Transcript: Dr Rhonda Patrick on Exploring Smart Drugs, Fasting, and Fat Loss (#237)

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 from broccoli. One of the main reasons I eat eggs is that eggs is provide me with choline. We already talked about how choline affects acetylcholine but it also serves as a methylation source and thus affects global epigenetics, which is a way of changing the activation or deactivation of various genes.

One extremely common genetic polymorphism is in a gene that encodes for an enzyme that catalyzes the synthesis of phosphatidylcholine and thus choline. Post-menopausal women in particular with this polymorphism need to increase their dietary intake of choline. Eggs happens to be a great source of choline. I spread some tomatillo salsa on top of my eggs because I like it, foremost but it helps that it’s also high in tomatidine, which has been shown to boost muscle mass in mice by reducing the activity of a gene called ATF4, known for inhibiting muscle protein synthesis.

One reason why I like Kale a lot is because it is one of the vegetables that is highest in lutein and zeaxanthin, two carotenoids that most people associate with eye health because they accumulate in the rods and cones of the eye and protect them from singlet oxygen which is generated from blue light and can be very damaging to the eye. But recently there have been a fair amount of studies published showing that these carotenoids accumulate in large quantities in the brain. I mean what are they doing in the brain? There is no singlet oxygen from light exposure in the brain. Plasma and brain levels of lutein turn out to be associated with a higher volume of grey matter in the brain and improved crystallized intelligence in elderly, which is the ability to use the skills and knowledge that one has acquired over a lifetime.

A double-blinded, randomized controlled trial showed that lutein and zeaxanthin supplementation including 8 mg of lutein and 26mg of zeaxanthin improved neural processing speed time in young individuals. Decreased processing speed is a major hallmark of cognitive decline. Lutein and zeaxanthin have also been shown to improve memory recall while using less brain brain power in older individuals, something that’s known as neural efficiency.

An aging brain has to use more and more energy to maintain normal brain functions and so neural efficiency is said to have declined. The icing on the cake is that eating eggs with a salad increases the absorption of carotenoids like lutein and zeaxanthin, which are found in dark leafy greens particularly high in kale by up to 4-fold. Which is one reason why I do like a side of eggs with my kale. The grapefruit provides me with ferulic acid, a potent molecule that inhibits the proinflammatory cytokine TNF-alpha and E2 series prostaglandins, also inflammatory. Ferulic acid has also been shown to be anti-carcinogenic. The grapefruit is also a source of naringenin has a variety of interesting properties.

Another breakfast that I have is a nut and berry cereal with hydrolyzed collagen powder and coconut milk. My cereal also contains an array of chopped nuts including walnuts, pecans, and macadamia nuts. The nuts provide me with a host of micronutrients including magnesium, calcium, zinc, a modest amount of protein and the omega-3 fatty acid ALA which is not meant to be a substitute for the marine omega-3s. Along with the nuts, I often toss in some blueberries for pterostilbene, which is a plant compound present in blueberries that is chemically related to resveratrol except it is about four times more bioavailable than resveratrol.

Test-tube and rodent studies also suggest that pterostilbene is more potent than resveratrol when it comes to improving brain function, warding off various kinds of cancer and preventing heart disease. The blueberries are also high in anthocyanins, which evidence suggests can lower DNA damage. DNA damage has been shown to cause cancer and lead to depletion of stem cell pools so it also plays a role in the aging process as well. I also like to add some pomegranate into the cereal. One of the compounds in pomegranate is transformed by gut microbes into a molecule called urolithin A, which causes mitophagy a process important for the renewal of mitochondria, mentioned in an earlier question. Urolithin A has shown some pretty spectacular things in research on other organisms, including improving muscle function and endurance by up to 42% in mice and increasing lifespan by more than 45% in worms.

Finally, as a finishing touch to the breakfast cereal I often throw in some flaxseeds for more of the omega-3 ALA and fiber, some unsweetened coconut milk which contains some medium chain triglycerides, some raw cacao nibs which have a plethora of polyphenols including EGCG which activate many antioxidant genes and has been shown to kill cancer cells, occasionally some almond butter for some protein and to sort of make it delicious, hydrolyzed collagen powder which provides me with proline (as I mentioned is important for wound healing) and glycine (an important inhibitory neurotransmitter).

One reason I use coconut as opposed to milk is because milk contains salivary proteins which bind to anthocyanins and polyphenols and limits their bioavailability. Sometimes I’ll also throw in the cereal concoction some yogurt and possibly a packet of the probiotic VSL#3, which contains 450 billion probiotic cells per serving. Okay, let’s talk lunch. This is where the smoothie often comes in. As a base, it can often contain kale, frozen berries, avocado, hydrolyzed collagen powder and water… then a number of variations on top of those.

I have a couple of popular smoothie recipes that are floating around on the internet and a person can find by searching “Rhonda Patrick smoothie.” As a breakfast or lunch I occasionally have an avocado topped with fresh lemon juice and wild Alaskan salmon roe, possibly accompanied by a side of sauerkraut. This another variation I sometimes do. Avocados are really high in potassium and provide all of the various forms of vitamin E (in other words both tocopherols and tocotrienols), something it’s good to get a balance of via diet instead of only one form as from some supplements.

The avocado is also a great source of monounsaturated fat. Salmon roe caviar is a very good source of omega-3 fatty acids (~438 mg of EPA and 514 mg of DHA per ounce). I particularly like this source of omega-3 because the fats are in phospholipid form which has greater bioavailability to be transported into the brain via the mfsd2a transporter. This is the form that is best taken up by the brain (including the developing fetal brain). It also has a good amount of astaxanthin which protects the omega-3’s from oxidation and does the same for neurons. Studies looking at DHA and EPA levels in red blood cells have shown a correlation between higher omega-3 status and having a to 2 cm larger brain volume… getting omega-3 into and keeping it in the brain is definitely a brain aging priority for me.

The sauerkraut is a good source of fermentable fiber aka prebiotics that is fuel for the commensal gut bacteria so that they can produce compounds (such as short chain fatty acids) that feed more commensal bacteria and feed gut epithelial cells which are required to make the gut barrier. These compounds produced by the gut bacteria serve as signaling molecules to make specific types of immune cells, an important indirect role that fiber also has in the diet that helps it influence immune activities. The sauerkraut itself contains various probiotics (mostly the lactobacillus strains) which are beneficial lactic acid producing bacteria which have recently been suggested to possibly play a role in cancer prevention.

For dinner, I usually have some cooked vegetables like sauteed spinach which is very high in folate (as are all greens). Folate provides a precursor that makes a DNA nucleotide called thymine. Every time you repair a damaged cell or make a new cell in your liver, muscle, brain etc., you need to make new DNA which means you need folate. Folate was also very recently shown to increase the growth of stem cells, which is important because stem cell pools deplete with age and are a major cause of organ aging and dysfunction. Folate has recently been shown to play a role in protecting telomeres, the tiny caps on the ends of chromosomes that are a biomarker for age because they get shorter every year.

A recent study showed that mothers with highest folate levels had newborns with telomeres 10% longer and every 10 ng/ml increase in serum folate levels, newborns had a 5.8% increase in telomere length which actually suggests that maternal nutrition may actually play a role in determining the length of telomeres that we have to start with. Sometimes, instead, I’ll have some collard greens, bok choy, broccoli, brussels sprouts, parsnips (of course, since these are all cruciferous vegetables I eat these usually with mustard powder sprinkled on top since that provides an additional source of myrosinase). Cruciferous vegetables in general are among my favorites types of vegetables to eat because they contain isothiocyanates. Associative studies have shown that the top 20% of consumers of cruciferous vegetable have a 22% reduction in all-cause mortality.

Or, instead, I’ll have a big salad full of greens which provide me with a cornucopia of micronutrients including folate, magnesium, calcium, vitamin K1, lutein, zeaxanthin and sulfoquinovose, a prebiotic that feeds beneficial bacteria in the gut. For my protein I often have a big serving of baked wild Alaskan salmon.

I try to eat salmon 2-3 times per week, which is what the American Heart Association recommends. They recommend that adults consume 500 mg/d of EPA and DHA (~2-3 servings of fatty fish per wk or ~8 oz of fish/wk). However, the mean intake in Western society is ~135 mg/d and about ~2 servings of fish/mo. EPA, as mentioned in another question earlier, is a powerful anti-inflammatory fatty acid that has been shown to lower brain inflammation. As I mentioned earlier DHA is a critical component of all cell membranes that makes up 30% of the fatty acids in the brain, or about 8% of the total weight. Omega-3 fatty acids have recently been shown to positively change gene expression in several brain regions and also generally shown to stave off brain aging. But also important is just not dying. People with the highest omega-3 fatty acid intake have been associated with having a 9% reduced risk of all-cause mortality. For each 1% increment of omega-3 fatty acids in the blood there was associated a 20% decrease in risk of all-cause mortality. Another protein that I rotate for dinner is chicken legs from pasture-raised chicken which I like because in addition to the protein I also get some cartilage which is high in collagen, proline and glycine which is interesting for reasons already discussed earlier.

Sometimes I throw the chicken bones in some water with some spices and vegetables and make chicken bone soup which gives me all the same goodies I talked about with hydrolyzed collagen powder. Chicken is also very high in selenium which is a cofactor needed for all glutathione-related enzymes to work and also has a modest amount of zinc, copper, and iron.

Finally, I also sometimes have a grass-fed filet steak a few times per month which is a good source of vitamin b12, iron, and zinc. ~16% of all menstruating women are actually iron deficient. For the vegetarians out there…it has been recommended to take in about twice the RDA for iron since iron which is bound to phytate in plant sources is ~2-times less bioavailable. As I mentioned earlier I also make a broccoli sprout smoothie usually consisting of anywhere between 100 g fresh weight or sometimes a bit less of frozen since freezing them actually increases the sulforaphane content. I do this about 3 times a week usually.

I talked about some interesting effects that sulforaphane has on the brain but I actually think that it may be, in some respects, a compound versatile enough to actually possibly even slow the aging process in general. We’ll need more studies to establish that fact, but I’m optimistic because of the already numerous associative studies showing that humans that have a high intake of cruciferous vegetables have 40%-50% reduction in multiple cancers ranging from bladder to breast to prostate to lung cancer. But that’s the associative studies… What gets me really excited are the clinical studies on sulforaphane that show some pretty amazing things. For example, men with prostate cancer that were given 60 mg of stabilized sulforaphane per day resulted in slowing the doubling rate of a cancer biomarker (known as prostate-specific antigen or PSA) by 86% compared to placebo, which is pretty amazing! Another really cool thing about sulforaphane is that it activates detoxification enzymes and causes our bodies to excrete carcinogenic compounds.

For example, people that were given a daily broccoli sprout beverage containing around 262 mg of glucoraphanin (the precursor to sulforaphane) plus an additional 7 mg of sulforaphane increased the rate of excretion of benzene by 61% and acrolein by 23% beginning on the first day of consuming the drink and continuing throughout the entire 12-week period of the trial. Benzene is a nasty carcinogen that is known to cause cancer in humans and animals, particularly leukemia. Some of the major sources of benzene that people are exposed to are from automobile exhaust fumes and air pollution and cigarette smoke. Acrolein is found in most of the major sources already mentioned for benzene including air pollution, but it is also be formed when carbohydrates, proteins, and fats are heated. So we get exposed to a fair amount of acrolein from cooking food. Sulforaphane has been shown to improve markers of cardiovascular health.

For example, people with type 2 diabetes given 10 grams of broccoli sprout powder per day for 4 weeks, lowered their serum triglycerides by around 19% and lowered oxidized LDL to total LDL cholesterol ratio by around 14% and reduced their atherogenic index by 50%, which is a measure of cardiovascular disease that incorporates a wide variety of factors. Again, pretty amazing results for not changing anything else in the diet/lifestyle except adding sulforaphane to their diet. Finally, sulforaphane also lowered inflammatory biomarkers in people with type 2 diabetes who were given broccoli sprout powder containing approximately 40 mg of sulforaphane for four  weeks, reducing TNF-α, by 11% and lowering C-reactive Protein by 16%. I can tell you from my experience being involved in clinical trials with unhealthy people with metabolic syndrome, it is VERY hard to get drops in biomarkers of inflammation after just one month with no other dietary or lifestyle changes.

The fact that sulforaphane has such a profound impact on lowering inflammation is of great interest to me because it is now believed that suppression of inflammation is the single most important driver of successful longevity and that this actually increases in importance with advancing age. And I don’t just mean living long either but also a strong association with capability, meaning the ability to adequately perform activities of daily living, as well as cognition in all major age groups: elderly, centenarians (100), semi-supercentenarians (105-109), and supercentenarians (110+). In fact, inflammation has been shown to be the single most important predictor of cognitive ability, surpassed in its predictive ability only by a person’s chronological age itself. This Japanese study that I’m referring to was a bit of a surprise to be because several different biomarkers were looked at including blood glucose levels, insulin sensitivity, blood glucose levels, and even telomere length but none of those predicted successful aging in each age group up to supercentenarians. Low inflammation was the only predictor of successful aging in all age groups.

So now you know in a more comprehensive way, for those of you that have heard me mention sulforaphane a few times already, what’s behind some of that. To sort of dive into some of the supplements I happen to be taking this moment: I’m taking a multivitamin called ONE by a company called pure encapsulations. People ask the brand, so I’m sharing that. I like this multivitamin because it covers some bases for various micronutrients I just talked about and also, interestingly, has some trace elements including boron which has been shown to reduce double stranded breaks, accelerate wound healing, significantly increased mean plasma free testosterone in a small trial in men, and increased the half-life of vitamin D. Boron is definitely sort of interesting and has caught my attention recently.

The multivitamin I just mentioned also has 2,000 IU of vitamin D. So if I’m getting a lot of sunshine, I might leave it at that… or more often, I’ll add an additional 2,000 IU of vitamin D. I also usually take around 135 mg of magnesium citrate-malate from Thorne. I try to get most of my magnesium from my foods since it’s a measure of how many green leafy’s I’m getting. Even with my modest supplementation, I get a good bit… but around 45% of the US does NOT have an adequate intake of magnesium which, for adults, is roughly 400 mg/day. For a little perspective, 1 cup of cooked spinach contains around 156 mg. I’ll save a little bit magnesium for some later discussion in a few moments, but it’s important.

Another supplement that I take every other day is vitamin K2 which is found in fermented foods particularly natto but also in organ meat. This is thought to be a good one to take with vitamin D since both are involved in calcium homeostasis. I usually take 100 micrograms in the form of menaquinone otherwise known as MK4. Lastly as a part of the core supplements I take daily is… fish oil, which I take a lot of. I usually take two omega-3 phospholipid gel capsules by nordic naturals (which is omega-3 isolated from herring roe) because the DHA is in a specific form known as lysophosphatidylcholine-DHA. This form has been shown to be taken up by the brain best via the mfsd2a transporter. This is also the form you can get from krill oil as well.

In addition to this, I also take 4 gel capsules of promega 2000 fish oil by nordic naturals. One of the key things to know about fish oil is that it’s one of the supplements that you really need to watch out for quality on. It should be kept refrigerated and you ideally want a brand that is trustworthy and not arriving to you already oxidized. In fact, varying degrees of fish oil oxidation is of great concern to scientific study design when it comes to fish oil if researchers fail to ensure the fish oil used in their study is high-quality, weird mixed results surrounding supplementation can very well be expected. This is a characteristic that is sort of unique to fish oil unfortunately.

What I like about Nordic Naturals is that they are NSF certified, which is one of the certifications for quality I mentioned when responding to an earlier question. In addition to that, my understanding from having inquired is that they also isolate their fish oil under nitrogen conditions (meaning no oxygen present) so as to minimize any oxidation during the isolation process. They are by no means the only option out there, but I’ve felt pretty good about using their products and have used them for many years.

Okay, a little bit more about the fish oil habit. I’ve taken fish oil daily for about 9 years now. Some of the studies that have kept me taking fish oil have to do, in particular, with brain health. For example, supplemental fish oil DHA (2g/day) has been shown to increase the clearance of amyloid plaques in people with mild cognitive impairment after 4-17 months. But I also take it because it has been shown to slow the aging process in general. For example, supplemental fish oil of 2.5g/day has been shown to slow telomere shortening (a biomarker for aging) and lowers biomarkers of oxidation in blood cells in overweight middle-aged and older adults. In another study, supplemental fish oil of 1g/day increased muscle mass, handgrip strength, upper- and lower-body muscle strength, and leg power in older women after 6 months.

Another study showed that high dose supplemental fish oil of 3g/day increased resting metabolic rate by 14%, energy expenditure during exercise by 10%, and the rate of fat oxidation during rest by 19% and during exercise by 27%, lowered triglyceride levels by 29% and increased lean mass by 4% and functional capacity by 7% in healthy older females. There’s been studies that even show that it can affect the metabolic activity of brown fat. There are hundreds of studies like these that have convinced me to take fish oil daily but you get the point. Moving on from fish oil, I also take the probiotic VSL#3 sachets either once a week or once every two weeks.

I’ll talk a bit more about probiotics and this one in particular when following up in another question. I mix in some other supplements like the meriva formulation of curcumin, which I already talked about earlier, and I am just starting to mix in a little nicotinamide riboside into the mix. Nicotinamide riboside is a form of vitamin B3 that gets converted into NAD+ , which I already explained the importance of when I talked about fasting… but a brief recap: NAD+ status improving is generally perceived as one of the benefits of fasting that improve mitochondrial and metabolic function. Declining NAD+ status can be one of the unfortunate negatives of inflammatory processes. Nicotinamide riboside supplementation (100 mg up to 1000 mg) has been shown safe in humans and increased NAD+ levels in a dose dependent manner with 1,000 mg per day raising NAD+ levels up to 2.7 fold over baseline.

There have been several animal studies showing nicotinamide riboside improves mitochondrial function, mitochondrial biogenesis, muscle mass, and metabolism but this is important and easy to miss.. the doses that were given to animals involved in studies were so high that I’m afraid that the supplement I’m taking right now, which is by Thorne and only has 125 mg per capsule, won’t quite cut it to meet some of the robust results being seen in animal studies. I think there is potential here but more studies in humans definitely need to be done at this point. Still interested though.

The last part of my weekly health routine has to do with exercise. I like to mix up my weekly exercise routine with aerobic exercise, high-intensity training, strength training, and yoga/ballet exercises. I usually do some form of exercise everyday even if it is only 15 minutes. I usually like to do a 20 to 30 minute sauna 3 times a week but I recently moved and have not got back in the sauna routine but I hope to change that soon.

Usually I go for about 3 mile run about three times a week. I’m not really an endurance athlete, clearly, but I do enjoy it for the cognitive boost it gives me. Whenever I have a big decision to make or if something is causing me anxiety, these are times I’m especially enthusiastic about going for a run. Aerobic exercise has been shown to increase the growth of new neurons in the brain by two-fold. Aerobic exercise even starting in mid life has been shown to almost completely reverse the structural changes that occur in the brain with aging.

It has been shown that 20-40 minutes of aerobic exercise can increase serum brain-derived neurotrophic factor (in healthy men) by up to 30%, and similarly even 15 minutes of aerobic exercise can increase some BDNF albeit to a lesser extent. BDNF robustly increases the growth of new neurons in the brain and… sort of interestingly, in the muscle it plays a role in repairing damaged muscle. It combats brain atrophy which actually begins at 20 years of age and by the time a person reaches 100 (if they do) they usually will have lost an average of about 20% of their brain mass. BDNF is not only good for combating brain atrophy by growing new neurons, it also has been shown to help prevent neuropsychiatric disorders like bipolar disorder, schizophrenia, and depression. Good stuff you don’t want in short supply.

To try to get a little bit of high intensity workout I’ll do squat jumps for a few of minutes at a time. High Intensity training has been shown to improve learning and memory and when done for 8-20 minutes it increases the production of the neurotransmitters glutamate by 5% and GABA by 7%, as well as norepinephrine, a catecholamine involved in attention and focus. Interestingly, the production of norepinephrine is associated with the amount of lactate generated from the high intensity workout. A highly vigorous exercise causes demand for energy to become too high for the mitochondria to use glucose or fatty acids to generate energy so glucose is used as energy without the mitochondria via a process called glycolysis.

Lactate is then produced as a byproduct. Lactate is very similar to ketone bodies in that it is transported to other tissues including muscle, brain, heart, liver, utilizing the same transporter known as the monocarboxylate transporter which is used by ketones. Then lactate is able to shunt into the mitochondria to be used as an energetically favorable source of energy, such as in the brain, where it can then be used preferentially as a source of energy by these norepinephrine producing neurons. This idea that we can use lactate, possibly produced by our muscles to help out brain tissue or other tissues not responsible for its generation, is known as the lactate shuttle theory which is an idea that was pioneered by Dr. George Brooks that lactate produced by the muscles might be utilized or “shuttled” elsewhere.

In addition to squat jumps and running, I also lift some weights and do lunges and squats with weights either two to three times per week. It is really important to maintain muscle mass. Starting in middle age, people lose between 0.5% to 1% of muscle mass per year. One study involving over 300 twins speaks to the importance of the legs in particular: greater strength and power in the legs in particular was associated with an increased brain volume 10 years later and less brain aging in over 300 twins. Other fitness measures besides that of the legs, such as forced expiratory volume or grip strength, were not associated with brain aging when leg power was excluded. Other lifestyle and health measures such as frailty and telomere length indicated that reverse causation is not likely. To get right down to it: don’t skip leg day.

Lastly, I do some yoga and ballet exercises 3-4 days a week. I really like to do these exercises because they increase my flexibility and tone very specific muscle groups. I like it… but your mileage may vary.

Russ Thallheimer: What small change can you make in your lifestyle that leads to the biggest impact on your health and wellbeing? Essentially, what is the 80/20 of lifestyle changes?

Rhonda Patrick: Okay, so to summarize Russ’s question: what 20% of lifestyle inputs are leading to 80% of the positive effects. I think for people starting from ground zero one of the easiest lifestyle changes to make with the biggest impact on health is to cut out refined sugar. Meaning any processed cookies, cakes, candies, crackers, drinks, etc. Refined sugar intake in the US is a big problem. Around 10% of adults in the United States get 25% or more of their daily calories from added sugar and over 70% get at least 10% of their daily calories from sugar! It has been estimated that consumption of sugar-sweetened beverages in 2010 may have been responsible for approximately 133,000 deaths from diabetes, 45,000 deaths from cardiovascular disease, and 6,450 deaths from cancer worldwide. Let that sink in. We’re not talking about smoking or alcoholism.

We’re not even talking about just sugar in general, we’re talking about sugar sweetened beverages by themselves. But to give an idea of some of the magnitude of effect that sugar consumption can have in terms of sodas: associative studies have shown that adult Americans who consumed roughly one can of soda per day had a 46% higher risk of developing prediabetes compared to low- or non-consumers over the same 14-year period. In a similar vein, another study showed that replacing ONE sugar-sweetened beverage such as a soda or a sweetened juice with water or unsweetened coffee or tea reduces the type 2 diabetes risk by up to 25 percent.

Dropping refined sugar seems to also be able to take effect pretty quickly too: in another study in obese children that were put on a diet with no added sugar for just 10 days, it was shown to decrease fasting blood glucose by 5 points, reduce insulin levels a third, and also improve cholesterol and blood pressure. Cutting out the refined sugar may be the single easiest thing a person can do to dramatically improve their health. Not only is refined sugar associated with higher risk of many diseases, refined sugar literally accelerates the aging process itself.

Healthy adults that drink 12 fluid ounces (or roughly a can) of soda per day had much shorter telomeres in their white blood cells than people the same age but do not drink soda everyday, a reduction in telomere length roughly equivalent to 4.6 years of biological aging. Telomere length is a well-established biomarker for aging since our telomeres get shorter every year… and for that reason, it should be at least a little alarming when you see an amount that is equivalent to 4.6 years of aging getting trimmed off. Inflammation, one of the factors that are very important to aging, may also be at play here. One trial found that giving healthy, normal weight young men 20 ounces of a sugar-sweetened beverage that was more or less similar to drinking a similar amount of soda daily for 3 weeks was enough to trigger an increase in the biomarker of inflammation C-Reactive Protein between 60% to 100% higher levels than they started with.

What about hormones? In one study, men experienced a 25% decrease in testosterone for up to 2 hrs after 75g of sugar intake. There is nothing good about consuming refined sugar except for that short-lived dopamine hit you experience, which by the way, it’s also been shown that refined sugar increases dopamine and activates the brain’s reward pathway in a way that is in some respects similar to other drugs like tobacco, cocaine, and morphine. It also affects the opioid system. The effects in terms of magnitude are smaller than these substance abuse drugs. But the pattern ultimately follows a similar trajectory: you continually activate the brain’s reward system, you begin to lose self control, start to crave it, and eventually build up a tolerance to it so you need more and more.

These same mechanisms are at play when we talk about sugar addiction too. In my opinion, the best thing you can do is to cut it out!! You will be so much healthier by just cutting out this one thing. Once you stop eating refined sugars foods begin to actually taste sweeter that’s a real effect that’s been shown in clinical studies. Moving on, the second thing easiest thing you can do that will have a big impact on health is to begin doing time-restricted eating within a 9-12 hour time frame in accordance with circadian rhythm where, unless you are a night shift worker, you try to eat your meals earlier in the day as possible like discussed earlier.

If you’re looking to start out, I think 10-hour is a very good middle of the road approach. A fact I mentioned earlier does a great job at establishing magnitude of impact: women that previously had breast cancer and ate all their food within an 11-hour time period and changed nothing else in terms of their dietary composition reduced their breast cancer recurrence by 36%. Mice that were fed a high sugar, high fat diet but could only eat within a 12-hour window and still ate the same number of calories as mice that were allowed to eat within a 15-hour window ended up being 28% leaner, had 70% less body fat, did not get fatty liver compared to the mice splitting their meals over a longer period of time which did end up with fatty liver. The timed-restricted mice also had better blood glucose levels, cholesterol profile, and were more active, and could do complex motor tasks better.

This even included two cheat days per week in which the time restriction wasn’t in place to sort of simulate a human weekend off. It’s really important to drive home the fact that the impact of time-restricted eating was made without other improvements in food quality… the versatility factor is of huge benefit here and what makes it appealing is it is broadly applicable for people. So that’s two. So far to answer this question, the big lifestyle inputs I’ve suggested are: remove all refined sugar as much as humanly possible, especially sodas… and implement time-restricted eating regardless of diet, preferably earlier in the day.

The third huge lifestyle input that I think can make a big, big difference is simply doing whatever it takes to potentially triple the amount of vegetables you take in on a daily basis. For me, the way I’ve gone about this has been to make a habit out of creating a micronutrient smoothie, as I’ve termed it. Basically, I grab various combinations of vegetables and sometimes a few fruits to balance it out, drop them all into a powerful blender or food processor and drink drink it down.

Going about it this way means that all of the hugely beneficial fiber still gets ingested. This is important because commercial juicers remove the fiber, which is problematic since fiber is highly beneficial for the microbiome, important for health and the regulation of blood glucose levels, and often in short supply in the diet of the typical Westerner. We’ll talk about the implications of that in a question that comes up later. One important tip is that using an especially powerful blender makes sure that the smoothie has a consistent texture, enhancing palatability, which may be a drawback for some folk that may otherwise have prefered juicing. You learn over time adding in certain things like avocado also can greatly change the texture, usually improving it. Having done this micronutrient smoothie “hack” 4-5 times per week for the past 6 years, often without great regard of where it may fit in with the rest of my diet, even adding it on top, I noticed something pretty interesting early on: I noticed that the amount of vegetables I was buying almost quadrupled. Vegetables are a rich source of many important micronutrients and other compounds like lutein and zeaxanthin that have important functions that I mentioned earlier when talking about the foods I eat.

The smoothie that I make at the very least usually has kale, berries, and an avocado but I usually also add chard and possibly some other veggies like carrots and a tomato. In the U.S. micronutrient deficiencies are especially common, but this is probably true elsewhere abroad as well. RDA’s have been set to make sure people meet their daily intakes but even still people don’t meet them.

Some micronutrients that are abundantly found in greens just happen to be the ones that people in the US are the most deficient in somewhere around 45% of people are deficient in magnesium, 35% in vitamin K, 24% in vitamin C, 34% in vitamin A, 38% in calcium, 8% in folate. Magnesium, because of it’s location at the center of the chlorophyll molecule, is especially telling when it comes to the root cause of the problem… a lack of consumption of green leafies.

Earlier I mentioned that around 22% of all enzymes require a micronutrient to function. These micronutrients are necessary for metabolic pathways that are essential for short-term survival and metabolic processes that are important for long-term health. Sometimes these different processes both require the same micronutrient to function. So what happens in a person that happens to be deficient in that particular micronutrient? My former postdoctoral mentor, Dr. Bruce Ames, proposed that those metabolic processes that are required for short term survival will get their share of the micronutrient first because nature wants you to survive long enough to reproduce and pass on your genes, whereas processes that are more concerned with the long-term maintenance, processes involved in mitigating aging in the long-term ultimately get neglected.

Bruce calls this evolved strategic rationing of micronutrients the triage theory. It’s a helpful way to think about how the body deals with micronutrient inadequacies and deficiencies and he’s published a couple of studies providing the theoretical backing to support the idea. While nature has devised this elegant way of allocating vitamins and minerals to ensure survival during periods of food scarcity, which has occurred throughout evolution, the tradeoff is it results in insidious types of damage that accumulate with age, accelerates the aging process and leads cancer and neurodegeneration.

In the case of magnesium over 300 different enzymes in the body require magnesium, including all the enzymes that use and produce ATP, the energetic currency of the cell. ATP must be bound to a magnesium ion in order to be biologically active. These functions of magnesium are required for short term survival. If you can’t make ATP you simply can’t live. But the enzymes that are involved in the generation of ATP are not the only enzymes in the body that require magnesium.

Magnesium is also required for enzymes that repair damage to DNA which has been shown to lead to cancer and damage mitochondria, which can accelerate the aging process. But optimal DNA repair function is not critical for short-term survival so those enzymes, it would logically follow, would not not get their first pick of magnesium. Putting aside the micronutrients for a moment, of course, along with the kale you get some isothiocyanates like sulforaphane which we talked about quite a bit earlier. Finally, for lifestyle input #4, the other really, really easy lifestyle change that I think has a potentially big impact, for many, many people, is probably taking a vitamin D supplement.

Vitamin D is actually converted into a steroid hormone in the body and regulates around 5% of the human genome. Let that sink in and recall back to the fact that approximately 70% of the US population does not have adequate levels of vitamin D, which is an amount of 30 ng/ml or greater. Or 75 nmol/L if your test uses that unit. That means 70% of people in the U.S. are experiencing some dysregulation of their genes due to poor vitamin D status.

As I mentioned earlier this is largely due to people spending more time indoors, wearing sunscreen which blocks the ability of your skin to make vitamin D, darker skin pigmented people living in more northern latitudes age etc. Earlier when discussing vitamin D in the context of serotonin production as a nootropic, I mentioned that I like my vitamin D levels to be between 40-60 ng/ml.

Here’s part of the basis of that: a meta-analysis including around 30 studies from 1960 to 2013 showed that people with vitamin D levels between 40-60 ng/ml had the lowest all-cause mortality and another study found that people with those same vitamin d levels had the longest telomeres compared to age-matched controls with lower vitamin D levels. And sort of just generally establishing again the importance of vitamin D: yet another study involving a couple thousand twins found that those with the lowest vitamin D levels had shorter telomeres that corresponded to 5 years of accelerated aging.

Vitamin D activates the expression of DNA repair genes and anti-inflammatory genes and thus lowers DNA damage and inflammation, both of which accelerate the attrition of telomeres. So I think having adequate vitamin D levels definitely has an effect on long-term health. But it also affects short-term health as well. A meta-analysis of 25 randomized clinical trials conducted in 14 countries showed that vitamin D supplementation cut infection risk by 50% in people that were deficient and by 10% in people with normal vitamin D levels. It also affects muscle mass and exercise performance. For example, 2,000 IU of vitamin D3 per day for 2 weeks increased exercise performance (cycling) by 30% while lowering physical exertion. Postmenopausal women receiving a vitamin D supplement had a significant increase 25% in muscle strength, while those receiving the placebo actually lost an average of 7% of muscle mass.

There are so many studies showing that vitamin D improves health including brain health, you do not want to be deficient in this and yet so many people are. The solution is to take a vitamin D supplement. Generally speaking, as a rule of thumb, 1,000 IU of vitamin D usually raises serum levels of vitamin D by 5 ng/ml. This is sort of useful as a course correction when you’ve got a vitamin D test coming back outside of the range you want to see it. It really is important, however, to measure your blood levels of vitamin D after supplementing as well. Okay, so with that last one I think that sort of wraps up my high level thoughts on lifestyle strategy choices that might drive big changes in a pareto’s principle sort of fashion.

To recap:

• #1 – Eliminate refined sugar from the diet to the greatest extent possible.
• #2 – Practice time-restricted eating and eat generally in accordance with your circadian rhythm.
• #3 – Do everything in your power to maximize vegetable intake, possibly using the micronutrient smoothie method as a way to jumpstart the habit.
• #4 – Enlist your physician in helping you monitor your vitamin D blood status and then attempting to titrate your dose to an above 30 ng/ml range, possibly trying to land between 40 and 60 ng/ml.
• #5: try to get some form of meaningfully vigorous cardiovascular exercise, at least 30 minutes, a few times per week.
• And #6: get bright blue light during the day, as early as possible, and avoid that same blue light as much as you can in the evenings.

Sean Ballard: Rhonda, have you considered taking meat completely out of your diet? Also, which meats do you consume, where do you get them, and how frequently do you consume meats

Rhonda Patrick: The truth of the matter is that there have been many, many correlative studies that have found that higher meat consumption is associated with a significantly higher risk of cancer and cancer mortality. This fact alone should be enough to at least make a person give thought to their position on the subject especially when it’s a relationship that keeps showing up.

That said, one of the largest studies to-date, which was published in JAMA Internal Medicine in 2016, and looked at meat consumption and all-cause mortality and cancer-related mortality found something interesting that is important to the narrative: specifically, it found that a high intake of meat from animal sources was only associated with a higher mortality rate and cancer mortality rate in people that had at least one other factor associated with an unhealthy lifestyle such as being obese, or having a history of smoking or being physically inactive or being a heavy consumer of alcohol.

Meat consumers that were healthy by not having any of these aforementioned unhealthy lifestyle factors did NOT have a higher mortality rate or cancer mortality rate. Critical to the meat consumption and cancer link is the fact that protein increases IGF-1, something that research suggests may be an important link in this meat-cancer relationship.

Earlier we talked a little about the importance of IGF-1 in its beneficial context for muscle hypertrophy, but this cancer link is a trade-off that’s worth paying attention. Amino acids and particularly essential amino acids (such as leucine) which are more abundant in meat are the most potent dietary activators of the IGF-1 pathway. IGF-1 does a lot of stuff. It’s a growth factor that plays a very important role during early growth development and also is important in promoting and maintaining muscle mass, as we discussed, and also neuronal function.

There are many positive benefits to IGF-1 but there is also a tradeoff, as there so often is in biology. IGF-1 is a very potent growth factor that allows cells that have been damaged to survive when they otherwise would die. It is important to understand that IGF-1 does not cause damage to the cell, rather, it allows damaged cells to live and reproduce so that it can make more copies of the damaged cells. IGF-1 is known as a tumor promoter because it promotes the growth of cancer cells.

Other factors that cause DNA damage such as reactive oxygen species (byproducts of metabolism) and inflammatory cytokines (byproducts of immune activation) can initiate cancer by causing DNA damage, which is the initial insult that can lead to a damaged cell. Our body has protective mechanisms that sense a damage cell and kill it but the presence of an abundance of IGF-1 overrides this mechanism and can allow that damaged cell to survive. This is why IGF-1 can be fuel for cancer growth. Not initiation, but growth. That distinction may be important.

As a pathway, IGF-1 is actually of great interest in both cancer and longevity research. We know from animal evidence that growth hormone and IGF-1 deficient mice are resistant to cancer. Interestingly, this evidence isn’t limited to animal research: some humans also have polymorphisms in the gene that encodes for the IGF-1 receptor, which leads to a decrease in IGF-1 activity in these individuals. Similar to animal research, we see a decreased incidence in cancer and also longer lifespans in these people.

Human evidence also exists for the exact opposite, where people that have genetic polymorphisms that cause them to have increased IGF-1 also have an increased cancer risk. If we get away from genetic polymorphisms and just look at people with higher circulating IGF-1 in their serum, something that can be quantified, this has also been associated with an increased risk of several common cancers, including breast, colon, and prostate.

So, high IGF-1, higher cancer risk. Low IGF-1, reduced cancer risk and even longevity. With this new understanding of the relationship of meat consumption to IGF-1 production and IGF-1’s relationship with cancer and longevity, where it even inhibits the longevity gene FOXO3, it would be very tempting and very easy to take an absolutist position and never touch meat again, putting aside all of the other reasons why someone might make such a choice.

But as I mentioned there are good aspects to IGF-1. IGF-1 has been shown to increase lean muscle and and reduce adipose tissue simultaneously, it acts as a neurotrophic factor increasing the growth of new brain cells, it prevents brain cells from dying. It’s pretty clear that I actually want some IGF-1 activity. I think this is a really important take-home with respect to IGF-1 because IGF-1 has a good and a bad side but I think exercise is a way to tip the balance towards the good. Exercise, whether we’re talking about aerobic or resistance training has been shown to to lower serum IGF-1 because exercise causes our muscles to take up IGF-1. Additionally, IGF-1 has been shown, in rat studies, to cross the blood-brain barrier in response to exercise and increases neurogenesis.

This also means the exercise lowers circulating concentrations of IGF-1 which means it has less of a chance to promote the growth of damaged cells or inhibit Foxo3 in other tissues. If we circle back to the original study I mentioned where meat consumption was only associated with a higher all-cause mortality if one other unhealthy lifestyle factor was present this makes perfect sense if most of the bad effects are mediated through IGF-1.

Since I do not have any of those unhealthy lifestyle factors and I understand what I perceive to be the mechanism behind the relationship between cancer and meat consumption, I have decided to keep some meat in my diet. Since I already got into a meal breakdown where I talk about the meals I eat in a typical week in another question, I’lI skip to the last part of the question which is where do I get my meat from: I usually get them from the local grocery store or the farmers market. I buy wild fish (mostly Alaskan salmon), grass-fed beef, and pasture-raised chicken with no antibiotics or hormones.

Andrea Kurland: I would like to hear your thoughts on some of the fad diets that have been circulating. Paleo/ketogenic/vegetarian. Advocates of each of these often claim that their diet is the best for inflammation…yet they are all different.

Rhonda Patrick: I think there are benefits to the perspectives that are brought by each of these various philosophies, though there might be contexts that may make one or another make more sense. I personally choose a more middle of the road route and eat what might be loosely termed a Paleo-ish type of diet. The good news is that some of these diets have aims that sort of overlap with one another.

For example, both paleo and ketogenic-style diets emphasize cutting out refined carbohydrates and refined sugar which in and of itself has a dramatic effect on lowering inflammation, lowering cancer risk, cardiovascular disease risk, dementia risk, and delays aging all of which we talked about in more detail a minute ago when discussing how cutting out refined sugar is one of the big changes a person can make to have a rapid impact on personal health. The paleo diet, in contrast to some of the popular culture’s flavors of keto, emphasizes eating a lot of vegetables and fruits, which also comes with the package in vegetarian diets as well.

As I mentioned earlier fruits and particularly vegetables are a great source of micronutrients and other important compounds such as folate, magnesium, vitamin K1, calcium, vitamin A, vitamin E, vitamin C, potassium, lutein, zeaxanthin, pterostilbene, anthocyanins and other polyphenols and flavanols.

I already mentioned how incredibly important these micronutrients are, how 22% of all enzymes require some micronutrient to work properly and how important they are for metabolism, mitochondrial function, neurotransmitter production, antioxidant and anti-inflammatory pathways, immune function, brain function, repair enzymes…basically everything important for preventing disease and healthy aging.

One of the problems with certain variations of the ketogenic diet is that, without a great deal of care to avoid this pitfall, it can lead to inadequacies or deficiencies in some of these micronutrients and you may not get as many of the other beneficial compounds present in plants as well. A great example of this might be the flavanols in blueberries, just by way of example. Fruits and vegetables, which, again, it seems like the paleo diet and vegetarian diet focus a bit more on, are also a great source of various types of fiber including fermentable fiber and non-fermentable fiber. Fiber is not a single nutrient, which is why fiber supplements are no magic bullet either. It’s not just about quantity, but also diversity of complex carbohydrates.

There are hundreds of different polysaccharides — complex carbohydrates, in plants. Gut microbes reflect this same diversity, specializing in using different types of complex carbohydrates and even the metabolic byproducts of other microbes. These microbes then produce short-chain fatty acids that impact our health in a variety of ways. This is why eating only one type of fiber, as from supplementation, is ultimately a failed strategy.

The best way to increase your microbial biodiversity is to actually eat a variety of polysaccharides from a diverse diet of plants and vegetables as well as fruits. For example, lignins and cellulose (which are found in plant cell walls) are non-fermentable fiber that help move food and other byproducts through the intestines. Examples of fermentable fiber that are eaten by a wide-variety of commensal bacteria in the gut include pectins (which are found in fruits and berries,), gums (which are found in seeds), inulin (which is found in plants and onions, garlic, and artichokes), resistant starch (which is found in legumes like beans also in bananas).

Green leafy vegetables also contain a prebiotic known as sulfoquinovose which also feeds beneficial gut bacteria in the gut. In addition to diversity, however, we also need volume of dietary fiber. Figuring out what this golden amount is to keep our microbes metabolically satisfied and not literally starving is a tricky issue. The institute of medicine recommends men 50 years of age and younger get at least 38 grams of fiber per day and women 50 years of age and younger get 35 grams of fiber per day. Those numbers drop slightly for adults older than 50. But traditional societies, for example those that still exist in places like in Tanzania that are living a hunter gatherer lifestyle, can get around 200 grams of fiber compared to the norm for U.S., which is shockingly only about 15 grams per day on average. Either by comparing to traditional societies or just taking the institute of medicine’s recommendation most miss this mark.

It is therefore, important that whatever diet you do choose you ultimately ensure your microbiome has adequate substrate which survives digestion to make it toward the end of the digestive tract where the majority of these microorganisms live and interact with our immune systems and our brains. The big problem with a low fiber diet which in the context of this discussion may possibly be a version of the ketogenic diet — again, unless special care is taken, is that it may not provide this substrate. Fats, proteins, and sugar are all absorbed in the small intestine earlier on but all the 100’s of trillions of bacteria that are in our gut and regulate our immune system, brain function, and more are at the end or “distal” part of our large intestine, called the colon.

When we eat fiber-deficient foods, our gut microbes starve but to keep from starving they eat and cannibalize the gut barrier (which is made of carbohydrates and mucin). In terms of magnitude, low fiber has the largest negative effect on breaking down the gut barrier. Additionally, one study showed that a low-fiber diet caused up to 75% depletion in half of gut bacterial species. That’s a magnitude of effect that sounds almost on par with actually taking a round of antibiotics, if you think about it.

Okay, so I’ve voiced some real concerns about possible implementations of certain variations of ketogenic diets. But there are other benefits of a ketogenic diet. In my opinion one of the main benefits from the ketogenic diet is a steady stream of ketone body production particularly beta-hydroxybutyrate (BHB). BHB is a fascinating mostly anti-inflammatory compound and plays an anti-oxidative role as well. Altogether, most studies in animals link the production of beta-hydroxybutyrate to lower oxidative stress, lower inflammation, improvements in mitochondrial respiration and ATP production, and improved brain function. It also may change gene expression in a positive way by regulating class 2 histone deacetylases.

As I mentioned earlier in another question, the ketogenic diet has also been shown to lower blood glucose levels and improve insulin sensitivity and lead to weight loss in some individuals. But this is not true for everyone as some people do experience negative metabolic effects likely due to genetic variation which is why it may be helpful, if you experiment with this diet, to keep an eye on some of the blood biomarkers mentioned earlier to make sure that, if you do experiment with it, you’re not one of the folk that it may not be ideal in the long-term for. It’s also possible to ramp up ketone body production for short bursts by kicking off evening fasts a bit earlier, playing it strict and following some of the time-restricted eating or intermittent fasting protocols out there.

Going back to the paleo and vegetarian diets, while they both focus on eating whole vegetables and fruits…they obviously differ in that vegetarian diets lack meat and have an even heavier emphasis on plants, obviously. One potential drawback from the vegetarian diet is that people on this type of diet must put in a little more effort to get some of the micronutrients that are found in meat such as the marine omega-3 fatty acids (EPA and DHA), iron, zinc, vitamin B12, selenium. For example, iron (which in addition to being important for red blood cells to carry oxygen to all tissues, is also required to produce neurotransmitters and myelin).

Non-meat sources of iron such as kidney beans or lentils contain iron that is bound to something in the legumes called phytate. There are large bioavailability differences between iron that is in heme (which is how it is found in meat) compared to iron that is in in phytate from a plant source. The bioavailability of iron in phytate is about 1.8 times lower than the iron bioavailability from heme. The poor bioavailability of iron that is bound to phytate has to do with the fact that humans cannot digest phytate so most of that iron does dot get absorbed. For this reason, the RDA for iron for vegetarians should be 1.8 higher.

The RDA for adult males is 8 mg and pre-menopausal women is 18mg. A lot of iron is lost during menstruation which is why menstruating women are at high risk for deficiency. In fact, approximately 16% of all menstruating women are iron deficient. Too much iron, however, can cause serious oxidative damage and other problems, which is why it’s a good idea to get iron levels measured instead of blindly supplementing.

This is just one example of what I mean by vegetarians having to work a little harder and think about complexities like this to make sure they get all of their micronutrients. There are other examples. A great one I mentioned earlier are the omega-3 fatty acids. It may be tempting for vegetarians to dose up on conventional plant sources, like flaxseed. Some people have a gene polymorphism in the gene that encodes for the enzyme that converts the plant omega-3, ALA, into EPA and DHA, the ones I referred to as marine omega-3 fatty acids a moment ago, and this can cause them to not convert as well others.

This can be circumvented by supplementing with microalgae oil and possibly eating higher concentrations of ALA, however. Or you may just be lucky and be a highly efficient converter of ALA in which case, it may not be a problem. Similarly, essential amino acids are much more abundant in meat and may be something that vegetarians may need to work a little harder to make sure they are getting enough of particularly in older age.

One study looking at people over 65 found that there was an increased mortality with low protein intake, likely due to frailty. As I mentioned earlier, Starting in middle age we lose about 0.5-1% of muscle mass a year and essential amino acids are important for maintaining muscle mass along with putting those muscles to work, of course. But, if you recall earlier, there may be a flip side to that. Folks on paleo or keto diets do include meat. This means that they may need to take special care to be active and not sedentary to put that IGF-1 to use. Remember that eating meat increases IGF-1 and for people that have even one component of an unhealthy lifestyle such as obesity (without trying to lose weight…paleo and keto diets have been shown to result in weight loss), being sedentary, smoking, or excessive drinking… this may increase all-cause mortality and cancer-mortality.

So that is my sort of high level general summary of these three diets. Like I said, I personally choose to try and get the best of all worlds. I eat paleoish, including fish and other meats, but with a big emphasis on plants that might be more common among vegetarian eaters. I am very vigilant about avoiding refined or processed foods and especially sugar.

I practice  time-restricted eating and intermittent fasting to get the occasional dose of the ketone body beta-hydroxybutyrate. I do not smoke or drink excessively, and I make sure to exercise! This protocol works really well for me. But there may be life contexts, being honest-to-god sedentary for example, or possibly even genetic backgrounds in which we need to emphasize one philosophy more over another. Similarly, a person might have important clinical reasons for pursuing a ketogenic diet, in which case, avoiding pit-falls like poor micronutrient intake can become especially important.

Either way, I think there’s a rich future in figuring out where individual variation and genetic polymorphisms come into play in the pursuit of a healthy lifestyle… and conversely, what approaches are more broadly applicable, like time-restricted eating.

Luke Hoskovec: Do probiotics need to be taken forever or do the different strains of bacteria gain a foothold at some point? If I take probiotics for six months and stop, will the introduced colonies survive?

Rhonda Patrick: Your question actually highlights one of the important drawbacks of taking supplemental probiotics. In order for probiotics that are introduced to actually remain in the colon (which is where the majority of our gut microbiome resides) there has to be space for these tiny microbes to stay.

The predominant way bacteria take up residence long-term in the large intestine is by sticking to the mucin, which is the mucus-like material that makes up the gut barrier and lines the interior of the gut. The problem is that unless a person has just taken a course of antibiotics that mucin is already effectively colonized with bacteria that already reside there, which can be a limiting factor that reduces the foothold that new species are able to gain. What this effectively means is that often the probiotics that make it to the colon, if they were alive when you took them, end up being flow through instead of sticking around. BUT! What’s interesting, however, is that probiotics can, while passing through, facilitate population shifts that may be otherwise less than straightforward while they pass through. Sort of like you introduce population A and B but resident populations X is diminished and resident population Y is increased… or, alternatively, the probiotics may also interact more directly with our immune system while they pass through.

Basically, there’s still a ton of research to be done on probiotics… it’s clear that, in some cases, they can be highly, highly effective for a variety of purposes, but sometimes the exact mechanism is a bit elusive and may not be strictly intuitive. This issue of already being colonized and existing biota taking up space does, however, come with certain obvious conclusions. The first of which is that you are perhaps most advantaged in taking probiotics shortly after you’ve wiped out your existing populations with antibiotics. It’s important to note, however, that the cumulative effect of repeated use of antibiotics is pretty much unambiguously negative from the perspective of gut microbial communities, with each additional course causing even greater changes that shifts the community further away from its natural starting state… so it would not be prudent to seek out antibiotics strictly to try to liberate a little space in the gut. Interestingly, another good time to take them may be while taking antibiotics too.

Clinical studies have shown this can reduce the potential of later c. difficile infections, among other things. Gut researcher Dr. Justin Sonnenburg out of stanford has characterized probiotics as potential placeholders that prevent pathogens from gaining a foothold during recovery, which may be an interesting way to look at it. However, with that said it is possible that with repeated use (as is the case with 6 months) that some can get a foothold in the mucin and stick there.

To have a better chance of that happening or having any sort of therapeutic effect whatsoever, however, it’s helpful to first have a product that you’re confident is alive when it arrives to you and also has a sufficient quantity of bacterial cells that it can actually make an impact. There’s one particular product that stands out for this reason and also because of the sheer volume of clinical evidence that you can find just by searching its name in google scholar or Pubmed. The product to which I’m referring is known as VSL#3, particularly the unflavored sachets, which has 450 billion probiotics per serving packet. They also get shipped in an actual cooler with ice packs to ensure they’re viable when you get it.

By way of comparison, you might be lucky to find a probiotic with 100 billion but most contain more like 10 billion or sometimes even less and the viability of those bacterial cells by the time it makes it off the shelf or out of a warehouse and into your refrigerator may or may not be effectively zero.

There are dozens of publications showing the effectiveness of VSL#3 both in humans and animals looking at its effect on a wide variety of conditions ranging from the more obvious, like antibiotic-induced diarrhea, but also its effect on insulin signalling, atherosclerosis, food allergy, colitis, liver dysfunction, lipid profile, blood pressure and more. But to speak to Luke’s question about whether species in probiotics are able to gain a foothold, I have, anecdotally, measured both mine and my husbands microbiome species using a consumer service both before and after taking VSL#3 for several months and did find that the VSL#3 caused new species of commensal bacteria to crop up that were not quantifiable when at my baseline and were not even species of bacteria that were present in the VSL#3.

I think it is possible that some of the probiotic strains that WERE in the VSL#3 produced what are known as short-chain fatty acids, small molecules like lactate, which then ultimately provide fuel for other neighboring strains of bacteria that I may have had in very small quantities already present in my gut which then became detectable once they sufficiently increase in quantity. So this sort of feeds into that earlier discussion about how probiotics can have positive effects but then once you go in to actually look at the changes from the probiotics, they may be somewhat unexpected. Additionally, however, in my experience some of the strains actually present in the super probiotic VSL#3 did begin to show up as well.

All of that said, as a person with former gut problems that seem to have been resolved, I no longer take VSL#3 everyday because, frankly, it is a bit cost prohibitive and probably not even necessary for me at this point. Instead, I take a maintenance dose every week or so and generally keep what I consider an airtight diet that promotes a healthy microbiome through the consumption of an abundance of various types of healthy fermentable fiber. If you’re listening this and look up VSL#3 online, again — no affiliation here — be aware that it can be bought direct from the manufacturer and shipped to your home without a prescription, but they do advertise it as a medical food with the expectation that you’re taking it under the care of a physician. While I don’t know of any particular risk from taking probiotics, it’s always good to follow the prudent podcast listener’s rule and consult a physician before trying to treat what may be a medical condition.

Mary Maxey: Are artificial sweeteners bad for gut health or overall health? Should they be avoided?

Rhonda Patrick: I try to avoid them because they may have adverse effects on gut health and, through that, overall health too. Once in a great while it’s probably fine but everyday use, as in the case of a daily diet soda, is not a good idea in my opinion. There was a study published in 2015 that showed that artificial sweeteners alter the gut microbiome both in mice and in a small group of human trial participants. In the mice, they tested saccharin, sucralose and aspartame and found that they increase a population of bacteria that are better at extracting energy (specifically glucose) from food and then store that energy as fat.

This ultimately altered gene expression which then allowed for increased fat storage and decreased fat burning. Similarly, humans that were given a high-dose saccharin showed a rapid alteration of the gut microbiome and also had decreased glucose tolerance sort of showing proof that the same mechanism in mice does seem to cross over when we’re talking about people too. This sort of hints at a potential bitter irony whereby people having switched to drinking diet sodas, for example, may actually be affecting their microbiome in such a way as to actually make themselves more obese, even if the empty sugar calories they’re taking in have been reduced. In general, if we think more about overall health, putting aside whether the effects mediated by the microbiome or not, artificial sweeteners in particular have been linked to metabolic syndrome, coronary heart disease and other cardiovascular events.

I’m somewhat optimistic that the effects of the natural non-nutritive sweetener stevia are somewhat more benign, especially in light of a 2016 study showing lipid improvements and even therapeutic potential in a rodent model of obesity. This sort of hints at the fact that it may be a totally different can of worms. But, even so, I do still think it may be worth exercising some degree of caution. In general, when talking about artificial sweeteners or even the non-nutritive sweetener stevia, proper randomized controlled trials are lacking. I’m sure the debate will continue until these sort of gold standard trials emerge that can move the conversation forward by firming up the details more. For now, I personally avoid artificial sweeteners altogether and only use stevia in moderation.

Emily St Clare: Is metformin really damaging to the mitochondria or is it more of a hormetic stressor?

Rhonda Patrick: Briefly for those of you that do not know what metformin is — Metformin is a drug, specifically a biguanide derivative, that is primarily used for the treatment of type 2 diabetes. It helps control blood glucose levels and restore insulin sensitivity. It decreases the amount of blood sugar that the liver produces (mostly through reducing gluconeogenesis in the liver via AMP Kinase activation). It also reduces the amount of glucose that the intestines or stomach absorb.

In addition to affecting blood glucose, metformin affects other pathways involved in metabolism, inflammation, and growth. That said, the reason why Emily may be asking this question, if I were to venture a guess, is because over the last few decades there have been hints that metformin, in addition to regulating blood sugar in people with type 2 diabetes, might also prevent diseases associated with aging.

In the late 1990’s a study in the UK found that type 2 diabetics taking metformin lowered all diabetes-related complications by 32% and also lowered the risk of cardiovascular disease. Other studies have found that taking metformin is associated with a reduced cancer risk and it preserved cognitive function. But the study that got the most attention and certainly piqued my own attention was a British study involving around 78,000 individuals that found adult type 2 diabetics who took metformin, on average, lived longer than healthy age-matched controls.

That was kind of mind blowing for me. Oddly enough among many of the compounds that have been shown to affect lifespan in animals, including metformin, rapamycin, resveratrol, etc., metformin has generally not been THAT impressive. but, metformin has a long reassuring track record since people with type II diabetes have been taking it since the 1960s. Still, I don’t take it but I’m interested for its future and will be keeping an eye on emerging research.

To more directly answer the original question, metformin does inhibit complex I of the mitochondrial respiratory chain (which is a very important complex in the mitochondria that is responsible for energy production) and, thus, inhibits oxygen consumption in the mitochondria. Believe it or not, several researchers actually think that this may be the important mechanism by which metformin affects aging. This is because, by inhibiting the mitochondria, this turns down mitochondrial metabolism which may mean the mitochondria accumulate less damage since they aren’t working as hard.

The consequence of complex I inhibition by metformin is a decline in ATP production and an increase in ADP and AMP and this activates AMP kinase. So far as I am aware, the complex I inhibition in mitochondria does not appear to cause mitochondrial toxicity. Future studies will help better illuminate if and how metformin can reliably extend human healthspan and whether or not this doesn’t come with some sort of drawback that just hasn’t been teased out yet.

Sarah Fox: For superior health, do you recommend to stay away from any alcohol? Or, are an occasional couple glasses of red wine on the weekends ok?

Rhonda Patrick: Sarah, you and, indeed, probably Tim, will be relieved to know that I think a couple of glasses of red wine on weekends are probably OK.

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