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Nick Norwitz

@nicknorwitz

Jun 29

The Molecule Behind Exercise’s Anti-Aging Effects

*Today's letter (link in 6/6) reviews a new paper in @CellCellPress published 2 days ago. And includes a shoutout to someone special.

💪1/6) Nothing matches the health benefits of exercise. It’s the closest thing we have to a universal prescription for healthy aging.

But have you ever wondered how movement actually slows aging?

Movement isn’t magic. Exercise initiates a complex cascade of biochemical events that lead to adaptations designed to improve whole-body health. By identifying what those adaptations are, we can tap into the systems nature has evolved to optimize our health.

That’s the question the researchers behind today’s study explored. They weren’t trying to replace exercise — but they were curious if they could “bottle up” part of its benefits.

Method: In this study, 13 relatively sedentary men were instructed to exercise by running 5 kilometers — first every other day, then every day — for 25 days. The researchers measured a broad suite of metabolites in their bodies before and after the exercise regimen...

#exercise #healthspan #longevity #staycurious

2/6) Exercise is Good for you (and water is wet). But there’s more…

Exercise decreased markers of inflammation, including hsCRP and TNF-alpha, and increased so-called geroprotective(anti-aging) antioxidant proteins and pathways like Nrf2, SOD1, and Glutathione. These proteins and pathways help defend your body from oxidative stress — basically, the wear and tear that contributes to aging.

So, exercise is good for aging. No duh, right?!

But then the researchers dug deeper...

They wanted to know which metabolites were linked to these anti-inflammatory and geroprotective effects of exercise.

One molecule stood out — betaine.

3/6) Betaine Fights Aging at the Cellular Level

Betaine was originally discovered in beets — hence the name — and is also known as trimethylglycine. While betaine is easier to say, tri-methyl-glycine tells you exactly what it is: the amino acid glycine with three (tri) methyl groups attached to it. Fancy that — terminology that actually makes sense!

Betaine can be consumed through the diet as from beets (114-297 mg/100g) or spinach (600-645 mg/100g) or can be produced by the body. It plays a key role in metabolic pathways as a methyl donor and is generally thought to support cardiovascular health and physical performance.

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Nick Norwitz

@nicknorwitz

Jun 24

Untangling the Seed Oil Debate: ⚠️WARNING ⚠️Don’t Read If You Like Your Echo-Chamber
(🔗 at the end)

1/11) One of the most heated and fascinating debates in the nutrition space right now is that of “seed oils.”

It’s one of the keystone issues for the “Make America Healthy Again” #MAHA movement.

Robert F. Kennedy Jr., who calls the seed oils in which fast food chains now cook their French fries, “one of the most unhealthy ingredients we have in foods.”

This has led to a counterculture movement to replace industrialized plant-sourced fats, i.e., “seed oils,” with animal fats. There are cries to “Bring Back the Tallow Fries” to fast food chains like McDonald’s—the dietary version of “Make Fries Great Again.”

Up-front Acknowledgement

I spoke with several others composing this letter, including @drmarkhyman @paulsaladinomd @Physionic_PhD. Each provided references, input and/or feedback that was included in this letter in some form, and I look forward to ongoing conversations with each about this particularly controversial topic.

In fact, I’m releasing this letter now, rather than late July as originally planned, because I have a conversation planned with one of these men next week and thought community feedback would be ‘interesting’ fodder for our discussion.

The letter, should you choose to read it, may end up being a living document…

2/11) Restaurant chains are responding, literally “RFK’ing the fries,” meaning trading the seed oils for tallow for presumed health benefits.

But this isn’t really an issue or video about French fries. It’s about something much larger and more important.
It’s about how we dissect conflicting data in nutrition.

The reason there is such profound confusion on the topics of animal vs. plant fats and “seed oils” is because different sources of evidence make opposing arguments, and each side thinks their argument is best.

Rather than try to resolve the inconsistencies, we dismiss and bicker.

But in today’s letter, we try to dig into the details with data (nor dogma). This one is intense, but I hope you find it valuable.

3/11) Let’s start with a roadmap.
👉 I want to discuss the physiological rationale for why seed oil fries are presumed to be harmful, and why tallow fries might be better.
👉 Building on this French fry case in point, I want to expand the discussion to the human trial data on omega-6 fats and cardiovascular disease.
👉 Then, we will resolve the apparent contradictions that emerge.
👉 Finally, I’ll close by telling you what I think is practical and reasonable when it comes to handling fries, nuts, cooking fats, and making your food choices healthy (again?).

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Nick Norwitz

@nicknorwitz

Jun 21

Salmon Savvy: The Ultimate Guide to Choosing the Cleanest, Healthiest Fish

1/6) Salmon might wear the health halo, but not all salmon are created equal. Some are top-tier nutrition, and others are … well… toxic might not be an overstatement. Let’s talk fish fraud and how to avoid getting catfished at the seafood counter.

Let’s start with the elephant in the room—or manatee in the pool, as it were: farm-raised vs. wild salmon.

Is wild really better? YES.

The primary reason I always go wild over farm-raised is that farm-raised salmon tend to have much higher levels of chemicals like polychlorinated biphenyls (PCBs), pesticides, and dioxins, which largely derive from their feed and all of which have serious negative consequences on human health.

2/6) To take one of these as a representative example: dioxins, which are byproducts of various industrial processes such as burning waste, smelting metals, and bleaching. Some dioxins, like TCDD, are classified as Group I carcinogens (known to cause cancer in humans).

One study found that when eating farm-raised salmon, it would be easy to exceed the tolerable daily intake (TDI) of dioxins based on thresholds set by the World Health Organization. In some cases, as little as 4 servings of farm-raised salmon per month would push you past the dioxin TDI. By comparison, this analysis found that you could eat wild salmon every day (even twice per day!) and remain within safe levels of dioxin exposure.

What you’re seeing in the graph is the number of meals per month you’d need to eat of farm-raised salmon (white and light blue) or wild salmon (dark blue) to breach the safe intake limit. For farm-raised salmon, you can see only a handful of small servings will push you beyond the safe limit. But for wild salmon, they actually capped the analysis at “a practical consumption rate” of 60 meals/month.

3/6) Now let’s begin to revie some salmon types & terms. Most of the salmon you’ll see is Atlantic salmon, which is mostly farm-raised. These include Faroe Island, Norwegian, and Scottish, named for their geographic origins.

*Faroe Island salmon are often sold at restaurants at a premium price because they tend to be extra fatty and tasty. However, one credit I’ll give Faroe Island salmon is that they are generally raised without antibiotics.

*Norwegian salmon is quite common. About one-fifth of the salmon in the United States comes from Norway, and they are antibiotic-free 99% of the time.

*Scottish salmon. I don’t have much to say on these, although I’ve noted some scandals in the media. So, I suppose I’d just say so Scottish salmon are like a kilt… look traditional, but underneath it might be hiding something questionable.

(the difference you're seeing there is Faroe Island vs Alaskan Sockeye... to come)

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Nick Norwitz

@nicknorwitz

Jun 14

🥛This Saturated Fat Can Burn Fat: A Milkshake Experiment?!🥛 (🔗at the end)

Saturated fat is one of the most misunderstood nutrients in nutrition. Part of this misunderstanding stems from a stereotype: Saturated fats are often lumped together as if they are homogenous entity.

But they are not.

1/7) In today’s StayCurious Metabolism Letter, I make the point by reviewing data showing how one specific saturated fat, stearic acid, positively influences mitochondrial fusion-fission dynamics and fat metabolism.

At the end I also provide you a boarder evolutionary framework in which to understand these data and related general principles of nutrition and offer some practical takeaways

Let’s dig in...

#saturatedfat #mitochondrialhealth #stearicacid #staycurious #metabolichealth

2/7) Stearic acid is an 18-carbon saturated fat found in certain tallow, cocoa butter, and shea butter.

👉The study in question set out to investigate the effects of stearic acid, an 18-carbon saturated fat (C18:0), on mitochondria. The researchers took a diverse group of individuals—including those who were healthy and those with type 2 diabetes—and placed them on a low-fat vegan diet for two days in order to reduce their saturated fat and stearic acid intake.

They then gave the participants a stearic acid milkshake (24g of C18:0) or a mock control shake looked at the participants’ mitochondria at 0, 3, and 6 hours later.

🚨When given stearic acid, but not the control, the percentage of “fused” mitochondria increases ~4-fold. This did not happen with the control drink.

🚨By contrast, stearic acid restriction in the form of the low stearic acid vegan diet caused mitochondria to fracture and fragment. (More on the long-term effects later.)

3/7) In the simplest possible terms:

👉Lower stearic acid intake = fragmented mitochondria
👉Higher stearic acid intake = fused mitochondrial

If you want a pop-culture analogy, think of it like assembling the Avengers. Individually, they’re impressive, but together, they’re more powerful. In fusing, the mitochondria become temporarily more efficient and productive.

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Nick Norwitz

@nicknorwitz

Jun 7

1/8) Vitamin C is everywhere 🍊🍋🥝🍓👀

But when it comes to heart health 🫀, Vitamin C is wildly underrated. We think we understand it. But we don’t. And what I found when I dove into the science shocked me. (🔗 with all references at the end)

First, a quick hat-tip to what had me running down this rabbit hole. I recently wrote a newsletter on Lp(a) that was my most popular to date. I encourage you to check that out if you’re interested in heart health.

But here’s what you need to know: Lp(a) is like LDL’s evil twin—the one that went to villain school and graduated top of its class in blood clotting. And Lp(a) is that’s thought to be genetically cemented.

However, some people have had anecdotal success lowering Lp(a) with high-dose vitamin C supplementation.

Weird, right? But it got my curious and started down another rabbit hole. I’ve broken today’s newsletter into 8 chapters:

1. Vitamin C & Lp(a) – Nature’s substitution
2. Vitamin C & Heart Disease – The human data
3. Vitamin C & oxLDL – Can it stop cholesterol from turning toxic?
4. Vitamin C & Nitric Oxide – Why your blood vessels care
5. Mechanistic Summary – Piecing together the puzzle
6. Vitamin C Dosing – How much do you really need?
7. Vitamin C & Lysine – Batman & Robin
8. Puzzling Together the Protocol

2/8) Vitamin C and Lp(a)

Lp(a) is a spherical particle that floats around in the blood. It looks like an LDL particle, except Lp(a) also has a protein tail called apolipoprotein(a). This tail endows Lp(a) with the ability to promote blood clots and is one way in which Lp(a) is thought to promote cardiovascular disease, atherosclerosis.

But in 1990, the double Nobel Laureate Linus Pauling and his colleague Dr. Rath came up with an interesting idea about Lp(a). They hypothesized that Lp(a) was a surrogate for vitamin C.

Most mammals can synthesize their own vitamin C. But about 40 - 60 million years ago, our primate lineage developed a mutation in the GLO gene that prevents us from synthesizing vitamin C. Since vitamin C helps to promote wound healing, this would have placed an environmental pressure to develop an alternative means to promote wound healing and halt bleeding. In effect, evolution called for a substitute: Lp(a), which can likewise promote wound healing.

Now, if it were true that Lp(a) is an evolutionary substitute and surrogate for vitamin C, we might expect a pattern whereby animals that can synthesize vitamin C lack Lp(a). This is indeed the case!

What’s more, species that have also lost the ability to synthesize vitamin C, including guinea pigs and the European hedgehog, also produce Lp(a).

3/8) Across the animal kingdom, there’s a pattern: Where the ability to synthesize vitamin C remains, Lp(a) is missing. Where the ability to synthesize vitamin C is lost, Lp(a) is present. This provides one comparative evolution argument that Lp(a) is a surrogate for vitamin C.

But the intrigue doesn’t stop there. Chasing these observations, Pauling and Rath performed experiments where they deprived guinea pigs of vitamin C, which was sufficient to cause them to develop rapid atherosclerosis characterized by plaques filled with Lp(a). Conversely, when guinea pigs were given vitamin C, negligible amounts of Lp(a) could be found in their arteries.

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Nick Norwitz

@nicknorwitz

Jun 5

☕How to Drink Coffee for Heart Health (Backed by Science)🫀🔗at the end (5/5)

1/5) What if I told you coffee was good for your heart?
Indeed, coffee isn’t just keeping you alive during Zoom meetings—it might actually be keeping you alive. In today’s letter, I’ll break down two human trials, one remarkable mouse study, the key molecule behind coffee’s heart benefits, how to dose and time your coffee for maximum impact, and what I enjoy even more than coffee these days.

First, let’s establish that there is a well-known association between coffee intake and reduced risk of cardiovascular disease—at least up to a point. But large-scale epidemiological studies provide limited insight on cause-effect relationships or mechanisms.

👉So, we turn to controlled trials and animal studies.
I want to review two human randomized controlled trials, and one fascinating animal study centered around a special chemical in coffee that is responsible for many of its health effects: chlorogenic acid.

If you follow me, you may recall chlorogenic acid from our discussions on how to stop sugar cravings or how the heart talks to the brain (these letters can be found at staycuriousmetabolism. com).

Briefly, it’s a well-studied polyphenolic compound enriched in coffee—especially lighter roasts, unroasted ‘green’ coffee, and Yerba Mate.

#coffee #hearthealth #cardiovascularhealth #LDL #ApoB #atherosclerosis #metabolichealth #metabolism #yerbamate #educational #coffeelover #staycurious

2/5) Human Randomized Controlled Trials

Let’s discuss two human randomized controlled trials. Both studies aimed to assess the effect of coffee and/or chlorogenic acid on vascular function. They measured vascular function using flow-mediated dilation (FMD), which evaluates the ability of the endothelium (the inner lining of blood vessels) to dilate in response to increased blood flow. It's a way to assess the health of blood vessels.

👉In one study, they gave participants one of two different coffees differing in chlorogenic acid content (89 mg or 310 mg), or a placebo control, and then measured FMD. As compared to the placebo, both coffees improved FMD, with the higher dose (310 mg) of chlorogenic acid appearing to have a larger effect.

To further prove it was the chlorogenic acid improving vascular function, they conducted another experiment in which they provided isolated chlorogenic acid rather than coffee. Again, the chlorogenic acid improved FMD.

👉These findings have been independently replicated. In another double-blinded randomized controlled trial, decaffeinated unroasted ‘green’ coffee containing chlorogenic acid at three different doses (302 mg, 604 mg, 906 mg) was compared to a placebo control for its effects on FMD. The chlorogenic acid significantly improved FMD versus placebo, although the higher doses did not provide additional benefit.

All in all, these studies suggest that chlorogenic acid in coffee improves vascular function.

3/5) But What About Long-Term Heart Health?🫀

Now, that’s interesting—and perhaps sufficient to justify your coffee habits. However, when it comes to long-term health, what you really want to know is whether chlorogenic acid could slow the progression of atherosclerosis, the buildup of plaque in your arteries.
Here, we can’t conduct human controlled trials because atherosclerosis takes too long to develop. Instead, we turn to animal models.

In what may be my favorite coffee-relevant paper to date, researchers gave ApoE-/- mice (predisposed to heart disease) a control diet or one supplemented with either 200 mg/kg chlorogenic acid, 400 mg/kg chlorogenic acid, or a statin (4 mg/kg atorvastatin).

Strikingly, chlorogenic acid reduced the progression of atherosclerosis at both doses, with the higher dose having the same effect size as the statin. You can see this clearly in the images on showing part of the heart with plaques circled, and in the bar graph showing atherosclerotic plaque area.

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