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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 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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Nick Norwitz

@nicknorwitz

Dec 5

🚨Ketogenic Diet Reduces Visceral Fat & Improves Quality of Life Across All Domains!

1/5) 3 days ago, I released a video covering an 18-month randomized controlled trial suggesting that specific foodstuffs, including green tea and a specific “space vegetable” that may help preferential burn visceral fat.

Coincidently, after I released this video, a brand new interventional trial was published on #ketodiet that also looked at Visceral Fat... but also MUCH more!

👉It showed Ketogenic Diets would reduce visceral fat, even in healthy, lean persons on average >10% in just 3 weeks

👉And it revealed universal improvements in quality of life!

Let's Dig in!

2/5) The study itself had two stages.

The first was a 3 week feasibility study in healthy, lean participants.

The second was an expansion including adults with overweight/obesity for 3 months of ketogenic diet therapy.

👉Eucaloric Keto Diet
The KDs were designed to be eucaloric (i.e. to maintain weight) based on standard Calorie Counting Calculators (specifically, “Harris-Benedict-Equation, adjusted to the respective [participant’s] physical activity.

👉Measures
The study measured body composition, metabolic panels, and quality of life (QoL).

QoL measures were based on the World health Organization’s quality of life assessment (WHOQOL-BREF), which consists of four domains: "Physicalhealth," "Mental health," "Social relationships," and "Environmental quality." They also used the Short form health survey (SF-36) survey to assess quality of life. For each of the Quality of Life Scales (WHOQOL-BREF and SF-36), the final score ranges from 0 to 100, where higher is better.

And to assess fatigue they used the FAS scale. For the fatigue scale scores ranged from 10 to 50, with a higher score indicating more severe fatigue.

👉Ketone Monitoring
They also confirmed dietary compliance with routine ketone measurements.

👉Control Group:
While this wasn’t a randomized trial, they did include a eucaloric standard mixed macronutrient diet control in the 3 week study, with “detailed nutritional counseling from a board-certified nutritionist” This control “standard” diet intervention resulted in “no significant changes to any parameter.”

3/5) 🚨Visceral Fat Reduction

They found, despite the “eucaloric” nature of the diet, participants lost weight - in both the 3 week and 3 month studies

🔥That’s -1 Point for "CICO”🔥

And those with higher starting BMI tended to lose more weight.

More importantly total and visceral fat were reduced, but muscle mass and bone mass were maintained.

🚨Even in the 3 week study, visceral fat was reduced 10.8% (shown below).

🚨And in the 3 month trial, visceral fat mass was reduced 14.7%!

In terms of metabolic changes in the 3 week trial in healthy subjects:

👉C-reactive protein (CRP) trended downward without statistical significance (- 0.19 mg/dL). Cholesterol, LDL cholesterol, ApoB, and triglycerides (TG) remained unchanged. HDL cholesterol increased (+4.8, p = 0.047). Ketosis was confirmed, with mean beta-hydroxybutyrate levels of 1.45 ± 0.95 mmol/L at the end of the diet.

In terms of metabolic changes in the 3 month trial in subjects with overweight or obesity:

C-reactive protein (CRP) trended downward without statistical significance (- 0.11 mg/dl). Cholesterol, LDL cholesterol, ApoB, and triglycerides (TG) remained unchanged. HDL cholesterol increased (+5.7, p = 0.012). Ketosis was confirmed, with 25 of 30 enrolled participants maintaining ketosis throughout the whole 3 months.

4 dropped out early and one was excluded for not maintaining ketosis.

Otherwise stated, 83.3% of participants were able to maintain nutritional ketosis throughout the 3 month trial

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Nick Norwitz

@nicknorwitz

Dec 3

1/7) New Mechanism (Published Yesterday) on How Ketones Clean a Messy Brain in Alzheimer's Disease

🧐From the paper: "Ketone bodies are janitors of damaged proteins, chaperoning away molecular waste so organisms can operate at peak molecular fitness."

I'm going to break it down in this thread, or skip to the end for the easy-to-read🔗Newsletter version🔗

🧠Background: Protein Misfolding and Alzheimer’s🧠

Alzheimer’s is one of many different horrifying neurodegenerative diseases. Most are related to aging and characterized by the misfolding of proteins.

This is Biology 101: Proteins are the micro-machines that govern how the body works. And a proteins structure (how it folds) determines its function. If it misfolds, disease can ensue – especially neurodegenerative diseases like Alzheimer’s.

In fact, you may have heard of the products of some of these misfolded proteins, like amyloid plaques and tau neurofibrillary tangles...

2/7) Okay, now some more background on ketogenic diets and Alzheimer’s disease.

There is a body of literature supporting the use of ketogenic diets for Alzheimer’s disease, including mouse models where ketogenic diets extend cognitive longevity, data showing the ketones can protect against amyloid toxicity and reduce amyloid plaque burden, and even human randomized trials showing the benefits of ketogenic diets in persons already exhibiting signs and symptoms of dementia.

Also, on first principles, ketones could help in Alzheimer’s disease, by providing an energy substrate when brain glucose metabolism is impaired, reducing neuroinflammation, and rewiring metabolism through changing how genes are expressed via HDAC inhibition, or altering protein function through post translational modification.

This is all very cool and exciting and provides a framework for what I’m about to share.

But this research goes a step further...

3/7) In brief, they find that ketones can target specific pathological misfolded proteins, help them transition from a "soluble to insoluble" state – we will elaborate on that in a moment - and ultimately help clear them out and clean up the brain.

In the authors words:

“ketone bodies are janitors of damaged proteins, chaperoning away molecular waste so organisms can operate at peak molecular fitness.”

But let’s unpack that a little bit more because it’s complicated.

You see, when proteins misfold they can be soluble - meaning dissolved in the fluid in and around out cells – or insoluble – meaning that are clustered up discretely. Transitioning from soluble to insoluble is almost as if you could reverse dissolve salt from salt water into fresh water and a salt cube.

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