AcAc binds to the GPR43/FFAR2 receptor to promote Lipoprotein Lipase activity and help burn fat.
Some more details...
2/ Short-chain fatty acids (SCFAs) in the gut r known to modulate energy homeostatis. Butyrate, acetate, proprionate all have recptors. The acetate receptor is GPR43.
The ketone BhB is all well studied as a signaling molecule, and binds HCAR2 etc., but AcAc is less well studied.
3/ This paper provides good evidence that, during fasting and ketogenic conditions, its AcAc that helps promote fat burning (lypolysis) throughout the body (except in the gut, more on that in a bit). Again, AcAc binds GPR43 and promotes Lipoprotein lipase (LPL activity)...
4/ The researchers were able to demonstrate this phenomenon using mice that didn't express GPR43, this lead to decreased LPL in their fat cells, elevated Trig levels, decrease energy expenditure, and less weight loss...
5/ Interestingly, they also found that the AcAc-->GRP43 --> LPL signaling axis, while increasing LPL expression, decreased ANGPLT4 expression - with ANGPLT4 being a protein that inhibits LPL activity. The reason I mean to highlight this is...
6/ ... is loss of function in LPL and gain of function in ANGPLT4 are each linked to decreased turnover of Trig-rich lipoproteins that are now the subject of scrutinity in terms of development of CVD.... nature.com/articles/s4158…
7/ They also observed GPR43 signaling was important to regulate energy homeostasisunder ketogenic conditions. GPR43-/- mice actually gained weight (body fat) when fed a ketogenic diet...
8/ But while fasting and #keto increase AcAc to increase GPR43-mediated LPL activity in fat cells around the body, fasting also decreases acetate production in the gut (of course, because you're not eating). In the gut, acetate remains the main GPR43 ligand. Therefore...
9/ The AcAc / acetate-->GPR43-->LPL axis actualy helps w the choreography of energy homeostasis when fasting
Fat burning is upregulated around the body to supply energy, while LPL activity is decreased in gut to prevent wasting energy on the digetive track
Pretty logical to me
10/ I just thought this was a cool one because we don't often talk about acetoacetate signaling. Also LPL dysfunction may be a common feature in metabolic diseases leading to lipid abnormalities. See where I'm going with this train of thought...
Cool stuff :).
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🧠Saffron for Depression: The Science, the Studies, and the Recipes🧠
1/5) What if I told you that the kitchen spice – Saffron – could treat depression?
It may sound too good to be true, but that claim is supported by a growing pile of human randomized controlled trials (RCTs) and sensible biological mechanisms.
I’m going to share two of these studies, explain the neuroscience, and direct you to more learning.
This golden spice really might be the next big thing in mental health!
References are in the newsletter linked at the end. #saffron #depression #mentalhealth
2/5) Saffron vs SSRI (RCT)
This double-blind randomized controlled trial compared 6 weeks of saffron supplementation (30mg/d) vs Prozac (fluoxetine), a commonly prescribed selective serotonin reuptake inhibitor (SSRI).
Impressively, the saffron performed equal to the fluoxetine!
You can see the results over 6 weeks here, with the Hamilton Rating Scale for Depression dropping in lock step between the treatments.
The absolute decrease in both treatments was >12. What does that number mean?
Well, in clinical trials, there’s a key distinction between a “statistically significant” difference and a “clinically significant” difference. A “statistically significant” difference means there was a detectable numeric difference, as in over time or between groups. Conversely, a “clinically significant” difference means that size of the change was detectable and meaningful for the patient.
Now while it’s somewhat arbitrary, a clinically meaningful change in this depression scale is ~5 points, which means a ~12-point drop is impressive and is clinically substantial!
Note on Side Effects: One presumed advantage of saffron is that it could have fewer side effects than prescription medications. In this first small pilot trial, there is an apparent trend to lower side effects in the saffron group vs SSRI. To see that table, click on the link at the end of this thread.
3/5) Saffron for Mental Health - Meta-Analysis
Rather than working through another 20+ studies, I want to share with you excerpts from a meta-analysis of 23 RCTs conducted on saffron for mental health, including depression and anxiety:
👉 [M] eta-analysis found a significant and large positive effect size for saffron reducing symptoms of depression in comparison with placebo.
👉When compared with antidepressants medications, there was no significant difference between saffron and medications.
👉Meta-analysis of studies that investigated the effect of saffron as an adjunct to pharmacotherapy reported a large significant benefit from saffron supplementation.
In simpler terms:
👉Saffron’s effect alone with large and positive for mental health
👉Saffron performed as well as commonly prescribed medications
👉Saffron provided additional benefit when stacked on prescription medications
1/5) In this study, 64 adults endured 2 hours of cold exposure near their shivering threshold.
🤔Results🤔
Massive changes in signaling lipids, including omega-6 and omega-3 fats and their derivatives, endocannabinoids and specific pro-resolving mediators.
On net, the changes reflected a signature of improved cardiometabolic health 🫀❤️🔥 #coldplunge #hearthealth
2/5) 🥶Some specific Omega-6 and 3 Changes🥶
👉39% Increase in the omega-6 oxylipin 12,13-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME). This oxylipin has been shown to increase the uptake of
fatty acids by brown fat and skeletal muscle.
🔥But even more impressive than the omega-6 response was the omega-3 response...
👉17 out of 17 omega-3 fats and their derivatives increased in the blood after cold exposure, by an average of 77%
👉The most prominent change, with an increase of 155%, was in 14- hydroxy-docosahexaenoic acid (14-HDoHE), which has been shown to inhibit activation of platelets involved in blood clots, increase blood flow, and inhibit inflammation.
👉And increases were noted in Resolvin D5, a powerful anti-inflammatory compound that inhibits the production of inflammatory molecules, like IL-6, reduces pain and protects various organs from inflammatory challenges.
3/5) And there were changes in endocannabinoids!🪴
There was an increase in anandamide, which binds the CB1 receptor – a key receptor involved in the effects of THC.
So, I’ll let you put 2+2 together on that... I’m not saying that a cold plunge will make you ‘high’ per se, but it’s an interesting mechanistic overlap… and one that overlaps with people’s experiences.
☕️Coffee for Gut Health?! 🦠 New Research will have you Express-O-ing excitement!
This thread will reveal what new research in Nature Microbiology has discovered, tell you how much coffee to drink to get the health benefits, compare caffeinated vs. decaf, and more. I hope you’ve had a cup or two because you’ll need focus for this. (🔗link at the end)
1/8) Quick Background on the Health Benefits of Coffee
First, coffee intake has already been associated with lower mortality, reduced cardiovascular disease-related death, and a lower risk of type 2 diabetes. But nutritional epidemiology—the study of diet and health outcomes in large populations—has its limitations because it can only look for correlations.
To solidify coffee’s health halo, what we want is a complementary biological mechanism, a physiological story that helps it all make sense. #coffee #microbiome
2/8) Coffee Changes the Microbiome: Lawsonibacter asaccharolyticus
So, let’s introduce the protagonist of this story, a gut bacterium named Lawsonibacter asaccharolyticus. (I know, it sounds kind of like a Harry Potter spell.)
To discover the Lawsonibacter asaccharolyticus–coffee link, the researchers took information on food intake, including > 150 specific foods with associated and microbiome samples, then look for connections between specific foods and microbiome signatures.
☕️Among the >150 foods analyzed; coffee stood out for having the clearest microbiome signature.
3/8) For further analyses, they broke participants into three groups:
👉“Never” drinkers: Consumed less than three cups per month
👉“Moderate” drinkers: Consumed more than this but fewer than three cups per day
👉“High” drinkers: Consumed more than three cups per day
The strongest correlation between coffee consumption and the microbiome was Lawsonibacter asaccharolyticus. And—because I know you’re wondering, as I was when reading the paper—this association was independent of caffeine.
Why do we sleep? 😴And what caused “Brain Constipation? 🧠💩 New research in @CellCellPress
(Link at end, w/ exclusive clip from first author 🤓)
1/4) A Key Function of Sleep is to clear metabolic wastes from the brain.
This function is carried out by the “glymphatic system,” a series of channels that expand as blood vessels constrict. Deep non-rapid eye movement (NREM) sleep is prime time for glymphatic systema and brain waste removal. But a key question that has remained unanswered until now is *HOW* is this system regulated?
🧠Norepinephrine Regulates Glymphatic Flow🌊
The researchers find a group of neurons in the brain stem bathes the brain in norepinephrine pulses while we sleep. Norepinephrine is a vasoconstrictor, and these pulses therefore generate waves of blood vessel constriction that enhance glymphatic flow and metabolic waste removal from the brain.
🧠 Brain Constipation?💩
By way of analogy, think about your gastrointestinal system: Your intestines use rhythmic contractions to move waste out. If that process stops—you get constipated. Now imagine your brain has a similar waste-removal system... but instead of food, it’s clearing out toxic metabolic byproducts. If something blocks that process, you get brain constipation.
What causes brain constipation?
* if I do say so, I think this is a video @hubermanlab, cc @IanGMackey @R_Mohr, and @bryan_johnson and @NTFabiano will each enjoy -- ... and if you want more on glymphatics and sleep, let me know
* Don't miss an exclusive clip from the first author of the research in the full video, link at the end.
2/4) The researchers then asked the provocative question: What do certain sleep medications, specifically Zolpidem, do to norepinephrine pulses and glymphatic function?
💩 In brief, they find that the sleep medication impairs the normal oscillations in norepinephrine and decreases glymphatic flow. The implication is that long-term use could contribute to a build-up of metabolic debris in the brain and, possibly, long-term negative consequences like cognitive decline.
Indeed, long-term human studies have linked Zolpidem to higher rates of dementia and Alzheimer’s disease.
Fortunately, this does not appear to be the case for other medications that are often used to help with sleep, like the atypical anti-depressant trazodone. In fact, there are suggestions that this medication might improve sleep architecture and is associated with lower rates of dementia.
3/4) The Good News: With advancements in technology, maybe we will soon be able to enhance glymphatics efficiency and ‘brain cleaning,’ including during sleep and perhaps even during waking hours. In my biomedical fantasy, I could rinse my brain between blocks of work while watching a Marvel Movie, or Harry Potter, Game of Thrones. What a dream!
1/8) Yesterday @bryan_johnson claimed he's "aging slower than anyone in the world." This is incorrect by his own measurement tool.
But this thread isn't just a fact-check. It's an assessment of the "Pace of Aging Clock," and how I think one should interpret these data.
🔗 to letter and more data at the end🔗
cc @Derek_Fitness @JEverettLearned
2/8) First, what is the DunedInPACE Score?
PACE stands for Pace of Aging Calculated from the Epigenome—and the score is meant to measure the rate of biological change, with a value of 1.0 = 1 year of biological change per calendar year.
As opposed to the other aging clocks, which were developed by comparing people of different ages, DunedinPACE was developed by following a cohort of individuals who were all the same chronological age and measuring changes in biomarkers reflecting the health and integrity of different organ systems (cardiovascular, renal, hepatic, immune, etc.), then normalizing to 1, such that 1.0 indicates 1 year of biological change per 12-month calendar year.
3/8) Bryan Johnson previously boasted a value of to 0.66 as his DunedinPACE rate of aging score, suggesting that he’s biologically aging at ~66% or ab out 2/3rd of the average person. Then, around this past New Year's, he reported a DunedinPACE score of 0.57, a ‘personal best’ according to Bryan, claiming that his birthday is every 21 months (12 / 0.57). Yesterday, he claimed a score of 0.48.
Nuance Note: It’s not clear to me if this is a result of:
1. an actual downward trend in his score reflecting true slowed pace of aging
2. a function of test variability and the fact he just has more measures from which to choose and report
3. if he’s modifying his protocols to ‘optimize’ his metric, but without translation to bona fide slowing of biological age. More on this in a moment…
Ketogenic Diet for Parkinson's Disease - Mega Post
(🔗 to Deep Dive Video at the End.)
Let’s cut to the chase: my answer is a cautious but confident “Yes.”
However, it’s not that simple. In this thread, I’ll break down the “what,” “how,” and “why” of a Ketogenic Diet for Parkinson’s Disease.
1/9) First, what is Parkinson’s disease? 🧠
Parkinson’s disease is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. The motor symptoms are what most classically stand out and include cardinal features of:
👉1) Tremor
👉2) Bradykinesia, which means slowness in movement
👉3) Rigidity, that can make it hard to walk, write, speak, or express facial expressions
👉4) Postural instability, which can lead to falls.
In terms of non-motor symptoms, patients often experience issues with smell, gastrointestinal upset, and sometimes mood disturbances like depression.
How common is Parkinson’s disease?
👉Second most common neurodegenerative disease, behind Alzheimer’s.
👉Impacts >10 million people worldwide and is growing in prevalence much faster than Alzheimer’s disease. If it were an infectious disease, Parkinson’s would be labeled a pandemic.
cc @Metabolic_Mind @bschermd @janellison @ChrisPalmerMD
2/9) What causes Parkinson’s disease? 🧠🤔
Parkinson’s disease is caused by the death of dopamine producing neurons in the brain’s “substantia nigra.” This translates to ‘black substance’ and is a little patch of brain in the midbrain motor system in the brain.
Specifically, Parkinson’s disease is characterized by the aggregation of misfolded “alpha synuclein” protein – the hallmark of Parkinson’s disease – leading to the death of these dopamine producing substantia nigra neurons.
As more neurons die… the disease gets worse. And current standard of care is, basically, replacing the missing dopamine with dopamine supplementation of some form. However, as more neurons die, the underlaying disease progresses, the medications become less effective, and the disease typically gets worse until…
👉👉Well, that’s why we really need better treatments.
3/9) But here’s something interesting about these dopamine neurons in the midbrain that die off in Parkinson’s disease: They are huge with many branches (this is called arborization), are relatively few, and are very energy hungry. ⚡️⚡️⚡️
They also have a calcium-pacemaking activity that gobbles up energy like a hungry teenager.
All this means, these substantia nigra neurons are particularly metabolically active cells and are, therefore, especially susceptible to energy deprivation. And when the neurons are starved of energy, they die.
But what if we could rescue energy metabolism in substantia nigra neurons? Could we slow or stop Parkinson’s disease?