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Nick Norwitz

@nicknorwitz

Dec 26

GLP-1s: The Weight Loss Drug That’s NOT Just About Weight 🧵

1/6) One year ago, I thought if I said “GLP-1” your average non-medical person would have no idea what’s I’m talking about. Oh, how that’s changed.

This family of weight loss drug has taken the #obesity and #metabolism world by storm, with mixed opinions.

🤲Some people think they’re God’s Gift to Modern Medicine, a secular scientific miracle.

🤔Others are skeptical, given the history of weight loss drugs in medicine is riddled with missteps.

What if GLP-1 receptor agonists are not only weight loss drugs?

2/6) GLP-1, Beyond Weight Loss: Inflammation 🔥

A recent review article published in @ScienceMagazine discussed the many applications of GLP-1 medications, including cardiovascular disease, liver disease, mental health and neurological disorders, and so on.

It makes the point that the benefits of GLP-1s are not just related to weight loss but also that a “potentially unifying mechanism of action for GLP-1R agonism is the reduction of inflammation.”

This led me to another paper, published in @Cell_Metabolism, where they showed that the action of GLP-1 on the brain causes a decrease in inflammation in the body...

(references are nested in the link at the end, ht/ @DanielJDrucker, author on both manuscripts)

3/6) 🚨This suggests that it’s the action of GLP-1 on the brain that mediates the systemic, whole body anti-inflammatory effects of GLP-1 drugs 👇

In this study, they treated mice with a substance that causes inflammation, Lipopolysaccharide (LPS), which can be measured as increases in an inflammatory signaling molecule, TNF-α.

They also treated some mice with GLP-1 receptor agonists and observed this reduced inflammation in the mice. But then… they did something else.

They did the same experiment, treating mice with the inflammatory substance (LPS) and trying to dampen the inflammation with a GLP-1 receptor agonist, BUT in mice missing the receptor for GLP-1 in various tissues and organs…

🫀Deleting GLP-1 Receptor in Bloods Cells and Blood Vessels (A): In one experiment, they deleted the GLP-1 receptor from various blood cells and cells that line blood vessels. Interestingly, GLP-1 receptor agonism COULD still reduce inflammation in these mice (note in blue, how the GLP-1 drug, Exendin-4, decreases TNF-α relative to vehicle control).

🧠Deleting GLP-1 Receptor in the Brain (C): In another experiment, they deleted the GLP-1 receptor from the brain. In these mice, GLP-1 COULD NOT reduce inflammation in these mice. (note in purple, how the GLP-1 drug, Exendin-4, did not decrease TNF-α relative to vehicle control).

And they even verified this was the case in another mouse model lacking GLP-1 receptors in the brain.

🚨Takeaway: This suggests that it’s the action of GLP-1 on the brain that mediates the systemic, whole body anti-inflammatory effects of GLP-1 drugs

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Nick Norwitz

@nicknorwitz

Dec 22

New research in @Nature has identified a bile acid called Lithocholic Acid (LCA) that could be the missing link between caloric restriction and improvements in lifespan and health span. (Link at end 🔗)

🤔1/6) Brief Background
For background, caloric restriction has been shown repeatedly in lower organisms, like fruit flies and worms to extend lifespan.

In mammals, the effects tend to be smaller in terms of lifespan; however, can still be sizable with respect to healthspan, which one could argue is at least equally important.

But the cascade of mechanisms linking caloric restriction to lifespan and healthspan has remained murky.

🚨And we need to consider serious tradeoffs in humans...

In particular, low-calorie diets can lead to muscle loss and frailty, which is a serious problem.

We will hit on that below, with some very exciting muscle-centric findings.

#Longevity #Muscle #GLP1 #IntermittentFasting cc @bryan_johnson @agingdoc1

2/6) Finding Lithocholic acid (LCA)

To identify "longevity" and "healthspan" biomolecules, the researchers subjected mice to calorie-restricted diets for 4 months and looked in their blood for metabolites that stood out as distinct from control mice and could be transferred to control mice to replicate the health benefits of calorie-restriction.

One stood out, a bile acid called Lithocholic acid (LCA).

LCA is a secondary bile acid made by gut bacteria in both mice and humans, and has similar concentrations in both mice in humans.

(Nuance Note: Since bile acid metabolism in mice and humans does have differences, the researchers generated “bile acid humanized mice” that more closely replicated the bile acid profile of humans, and LCA concentrations remained similar between the squeakers and naked big-brained apes. That’s a way of building a case towards the ultimate findings having relevance in humans. But more on that momentarily.)

3/6) They then went on to see what benefits feeding LCA directly to mice has on their physiology, and found that LCA:

🩸lowered blood glucose
🩸increased GLP-1 levels
💪improved various aspects of muscle performance
💪increased the number of oxidative fibers
💪improved grip strength
💪increased running distance
💪increased mitochondrial content
💪increased muscle regeneration after damage by activating muscle stem cells

The benefits on muscle are notable, particularly because normal caloric restriction can lead to muscle wasting, as can GLP-1 receptor agonists for that matter.

But LCA appears to benefit muscles, meaning the benefits of caloric restriction without one major potential downside.

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Nick Norwitz

@nicknorwitz

Dec 20

1/6) 🔥Seed Oils and Science👀: What the Media Gets Wrong (and Right) (Sound On🔊)

I bit the bullet and decided to provide my 2 cents on the Controversial Topic of Seed Oils. Here are some things you should know…

“Seed Oils” is a term often poorly defined, leading to confusion. While they’re characterized by high Omega-6/PUFA content, the omega-6 & PUFA are not themselves per se “bad” as some may have you believe

TLDR: Overheated, oxidized soybean oil should not be “lumped” with minimally processed whole foods rich in omega-6, like walnuts or sesame. (Continue…) 👇

#metabolichealth #seedoil #omega6 #PUFA #staycurious

2/6) That said, it’s possible to have an imbalance of Omega-6/3 in the body, which can itself lead to inflammation 🔥

Insofar as diet contributes to the Omega-6/3 imbalance, and the fact that the Western dietary environment is overflowing with Omega-6, it’s reasonable to be “mindful” of one’s intake.

But this does not mean “fearing” any food rich in Omega-6, as if it were spiked with high potency poison ☠️... Importantly, there are non-direct determinants of omega-6/3 ratio – other than direct omega-6 and omega-3 intake.

Remember “you are what you eat?”

🗑️Trash that heuristic. It does more harm than good.

🧈And just as eating butter doesn’t directly translate into increased saturated fat in the blood (hello, de novo lipogenesis!), eating a given ratio of omega-6 to omega-3 doesn’t necessarily translate into your body’s omega-6/3 ratio.

FWIW, I happily consume some higher omega-6 foods, and boast a 1:1 omega-6/3 ratio, with 17.2% EPA/DHA index (see 5/6 for what I do personally)

3/6) Building on the prior point, Metabolic Context Matters

🥓🍳As an example, for those who eat a ketogenic diet, omega-6 are very efficiently burned and/or converted into ketone bodies, leaving less for structural purposes.

(I’ll caveat that this is based on physiologically informed extrapolations – rather than randomized controlled data – but I’d bet my liver on the matter.)

Furthermore, particular foods can contain compounds that protect omega-6 from oxidation. Sesame is a prime example, containing lignan antioxidants that massively reduce omega-6 oxidation.

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Nick Norwitz

@nicknorwitz

Dec 17

👩‍🦲Intermittent Fasting Impairs Hair Growth - What To Do About It👩‍🦲

1/9 New research published in @CellCellPress has me scratching my beard… while I have it.

I’m going to break down the data and convince you why this all makes sense and reveal what you can do to stop fasting-induced hair loss.

👩‍🦱Background👩‍🦱
First, it’s important to understand a bit about the biology of hair growth.

In the skin, the hair follicles undergo cyclic phases of growth (anagen), regression (catagen), and rest (telogen) to produce new hairs. This is driven by the cyclic activation of hair follicle stem cells (HFSCs).

The stem cells reside in a “niche,” which is like a metabolic pocket within the body.

“Niches,” be they in the skin, gut or elsewhere, are critical because they allow for the integration of whole body (systemic) and local signaling to generate outcomes that are adaptive for the whole organism given a particular state or environmental stressor, like fasting.

2/9) The New Research

The researches began in mice, applying common intermittent fasting routines (16-8 time-restricted feeding [TRF] and alternate day fasting [ADF]), and found that each impaired hair follicle regeneration and slowed hair regrowth.

Shown is Figure 1B. Mice were shaved and their hair left to regrow. Time-restricted feeding (TRF) and alternate day fasting (ADF) clearly slowed hair regrowth.

3/9) Additionally, markers of programmed cell death (apoptosis) increased among the hair follicle stem cells (HFSCs) when the animals were subjected to fasting.

Shown is Figure 2C. The HFSC stained in red for a marker of apoptosis (active caspase-3). In other words, more red = more programmed cell death of the hair follicle stem cells, as quantified to the right.

Furthermore, there was a dose-response effect whereby longer fasts had a worse effect on hair growth.

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Nick Norwitz

@nicknorwitz

Dec 16

Does Dark Chocolate Prevent Diabetes? 🍫🩸

1/5) 🧵A new study in BMJ claimed 5+ servings/week of dark chocolate reduced T2D risk by 21%. Let’s break it down...

🍫The Study🍫
This was a large-scale observational study where they looked at associations between chocolate intake and the development of T2D over three cohorts:
👉Nurses’ Health Study (NHS)
👉Nurses’ Health Study II (NHSII)
👉Health Professionals Follow-up Study (HPFS).

A total of 111,654 participants were included where they looked at association between types of chocolate (dark and milk) versus T2D.

The main reported findings were as follows:

(1) “Participants who consumed ≥5 servings/week of dark chocolate [but not milk chocolate] showed a 21% lower risk of T2D

(2) Intake of milk, but not dark, chocolate was positively associated with weight gain.

2/5) Major Healthy User Bias Confounding

Unfortunately, there was a clear signal of healthy user bias in the study.

You can see that there is a consistent and mostly dose-dependent trend towards those who ate more dark chocolate exhibiting
👉more physical activity (red)
👉more multivitamin use (blue)
👉higher overall diet quality score (purple)
👉lower BMI (pink)

Conversely, for high milk chocolate users had suggestions of less healthy living, including higher smoking rate and lower diet quality score.

Furthermore, in a subgroup analysis, there also found no association between dark chocolate consumption and T2D risk among individuals with a lower quality diet, consistent with the idea that confounders (the healthy user bias we mentioned) were carrying the lion’s share of the reported effect.

And, of note, the authors wrote, “we cannot entirely rule out the role of confounding in our observed associations… residual or unmeasured confounding, or both, may still exist.”

3/5) Internal Inconsistencies Among the Cohorts

Another big red flag is that there was massive heterogeneity among the studies.

In fact, they were primarily driven by one of the three, with a supposed 51% reduced risk of T2D in heavy chocolate users in the Health Professionals Follow-up Study (HPFS), which I think it quite an absurd value, and one with a giant confidence interval at that (8% to 74%), and no association noted in the Nurses’ Health Study (NHS).

The paper reads, “In NHS, neither total nor subtypes of chocolate consumption were statistically significantly associated with risk of T2D.”

If this was a biological phenomenon based on reliable data, one would expect the data to be more consistent. Instead, the data appear as noisy as an attention-hungry elephant with a bullhorn.

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Nick Norwitz

@nicknorwitz

Dec 13

🚨Is Red Light an Essential Nutrient? - Illuminating The Science

In Today’s Breakdown Video (links at the end), I make the case the answer is “Yes.”

👉Here are a couple highlights:

1/4) Mitochondria are red/infrared light receptors. Mitochondria make energy using the “electron transport chain.”

And within this chain complex IV (cytochrome C oxidase) is particularly sensitive to red light.

When complex IV is struck by the right wavelengths and “charged” (so to speak), it can increase the gradient of protons across the inner membrane, generating more stored energy to spin the ATP rotor and make ⚡️ATP⚡️, the energy currency of the cell.

(see clip, sound on)

2/4) Now, if you can “super charge” energy production in this way, and it’s biologically relevant, you might expect to see functional results. Indeed, you do!

For example, in this human double blinded, randomized control, trial, red light therapy (low laser light therapy, LLLT) pretreatment before an exercise test on a treadmill increased endurance (time to exhaustion) and VO2max significantly 🏃‍♂️💪

(references in video notes, at end)

3/4) While the RCT mentioned in (2/4) is interesting, a key question remains, just how important is light (and red light), clinically? 🤔

And what are the best settings, exposures and protocols to get the results we want?

In fact, the objective of today’s post and video is not to make the case that “we know” X light protocol has Y outcome, but rather to make the case that the light-metabolism connection is “understudied and underappreciated.”

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