Micronutrients for Health & Longevity | Dr. Rhonda Patrick

The episode is framed around the major categories of micronutrients essential for brain and body health, with Huberman confessing that before the discussion he was aware of only one of the categories they cover, and that he remains rapt with attention throughout. He also flags behavioral protocols — the sauna and the use of heat and cold for metabolism, longevity, and cardiovascular health — and how those can interface with supplement-based and nutritional protocols. Patrick is introduced as a podcaster and an educator in mitochondria, metabolism, stress, and brain and body health, and as the host of Found My Fitness.

Huberman credits Patrick with formal training in cell biology, exploring links between mitochondrial metabolism, apoptosis (naturally occurring, healthy cell death occurring in the brain and body throughout the lifespan), and cancer biology, followed by postdoctoral training with Dr. Bruce Ames on how micronutrients — vitamins and minerals — affect metabolism, inflammation, DNA damage, and the aging process. He points to landmark review articles and primary research in Science, Nature Cell Biology, Trends In Cell Biology, and FASEB.

The substantive starting point is a conundrum Huberman raises: temperature is a powerful biological stimulus, and cold can stimulate increases in metabolism and brown fat, yet heat seems able to do many of the same things. He wonders whether the discomfort of deliberate cold exposure and the discomfort of heat might be anchoring to the same pathway, and asks what happens in a cold environment on purpose versus a hot one, in the hope of reaching some point of convergent understanding.

Patrick steps back to a broader principle: the intermittent challenging of yourself, whether through temperature changes like cold or heat, other stressors like physical activity, or dietary compounds found in plants such as polyphenols or flavanols. She frames humans as having evolved to intermittently challenge themselves — before Instacart and before the industrial revolution, hunting and gathering required movement and physical fitness — with caloric restriction or intermittent fasting, food scarcity, and eating plants all described as additional types of intermittent challenge that activate genetic pathways in the body.

Humans, we evolved to intermittently challenge ourselves.

These are often called stress response pathways, and Patrick emphasizes crosstalk: the pathways activated by one stressor help the body deal not only with that stressor but with the stress of normal metabolism, normal immune function, and aging.

She names the concept hormesis — a little bit of stressful challenge that activates stress response pathways in a way that is a net positive — and lists possible downstream responses: a profound antioxidant, anti-inflammatory response, the production of more stem cells that help regenerate cells within tissues, and autophagy, a process that can clear away the gunk inside cells, including pieces of DNA and protein aggregates.

This is a little bit of stressful challenge that activates these stress response pathways in a beneficial way that is a net positive

Heat shock proteins are the concrete example. Their name suggests heat, and heat does activate them very robustly, yet Patrick notes that eating broccoli sprouts, which are high in sulforaphane, also activates them. She describes sulforaphane as a hormetic compound — or, in David Sinclair's term, a xenohormetic compound — that activates heat shock proteins and also Nrf2, a powerful detoxification pathway involved in handling carcinogens; heat activates Nrf2 as well.

The overlap is the point: cold also activates heat shock proteins, though heat does so more robustly than cold. Patrick offers this crosstalk as the foundation for resolving Huberman's conundrum.

Huberman draws a parallel from the nervous system: biological systems work with a small kit of generic neurochemicals — there is not a separate dopamine for Netflix, relationships, and work — so it is their job to take a diverse range of inputs, even unknown future ones, and he expects that novel technologies and other stressors to come will tap into the very same pathways.

Huberman sets aside the online debate between pure carnivore diet types, who say plants are trying to kill us, and plant-based-diet folks focused on the planet, animals, and perhaps us. Instead he raises a hypothesis: plants have compounds that are bad for us, but consuming them in small amounts might create a hormesis-type scenario, so that, like too much heat or cold (which can kill us and kill neurons) appropriately dosed as an intermittent challenge they can be good for us. He calls them a very sharp blade to be used potently and asks whether Patrick thinks of them as good or bad for us.

They're a very sharp blade and we want to use them potently.

Patrick's answer is that making these compounds toxic is almost impossible: their bioavailability in plants is attached to a food matrix, unlike taking them in supplement form. She allows exceptions — a group in Africa eating nothing but cabbage, where a goitrogen in cabbage combined with iodine deficiency produces goiter, and hemlock, which will kill you — but insists that you are not going to get poisoned from eating your serving of broccoli at dinner, that it depends on the plant, and that such generalizations are not useful, even though the blogosphere gravitates toward them because they are easier and a lot more sensational.

These generalizations, they're just not useful.

The exchange turns to diet labels. Both describe themselves as omnivores, and Huberman speculates that 99 percent of people on the planet are probably omnivores and that he doubts the number falls below 98. On carnivore diets, Patrick says the current evidence is largely anecdotal — a starting point, but people change a thousand things at once and do not realize it — so we do not really know long-term what carnivore diets are going to do; they may be beneficial short-term, may be beneficial for reasons of elimination of other things, and she closes by allowing that there are lots of possibilities.

we don't really know long-term what carnivore diets are going to do

Patrick's preferred example is sulforaphane, which she calls a very powerful activator of the Nrf2 pathway. Nrf2 regulates many genes, including genes related to glutathione production and genes involved in detoxifying compounds we are exposed to from food, like heterocyclic amines.

She cites GWA (genome-wide associated) studies: people have a variety of versions of genes, and those without a version that detoxifies heterocyclic amines well are very prone to colon cancer and increased cancer risk, but eating a lot of broccoli and cruciferous vegetables negates that risk, because the sulforaphane activates glutathione transferase and synthase genes.

Glutathione is described as a major antioxidant in the brain, the vascular system, and the body basically. Patrick points to broccoli sprouts — which have up to a hundred times more sulforaphane than broccoli — as activating glutathione in the brain, and stresses that there is human evidence of that, which Huberman echoes as amazing.

A practical thread follows about preparation. Huberman confesses that eating raw broccoli is aversive to him, and asks whether the nutrients survive cooking. Patrick explains that sulforaphane is formed from glucoraphanin by the enzyme myrosinase, which is heat sensitive, so cooking somewhat lowers sulforaphane levels. She reports a study from a few years back in which adding one gram of ground mustard seed powder — which also contains the myrosinase enzyme — to cooked broccoli increased the sulforaphane fourfold.

Her own practice is to lightly steam broccoli, add a little Kerrygold butter, and sprinkle mustard seed powder on top; she notes it has a little kick or spice, and that if you do not taste that kick, it is expired.

On supplementation, Patrick admits she had shifted to sulforaphane supplementation and had been terrible about it for the past six months or so. She introduces moringa, which Dr. Jed Fahey — described as really the expert on sulforaphane and a friend who has been on the podcast a couple of times — thinks of as a cousin that activates the Nrf2 pathway similarly to sulforaphane. She buys Kuli Kuli moringa powder, states she has no affiliation with the brand, notes that Fahey has researched that specific brand so it is science-backed in terms of actually containing moringa and activating Nrf2, and adds a big heaping tablespoon to her smoothies.

The rationale she gives is wide-ranging: glutathione in the brain and plasma, DNA damage lowered in people and white blood cells, and several studies in China, where there is a lot of air pollution. She explains Nrf2 as a transcription factor that binds to specific sequences in a variety of genes, turning them on or in some cases off, regulating detoxifying pathways — including ones for airborne carcinogens like benzene, found in air pollution and cigarette smoke.

She reports that this has been repeated in more than one study: literally after 24 hours of taking broccoli sprouts extract (the sprouts, not the seed), people started excreting like 60 percent benzene and acrolein in their urine, something also gotten in cooked food. She explicitly says she cannot remember off the top of her head what the dose of sulforaphane from broccoli sprouts extract was.

Huberman's takeaway is that plants have compounds that are good for us — not merely stressing us but activating reparative pathways — and Patrick adds that our bodies were supposed to be getting that stress, that this is conserved among different animals, and that in the modern world we have the conundrum of never activating these stress response pathways that we are supposed to activate.

we're never activating these stress response pathways that we're supposed to activate

Huberman extends the parallel to dopamine: there is nothing wrong with dopamine, the problem is high levels released without the need for effort — a line of cocaine giving a ton of dopamine with no effort versus working for four years or more to get a degree — and he reads hormesis as a case of what does not kill us makes us stronger, with intermittent challenge rewarded by reparative compounds.

Hormesis really is, it seems, a case of what doesn't kill us makes us stronger.

Patrick adds an animal-study example: preconditioning with sulforaphane and then exposing animals to hypoxia or some kind of induced ischemic stroke condition primes their stress response pathways, so outcomes are so much better than in animals that did not get the sulforaphane 48 hours before. She says this has been shown in multiple animal studies with sulforaphane, specifically in the brain, and mentions Dr. Mark Mattson, often thought of as the intermittent fasting king but a neuroscientist who published some work and talks about sulforaphane as well.

Huberman editorializes that 90 percent or more of traumatic brain injury is construction work and at-home accidents, that football players, hockey players, and martial artists are a tiny fraction of people who have TBI and concussion of various kinds, and that within those communities 75 percent or more experience them. He says it has been a tough question because we really do not have anything for people asking what to do about a concussion, beyond telling them to sleep well, eat well, and exercise.

Patrick calls TBI terrible but interesting as literal real-time brain aging that can be accelerated and understood, and sees so much overlap with Alzheimer's disease, dementia, and these neurodegenerative diseases. She says there has been some animal research with TBI and sulforaphane, mostly preconditioning rather than treatment.

On where protection might apply, she says Nrf2 is pretty ubiquitously expressed — lungs, plasma cells, liver, and neurons — and that there are many animal studies, though she tries to gravitate toward human ones because they are a lot more relevant. Her concrete human figure is that DNA damage was 24 or 34 percent lower in human blood cells after broccoli sprout powder supplementation, from a 2016 video she made whose exact amounts she cannot remember.

She also notes it has been shown in randomized controlled trials to help treat autism and autistic symptoms, and thinks it does have something to do with oxidative stress and glutathione, which would be relevant for TBI treatment — but is explicit that it has not been shown empirically to help with that treatment, that someone could do that study and she thinks it should be done as low hanging fruit, and that there is at least one preliminary study that glutathione is increased in the brain after humans take sulforaphane. Huberman calls the brain point very reassuring because a number of supplement compounds do not cross the blood-brain barrier or get metabolized so that what is listed on the bottle almost becomes irrelevant for what cells actually experience.

It hasn't been shown empirically that that helps with treatment

Asked for her top-tier nutrients for the brain and body, Patrick names the marine omega-3 fatty acids found in fish, cold water fish, and fatty fish. She lists three fatty acids: ALA (short for alpha-linolenic acid) from a plant source, eicosapentaenoic acid or EPA, and docosahexaenoic acid or DHA.

The krill-oil versus fish-oil supplement question draws a chemical distinction. Krill is mostly a source of DHA and EPA in phospholipid form — a phosphatidylcholine omega-3 fatty acid — whereas a high-quality fish oil supplement is in triglyceride form, with a glycerol backbone and three attached fatty acids. Lower-quality fish oil is in ethyl ester form, produced when purification runs the oil through a column and cleaves fatty acids off the glycerol backbone, after which it is easier and cheaper not to re-esterify; it is not as bioavailable, and if you do not take it with food you are not going to absorb much of it at all. Higher-end brands will market the triglyceride form, while ethyl ester is described as not bad, just something to take with food.