: I know most people are very focused on macronutrients. That makes sense in certain contexts so long as it isn’t to the complete and utter exclusion of all else. Instead, I just mainly follow a rule of thumb that I should eliminate refined carbohydrates in particular, and refined sugar especially and then try to eat with a special attention to nutrient density. I often enjoy wedging a smoothie in, sometimes as a partial meal substitute, that is particularly focused on cramming in some extra servings of some fruits and vegetables. I consider this a pretty important lifestyle hack that can sort of just be thrown on top of whatever else you’re doing and will help recalibrate a lot of important health parameters in a useful way.

As for actual meals, I always eat breakfast and as I mentioned earlier I practice time-restricted eating so that all of my meals are consumed earlier in the day and within a sensible time window. While some degree of diversity is ideal, for breakfast I do often rotate between a few reliable meals.

First, one of the main meals that I eat for breakfast are scrambled eggs usually topped with tomatillo salsa (which helps make the eggs less boring), sauteed kale and garlic topped with olive oil salt, and mustard powder and a grapefruit on the side. I scramble my eggs and sautee my kale in avocado oil because it is high in monounsaturated fat, low in polyunsaturated fat (I stay away from cooking oils that are high in polyunsaturated fat because it is so easily oxidized and it can be very harmful consuming oxidized fat), the avocado oil also has a very high smoke point so it can withstand some heat. The reason why I sautee the kale is very practical… it’s easier to eat. I add mustard powder to the kale as well as other cruciferous vegetables I may cook at other meals to facilitate conversion of precursors into isothiocyanates, like the sulforaphane 