Nick Norwitz MD PhD Profile picture
Sep 28 8 tweets 5 min read Read on X
The Oldest Woman (117) Had “High” Cholesterol 🩸— Here’s What That Really Means🤔(Link 🔗 in 8/8)

1/8) The world’s oldest woman just died. Before she passed, she pleaded, “Please study me.”

A new paper in Cell Reports Medicine (PMID: 39322234) just published provides a deep dive into her genes, metabolism and microbiome. What made this 117-year-old such a supercentenarian?

As a metabolism scientist, this is the kind of data I’d die for (figuratively speaking). Stick with me. I’ll break down what her biology really tells us about aging, and why we might be obsessed with the wrong biomarkers.Image
2/8) When I first read the paper, I noticed something odd.

The authors detailed her lipid profile (HDL, VLDL-TG, etc.) but her LDL-C and ApoB—the numbers most doctors obsess over—was nowhere in the main text.

I had to go hunting in the supplementary data. There it was, buried in a single line of Supplemental Figure 8B: elevated, and in the “red.” -- Granted, it wasn’t super high… but it wasn’t low either.

So what gives? Why was it not mentioned in the main text. I provide thoughts (not conspiracy theories) in the letter. But now I know I have your attention…

cc @realDaveFeldman @AdrianSotoMotaImage
3/8) Now for the next “paradox” - her telomeres 🧬😲

Telomeres are the protective caps on our chromosomes. Think of them like the plastic tips on a shoelace. The prevailing wisdom is that as they shorten with age, our health declines.

You’d expect a 117-year-old to have either freakishly long telomeres or be riddled with disease. Maria Morera had neither.

Her telomeres were tiny!!! I was expecting Godzilla telomeres and was met with chihuahuas exactly as short as you'd predict for her chronological age.

Yet, she was remarkably healthy. This is a crucial finding: telomere length may simply be a clock, not a direct measure of your healthspan.

cc @bryan_johnson, of interest?Image
4/8) So if it wasn't long telomeres, what set her apart?

Her mitochondria. As every high schooler knows, these are the “powerhouses in our cells,” and their decline is a key hallmark of aging.

Maria’s, however, were functioning like those of someone decades younger. The paper notes her mitochondria showed "not only preserved but also robust mitochondrial function."

cc @ChrisPalmerMD @MitoPsychoBioImage
5/8) The evidence for her low "inflammaging" status is compelling. Beyond her genetics, her bloodwork showed remarkably low levels of GlycA and GlycB—advanced biomarkers of systemic inflammation. 🔥

Summary so far: Genetics gave her an edge → leading to highly efficient mitochondria and a low inflammatory burden → which created a biological environment where factors like high LDL or short telomeres didn't lead to disease.Image
6/8) So, what about her lifestyle? For the last 20 years of her life, she ate a consistent diet that included a conspicuous amount of yogurt—three servings per day.

And the paper even specified the bacterial strains: Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus. She was also a heavy user of egg protein and olive oil.

I feel almost as if I designed her diet!

P.S. Smoked Maldon Salt Greek Yogurt is a 12/10
7/8) The clinical implications here are profound. Her case suggests that a state of low inflammation, a “highly engaged lipid metabolism,” and good mitochondrial health can grant resilience against factors we typically view as "bad." Yes, she was genetically gifted. But we can still turn her insights into action… What do we do with this knowledge?
8/8) In the rest of the letter (linked below), we turn these insights into action.

While you can't change your genes, you can support your mitochondria.

I break down her full meal plan, the specific U.S. yogurt brands I found that contain those exact bacterial strains, and actionable strategies — from fasting protocols to light exposure — that support the same mitochondrial resilience seen in this remarkable supercentenarian.

Premium subscribers get full access for less than 67 cents per letter. Read the full breakdown here → staycuriousmetabolism.substack.com/p/the-oldest-w…Image

• • •

Missing some Tweet in this thread? You can try to force a refresh
 

Keep Current with Nick Norwitz MD PhD

Nick Norwitz MD PhD Profile picture

Stay in touch and get notified when new unrolls are available from this author!

Read all threads

This Thread may be Removed Anytime!

PDF

Twitter may remove this content at anytime! Save it as PDF for later use!

Try unrolling a thread yourself!

how to unroll video
  1. Follow @ThreadReaderApp to mention us!

  2. From a Twitter thread mention us with a keyword "unroll"
@threadreaderapp unroll

Practice here first or read more on our help page!

More from @nicknorwitz

Sep 24
Tylenol and Autism: Let’s put Science Over Politics

1/8) I’m not surprised today’s mini letter is getting spirited comments. But this needs to be my favorite. Why?

Because Certainty is the Coffin of Science.

Science doesn’t operate in absolutes and medicine is the art of making life-altering choices with imperfect information.

With the said, please hear me out before jumping to conclusions…Image
2/8) First, a promise: There are many ways I could respond to the present moment — but I’m going to try to choose compassion and understanding. By that I mean I’m not going to point fingers or make fun. This moment calls for less fighting, less politics, and more humility.
Full letter here: staycuriousmetabolism.substack.com/p/tylenol-and-…
3/8) Now, the suggestion that Tylenol may cause autism itself is not all that easy enough to address because of that sneaky little word, “may.”

“May” can imply almost anything. It could mean me telling my girlfriend: “Hey babe, I may have bought you those earrings you wanted.” (If “may” in this case meant anything less than 100%, I should probably be worried for my health.)

Or it could mean: “There may be a purple and blue striped unicorn named Camillo on the far side of Neptune.” (You can’t rule that out, because in science you can’t disprove a negative.)
Read 8 tweets
Sep 20
🤯The INSANE Mitochondrial Economy in Your Body that could save your Heart 🫀! (🔗 in 7/7)

1/7) Sometimes I read a paper that literally gives me goosebumps—not because it gave me the answer to a question I’ve been seeking, but because it blindsided me with an idea I couldn’t have imagined. This is one of those times. And my challenge in this letter will be communicating in text why I’m so excited.

Let me not make you wait any longer and get to the punchline: mitochondria—the powerhouse of the cell—aren’t just little engines, but part of a complex signaling network whereby cells and organs can trade mitochondria as part of a systematic energy economy throughout the body.

If you want the full story, skip to the end and click the link to the full letter. If you want to wade in, continue…Image
2/7) The first paper of a triad that gave me the goosebumps was published in Cell Metabolism and found, now paraphrasing: Fat cells and immune cells employ intercellular mitochondria transfer as a mechanism of crosstalk that regulates metabolic homeostasis and is impaired in obesity.”

What you’re looking at below is a time-lapse image of a mitochondrion (arrow), released from fat cells, being taken up by an immune cell (the red blob). That we can visualize this mitochondrial transfer event in living mammals is quite a feat of engineering!Image
3/7) They next wanted to know how this works. Using state-of-the-art gene editing (CRISPR-Cas9), they performed a ‘knock-out screen,’ effectively deleting a bunch of different genes to identify which were essential for this process to occur.

They ultimately landed on those related to the synthesis of heparan sulfate (HS), a complex carbohydrate found on the surface of cells and in the extracellular matrix of all multicellular animals. It plays crucial roles in various biological processes, including development, cell signaling, and immune responses.

Effectively, HS is the receptor, bridge, and/or tool that macrophages need to take up mitochondria from fat cells. Now here’s where things get extra interesting…Image
Read 7 tweets
Sep 11
Stress Makes Sugar (Literally!) - New Study Blew my Mind...(🔗 at the end)

1/8) Groundbreaking research just published in @Nature shows that stress can trigger brain circuits with a direct hotline to the liver to make new sugar.

🚨TL; DR Stress can Make Sugar, even independent of eating carbs.

This newly discovered brain-liver axis bypasses the usual hormonal regulators of blood sugar—like cortisol, adrenaline, insulin—and instead sends a direct signal that forces the liver to make and dump sugar into the bloodstream.

Let’s break it down…Image
2/8) Let me start with an analogy: Imagine if I told you that I could instantly communicate with a friend on the other side of the world. You wouldn’t be shocked—you know I have access to email and a phone. But if I clarified, “No, I’ve invented telepathy,” and could somehow prove it to you, is it fair to say you’d be impressed? That’s analogous to distinction we’re dealing with here: an entirely new and direct line of communication between the brain and liver to influence blood sugar.
3/8) First, researchers first confirmed what we already know: different stressors—physical restraint, social stress, etc.—increase blood sugar and activated a particular region in the brain, the medial amygdala (MeA) that is associated with a stress response. That wasn’t shocking and is already a well-documented phenomenon in humans and animals.

The stressors also elevated the usual hormonal suspects like cortisol.

If the story stopped here, we might be tempted to conclude that stress hormones raise blood sugar. End of story. The end. Goodbye.

But that’s not the full picture. Not even close…

*Image Note: FOS is a label for early neuron activity. More green dots under the stress condition (bottom middle panel on the left) reveal more neuron activity as compared to the control (un-stressed) condition. This is quantified on the right. Stress increases neuron activity in both the anterior (front) and posterior (back) portions of the medial amygdala.Image
Read 8 tweets
Sep 8
Four Subtypes of Diabetes: Groundbreaking Research Out of Stanford (🔗in 7/8 and 8/8)

1/8) Overview:
👉New technologies reveal four subtypes of diabetes
👉Knowing your ‘flavor’ of diabetes (or prediabetes) can guide lifestyle and medical treatment
👉Combining bio-monitoring with big data and machine learning will bring forth a revolution in diabetes care and personalized medicine

*I’m releasing this letter early because the data it covers was conducted by one of my scientific heroes, Stanford’s Professor Michael Snyder @SnyderShot, who happens to be the guest on today’s @hubermanlab podcast episode.

*In fact, Professor Snyder is the only person I’ve pestered Andrew to have on his show, although I suspect the conversation would have happened anyway.

*My two-part interview with Professor Snyder, where we dig into some of his specific studies (Sub-phenotypes of diabetes, personalized medicine, and the famous two peaks of aging) will release part one later this week.

But first, let’s dig into these data!Image
2/8) The most common form of diabetes — Type 2, often associated with obesity and adult onset — isn’t one disease. It’s actually four different underlying pathologies, showing up in different proportions in different people.

Here’s a metaphor that might help: Imagine a dish made from bread, vegetables, and cheese. The general ingredients stay the same — but their ratios define what you’re eating.

Pile on the vegetables, go easy on the bread, toss in some protein — and you’ve got a Caesar salad with croutons. Flip the script: make bread the base, add a smear of sauce and some melted cheese — and now you’ve got a pizza.

Now imagine if we called both dishes the same thing. That’s what we’ve been doing with Type 2 diabetes.Image
3/8) First question: Why have we lumped different biological patterns under one umbrella?

The short answer: tools. In medicine, our understanding is often shaped — and limited — by what we’re able to measure.

For diabetes, it’s been easiest to classify people based on average blood sugar levels (for example, an HbA1c >5.7% indicates prediabetes, and >6.5% indicates diabetes) or based on their blood glucose levels at a singular timepoint on an oral glucose tolerance test (OGTT).
Read 8 tweets
Sep 6
Can Visceral Fat Cause Depression? (🔗at the end)

1/7) New data reveals how molecular packages called extracellular vesicles (EVs) can travel from visceral fat in the abdominal cavity, through the bloodstream, and into the brain, where they alter the function of specific brain areas and promote depression.

This is no joke. It's (literally) mind-bending science. Let's dig in...Image
2/7) First, some human context: depression and obesity are highly 'co-morbid'—meaning they often occur together.

Individuals with obesity are twice as likely to experience depression as those with a healthy weight.

Moreover, those diagnosed with depression are similarly at (58%) higher risk of developing obesity down the line, in part due to the adverse effects of certain antidepressant medications.

This can establish a vicious cycle between obesity and depression—a descending spiral with social, psychological, pharmacological, and metabolic components.

But one big question remains unanswered: How does fat tissue contribute to depression?

This is a very difficult question to answer in humans. You can’t perform controlled trials, and the social baggage of living with obesity introduces many psychosocial confounders. So, we turn to animal models.

We return to the human story in the letter—but first, let’s get murine and mechanistic.Image
3/7) Visceral Fat Transplant Causes Depression in Animals

In this study, researchers first demonstrated that a high-fat, high-sugar diet designed to cause obesity in mice also induced depression-like behaviors.

...But here’s where things get interesting: to test the hypothesis that visceral fat was responsible for the depression-like behavior, researchers transplanted visceral fat from the obese mice into normal, healthy mice.

Compared to a control group that received fat from lean mice, the mice that received visceral fat from obese donors similarly exhibited depression-like behavior. This suggests that transplantation of visceral fat alone is sufficient to cause depression.

But how?Image
Read 7 tweets
Sep 1
Causality is Overrated” – A Respectful Rebuttal to Dr @PeterAttiaMD cc @hubermanlab (🔗at the end)

This thread is about one word: causality.

1/8) People are obsessed with it. But first, let me identify the causal stimulus for this nibble: the quotes Huberman podcast clip @HLPClips (posted yesterday on X) in which Peter Attia expounds upon his “obsession” with causality.

To quote Peter: “Causality is an obsession of mine. Most of the day, on some level, I sit around thinking about causality.”

In this thread I’m going to make the case, respectfully, that Peter misses a big-picture point. This isn’t to ‘mic drop’ or puts points up on some imagined. This is not to end a discussion – it’s to reopen one that is desperately needed.

cc @realDaveFeldman @AdrianSotoMotaImage
2/8) The first three minutes of the clip are devoted to lung cancer, where Peter uses the Socratic method with Andrew to examine the causal relationship between smoking and lung cancer. He ultimately lands on the point:

“If you believe smoking is causally related to lung cancer, then smoking cessation reduces the probability of lung cancer. That is a logical equivalency. There can be no debate about that.”

He then pivots, replacing smoking with ApoB and lung cancer with atherosclerosis, stating: “There is no ambiguity that ApoB is causally related to atherosclerosis.”

Peter even goes so far as to argue that not treating elevated ApoB—even if the a person’s overall major adverse cardiovascular event score is low—is “as idiotic” as permitting someone to smoke.

But here’s where I think Peter is wrong because causality is not the same as importance.Image
3/8) 🚨Again, here’s the point: Causality is not the logical equivalency of importance, nor does the presence of a causal stimulus necessitate a causal intervention.🚨

To illustrate, let’s return to Peter’s analogy: “If you believe [X] is causally related to [Y], then [X] cessation reduces the probability of [Y].”

Now swap smoking and lung cancer for oxygen and fire: “If you believe oxygen is causally related to fire, then oxygen cessation reduces the probability of fire.”

Technically true. But that does that mean I should deplete my environment of oxygen to prevent spontaneous combustion?

What Peter knows—but underemphasizes—is that causality does not imply sufficiency. And often, targeting a “causal” factor has consequences far beyond reducing the risk of the primary undesired outcome.

Yes, if I remove oxygen, I’m less likely to burst into flames—but I’ll also suffocate.Image
Read 8 tweets

Did Thread Reader help you today?

Support us! We are indie developers!


This site is made by just two indie developers on a laptop doing marketing, support and development! Read more about the story.

Become a Premium Member ($3/month or $30/year) and get exclusive features!

Become Premium

Don't want to be a Premium member but still want to support us?

Make a small donation by buying us coffee ($5) or help with server cost ($10)

Donate via Paypal

Or Donate anonymously using crypto!

Ethereum

0xfe58350B80634f60Fa6Dc149a72b4DFbc17D341E copy

Bitcoin

3ATGMxNzCUFzxpMCHL5sWSt4DVtS8UqXpi copy

Thank you for your support!

Follow Us!

:(