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Nick Norwitz

@nicknorwitz

Jan 6

🚨GLP-1: “It’s Not That Simple”💉

1/4) There are many strong, often dogmatic, opinions on GLP-1 receptor agonists. One interesting, and under-appreciated, fact is that GLP-1 aren’t "just" weight loss drugs.

They have complex metabolic effects, including reducing whole body inflammation by acting on the brain, partly in a weight-loss independent manner.

GLP-1 receptor agonists, and related medications, can help people but can also be misused at a societal level.

Let me elaborate (link 🔗 at the end)...
#GLP1 #inflammation

2/4) In their best use case, the metabolic actions of GLP-1 can catalyze lifestyle change. For example, reducing “food noise” permits patients to make healthier choices when set in a modern food environment that is itself obese with UPFs, sugar and temptation.

3/4) However, at a societal level, we should be cautious not to forget that the root cause obesity is metabolic dysfunction caused by an unhealthy lifestyle.

Thus, the core solution is lifestyle, and it’s unlikely we will “pharma” our way out of the obesity epidemic. However…

I am NOT saying “people should just live healthier.” Rather, I am saying that – as a society – we should push for a reevaluation of social norms around food and reconstruction of the food environment.

This can be in parallel to innovations in pharmacotherapy, deployed in the “right” patients. The determination of who those people are is not a matter for public discourse, it’s a private matter between physician and patient.

So, for our part, we should keep pushing for a change in the food environment, dysfunctional norms, and help people live a metabolically healthy lifestyle.

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Nick Norwitz

@nicknorwitz

Jan 4

🧬💥What if I told you that social stress doesn’t just mess with your head—it damages your DNA and biologically ages you? (link at the end)

🧵1/9) That’s not hyperbole; it’s hard science from new data published in @NatureAging

If you’re like me—juggling a life full of psychological stress—you might be wondering: How can I fight back?

Let’s break down the data...

(I'll tease: this thread also includes a little honest opinionated "revealer" about @hubermanlab)

2/9) Background on Aging (Senescence and p16)

Aging is complex, and there’s no one easy way to measure biological age.

However, certain hallmarks of aging—like DNA damage, telomere shortening, and cellular senescence—are widely recognized.

“Senescence,” the process by which cells age and stop dividing, accumulates as we age and plays a role in chronic diseases like heart disease and Alzheimer’s.

While senescence has some adaptive functions, for our purposes, it’s fair to call it a hallmark of aging.

Senescence can be triggered by inflammation and DNA damage.

👉And senescence can be measured by markers, like “p16”. (If you want to remember this, just imagine the stress of having a pissed off 16 year old kid.)

3/9) Social Stress Increases Marker of Senescence

In this study the researchers subjected mice to chronic social stress or, more specifically, “chronic subordination stress”: The experimental mouse is exposed to an aggressive dominant mouse daily.

The human equivalent would be like a bully at school, an abusive parent, or a hyper-aggressive boss.

In just 4 weeks, the experimental mouse (the one that got bullied) exhibited increases in markers of senescence, predominantly p16.

And this marker of senescence and aging accumulated over time, with levels as high as 12X that of control mice by 26 months of age in circulating blood cells.

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Nick Norwitz

@nicknorwitz

Jan 2

Unexpected Benefits of Compound Found in Olives on Muscles 🫒💪(link at the end)

1/9) High Level: These new data show how a specific compound found in part of the olive plant can improve muscle performance in the short term, and potentially fight off age-related muscle loss.

I’m going to first break down the data, and then tell you how to use it for maximal muscle benefit

#Exercise #Muscle #healthyaging

2/9 But first, I’m going to need to review with you a bit about how muscles work at the molecular level.

PLEASE bear with me here, because it will be fundamental to our discussion of the data – as well as your general understanding of how muscles work.

Inside muscles, there are long filamentous overlapping proteins called "actin" and "myosin." The myosin has these little heads that branch off and grab on to actin.

When a nerve impulse hits a muscle, it causes a release of calcium inside the cell, and this allows myosin to walk along actin, pulling them together and increasing the overlap between actin and myosin, which translates to shortening of the muscle – a muscle flex.

That, in effect, is a muscle contraction.

💪🧀Now, here’s something important: this process is highly dependent on calcium.

It’s calcium that allows the actin and myosin to interact. And its calcium that also signals to the mitochondria to meet the energy demands of a muscular contraction.

🏎️Analogy: Calcium is to muscle as a responsible driver of is to a car. Calcium presses the gas pedal (signals muscle contraction) and fuels the tank to keep the engines (mitochondria) running.

3/9 Okay, now let’s introduce 1 of 3 key players: the mitochondrial calcium uniporter (MCU).

MCU is what transports calcium into mitochondria, and thus enables signaling to mitochondria to boost energy production.

(We will explain how it does so momentarily.)

And the MCU is partnered with another protein, our 2nd player, MCU regulator 1 (or MCUR1), which is MCU’s essential sidekick: Like Batman and Robin.

MCU and MCUR1 work together to let calcium into mitochondria, and this is essential for energy production.

Read 9 tweets

Nick Norwitz

@nicknorwitz

Dec 31, 2024

Is Big Sugar Scared? 🤔🧵

1/5) Unfortunately, some of my "anti-processed food" & "anti-sugar" content is being shadow banned on other platforms.

In this 9 min video, I discuss data around Food Dyes; Comment on the state of Safety Testing; And Ultimately point the Finger at the Elephant in the Room: Sugar 🍩

Have a listen and tell me if I'm being reasonable. Then read on...

cc @QuitSugarSummit (see 4/5) @KenDBerryMD @RobertLustigMD @DominicDAgosti2

2/5) We're living in an interesting time where there are dual revolutions happening

On the one hand, a pocket of the population is waking up to the fact that our food system and social norms are both dysfunctional and harmful. “Toxic” is a strong, but accurate descriptor.

People are making individual changes to optimize their metabolic health in the context of a broken food environment, and this will is spreading like a mind virus… a good one.

And, on the other hand, GLP-1s are changing the obesity medicine/pharma game. This isn't just a "eat less" phenomenon, but also an "eat different" phenomenon whereby these medications may be used to selectively decrease desire for Ultra Processed Foods.

I know this is controversial, but credit where it’s due. There are optimistic and pessimistic ways to paint this picture. But if we infuse medical innovations with this rising will to optimize true metabolic health, there may be more synergy here than we realize. (More on this soon, and for more on recent news on GLP-1s, see):

Newsletter: GLP-1 beyond Obesity: staycuriousmetabolism.substack.com/p/glp-1s-the-w…

3/5) For my part, I’m all in about Making Metabolic Health Mainstream.

In 2025, we will be working on several “campaign,” including bringing metabolic health education to pre-medical student, providing doctors with CME-accredited content covering the latest metabolic health data, and scaling up my personal education and advocacy efforts as I emerge from an 11-year marathon through undergrad + an MD PhD (Yikes! Lots of school) with the autonomy and intellectual freedom to fight for the world’s metabolic health with a whole new level of vigor and ferocity.

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Nick Norwitz

@nicknorwitz

Dec 26, 2024

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

Read 6 tweets

Nick Norwitz

@nicknorwitz

Dec 22, 2024

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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