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Nick Norwitz

@nicknorwitz

Apr 3

Why do some people with crazy high LDL-C and ApoB develop no plaque in their arteries, while others – including those with far lower LDL and lower ApoB – do develop plaque? 🫀🤔(link 🔗 at the end) 🧵...

1/6) We know this is a phenomenon. So, let’s tackle one possible explanation centered around the following term: Transcytosis...

#LDL #ApoB #LMHR #LEM #Cholesterol #HeartHealth #CholesterolCode cc @realDaveFeldman @AdrianSotoMota

2/6) Transcytosis, Made Simple🫀🤔
Your arteries are lined by cells called endothelial cells. Endo- means within, as these cells are within the tube that composes your blood vessels. A coronary plaque grows when cholesterol-containing particles, including LDL particles, slip through the endothelial barrier and begin to seed a plaque.

But HOW do cholesterol-containing particles penetrate the endothelial barrier? It’s not like a healthy endothelial barrier is coarse chicken wire. It’s rather tightly knit.
That’s where “transcytosis” comes into the picture.

Transcytosis is the process whereby a cell – in this case, the endothelial cells lining your arteries – sucks up something from outside (here, an LDL particle containing cholesterol), passes that something through its interior, and then out the other side.

By way of analogy, think of your artery wall like an exclusive nightclub. Some particles get waved in VIP-style. Others get stuck outside. But what if LDL wasn’t just passively slipping through a hole in the wall, but was actually being escorted through by a bouncer? That is - more or less - transcytosis.

3/6) Your Coronary Epiphany! 🫀💡
Now, given this perspective, you may have just made a connection or had a coronary epiphany!
People often talk about the process of plaque development in a manner that suggests the more cholesterol-containing particles you have in the blood, the more that end up getting inside your artery wall and getting trapped there – in a rather linear fashion.

Let me be clear, this idea that more cholesterol containing particles in your blood automatically equals more flow of these particles into your artery walls (and more coronary artery disease) is a MASSIVE ASSUMPTION and likely incorrect, or at least incomplete.

Instead, transcytosis is an active, regulated process...

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Nick Norwitz

@nicknorwitz

Mar 29

🧠Saffron for Depression: The Science, the Studies, and the Recipes🧠

1/5) What if I told you that the kitchen spice – Saffron – could treat depression?

It may sound too good to be true, but that claim is supported by a growing pile of human randomized controlled trials (RCTs) and sensible biological mechanisms.

I’m going to share two of these studies, explain the neuroscience, and direct you to more learning.

This golden spice really might be the next big thing in mental health!

References are in the newsletter linked at the end. #saffron #depression #mentalhealth

2/5) Saffron vs SSRI (RCT)
This double-blind randomized controlled trial compared 6 weeks of saffron supplementation (30mg/d) vs Prozac (fluoxetine), a commonly prescribed selective serotonin reuptake inhibitor (SSRI).

Impressively, the saffron performed equal to the fluoxetine!

You can see the results over 6 weeks here, with the Hamilton Rating Scale for Depression dropping in lock step between the treatments.

The absolute decrease in both treatments was >12. What does that number mean?

Well, in clinical trials, there’s a key distinction between a “statistically significant” difference and a “clinically significant” difference. A “statistically significant” difference means there was a detectable numeric difference, as in over time or between groups. Conversely, a “clinically significant” difference means that size of the change was detectable and meaningful for the patient.

Now while it’s somewhat arbitrary, a clinically meaningful change in this depression scale is ~5 points, which means a ~12-point drop is impressive and is clinically substantial!

Note on Side Effects: One presumed advantage of saffron is that it could have fewer side effects than prescription medications. In this first small pilot trial, there is an apparent trend to lower side effects in the saffron group vs SSRI. To see that table, click on the link at the end of this thread.

3/5) Saffron for Mental Health - Meta-Analysis
Rather than working through another 20+ studies, I want to share with you excerpts from a meta-analysis of 23 RCTs conducted on saffron for mental health, including depression and anxiety:
👉 [M] eta-analysis found a significant and large positive effect size for saffron reducing symptoms of depression in comparison with placebo.
👉When compared with antidepressants medications, there was no significant difference between saffron and medications.
👉Meta-analysis of studies that investigated the effect of saffron as an adjunct to pharmacotherapy reported a large significant benefit from saffron supplementation.

In simpler terms:
👉Saffron’s effect alone with large and positive for mental health
👉Saffron performed as well as commonly prescribed medications
👉Saffron provided additional benefit when stacked on prescription medications

Effects on anxiety were similar.

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Nick Norwitz

@nicknorwitz

Mar 28

Cold Exposure❄️, Omega-6 & Omega-3 🐟. Fats-cinating Research! Let’s dive in! (link at end)

1/5) In this study, 64 adults endured 2 hours of cold exposure near their shivering threshold.

🤔Results🤔

Massive changes in signaling lipids, including omega-6 and omega-3 fats and their derivatives, endocannabinoids and specific pro-resolving mediators.

On net, the changes reflected a signature of improved cardiometabolic health 🫀❤️‍🔥 #coldplunge #hearthealth

2/5) 🥶Some specific Omega-6 and 3 Changes🥶

👉39% Increase in the omega-6 oxylipin 12,13-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME). This oxylipin has been shown to increase the uptake of
fatty acids by brown fat and skeletal muscle.

🔥But even more impressive than the omega-6 response was the omega-3 response...

👉17 out of 17 omega-3 fats and their derivatives increased in the blood after cold exposure, by an average of 77%

👉The most prominent change, with an increase of 155%, was in 14- hydroxy-docosahexaenoic acid (14-HDoHE), which has been shown to inhibit activation of platelets involved in blood clots, increase blood flow, and inhibit inflammation.

👉And increases were noted in Resolvin D5, a powerful anti-inflammatory compound that inhibits the production of inflammatory molecules, like IL-6, reduces pain and protects various organs from inflammatory challenges.

3/5) And there were changes in endocannabinoids!🪴

There was an increase in anandamide, which binds the CB1 receptor – a key receptor involved in the effects of THC.

So, I’ll let you put 2+2 together on that... I’m not saying that a cold plunge will make you ‘high’ per se, but it’s an interesting mechanistic overlap… and one that overlaps with people’s experiences.

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Nick Norwitz

@nicknorwitz

Mar 22

☕️Coffee for Gut Health?! 🦠 New Research will have you Express-O-ing excitement!

This thread will reveal what new research in Nature Microbiology has discovered, tell you how much coffee to drink to get the health benefits, compare caffeinated vs. decaf, and more. I hope you’ve had a cup or two because you’ll need focus for this. (🔗link at the end)

1/8) Quick Background on the Health Benefits of Coffee

First, coffee intake has already been associated with lower mortality, reduced cardiovascular disease-related death, and a lower risk of type 2 diabetes. But nutritional epidemiology—the study of diet and health outcomes in large populations—has its limitations because it can only look for correlations.

To solidify coffee’s health halo, what we want is a complementary biological mechanism, a physiological story that helps it all make sense. #coffee #microbiome

2/8) Coffee Changes the Microbiome: Lawsonibacter asaccharolyticus

So, let’s introduce the protagonist of this story, a gut bacterium named Lawsonibacter asaccharolyticus. (I know, it sounds kind of like a Harry Potter spell.)

To discover the Lawsonibacter asaccharolyticus–coffee link, the researchers took information on food intake, including > 150 specific foods with associated and microbiome samples, then look for connections between specific foods and microbiome signatures.

☕️Among the >150 foods analyzed; coffee stood out for having the clearest microbiome signature.

3/8) For further analyses, they broke participants into three groups:
👉“Never” drinkers: Consumed less than three cups per month
👉“Moderate” drinkers: Consumed more than this but fewer than three cups per day
👉“High” drinkers: Consumed more than three cups per day

The strongest correlation between coffee consumption and the microbiome was Lawsonibacter asaccharolyticus. And—because I know you’re wondering, as I was when reading the paper—this association was independent of caffeine.

So yes, decaf counts!

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Nick Norwitz

@nicknorwitz

Mar 7

Why do we sleep? 😴And what caused “Brain Constipation? 🧠💩 New research in @CellCellPress
(Link at end, w/ exclusive clip from first author 🤓)

1/4) A Key Function of Sleep is to clear metabolic wastes from the brain.

This function is carried out by the “glymphatic system,” a series of channels that expand as blood vessels constrict. Deep non-rapid eye movement (NREM) sleep is prime time for glymphatic systema and brain waste removal. But a key question that has remained unanswered until now is *HOW* is this system regulated?

🧠Norepinephrine Regulates Glymphatic Flow🌊
The researchers find a group of neurons in the brain stem bathes the brain in norepinephrine pulses while we sleep. Norepinephrine is a vasoconstrictor, and these pulses therefore generate waves of blood vessel constriction that enhance glymphatic flow and metabolic waste removal from the brain.

🧠 Brain Constipation?💩
By way of analogy, think about your gastrointestinal system: Your intestines use rhythmic contractions to move waste out. If that process stops—you get constipated. Now imagine your brain has a similar waste-removal system... but instead of food, it’s clearing out toxic metabolic byproducts. If something blocks that process, you get brain constipation.

What causes brain constipation?

* if I do say so, I think this is a video @hubermanlab, cc @IanGMackey @R_Mohr, and @bryan_johnson and @NTFabiano will each enjoy -- ... and if you want more on glymphatics and sleep, let me know
* Don't miss an exclusive clip from the first author of the research in the full video, link at the end.

2/4) The researchers then asked the provocative question: What do certain sleep medications, specifically Zolpidem, do to norepinephrine pulses and glymphatic function?

💩 In brief, they find that the sleep medication impairs the normal oscillations in norepinephrine and decreases glymphatic flow. The implication is that long-term use could contribute to a build-up of metabolic debris in the brain and, possibly, long-term negative consequences like cognitive decline.

Indeed, long-term human studies have linked Zolpidem to higher rates of dementia and Alzheimer’s disease.

Fortunately, this does not appear to be the case for other medications that are often used to help with sleep, like the atypical anti-depressant trazodone. In fact, there are suggestions that this medication might improve sleep architecture and is associated with lower rates of dementia.

3/4) The Good News: With advancements in technology, maybe we will soon be able to enhance glymphatics efficiency and ‘brain cleaning,’ including during sleep and perhaps even during waking hours. In my biomedical fantasy, I could rinse my brain between blocks of work while watching a Marvel Movie, or Harry Potter, Game of Thrones. What a dream!

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Nick Norwitz

@nicknorwitz

Mar 6

1/8) Yesterday @bryan_johnson claimed he's "aging slower than anyone in the world." This is incorrect by his own measurement tool.

But this thread isn't just a fact-check. It's an assessment of the "Pace of Aging Clock," and how I think one should interpret these data.

🔗 to letter and more data at the end🔗
cc @Derek_Fitness @JEverettLearned

2/8) First, what is the DunedInPACE Score?
PACE stands for Pace of Aging Calculated from the Epigenome—and the score is meant to measure the rate of biological change, with a value of 1.0 = 1 year of biological change per calendar year.

As opposed to the other aging clocks, which were developed by comparing people of different ages, DunedinPACE was developed by following a cohort of individuals who were all the same chronological age and measuring changes in biomarkers reflecting the health and integrity of different organ systems (cardiovascular, renal, hepatic, immune, etc.), then normalizing to 1, such that 1.0 indicates 1 year of biological change per 12-month calendar year.

3/8) Bryan Johnson previously boasted a value of to 0.66 as his DunedinPACE rate of aging score, suggesting that he’s biologically aging at ~66% or ab out 2/3rd of the average person. Then, around this past New Year's, he reported a DunedinPACE score of 0.57, a ‘personal best’ according to Bryan, claiming that his birthday is every 21 months (12 / 0.57). Yesterday, he claimed a score of 0.48.

Nuance Note: It’s not clear to me if this is a result of:

1. an actual downward trend in his score reflecting true slowed pace of aging

2. a function of test variability and the fact he just has more measures from which to choose and report

3. if he’s modifying his protocols to ‘optimize’ his metric, but without translation to bona fide slowing of biological age. More on this in a moment…

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