Zone 2 training, which involves exercising at a moderate intensity (typically 60-70% of maximum heart rate), can reverse metabolic syndrome through several detailed mechanisms. This form of exercise enhances the body's ability to oxidize fat as a primary fuel source, thereby improving metabolic flexibility. By operating predominantly within the aerobic energy system, Zone 2 training increases the efficiency and capacity of mitochondria, the powerhouses of cells, thereby enhancing overall energy metabolism. The increased mitochondrial density and function allow for better utilization of glucose and fatty acids, reducing blood glucose levels and improving insulin sensitivity, which are crucial factors in reversing metabolic syndrome.
One significant benefit of Zone 2 training is the improvement in insulin sensitivity. Exercise at this intensity enhances the muscles' ability to uptake glucose, independent of insulin, through increased translocation of glucose transporter type 4 (GLUT4) to the cell surface. This effect not only helps in lowering blood glucose levels but also decreases insulin resistance, a key component of metabolic syndrome. Improved insulin sensitivity means that the body requires less insulin to manage blood sugar levels, alleviating the burden on pancreatic beta cells and reducing the risk of developing type 2 diabetes​ (BMJ Open Access)​​ (BioMed Central)​.
Another crucial mechanism is the reduction of visceral fat, which is closely associated with metabolic syndrome. Zone 2 training promotes lipolysis, the breakdown of fats, and enhances fat oxidation, leading to a decrease in visceral adiposity. Reduced visceral fat decreases the production of pro-inflammatory cytokines and adipokines that contribute to chronic inflammation and insulin resistance. Consequently, lowering visceral fat not only helps in managing weight but also mitigates the inflammatory state that exacerbates metabolic syndrome​ (Diabetes Journals)​.
Furthermore, Zone 2 training improves cardiovascular health by lowering blood pressure, enhancing endothelial function, and increasing HDL cholesterol levels while reducing LDL cholesterol and triglycerides. These cardiovascular benefits reduce the risk of atherosclerosis and other cardiovascular diseases, which are often comorbid with metabolic syndrome. By improving vascular function and lipid profiles, Zone 2 training addresses several risk factors associated with metabolic syndrome, leading to a comprehensive improvement in metabolic health​ (Diabetes Journals)​.
Overall, Zone 2 training offers a multifaceted approach to reversing metabolic syndrome by enhancing mitochondrial function, improving insulin sensitivity, reducing visceral fat, and promoting cardiovascular health. These combined effects lead to a substantial improvement in metabolic health and a reduction in the risk factors associated with metabolic syndrome.
Resistance training has a significant impact on reversing metabolic syndrome through multiple mechanisms, enhancing overall metabolic health. Engaging in regular resistance exercise leads to increased muscle mass and strength, which is crucial for improving metabolic rate. A higher metabolic rate helps in better energy expenditure and fat oxidation, reducing body fat and visceral adiposity, both of which are key factors in metabolic syndrome.
One of the primary ways resistance training helps is by improving insulin sensitivity. Muscle contractions during resistance exercises stimulate glucose uptake into the muscles independently of insulin. This increased glucose uptake helps lower blood glucose levels and reduces insulin resistance, a core component of metabolic syndrome. Studies have shown that resistance training can significantly reduce hemoglobin A1c levels, a marker of long-term blood glucose control, thereby improving glycemic control​ (BioMed Central)​.
Resistance training also positively affects lipid profiles, which are often dysregulated in metabolic syndrome. It helps lower LDL cholesterol and triglycerides while increasing HDL cholesterol levels. These changes contribute to a better cardiovascular risk profile, reducing the risk of atherosclerosis and other cardiovascular diseases commonly associated with metabolic syndrome​ (Diabetes Journals)​. Additionally, the reduction in visceral fat due to resistance training decreases the production of pro-inflammatory cytokines, further mitigating the inflammatory state associated with metabolic syndrome.
Moreover, resistance training improves cardiovascular health by reducing resting blood pressure and enhancing endothelial function. This is crucial because hypertension is a common component of metabolic syndrome. Improved muscle strength and endurance from resistance training also contribute to overall physical function and quality of life, making it easier to maintain an active lifestyle, which is essential for long-term metabolic health​ (Diabetes Journals)​​ (Oxford Academic)​.
Intermittent hypoxia (IH) involves short periods of low oxygen followed by normal levels. Studies show IH enhances mitochondrial biogenesis, crucial for cellular energy and metabolic health.
Research indicates IH increases mitochondrial DNA, biogenesis markers, and oxidative enzyme activity. In J Physiol, healthy adults showed significant mitochondrial improvements with IH. In Diabetes, obese individuals improved insulin sensitivity and mitochondrial function through IH.
IH appears effective for managing metabolic syndrome by enhancing mitochondrial function and metabolic health. Further research with larger samples and longer follow-ups is needed to confirm its long-term efficacy and safety.
HIIT significantly enhances mitochondrial biogenesis by creating high energy demands and producing reactive oxygen species (ROS), which act as signaling molecules for adaptive responses. During intense exercise bursts, localized hypoxia occurs in the muscles, stabilizing hypoxia-inducible factors (HIFs) that activate genes promoting mitochondrial biogenesis and improved oxygen utilization.
Intermittent hypoxia (IH) within HIIT plays a crucial role in these adaptations. The temporary hypoxic conditions during HIIT sessions induce similar responses to IH protocols, enhancing mitochondrial function and metabolic health. Thus, HIIT effectively boosts mitochondrial biogenesis through increased energy demands, ROS production, and HIF activation due to localized hypoxia.
To sustain the benefits of endurance training and boost mitochondrial function, several supplements and drugs are supported by varying degrees of scientific consensus.
Coenzyme Q10 (CoQ10) is well-supported by research for its role in enhancing mitochondrial ATP production and reducing fatigue. Numerous studies have shown CoQ10's effectiveness in improving exercise performance and overall mitochondrial health​ (BMJ Open Access)​​ (Diabetes Journals)​.
Acetyl-L-Carnitine (ALCAR) is also widely researched and known for transporting fatty acids into mitochondria for energy production, thus reducing oxidative damage and improving mitochondrial function and endurance​ (BioMed Central)​​ (Diabetes Journals)​.
Alpha-Lipoic Acid (ALA) acts as an antioxidant and has been shown to improve insulin sensitivity and mitochondrial function, making it a beneficial supplement for maintaining the effects of endurance training​ (BMJ Open Access)​​ (Diabetes Journals)​.
Nicotinamide Riboside (NR) has a growing body of evidence supporting its role as a precursor to NAD+, a crucial coenzyme for mitochondrial function and energy metabolism. Research indicates that NR supplementation improves mitochondrial function and supports healthy aging​ (BioMed Central)​​ (Diabetes Journals)​.
PQQ (Pyrroloquinoline Quinone) promotes mitochondrial biogenesis and has shown promise in enhancing cognitive function and energy metabolism. While the research is positive, it is less extensive compared to CoQ10 and ALCAR​ (BioMed Central)​​ (Diabetes Journals)​.
Urolithin A (Mitopure) stimulates mitochondrial biogenesis and has demonstrated benefits in clinical trials, including improved muscle function and endurance. The research is promising but still emerging​ (BioMed Central)​​ (Diabetes Journals)​.
Metformin, primarily used for diabetes management, activates AMPK and enhances mitochondrial biogenesis and insulin sensitivity. It has been shown to have positive effects on mitochondrial function, though it is primarily prescribed for its glucose-lowering effects​ (Diabetes Journals)​.
Rapamycin inhibits the mTOR pathway, enhancing mitochondrial function and potentially extending lifespan. Its use is more experimental and comes with potential side effects, making it less commonly recommended solely for mitochondrial health​ (Diabetes Journals)​.
CoQ10 and ALCAR are the most extensively supported by research, followed by ALA and NR. PQQ and Urolithin A have emerging support, while metformin and rapamycin are more specialized with broader implications for their use. Always consult a healthcare professional before starting any new supplement or medication.
Thoughts on Complex 1 inhibitors Some of these supplements are very speculative. Peter Attia is not convinced of NAD and neither am I. It might have an impact, but it's not been studied long term. Peter Attia also is not convinced of the utility of Metformin and neither am I. In my experience with Metformin and Berberine, while my fitness improved on some levels, my lactate levels were higher, it seemed to put me into a carb rather than fat burning mode of operations. Basically the same result Peter Attia experienced is what I experienced. As a result of this, it's a bad idea to use Metformin or Berberine.
Metformin blunts some benefits of exercise due to its activation of AMP-activated protein kinase (AMPK), a key energy regulator that both metformin and exercise activate. When both are active simultaneously, the overlapping pathways can reduce the exercise-induced improvements in insulin sensitivity and mitochondrial adaptations. This overlap leads to a state where the additive effects of exercise on these pathways are diminished, as the body is already experiencing heightened AMPK activation due to metformin​ (BMJ Open Access)​​ (Diabetes Journals)​.
Additionally, metformin interferes with mitochondrial biogenesis, a process that exercise naturally promotes to enhance cellular energy capacity. While metformin improves mitochondrial function in insulin-resistant tissues, it may hinder the exercise-induced mitochondrial adaptations in healthy tissues. This interference results in less pronounced improvements in muscle oxidative capacity and endurance performance during physical activities​ (Diabetes Journals)​​ (Diabetes Journals)​.
The increase in lactate levels observed with metformin use is primarily due to its inhibition of complex 1 in the mitochondrial electron transport chain, which shifts energy production from oxidative phosphorylation to anaerobic glycolysis. This shift increases lactate production as a byproduct of glycolysis. Furthermore, metformin disrupts the lactate shuttle, which involves the transport of lactate to the liver for gluconeogenesis, thus accumulating lactate in the blood. These mechanisms collectively contribute to elevated lactate levels during exercise in individuals taking metformin​ (Diabetes Journals)​​ (Diabetes Journals)​.
There are additional supplements I've tried like bergamot, but I'm not sure if this particular supplement helped or hurt. If I had to guess, it seems to have a mix between statin like effects and metformin like effects. It works by an entirely different mechanism from Metformin or berberine. Berberine itself works by a different mechanism from Metformin, but because it is a confirmed complex 1 inhibitor it's just as bad. The main difference is berberine has a very short half life while metformin has an unusually long half life. By inhibiting complex I, berberine reduces ATP production through oxidative phosphorylation and increases the reliance on glycolysis for energy production. This inhibition leads to a mild increase in the production of reactive oxygen species (ROS), which can have various signaling effects on cellular metabolism​ (BMJ Open Access)​​ (Diabetes Journals)​.
Lactate Shuttle Hypothesis, proposed by George Brooks in the 1980s, redefines lactate's role in metabolism. Traditionally viewed as a mere byproduct of anaerobic metabolism, lactate is now recognized as a crucial intermediary in energy production and metabolic regulation. During glycolysis, lactate is produced from pyruvate, especially under anaerobic conditions. This hypothesis posits that lactate is not just an end-product but a vital fuel source, transportable and oxidizable by various tissues, including the heart, brain, and skeletal muscles.
Lactate produced in one cell can be transported to another cell or tissue via monocarboxylate transporters (MCTs). This transport allows lactate to be converted back into pyruvate, which can then enter mitochondria for oxidation, contributing to ATP production during aerobic metabolism. This mechanism facilitates energy redistribution within and between tissues. For example, during intense exercise, lactate produced by fast-twitch muscle fibers can be transported to slow-twitch fibers for oxidation, optimizing energy utilization. The lactate shuttle thus supports the coordination of energy supply and demand across different organs and tissues, enhancing overall metabolic efficiency.
Numerous studies have confirmed the presence and function of MCTs in lactate transport and utilization. Research has shown that lactate can be taken up and oxidized by muscle cells' mitochondria and other tissues, providing a significant energy source during and after exercise. This concept has significant implications for understanding metabolic diseases and exercise physiology. It suggests that improving lactate clearance and utilization could benefit conditions like heart failure and diabetes, where metabolic flexibility is compromised. Understanding the lactate shuttle helps clarify the complex interplay of metabolic processes during exercise and in metabolic disorders, highlighting lactate's central role in energy metabolism.
Urolithin A is a metabolite derived from ellagitannins, compounds found in fruits like pomegranates, berries, and nuts. It is known for its potential benefits on mitochondrial health and muscle function. Urolithin A promotes mitophagy, a selective degradation process that removes damaged mitochondria, ensuring the maintenance and regeneration of healthy ones. This process is vital for maintaining mitochondrial quality, particularly in metabolically active tissues like muscle.
Urolithin A enhances mitophagy by activating the PINK1-Parkin pathway, which tags damaged mitochondria for degradation, promoting overall mitochondrial health and function. Additionally, by removing defective mitochondria, Urolithin A supports mitochondrial biogenesis, increasing the number and efficiency of mitochondria, which boosts cellular energy production and metabolic efficiency. It also exhibits anti-inflammatory properties, reducing chronic inflammation that can impair mitochondrial function and contribute to metabolic disorders.
Studies have shown the benefits of Urolithin A on mitochondrial health and muscle function. Preclinical studies indicate that Urolithin A extends lifespan and improves muscle function in animal models by enhancing mitophagy and mitochondrial biogenesis. Human clinical trials, such as one published in Nature Metabolism, have shown that Urolithin A supplementation can improve muscle endurance and mitochondrial health in older adults, suggesting its potential for mitigating age-related decline in muscle and metabolic health.
Integrating Urolithin A into a training program can enhance the benefits of exercise by improving mitochondrial function and muscle health. Urolithin A can be taken as a dietary supplement in the form of capsules or powder, ideally alongside meals for better absorption. Consistency is key, so it should be a part of the daily routine. Combining Urolithin A with regular exercise, particularly endurance and resistance training, can maximize its benefits since exercise itself promotes mitochondrial biogenesis and function. Monitoring improvements in muscle strength, endurance, and overall metabolic health can help assess the effectiveness of Urolithin A as part of a training regimen.
My experience with Urolithin A (mitopure) so far has been positive. This supplement seems to have a positive effect on mitochondria whether you exercise or not. When combined with exercise it seems to have only positive effects. This is in contrast to the complex 1 inhibitors or even certain statins which seem to have some sort of negative or blunting effect on the adaptations. Statins at least for now are necessary until better drugs become widely available and cheap, but metformin or berberine may be unnecessary for people who are willing to go the exercise route.
The PINK1-Parkin Pathway and Its Role in Mitophagy
Urolithin A activates the PINK1-Parkin pathway, a crucial mechanism for maintaining mitochondrial health through the process of mitophagy. Mitophagy is the selective degradation of damaged or dysfunctional mitochondria by autophagy, ensuring that cells maintain a healthy and functional mitochondrial population. Understanding how Urolithin A activates this pathway helps clarify its beneficial effects on mitochondrial health.

The PINK1-Parkin Pathway

PINK1 (PTEN-induced kinase 1) and Parkin are two key proteins involved in the identification and removal of damaged mitochondria:

1. PINK1:

• PINK1 is a serine/threonine-protein kinase that is normally imported into healthy mitochondria and rapidly degraded.
• When mitochondria become damaged (e.g., due to loss of membrane potential), PINK1 accumulates on the outer mitochondrial membrane instead of being imported and degraded.
• The accumulation of PINK1 on the outer membrane serves as a signal indicating mitochondrial damage.

1. Parkin:

• Parkin is an E3 ubiquitin ligase that is recruited to the outer mitochondrial membrane by PINK1.
• Upon recruitment, Parkin ubiquitinates various outer mitochondrial membrane proteins, tagging the damaged mitochondria for degradation.

Mechanism of Action

When mitochondria are healthy, PINK1 is continuously imported into the mitochondria and degraded. However, in the presence of damaged mitochondria with decreased membrane potential, PINK1 accumulates on the outer membrane. This accumulation acts as a signal to recruit and activate Parkin. Activated Parkin ubiquitinates specific proteins on the outer mitochondrial membrane, marking the damaged mitochondria for degradation by the autophagy machinery. This process involves the formation of autophagosomes around the damaged mitochondria, which are then delivered to lysosomes for degradation and recycling.

Urolithin A and the PINK1-Parkin Pathway

Urolithin A enhances mitophagy by modulating the PINK1-Parkin pathway. It promotes the accumulation of PINK1 on damaged mitochondria, leading to the recruitment and activation of Parkin. This activation results in increased ubiquitination of mitochondrial proteins and subsequent autophagic degradation of damaged mitochondria. By facilitating this process, Urolithin A ensures the removal of dysfunctional mitochondria, promoting the regeneration of healthy ones.

Supporting Studies

Research has shown that Urolithin A can activate the PINK1-Parkin pathway and enhance mitophagy in various models:

• A study published in Nature Metabolism demonstrated that Urolithin A improved mitochondrial health and muscle function in older adults by activating mitophagy through the PINK1-Parkin pathway​ (BMJ Open Access)​​ (BioMed Central)​.
• Another study in Cell Reports showed that Urolithin A induced mitophagy and improved mitochondrial function in aging muscle, supporting the idea that this compound can help mitigate age-related decline in mitochondrial health​ (Diabetes Journals)​.

Implementation in a Training Program

To implement Urolithin A in a training program, it can be taken as a dietary supplement alongside regular exercise. Consistency in supplementation and exercise is key, as both activities synergistically promote mitochondrial health. Monitoring progress in muscle strength, endurance, and overall metabolic health can help assess the effectiveness of this approach.
By activating the PINK1-Parkin pathway, Urolithin A helps maintain a healthy mitochondrial population, which is essential for optimal cellular energy production and metabolic health. This mechanism underscores its potential benefits for improving exercise performance and reversing metabolic disorders.
The problem with lifestyle measures is the endurance training benefits don't last long. It's not a cure for metabolic syndrome but it's more like an effective treatment. It can mitigate some of the risks. Insulin resistance for example might not be as bad if you spend a lot of time doing resistance training and Zone 2/Zone 5 cardio. The lifestyle measure seems to work better than metformin but only if you can do it consistently for years. The muscle you build will allow for more carbs to be consumed, and for more glucose to be stored in the muscles instead of the liver. Fatty liver disease and visceral fat are problems, and lifestyle can avoid these problems better than any drug so far. Genetic factors cannot be controlled for, and some new drugs may have to be created for people who are genetically highly likely to develop type 2 diabetes, or who have high cholesterol for no dietary reasons. PCSK9 inhibitors are an example of this and maybe alphaGO will be able to help find new targets or pathways for drugs to improve mitochondria function.
​

EARTHING- THE MOVIE & THE INCREDIBLE SCIENCE OF GROUNDING
Related to our current focus on the electromagnetic body
Electrical Grounding Improves Vagal Tone in Preterm Infants
https://karger.com/neo/article-pdf/112/2/187/3236168/000475744.pdf
Grounding or earthing is the physical exchange of electrical frequencies between the human body and the earth. The human body is a natural conductor, but with our modern-day lifestyle—connected to electrical appliances, smartphones, and computers—most don’t know or forget that we can discharge some of the frequencies and recharge ourselves with the beneficial free electrons from the earth.
This documentary shows the profound effects earthing can have on human health, cognition, and general biological function. And it shows how detrimental it can be when we miss out on the natural electrons Earth provides.
One of the culprits are the insulating soles of our shoes, mostly made of rubber and synthetic materials. Our immune systems function optimally when the body has an adequate supply of electrons, which are easily and naturally obtained by barefoot contact with the earth.
Walking barefoot on the ground can literally become the first step to lasting health.
7 Ways to Use Free Electrons to Stop Inflammation (rapidly and dramatically)
https://www.thehealthyhomeeconomist.com/how-to-use-free-electrons-inflammation/
Grounding – The universal anti-inflammatory remedy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10105021/
The effects of grounding (earthing) on inflammation, the immune response, wound healing, and prevention and treatment of chronic inflammatory and autoimmune diseases
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378297/pdf/jir-8-083.pdf
https://emfnews.org/Medical-Thermography-Clinical-Earthing-Application-in-20-Case-Studies.pdf
Medical Thermography CASE STUDIES
https://emfnews.org/Medical-Thermography-Clinical-Earthing-Application-in-20-Case-Studies.pdf
Schumann Resonance: Does Earth’s 7.83 Hz “Heartbeat” Influence Our Behavior? Yes, the earth has a heartbeat, and scientists theorize that it could affect brain and nervous system activity.
https://interestingengineering.com/science/what-is-the-schumann-resonance
5.4B: Electron Donors and Acceptors
https://bio.libretexts.org/Bookshelves/Microbiology/Microbiology_(Boundless)/05%3A_Microbial_Metabolism/5.04%3A_Glycolysis/5.4B%3A_Electron_Donors_and_Acceptors/05%3A_Microbial_Metabolism/5.04%3A_Glycolysis/5.4B%3A_Electron_Donors_and_Acceptors)
All About Grounding: Techniques to Connect to Nature
https://www.verywellhealth.com/grounding-7494652 The Electromagnetic Body with Dr. Tom Cowan
https://home.solari.com/coming-tuesday-the-electromagnetic-body-with-dr-tom-cowan/
https://home.solari.com/coming-tuesday-the-economy-of-the-energy-body-with-ulrike-granogge
Earthing The Most Important Health Discovery Ever By Clinton Ober 2010
https://archive.org/details/earthingthemostimportanthealthdiscoveryeverbyclintonober2010/page/n133/mode/2up
Guide: Earthing systems
https://web.archive.org/web/20231228021719/https://electrical-engineering-portal.com/res/res5/A-good-guide-on-how-the-earthing-system-should-be-correctly-implemented.pdf
earthing-your-questions-answered.pdf
Beginners-Guide-to-Earthing.pdf
https://earthingcanada.ca/wp-content/uploads/Beginners-Guide-to-Earthing.pdf
https://electrical.theiet.org/media/1698/earthing-your-questions-answered.pdf
Why The Body Needs Free Electrons The basic science behind the need for free electrons is that the earth’s surface contains a negative charge. This is in contrast to our bodies, which tend to accumulate an excess of positive charges.
Having too much positive charge in our bodies can trigger disrupted cellular function leading to increased oxidative stress from excessive free radicals, aka a cascade of inflammatory response.
Harnessing free electrons allows the body to pair these excess positive charges with a corresponding negative charge and instantaneously negate the inflammatory effects.
It happens so fast that scientists cannot even measure it!
Neutralizing Excess Positive Charges The easiest and fastest way to neutralize an excess of positive charge in the body is by walking barefoot on clean, unsprayed ground. This direct contact with the earth is called earthing or grounding.
Below is a thermographic photo of the inflammation in a person’s body before and after earthing.
Notice how the warm/hot colors indicating inflammation are noticeably muted to cooler colors after a short period of earthing occurs.
In essence, harnessing the power of free electrons rapidly promotes a more favorable internal environment within the body. Besides lowered inflammation, the benefits include improved mood and energy levels, deeper more restful sleep, and reduction or elimination of pain.
As a personal testimonial, I had a mysterious pain in my left foot a few months ago. I didn’t have an injury and there was no diagnosed issue such as plantar fasciitis.
I thought earthing might help it even though I am grounded most of the day in my home. So, I started making an effort to walk barefoot outside for at least 10 minutes per day. Alternatively, I would sit in a chair on the lawn with my bare feet touching the ground while reading.
Within a few days, the pain was dramatically less, and within a couple of weeks it completely disappeared and has not returned (I am still earthing).
The Science of Reducing Inflammation with Free Electrons The science of how free electrons neutralize inflammation in a hurry is covered best in the documentary The Earthing Movie. You can watch it here for free courtesy of the Solari Report. (1)
The fabulous explanation of the science behind free electrons reducing inflammation begins at 27:20, but I highly recommend watching the entire docu from the beginning.
Many Ways to Harness Free Electrons! Walking on the bare earth, aka “earthing”, is perhaps the easiest and most accessible way to get a massive infusion of free electrons to short-circuit the inflammatory response in the body.
However, there are a number of other ways to access free electrons with a negative charge to pair with and neutralize excess positive charges in the body.
All of the methods I know of are listed below. My recommendation is to do as many of them as you can, as often as you can!
Walking Barefoot on the Earth Walking barefoot on the ground is the most basic and essential way to harness free electrons for reducing inflammation.
If you live in an area or climate where this is difficult, then at least invest in shoes that have leather soles. This will ensure that you will at least be grounded when you are walking around outside.
Rubber and synthetic soled shoes are very bad for our health if we never take the time for earthing as a critical countermeasure.
Swimming in Natural Waters Swimming in clean, natural waters such as rivers, springs, lakes and the ocean is a fantastic way to ground and absorb free electrons into the body.
When you are swimming, it’s not just your feet that are earthing…it’s your entire body! Thus, swimming in natural waters has the potential for an enhanced free electron benefit.
My favorite way to enjoy this is to swim in the many natural, cold springs here in Florida.
Note that swimming in chlorinated pools will not have the same effect as the chemicals in the pool are counterproductive to the process. This is the case even if the pool is in-ground.
Grounding Inside Your Home If your home is one floor and directly contacts the foundational slab with no crawl space between, then you can actually ground inside your home.
Only certain types of flooring are appropriate for this purpose, however. Unsealed concrete, stone, unglazed tile, and 100% wool carpets are perhaps the best options. (2)
Sealed wood floors are not grounded despite being a natural material.
If you do not live on the ground floor or have a home with a basement or crawl space underneath, you can compensate by using grounding sheets at night while you sleep.
I have vetted and recommend this brand of earthing products if you are in the market.
Note that the reduced inflammatory effect of grounding is less than earthing. In other words, you won’t be getting as many free electrons simply by grounding as you will when your bare feet directly contact the earth.
Hence, grounding inside your home is wonderful, but not a complete substitute for earthing.
Gardening Without Gloves Gardening without gloves (or gloves made of leather) is what I call “reverse earthing”.
You are receiving the free electrons via your bare hands instead of the soles of the feet.
If you absolutely must garden with gloves, beware of “microfiber leather” as it is actually a form of synthetic leather!
Hugging a Tree While “tree-hugging” is a bit of a pejorative term in modern language, in reality, it offers each of us an easy way to absorb lots of electrons from many parts of our body at once.
Thus, if you are unable to swim in natural waters or walk barefoot on the ground, consider “forest bathing” instead.
Trees generate a steady stream of voltage which can even be harnessed for their electrical output. (3)
For the parts of your body that are in contact with the tree, make sure the clothing is made of 100% natural materials such as cotton, wool, or bamboo. Preferably touch the tree with as much bare skin as possible.
Touching and Petting Animals Ever wondered why petting animals is so therapeutic?
Could it be that we are receiving many free electrons through our hands into our body, which short circuits the inflammatory process?
If your pet is lying on the ground outside while you are petting them, so much the better! This way, their body serves as an electrical conduit to yours and is an indirect way to “earth”.
Hugging Other People Similar to tree-hugging and petting animals, simply embracing loved ones is also a source of inflammation-reducing free electrons.
Hugging on the beach while you are both earthing would be the most effective time to cuddle, but even if not grounded, you can still share free electrons between yourselves.
This is one of the reasons why massage and other hands-on therapy is so beneficial.
In particular, if a person is ill, hugging them or simply holding their hands can donate your free electrons to their body to literally help them get well!
I’ve written before about how when my children were babies and toddlers, I would hold them for as long as needed to provide comfort and absorb some of the heat with my body to cool them off. Remarkably, time and again, this would serve to break childhood fevers quite quickly.
It is my view that my body donating free electrons to theirs was at least in part why this was so therapeutic.
"The Destroyer of Weakness" - Nature's Super Tonic (Shilajit)
https://www.sweethealth.co.uk/blogs/sweet-natural-health/shilajit-the-destroyer-of-weakness-natures-super-tonic
original found on Earthing
https://youtu.be/44ddtR0XDVU
Show less

https://journals.physiology.org/doi/abs/10.1152/physiol.2024.39.S1.1858

Abstract

Polycystic kidney disease is a monogenic disease caused predominantly by mutations in the PKD1 or PKD2 genes. These mutations result in the formation of large fluid-filled cysts derived from kidney epithelial cells that slowly replace functional healthy tissue. Affected kidneys rely heavily on glycolysis to meet energy demands, and is accompanied by a reduction in fatty acid oxidation and mitochondrial function. We previously reported that interventions inducing a state of ketosis, including caloric restriction, time-restricted feeding (TRF), ketogenic diet, extended fasting, and ketone supplementation, ameliorate or reverse polycystic kidney disease progression in multiple animal models. To elaborate on the capability of ketosis to alter disease progression, we compared, head-to-head, the effects of a daily 16:8 TRF regimen to periodic 48-hour fasting (PF) in both juvenile and adult Cy/+ rats. We found that alternative fasting interventions prevent juvenile disease progression and partially reverse established kidney disease in adults. Further, to test our hypothesis that an increase in β-hydroxybutyrate (BHB) may mediate these beneficial effects, we administered BHB to adult Cy/+ rats and stereospecific isomers to two orthologous mouse models of PKD (Pkd1^RC/RC, Pkd1-Ksp:Cre). BHB recapitulates the effects of fasting in these models independent of stereoisomer, reducing mTORC1 signaling, increasing GSK-3β phosphorylation, expression and translocation of Nuclear factor erythroid 2-related factor 2 (Nrf2) in cystic epithelia, and subsequent downstream targets of Nrf2. These findings extend and expand our previous report on the beneficial effects of ketosis on cystic disease progression and suggest that ketogenic metabolic interventions and BHB supplementation are capable of metabolic reprogramming in polycystic kidney disease.

https://doi.org/10.1128/mbio.00649-24
https://pubpeer.com/search?q=10.1128/mbio.00649-24
https://pubmed.ncbi.nlm.nih.gov/38619236

Abstract

Invasive fungal infections are a significant public health concern, with mortality rates ranging from 20% to 85% despite current treatments. Therefore, we examined whether a ketogenic diet could serve as a successful treatment intervention in murine models of Cryptococcus neoformans and Candida albicans infection in combination with fluconazole-a low-cost, readily available antifungal therapy. The ketogenic diet is a high-fat, low-carbohydrate diet that promotes fatty acid oxidation as an alternative to glycolysis through the production of ketone bodies. In this series of experiments, mice fed a ketogenic diet prior to infection with C. neoformans and treated with fluconazole had a significant decrease in fungal burden in both the brain (mean 2.66 ± 0.289 log 10 reduction) and lung (mean 1.72 ± 0.399 log 10 reduction) compared to fluconazole treatment on a conventional diet. During C. albicans infection, kidney fungal burden of mice in the keto-fluconazole combination group was significantly decreased compared to fluconazole alone (2.37 ± 0.770 log 10 -reduction). Along with higher concentrations of fluconazole in the plasma and brain tissue, fluconazole efficacy was maximized at a significantly lower concentration on a keto diet compared to a conventional diet, indicating a dramatic effect on fluconazole pharmacodynamics. Our findings indicate that a ketogenic diet potentiates the effect of fluconazole at multiple body sites during both C. neoformans and C. albicans infection and could have practical and promising treatment implications.
IMPORTANCE
Invasive fungal infections cause over 2.5 million deaths per year around the world. Treatments for fungal infections are limited, and there is a significant need to develop strategies to enhance antifungal efficacy, combat antifungal resistance, and mitigate treatment side effects. We determined that a high-fat, low-carbohydrate ketogenic diet significantly potentiated the therapeutic effect of fluconazole, which resulted in a substantial decrease in tissue fungal burden of both C. neoformans and C. albicans in experimental animal models. We believe this work is the first of its kind to demonstrate that diet can dramatically influence the treatment of fungal infections. These results highlight a novel strategy of antifungal drug enhancement and emphasize the need for future investigation into dietary effects on antifungal drug activity.

Authors:

• Palmucci JR
• Sells BE
• Giamberardino CD
• Toffaletti DL
• Dai B
• Asfaw YG
• Dubois LG
• Li Z
• Theriot B
• Schell WA
• Hope W
• Tenor JL
• Perfect JR

------------------------------------------ Info ------------------------------------------
Open Access: True
Additional links:

• https://doi.org/10.1128/mbio.00649-24

------------------------------------------ Open Access ------------------------------------------
If the paper is behind paywall, please consider uploading it to our google drive anonymously.
You'll have to log on to Google but none of your personal data is stored. I will manually add a link to the file in this post when received.
Upload PDF

First of all, we’ve already established that human beings have been eating exclusively meat for millions of years, so fat had to have been our primary energy source during this time.
On the surface then, it can’t be too likely that carbohydrates were our preferred source of fuel, given that they also only were available during one season of the year, that being fruit season. Further, looking at it from a biochemical perspective, glycolysis (the oxidation of sugar for fuel) is a ten step process that grants us 38 net ATP per glucose molecule (when converting all pyruvate and NADHs that are yielded into ATP as well), while beta oxidation (the oxidation of long chain fatty acids for fuel), is a four step process which grants us 129 ATP per 16-carbon fat molecule, which, if we were to only oxidize 6 of those carbon chains, so as to theoretically equate the amount of carbons between the two molecules (since glucose has 6 carbons), would result in the production of 51 ATP, which is just slightly higher than 34% more in terms of ATP yield compared to one entire glucose molecule during glycolysis—and that’s with only 37.5% of the entire fatty acid; when calculating how much more ATP is generated from the entire fatty acid chain compared to glucose, the result is 339% more—more than triple the energy derived from one glucose molecule. On top of that, if the fatty acid is an odd-chain fatty acid particularly, it can help in producing hemoglobin, glucose, or more ATP. Some people may be led to believe, then, that since fat is a more concentrated form of energy, it is more fattening as a result, which is also not true. To understand this, we must take a look at ketones and uncoupled vs coupled mitochondria very briefly.
As we know, mitochondria use oxygen to take in fuel in the form of glucose and/or fat and catabolize it. Heat is one of the substances emitted, but so is ATP. The mitochondria only use as much food energy as is required to make chemical energy in the form of ATP; the ratio is 1:1. The mitochondria are “coupled” in this state. This also generates relatively little heat, as heat is an indication of chemical inefficiency. When mitochondria are uncoupled, they do something different: they spend more energy than is required to produce ATP, which results in more heat, because, once again, heat is caused by chemical inefficiency. This is an example of mitochondrial "inefficiency," in which they have become "uncoupled." This occurs in fat cells over long periods of time during ketosis, when the mitochondria transform into brown adipose tissue from white adipose tissue, which tends to release greater heat and “waste” more energy per unit of time.
What all of this means is that if you are eating fat, sure, it’s a more concentrated source of energy, but, since fat does not raise your insulin, you will be in a ketotic state for much, much more lengths of time throughout the day, which will lead to an uncoupling of your mitochondria, which expend more energy, leading to even less of a propensity to store fat (and this is not to mention the satiety signals you receive when eating fat compared to when one consumes carbohydrates). The uncoupling of one’s mitochondria is a very beneficial phenomenon today. Historically, this would not have been beneficial, because it used to be a very great thing to store fat whenever your body had the chance to. However, now, we don’t need to worry about harsh winters, and we can safely abstain from carbohydrates and from living with coupled mitochondria.
The other thing to mention in this section alongside the mitochondrial changes is about how much better your body operates on ketones themselves as compared to sugar. When fat catabolism is extremely high for an extended period of time, we begin to create ketones. When a person is in active ketogenesis or ketosis, the creation of ketones accounts for nearly 50% of total fat oxidation. This can only happen when insulin levels are low, which implies no (or very few) carbohydrates should be consumed. When fat oxidation is high (when insulin is low), an abundance of AcetylCoA accumulates, which can enter a variety of biochemical pathways. However, because insulin levels are low, it cannot commence lipogenesis (fat formation), and because AcetylCoA levels are high, it prevents its own entry into the citrate/krebs cycle, resulting in no gluconeogenesis and no additional energy production. Therefore, the only thing left to occur is ketogenesis.
The benefit of being in systemic ketosis is that mitochondria are much more responsive during beta hydroxybutyrate metabolism, and there is less H2O2 production during βHB metabolism, which is one of the main reactive oxidative species generated in the body. Also, when ketones are fed to muscle mitochondria, they are very well “coupled;” there is very little change in oxygen flux, there is increased mitochondrial “health,” increased cell viability (meaning muscles grew better and were more resistant to injury),, reduced ROS (reactive oxidative species) production, and the mitochondria maintained ATP production. Ketones also slightly increase muscle oxygen usage; even the heart (a muscle) within someone who has succumbed to heart failure starts to rely more on ketones, and in doing so increases ATP production.
https://europepmc.org/article/MED/30071599
https://pubmed.ncbi.nlm.nih.gov/27475046/
https://pubmed.ncbi.nlm.nih.gov/26819376/
On top of all of this, glucose within a cell destroys lipid rafts, destroys cell organelles, binds to DNA and causes mutations to it, and, in a high enough concentration, glucose will kill a cell outright, unlike what the process of fat oxidation induces.
So, let’s get this straight—beta-oxidation gives us more than triple the net ATP yield compared to glycolysis, is 6 steps shorter, the fat being oxidized doesn’t inherently damage our cells, contrary to glucose, and, if the chain of fat is an odd-chain fatty acid, can be used to assist in the creation of hemoglobin, and we have a process by which our body makes glucose itself? This seems like a pretty clear indicator as to what process is the one we are designed to be using throughout our lives.
I mean, think about it—can you name me one animal (terrestrial or aquatic) that uses glucose as their primary energy source? I’m guessing not. Even herbivores don’t derive their effective energy from plants themselves; they derive their energy from the breaking down of those plants into short chain fatty acids through the digestive tract (i.e. cows and other ruminants, as well as primates like gorillas).
There are only two reasons scientists came to the conclusion that glucose is our primary energy source. The first one is because when we finally discovered the methods of analyzing what our cells were using for energy, we were, at that point, eating primarily glucose. They then inferred consequently that glucose must’ve been our primary energy source. The second one is one that is most often espoused, which is that when consuming a mixed meal of fat and carbohydrates together, the sugar is utilized by your cells first, therefore supposedly indicating that sugar is what your cells want the most.
Except this is a complete misinterpretation of what is actually happening in this situation, as I have already explained in the Randle Cycle section. But, to explain once more, what is really happening is that your body recognizes that glucose is vastly toxic, and is therefore trying to expend it as quickly as possible. If it can’t do it fast enough (or if the cells are disallowing entry via the Randle Cycle upregulation as a consequence of consuming a mixed meal), then de novo lipogenesis ensues, which simply translates to the creation of fat, in which the sugar is transmuted in the liver to fat, thus to be stored for later use (side note—isn’t it interesting how the form of energy stored in our body is fat, not sugar, further indicating that fat is our preferred energy source? Add that to the list in the last paragraph too).

Click here to read my full article:
Recent research shows that advanced glycation end products (AGEs) are a causative factor in many degenerative diseases. AGEs have been linked to Alzheimer’s, heart disease, diabetes, chronic kidney disease, wrinkles and loss of skin elasticity, and more.
The term AGEs (advanced glycation end products) refers to a lipid or protein being glycated, meaning sugar or aldehyde binds with the protein or lipid. It is a general term applied to a bunch of different molecules, but the basic premise is certain byproducts of glycolysis (producing energy from sugar) can bind with a protein or fat in the body and alter it permanently.
AGEs naturally occur in the body as a result of normal metabolism. You can also consume AGEs in foods, and their production can depend on how you cook the food.

Preventing the formation of AGEs in the body:

The glucose metabolites that react to form AGEs can be stopped in multiple ways in the body. In fact, the body naturally has several ways to combat AGEs, and the key is to promote this along with decreasing production.
The enzymes glyoxalase I and II are tasked by the body to break down methylglyoxal, one of the main precursors for the production of AGEs in the body. Methylglyoxal can be formed as a side-product during glycolysis.
Decreased levels of glyoxalase I (GLO1 gene) are associated with higher AGEs in the plasma of hemodialysis patients. Another study found that upregulating the GLO1 gene (animal study) prevented AGEs formation in the presence of high blood glucose levels.[ref]
What does it take to make glyoxalase? Glutathione, one of the body’s main antioxidants, is a cofactor of glyoxalase. Low levels of glutathione can reduce the activity of glyoxalase 1.[ref]
Taking this one step further, the Nrf2 pathway stimulates glutathione production in the cells. It has been shown in recent studies that activating the Nrf2 pathway can stop the formation of AGEs by eliminating methylglyoxal.[ref]
Often, when thinking of advanced glycation end products the mind jumps to the idea that eating sugar is entirely to blame: Glycolysis is a glucose-based pathway, and the side-products of glycolysis (especially methylglyoxal) increase AGEs. High levels of glucose in the blood do increase AGEs. But one of the ketone bodies formed when eating a low-carb diet is acetone, and acetone can also be converted using the CYP2E1 enzyme into methylglyoxal.[ref][ref]
​

https://web.archive.org/web/20210419222349/https://breaknutrition.com/omega-6-fatty-acids-alternative-hypothesis-diseases-civilization/

Omega-6 fatty acids: the alternative hypothesis for diseases of civilization

by breaknutrition Aug 25, 2017

Diseases of civilization

The world is facing a health crisis of unprecedented proportions. What have become known as chronic diseases, Western Diseases, or Diseases of Civilization (DC), have become pandemic as populations around the world adopt the lifestyle that first became prevalent in the country that perfected industrialization, the United States.

What are they?

The DCs revolve around the Metabolic Syndrome (MetSyn), a set of signs of disease that include central obesity, excess fats (or fatty acids) in the blood, high blood pressure and excess blood sugar. The diseases that associate with the MetSyn include the biggest killers in the industrial nations: heart disease, cancer, diabetes, neurological illnesses such as Alzheimer’s and host of seemingly unrelated autoimmune conditions.
Many causes have been blamed for the spread of the DCs; including lack of exercise, wheat consumption, excess consumption of calories, carbohydrates, sugar, animal fats, meat, environmental toxins such as pollutants or pesticides, genetics (most implausibly) and any cluster of associations dreadfully referred to as ‘multi-factorial’.
Each of these proposed causal factors fails, in my view, to explain the pandemic. What I’d like to introduce is an alternative hypothesis, one that better fits the observed epidemiology and that has clearly-described mechanisms that explain much of the pathology for the DCs.
Since it started in America, we’ll start with America. In the late 1800s and early 1900s three events occurred almost simultaneously. First, a method of detoxifying cottonseed oil, which had been an industrial waste product of the cotton industry, was discovered . Next came a method to ‘hydrogenate’ cottonseed oil, or make it into a solid-at-room-temperature edible fat . Thus cottonseed oil and the hydrogenated derivative known as Crisco—introduced in 1911—entered the food supply in large quantities for the first time .
Simultaneously, America began to experience heart disease in large quantities. Previously a very rare condition, heart disease quickly became an epidemic, and the relatively new modern medical profession began to track it, and attempt to devise treatments . Similarly, cancer “control” became a concern, with the forerunner of the American Cancer Society being founded in 1913 .

The single biggest change in the American diet over the 20th century was the increase in seed oils, which increased 1000-fold

What changed?

America, a massive agricultural exporting nation, exported the fruits of the industrial revolution, which included new foodstuffs, including white wheat flour, sugar and vegetable fatty acids— so called to distinguish them from the traditional animal fatty acids that had been used as food since human evolution.

I will refer to vegetable fats (or fatty acids) as seed oils, to distinguish fats made from seeds such as cotton, corn, soy, rape and others from fatty acids made from fruit like olives or palm fruit. This will become important later on.

Wherever American industrially-produced foods were introduced, DCs soon followed. Although not generally well known now, a number of doctors and scientists recognized the impact of industrial foods on populations abandoning their traditional diets for what has become known as the Standard American Diet (SAD) . I prefer the acronym MAD, Modern American Diet, as the American diet prior to industrialization was a largely meat-based one, and did not produce the same diseases, and will use that throughout . Original graph is from Teicholz, N., The Big Fat Surprise, Simon & Schuster: New York, 2014.

Japan as the canary in the coal-mine

While there are many cases we could examine, perhaps the most telling was the MAD being introduced to post-WWII Japan. After the Japanese surrender, America took over the southern Japanese island of Okinawa, and used it for their base of operations. Unlike most other traditional cultures into which the MAD was introduced, Japan was a highly industrialized country. Yet Okinawans still ate a traditional diet that revolved around pork, yams, and fresh vegetables, and made them famous as one of the “Blue Zones”, a population with exceptionally long lifespans—in fact, the longest in the world .
What is less known is what happened after America took control. The first American fast-food restaurant opened in Okinawa, 9 years before Tokyo, to meet the American soldiers’ appetite. Okinawans also enjoyed American fast food and rapidly adopted it as their own . In that one generation, DCs exploded into Okinawa. Fathers attending the deaths of their sons became a common occurrence, with obesity, heart disease and cancer becoming common.
Hirome Okuyama, a Japanese scientist exploring the dramatic change in longevity in Okinawa, in 1996 published a paper pointing the finger clearly :

Dietary fatty acids – the N-6/N-3 balance and chronic elderly diseases. Excess linoleic acid and relative n-3 deficiency syndrome seen in Japan
“The age distribution of the survival rates of male Okinawans in 1990 is also interesting. The mortalities from all causes for the generations over 70 years of age were the lowest, whereas for those males less than 50 years old they were the highest among the 47 prefectures…”

In a single generation, Okinawa went from the lowest mortality in Japan to the highest

Seed-oils and refined flours brought DCs to Japan

This one incident clearly disproves a number of leading hypotheses on the emergence of DC. It’s clearly not genetic (although that’s a factor, especially in Japan), as gene networks underlying complex adaptations don’t change that quickly. It’s not just caused by total carbohydrates per se, as the Okinawans had a high carb diet with tubers, rice and fruit prior to Americans arriving .
Americans introduced much larger quantities of cheap refined flours which replaced the Okinawan carb sources. It’s not caused by meat, as the rest of Japan had a huge increase in meat consumption after WWII, and longevity increased, unlike in Okinawa. It’s not caused by animal fatty acids, as they were rapidly replaced by cheap seed oils imported from America—which introduced a program to ‘Americanize’ the Japanese diet.
It’s unlikely to be caused by saturated fatty acids, as consumption of saturated fat was and remains lower in Japan than it was or is in America, and there are no mechanisms to explain how natural saturated fatty acids causes disease. Environmental toxins are an unlikely explanation too, as, while Japan was industrialized, Okinawa didn’t experience a major change in that regard.
There’s also no possibility of a local environmental factor in Okinawa, as Japanese who moved to America saw a similar increase in DCs. And just to throw it out there, this also disproves the cholesterol-heart disease hypothesis, as cholesterol is not associated with heart disease in Japan, but with increased longevity .

Excess Linoleic Acid Syndrome (ELAS)

In my reading, the diseases that surround the MetSyn share common traits. Inflammation and insulin resistance are oft-cited, but perhaps more significant traits include mitochondrial dysfunction, apoptosis (cell death), necrosis (tissue death) and genetic damage.
These point to the common mechanism, named ELAS by Okuyama . I think it’s the best candidate for cause and best explanation of the MetSyn and related, chronic DCs.

What’s Linoleic acid?

Linoleic acid (LA) is an Omega 6 fatty acid (n-6 PUFA) fat which is considered essential to human and animal function. To head folks off at the pass, n-6 fatty acids are found in all natural foods, plants and animals, so this isn’t something you need to avoid entirely – it’s not possible, nor necessary.
There are three major kinds of fatty acids. LA is a polyunsaturated fatty acid (PUFA) . It’s joined by monounsaturated fatty acids (MUFA) such as oleic acid (named for olive oil) and saturated fatty acids (SFA) such as stearic acid (named for steers, beef) or palmitic acid (named for palm oil). Fish oil is also a PUFA, but of the omega-3 variety (n-3 PUFA).
Omega 6 fatty acids are primarily made by plants, as are the similar n-3 PUFAs, and are concentrated up the food chain by animals eating those plants. The major sources of Omega 6 fatty acids in the MAD are oils refined from seeds and animals fed a high proportion of seeds.
PUFAs have traits which make them of interest: they’re highly susceptible to oxidation (rancidity), unlike MUFA or SFA, and they’re used throughout the body as building blocks for tissues and for various signaling functions, after being converted into other chemicals.

The rancidity of PUFAs is the root of the problem

When food goes rancid, it usually smells and taste bad because the MUFAs and PUFAs have decomposed into peroxides . Both n-6 and n-3 PUFAs are highly likely to go rancid. Humans don’t detect the rancidity of Omega 6 fatty acids particularly well, they smell slightly stale and people actually prefer the taste.
Contrast this to rancid n-3 PUFAs and imagine eating a rotten fish. No thanks! This is likely because concentrated n-6 foods were rare until the modern era .

The problems with rancid PUFAs

Both n-3 and n-6 PUFAs going rancid produce toxins, but the n-6 fatty acids produce worse toxins. Most notable of these—and best studied—are acrolein, HNE, and MDA; although there are many others. Collectively, they’re called oxidized linoleic acid metabolites (OxLAMs). Acrolein is the acute toxin found in cigarette smoke. HNE is the best marker of effects of ELAS, as it is only produced from n-6 fatty acids. All three are both produced in cooking or heating n-6 fatty acids, but are also produced in the body. How toxic are these products? Cooking with seed oils is the leading cause of lung cancer in non-smoking women in China .
The list of toxicities of these three chemicals is most impressive. Acrolein is a biocide, meaning toxic to all life. HNE and MDA are less bad than that but are cytotoxic (kill living cells), mutagenic (induce mutations in DNA) and genotoxic (destroy DNA). OxLAMs are also highly reactive, which means they can combine with other molecules in the body, inducing and stimulating malfunction .

A primary mechanism of ELAS

An increase in Omega 6 fatty acids consumption rapidly remodels the tissues in the body, as the fats are replaced throughout. In some tissues it happens within weeks, in others, like the human brain, it appears to take much longer . Increased n-6 consumption rapidly remodels cartilage, for instance, in all species studied, driving out the more stable omega-9 fatty acids (Oleic acid is a n-9 MUFA) . The same happens in mitochondria . As mentioned, mitochondrial dysfunction and DNA damage is a signature of the MetSyn and all related diseases. It’s seen in the fat cells in obesity, in the pancreas in diabetes and in the lining of the vessels of the heart in atherosclerosis, as well as in conditions of heart failure, fatty liver disease, neurological diseases such as Alzheimer’s and Parkinson’s, and, most notably, cancer.

OxLAMs trigger destructive chain reaction events

The mechanism for this is well-described, although not well-recognized. Excess n-6 linoleic acid (LA) consumption causes a remodeling of a molecule called cardiolipin in the mitochondria, the key energy-producing part of cells in all higher life forms. Cardiolipin comprised of LA is uniquely susceptible to oxidation compared to n-3 PUFAs, MUFAs or SFAs and this can happen spontaneously, as LA oxidation can be catalyzed by iron and cardiolipin is in constant contact with iron atoms in mitochondria. When cardiolipin oxidizes, a chain reaction can start. In vitro, so on the lab bench, this reaction continues until all cardiolipin is consumed, but luckily our body has countermeasures .
In this process OxLAMs are produced. HNE, for instance, causes other cardiolipin molecules to oxidize, thus potentially causing a self-sustaining chain reaction. Reactive Oxygen Species (ROS) are produced in the reaction, which can also cause adjacent cardiolipin to oxidize .
However, OxLAMs are several orders of magnitude more damaging to the bodies than simple ROS . HNE itself can induce the production of ROS. Oxidized cardiolipin causes mitochondrial dysfunction, as mitochondria are impaired with oxidized cardiolipin .
What follows is mitochondria either collapsing, inducing apoptosis or necrosis . Apoptosis is seen throughout DCs—in cancer the cells are essentially ignoring the apoptotic signal and going rogue. The Warburg Effect noted in cancers is thought to be a cellular reaction to mitochondrial dysfunction in which the cells adopt an alternative energy pathway to better suit their uncontrolled proliferation.
Thomas Seyfried, who has contributed much to the field of cancer metabolism, notes that dysfunctional cardiolipin has always been observed in cancer cells so far . Necrosis is seen in late-stage DCs, such as atherosclerosis, cirrhosis of the liver, heart failure and Alzheimer’s.
Once loose in the cells, the OxLAMs rapidly propagate, in a process known as Oxidative Stress (OxStr). HNE and MDA are the primary markers used to measure OxStr. ROS cannot leave mitochondria which are well prepared for them, but OxLAMs, being water-soluble, rapidly distribute throughout the cells and beyond. OxLAMs are also a regular part of mitochondrial function: HNE induces mitochondria to downregulate as a basic negative-feedback mechanism.
Presumably this is to limit HNE creation and the spare the important antioxidant glutathione (GSH), as well as the aldehyde dehydrogenase enzyme (ALDH). GSH and ALDH are both important in protecting the body against evolutionarily-expected levels of HNE. Unfortunately for us, excess HNE can impair the function of both GSH and ALDH, thus allowing propagation of a runaway chain-reaction.
Decreased levels of GSH are a typical sign of excess production of HNE, and a dietarily induced deficiency in GSH production predisposes to the DCs . A genetic deficiency in ALDH, which is highly prevalent in Japan and China, predisposes to all DCs .

Tissue health as a function of levels of different fatty acids

Confusingly, assays of n-6 status in pathological tissues often show a lower level of n-6 than other fatty acids, and in these cases, addition of n-6 can actually improve function. This appears to be due to the chain reaction depleting LA or arachidonic acid (AA). The latter is a long-chain n-6 fatty acid produced in the body from LA. N-6 levels are lower, but HNE levels have risen as N-6 is converted into OxLAMs .
OxLAMs can bind to and alter the function of DNA, both in the mitochondrion and cell nucleus. In fact, they appear to be the leading cause of genetic damage, as the markers used for genetic damage are those generated by OxLAMs . Widespread generation of mutagenic and genotoxic chemicals in a live organism (in vivo) would go a long way towards explaining the genetic damage common in DCs.

OxLAMs are inflammatory

OxLAMs such as HNE directly induce inflammation, increasing inflammatory markers. Excess levels of LA-derived AA also induces inflammation, as it is used to build chemicals that send pro-inflammatory messages to the body. The mechanism of anti-inflammatory drugs such as aspirin, NSAIDs and Cox-2 inhibitors partially impairs this pathway.
It appears that a fundamental job of macrophages, an immune-system cell that attacks foreign cells, is to remove toxic OxLAMs from the tissues. Macrophage infiltration into tissue is seen in various DCs other than atherosclerosis, including obesity . One explanation is that the modifications made by OxLAMs to molecules cause those molecules to resemble Pathogen-Associated Molecular Patterns (PAMPs)—the molecules appear the same to macrophages as those on bacteria.
Antibodies for oxidized LDL cholesterol (OxLDL) exist and development of these antibodies for therapy against atherosclerosis has revealed the antibodies to be equally sensitive to bacteria-derived lipopolysaccharides and OxLDL .
Anti-cardiolipin antibodies are seen in several severe autoimmune diseases and are only sensitive to oxidized cardiolipin. Thus excess n-6 is a known cause of autoimmunity. It may be the fundamental cause of the increase in allergic diseases seen in Okinawa and around the world .

Specific disease pathologies

Cardiovascular Disease (CVD)

Goldstein and Brown received a Nobel Prize for discovering the LDL receptor . The next thing they tried to do was to induce the first stage of atherosclerosis, the conversion of macrophages into foam cells, which form the core of the atherosclerotic plaques that are thought to cause heart disease. They failed . Steinberg and Witztum then discovered that LDL must be modified through oxidation to cause macrophages to become foam cells

The nature of the substrate for lipid peroxidation, mainly the in lipid esters and cholesterol, is a dominant influence in determining susceptibility. As noted by Esterbauer et al. (52), there is a vast excess of in LDL, in relationship to the content of natural, endogenous antioxidants. The importance of the fatty acid composition was impressively demonstrated by our recent studies of rabbits fed a diet high in linoleic acid (18:2) or in oleic acid (18:1) for a period of 10 wk. LDL isolated from the animals on oleic acid-rich diet were greatly enriched in oleate and low in linoleate. This LDL was remarkably resistant to oxidative modification, measured either by direct parameters of lipid peroxidation

Esterbauer discovered HNE which is always present in atherosclerotic lesions in all species. Oxidized n-6 PUFAs comprise a large proportion of the fatty acids found in these plaques . OxLDL is the second-best known predictor of myocardial infarction, exceeded only by the OxLDL/HDL ratio (HDL is high-density lipoprotein) .
Other aspects of circulatory disease, such as varicose veins and erectile dysfunction, also display increased rates of OxStr, as determined by the presence of OxLAMs. HNE and oxLDL are active throughout the pathological process to create foam cells, induce macrophage entrance into the lining of the vessels and spur apoptosis, necrosis as well as DNA damage seen in atherosclerosis.
Steinberg and Witztum followed up their rabbit study with a human study, which confirmed the importance of LA in creating OxLDL . Other studies have confirmed the effect. The most successful CVD prevention trial ever, the Lyon Diet Heart Study, which produced a 70% reduction in CVD rates, specifically reduced the consumption of LA and increased the consumption of n-3 and n-9 fats.
It adds validation to the mechanism in humans but should be noted that the metabolites were not measured . Clearing HNE reduces atherosclerotic lesions in an animal model .
Similarly, oxidative activities of OxLAMs are seen in varicose veins, with these markers always being present at affected areas . Erectile dysfunction also appears to be a consequence of this process. Erectile dysfunction drugs, aside from the obvious effects, also have an antioxidant effect, and appear to prolong life in those with vascular diseases .

Cancer

Cancer is considered by many to not be a single disease but a wide array of diseases with, so far as we know, different causes. Viruses are a well-known cause of certain cancers, so it is safe to say that there is no single causal agent of cancer, however appealing that prospect would be.
Much of the pathological behavior of cancer cells can be explained by the effects of OxStr: mitochondrial dysfunction, genetic damage, and a shift to glycolysis despite the presence of oxygen. HNE damages and impairs the function of pyruvate dehydrogenase, the enzyme that allows substrates produced by glycolysis to enter the mitochondria .
This loss, combined with malfunctioning mitochondria emitting high rates of ROS and OxLAMs, may explain the metabolic dysregulation and anti-oxidant upregulation often seen in cancer cells.
Epidemiological work has shown low rates of cancer in populations eating traditional diets. In Asians, migration to industrialized countries increases breast cancer rates many-fold to the point where they reach Western levels .
LA in the diet is in fact required to induce cancer in animals experimentally. The cancer-promoting effects of LA increase as it increases in the diet. This effect plateaus at around 4.4% of total energy, well below levels of consumptions seen in industrial civilizations .
One of the hallmark traits of cancer cells is the seemingly random mutations pervading unstable and disorganized nuclear genomes. There can be tens of thousands of mutations, much fewer than that and sometimes none at all . For many cancers, the theory of it resulting from a single mutation doesn’t hold for most cancers. HNE and MDA both damage DNA in vivo and HNE preferentially damages the p53 gene. The latter is part of the body’s natural cancer-control mechanism and is defective in colorectal and hepatocellular cancers .

Obesity

Omega 6 fatty acids consumption appears to be involved in obesity through several pathways. HNE, which is elevated in obesity, directly induces fat-storage across species at an intra-cellular molecular level by inducing pathological behavior in adipose tissue. The latter then fails to differentiate normally, leading to engorged adipose cells typical of obesity . As LA converts to AA, AA upregulation leads to increased production of endocannabinoids anandamide and 2-AG.
Anandamide and 2-AG are the cannabinoids our body’s produce themselves and are so-called mimetics of trans-Δ⁹-tetrahydrocannabinol (THC) found in marijuana. Injection of endocannabinoids in animal models induces overeating, regardless of how full they feel . Elevated 2-AG is a typical feature in human obesity.
Several studies by a group at the NIH have shown that dietary LA modulates production and levels of 2-AG and can directly induce obesity . Blocking the endocannabinoid receptor using a drug prevents obesity and metabolic syndrome, in animals and humans; however the side-effects like increased rates of suicide are unacceptable, leading to withdrawal of the drug .

Diabetes

One long-observed medical observation is that insulin resistance (IR) accompanies sepsis, a condition caused by infection. OxStr precedes IR in humans and OxLDL antibodies acutely reduce IR in a primate model of atherosclerosis . So the PAMPs found in OxLDL appear to be preoccupy by the immune system, with IR maybe being a reaction to a perceived infection.
A reduced LA diet has been shown to reduce IR in two human studies; one measured OxLAMs, which were also reduced .
HNE injected into skeletal muscle cells directly induces IR in those cells . Mitochondrial dysfunction is a common feature of diabetes and the resulting shift in energy production may play a role in IR. LA directly induces hyperinsulinemia in vivo in animal models of beta cells (which produce insulin in the pancreas) and OxLDL directly causes beta-cell death.
High levels of blood sugar (hyperglycemia) is a central feature of type 2 diabetes. Shulman et al. argue an adipose-centric theory whereby hyperglycemia in type 2 diabetes results from uncontrolled adipose tissue lipolysis which feeds into liver metabolism as an excess of acetyl-CoA that will go on to spur further gluconeogenesis (the creation of new glucose).
Others postulate a liver-centric theory where insulin directly changes the liver’s insulin-to-glucagon ratio, lowering it and thus leading to further gluconeogenesis .
Regardless of the explanation one subscribes to about why type 2 diabetics have high blood sugars, high levels of HNE accompany dysregulation of gluconeogenesis. However, I’ve not seen a mechanism to explain it.
The relation between the food you eat and insulin secretion is represented by the food insulin index, an interesting metrics to watch if you are diabetic.

Neurological diseases

OxStr has become recognized as a major pathological factor in several severe neurological conditions, the incidence of which has been increasing along with increasing n-6 consumption, as seen with Alzheimer’s, Parkinson’s and Lou Gehrig’s disease (ALS). As opposed to rat brains, human brains appear to have a rate-limiter for uptake of LA. AA however, which is only produced in small quantities from LA but concentrates in tissues, does pass the blood-brain barrier.
It’s been observed that AA increases prior to the onset of Alzheimer’s but decreases after its onset . AA is more subject to oxidation to HNE than LA is. HNE and other OxLAMs increase as AA decreases, perhaps indicating the self-perpetuating reaction is underway.
HNE is always found in the pathological areas of the brain. Injecting HNE in an animal model induces the formation of beta-amyloid plaques , the signature of Alzheimer’s disease.
People suffering from epilepsy have been prescribed high-fat ketogenic diets and often benefited from them immensely .
This is possibly because of direct neuronal effects of the diet on “ATP-sensitive potassium (KATP) channel modulation, enhanced purinergic (i.e., adenosine) and GABAergic neurotransmission, increased brain-derived neurotrophic factor (BDNF) expression consequent to glycolytic restriction, attenuation of neuroinflammation, as well as an expansion in bioenergetic reserves and stabilization of the neuronal membrane potential through improved mitochondrial function” .
However, these ‘clinical’ or ‘classical’ ketogenic diets have used highly inflammatory fats like hydrogenated soybean oil and have even been given as replacement shakes instead of a meal . This likely renders the treatment much less effective given how triggering (epileptogenic) inflammatory factors can be for epilepsy . This is why more modern incarnations of the diet tend to use a variety of non-inflammatory fats like butter, lard, coconut oil and olive oil which also happen to taste better.

Liver Disease

Non-Alcoholic Fatty Liver Disease (NAFLD) is a new disease which only appeared when n-6 consumption levels reached the current high levels.
It mimics the effects of alcohol-induced Fatty Liver Disease (FLD). Like cancer, LA is required to induce FLD in animals. Very low levels of LA in the diet allows animals to consume up to 30% of energy as alcohol without pathology .
Total Parenteral Nutrition (TNP) is a feeding strategy in humans with damaged or malformed guts. Fatty liver is a common consequence in TNP and replacing LA-rich oils with fish oils cures the condition in human infants .
A small pilot study from Poland examining NAFLD in humans reduced the dietary levels of n-6 while providing the bulk of calories as carbohydrates.
OxLAMs were reduced, as was insulin, HOMA-IR, weight and NAFLD resolved in 100% of subjects . HNE directly induces the fibrosis seen in advanced liver disease and in other DCs.

Blindness

The leading cause of the blindness in the United States is Age-related Macular Degeneration (AMD). This is probably the only condition where the causal role of n-6 has not only been established but is becoming widely recognized. It’s illustrative of principles that should likely be informative for treating other DCs. The retina of the eye is rich in PUFAs and like other tissues is affected by diet.
N-3 supplementation does not affect the progression of AMD unless it’s accompanied by low n-6 intake . That combination is preventative—an evolutionarily-appropriate balance of the fats appears to be crucial. N-6 fatty acids are very susceptible to oxidation by radiation, even visible light; blue light will induce retinal n-6 PUFAs to oxidize to highly toxic HNE.
This may also be the causal pathway behind sunburn and skin cancer.

And more!

Osteoporosis, osteoarthritis, asthma, diabetic side-effects such as kidney failure, chronic pain and my personal favorite, sunburn, all have pathological roots in ELAS. Even high rates of violence have been compellingly linked to ELAS.

Pathological cofactors

Several cofactors induce worsened OxStr is humans. In vitro, mixing LA, glucose and water at physiological concentrations induces peroxidation of LA into OxLAMs; the same has been shown in an in vivo animal model where increased n-6 feeding induced cardiolipin breakdown with subsequent induction of hyperglycemia causing mitochondrial collapse and cardiac necrosis .
This is seen in heart failure, now epidemic amongst humans. Alcohol, fructose, smoking, radiation and infection all increased levels of OxStr and as in FLD, the effects of OxLAMs may play a role in the pathology associated with those factors. If two factors contribute to a disease but the disease only appears when one is present, it’s logical to conclude that the required factor is causal.

A final note on epidemiology

The epidemiology around n-6 consumption and DCs reminds me of an old joke. A policeman sees a drunk crawling around under a street light.

“What are you doing?”
“I’m looking for my keys!”
“You lost them here?”
“No, I lost them over there.”
“Why are you looking here, then?”
“Because this is where the light is!”

Applying epidemiology to nutrition is a very daunting task. Conducting it in a modern, industrial society is much easier than going to a traditional society with no government statistics or wealthy research institutions.

So most of the epidemiology looking at food consumption is done in the industrial nations, which have mostly had high incidences of seed oils for a very long time, before nutritional epidemiology became a science

Seed oils appear to cease increasing rates of cancer appearance after they comprise 4.4% of energy, and saturate tissues at 5% .
Most industrial populations get more than 5% of energy from seed oils , so comparing one to another is to compare high to high, when what one wants to see is high vs low.
Nevertheless, there are a number of studies looking at DCs in populations with differing food patterns, and they strongly support the hypothesis, with the incidence of DCs in populations consuming fewer seed oils being either fractional or non-existent . This likely explains the rapid increase in DCs seen in countries eating MAD-type diets.

What’s missing?

According to several scientists I’ve read the work of or listened to lately, funding is missing. This is highlighted by Dr. Ron Krauss who works at the National Institutes of Health (NIH). According to him, the NIH have largely stopped funding clinical nutrition research.
That, combined with the pro-n-6 PUFA bias in the American nutrition establishment, means that it’s unlikely much research will be done in the U.S. Much of the research seems to be done in either second-tier US institutions or in Europe and Asia.
There’s a lot of lab work looking at mechanisms but not a lot of human interventional studies. The few that do exist however, like the Lyon Diet Heart Study, Christopher Ramsden’s work and the pilot LA metabolite intervention from Poland are all very compelling .
Research I would like to see on this question is an examination of PUFA status and OxLAM load in those few people still eating a traditional diet free from DCs, as well as interventional studies lowering n-6 PUFA.

Most such studies make no attempt to lower n-6, but just add n-3 on top of it. Due to competition between the two types of fatty acids and as seen in AMD, this is unlikely to be a successful strategy

It’s essentially the modern Japanese diet: excess n-6 but good n-3. This has not prevented DC in Japan, but they do have lower rates of some diseases, like cardiovascular diseases.

Conclusion

HNE was discovered in the early 1980s, many decades after seed oils were introduced. The relationship between n-6 and endogenous production of signaling molecules was discovered later. N-3 fatty acids became recognized as important after that.
Research into this topic was in the 10s of papers in the 1970s and has increased by 135-fold today. It’s a burgeoning field but one that appears to be very much under the radar. In reading through the literature, I have come to the conclusion that the case for ELAS as the root cause of Diseases of Civilization is overwhelming.
Personally, I came to this topic through Stephan Guyenet and his excellent Whole Health Source blog. After months of reading his posts and reading the papers he linked to, I decided to cut seed oils from my diet on the spur of the moment, standing in front of the salad dressings in a cafeteria.
My irritable bowel syndrome of 16 years disappeared in two days. My carb cravings disappeared as quickly, allowing me to discover an underlying wheat sensitivity. Sunburn became a thing of the past and as a pale blonde who had always assumed I was ill-adapted to life under the sun, this was revolutionary.
My excess weight dropped off, along with my now too-large pants one morning, never to return. And after six broken bones in two years, I haven’t broken one since.
I started reading on the topic because I wanted to understand what had caused my personal health recovery – and I guess because I like puzzles.

What to do about excessive n-6 consumption?

Avoid eating seed oils, foods containing seed oils—junk food and animals fed high levels of grains and seed oils, like pork and chicken. Don’t go crazy with the nuts. Eat some fish. But no, you can’t fix ELAS with extra n-3 fatty acids like fish oil, as the Japanese case demonstrates.
Except for fasting, this is the simplest health intervention ever, as it’s impossible to become deficient in n-6 fatty acids when eating whole foods. Even if a fraction of the diseases with pathological signs pointing to n-6 are proven, you’ll still be far better off.
William E.M. “Bill” Lands spent his scientific career studying the role of n-6 and n-3 fatty acids in the body. His conclusion, the title of an article written during his retirement, deserves to be the note to end on here :

Prevent the cause, not just the symptoms

"ME/CFS Research Roadmap Priorities
The goal is to receive broad feedback on the research priorities being developed by the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Research Roadmap Working Group of Council that will result in a report presented to the National Advisory Neurological Disorders and Stroke (NANDS) Council in May 2024."
Here's a link to the campaign to get your feedback heard:
https://ninds.ideascalegov.com/c/campaigns/1286/about
I submitted my suggestion already and it's pending so I'll post it here but if you happen too see it on the ideas, please like it so it may help being seen:
​
"The Epigenetic Modulation via histone code behind self-sustaining immunometabolic dysfunction in the Pathogenesis of CFS:
A proxy model that is a working diagnostic tool.
For the past 2 years I have been conducting a systematic review of the scientific literature on CFS so that I might better advocate on behalf of a partner disabled by CFS to their doctors who have failed to diagnose them for a decade.
The evidence for an immunometabolic framework underpinning CFS symptomology is growing. From physical evidence of mitocondrial dysfunction in tissue, to studies giving hepatitis c patients InF-A treatment and the patients getting long term CFS.
However, an overwhelming majority of the work seen in CFS has very little consideration of the mechanical inner workings of immunometabolomics.
And even among the considerations that do factor these more formative operators within the cell, there is a lack of system coupling between the pathophysiological mechanisms at play between immunological signaling, metabolic homeostasis/signaling and histone code.
That is what I want to emphasize with urgency.
Until we elucidate all vectors of pathophysiological propagation on their most fundamental levels, informed speculation with never be elevated to understanding.
There is a plenty of evidence already showing how metabolic status modulates histone code and there is a very real case to be made for how this system coupling demonstrates a pathogenesis for CFS.
Due to the similarities between CFS and other disorders, focusing on mapping the mechanics of a unified immunometabolic-histone code framework is incredibly valuable research data. Even if one does not suspect it as an etiology, it is necessary work for the advancement of medical science.
I am writing a paper regarding the systematic review I've done that includes the citation and if you'd like a copy when I'm done, feel free to ask.
For now I will do my best to very briefly outline a proxy model for etiology building off of the INF-a/itaconate shunt framework.
​
In the Interferon alpha/Itaconate shunt framework, metabolic dysfunction is caused by the activation of the innate immune system. This dysfunction is characterized by the cell entering a "viral state" in order to diminish energy production, delaying harmful replication as a mechanism of defense to give the adaptive immune system time to kick in.
Signaling via JAK/STAT pathways activates an enzyme, Cis-aconitate decarboxylase, that reroutes the cis-aconitate in the TCA cycle into itaconate, hence the itaconate shunt.
This new metabolic pathway leads to a couple of other reactions but the problem there is that these reactions are much slower and involve Coenzyme A, ultimately leading to a metabolic state where all cellular CoA has been sequestered into this shunt.
This has several ramifications, primarily being that the TCA cycle cannot complete. With all the CoA being sequestered, you cannot get acetyl-CoA, which means you cannot get energy into the TCA cycle through glycolysis or beta-oxidation as they both require acetyl-CoA and must rely solely on amino acids, which disrupts homeostasis of neurotransmitter metabolites.
The cell resolves this disconnect by utilizing the GABA shunt, where GABA and thus glutamate are used to facilitate the completion of the TCA cycle. This shunt only produces around 43% of the energy the cell would otherwise normally produce.
The primary impacts of this immunologically induced mitocondrial dysfunction, when active, are elevated succinate, as it is a downstream outcome of the GABA shunt and itaconate creates a bottleneck on succinate by activating an enzyme inhibiting it's catalyzation into fumarate, strained glutamate status/adp (exertion) creates ammonia, and finally depleted GABA status once glutamate is depleted.
(Since doctors have been unable to help with my partner's disabling CFS symptoms, we've attenuated this shunt over the counter with an S-Acetyl L Glutathione centered protocol including cofactors to support glutamate status without using atp because the resulting adp catalyzes ammonia that glutamate status must be used to diffuse, as well as ALCAR and B5 to get CoA into the mitochondria. In the past year my partner has gone from nightly fevers and bedridden majority of the month, to being able to work part time 20 hours a week and understanding that during PMS pro-inflammatory cytokines must be mitigated.)
It is useful to note here that metabolites, like elevated succinate, signal to the immunological matrix via the succinate-HIF-1α signaling pathway, which is modulated by oxygen status and explains why HBOT is effective at attenuating some symptoms long term.
All my partner's metabolic labs reflected this flamework at a time when the initial trigger (OTA mycotoxin from a childhood through adulthood residence) was detected in their body as well as evidence of innate immune activation in the presence of IgM in labs.
While the shunts in this framework may explain symptomology, researchers exploring this proxy model are looking for why it persists when Interferon alpha signaling should be turned off at one of its signaling checkpoints facilitated by SOCS1 / SOCS3 pathways.
​
Here, I ask we look even deeper than the mitochondria and explore the mechanical implications of the resulting metabolic state induced by the innate immune system.
If you recall, the cellular CoA in cells affected by pro-inflamatory cytokine signaling is entirely sequestered. This means that acetate cannot participate in histone modulation as it can only enter via acetyl-CoA. Imbalanced acetylation has been show to lead to excess methylation of histones resulting in heterochromatin and ultimately impacting the chromatin structure and thereby inhibiting gene expression.
I propose that the prolonged interfacing of a viral-phase-metabolic state with histone code has led to alterations of heterochromatin transcription structures in an epigenetic modulation that inhibits gene expression associated with, but potentially not limited to, anti-inflammatory signaling is the patheogenesis behind CFS and, if given a different state of immunometabolic-histone code, potentially other disorders. This long term modulation suppressing anti-inflammatory cytokine signaling, is why INF-A signaling can become chronic and lead to the potential of resurgence during remission.
Reversing chromatin structure modulation may require a combination of therapeutic approaches. For example, using HDAC inhibitors, DNA demethylating agents, or histone methyltransferase inhibitors in conjunction with other epigenetic modifiers could potentially induce substantial changes in the chromatin landscape.
However, the extent to which this reversal can be achieved may vary depending on the specific context and the stability of the underlying epigenetic marks.
The theme that I'm placing urgency on here is systems coupling.
Any effective treatment must consider the impacts on more than one system.
You cannot just suppress immunological signaling because metabolic signals and histone methylation will modulate the accessibility of transcription factors to necessary genes.
And you cannot just correct metabolic homeostasis because the next time pro-inflammatory cytokine signaling happens, and it happens often naturally in my partner at least due to things like menstration or low TSH levels, the gene expression of immune regulators has been inhibited by the histone code's epigenetic modulations and immune signaling will cascade into metabolic dysfunction again.
It seems that any effective treatment would have to restore baseline immunometabolic homeostasis simultaneously with epigenetic modulation in the expression of SOCS via histone code modulation to achieve any potential long term remission or epigenetic correction.
Once we consider the disease of cellular autonomy is addressed, then individual considerations can be made for the cells of systems that may have had their baseline homeostasis modulated by the patient's initial trigger.
For example, my partner's initial trigger, OTA, impacts the kidneys, primarily concentrating in renal tubules. Chronic inflammation via INF-a signaling disrupted her aldosterone homeostasis, facilitated within the renal tubules, resulting in a dysregulated RAAS system and finally hypothyroidism that occasionally manifest's as hyperthyroidism in labs.
TSH levels have a dynamic relationship with INF-a signaling, so in this framework we have to consider that taking synthetic t4 for the hypothyroidism has historically led to downregulated TSH and that signals the metabolic shunts.
In fact, INF-a signaling is how the body tells the thyroid that it's conserving energy and activates an enzyme that turns t4 and t3 into their inactive forms, t2 and rt3.
Therefore, my partner, I, and hopefully one day their doctor, cannot rule out the possibility that the hypothyroidism is transient and due to the chronic signaling within the innate immune response via INF-a and may need to discontinue taking Synthroid to contribute to successful treatment.
This immunometabolic signaling matrix engendering epigenetic repression of it's own regulation would have precise implications for the cells and functions of too many systems and disorders to enumerate in detail here. However, that should highlight the usefulness of this framework.
A framework that only becomes more precise by elucidating the mechanisms of immunometabolic-histone code interfacing gene expression, a pursuit that benefits all of medical science by illuminating the machinery of the most formative governing operators in the human body.
Here a just a few ideas on how we could proceed with this framework:
Genome-wide Analysis of Histone Modifications:
Researchers could perform chromatin immunoprecipitation sequencing (ChIP-seq) or other high-throughput techniques to map the distribution of histone modifications across the genome in individuals with CFS compared to healthy controls. This analysis could identify specific changes in histone marks associated with regulatory regions of genes involved in relevant biological pathways.
Histone Modification Profiling in Specific Gene Regions:
Focusing on genes known to be associated with CFS or implicated in relevant pathways, researchers could investigate the levels and patterns of histone modifications (e.g., methylation, acetylation) in the promoter regions or enhancer elements. This could help identify differences in chromatin structure and epigenetic regulation specific to CFS.
Epigenome-wide DNA Methylation Analysis:
Researchers could perform genome-wide DNA methylation analysis, such as bisulfite sequencing or array-based methods, to identify differential DNA methylation patterns associated with CFS. Integrating these findings with histone modification profiles can provide a comprehensive understanding of the epigenetic landscape in CFS.
Functional Analysis of Epigenetic Changes:
To determine the functional consequences of identified histone code alterations, researchers could perform functional assays, such as gene expression analysis and in vitro or in vivo models. Manipulating histone marks using techniques like CRISPdCas9-based systems or pharmacological modulators could help establish causal relationships between specific histone modifications and CFS-related phenotypes.
Longitudinal Studies:
CFS is a chronic condition, and its etiology involves dynamic changes in the histone code over time. Longitudinal studies could track histone modifications and epigenetic changes in individuals with CFS at multiple time points to identify potential changes associated with disease progression or treatment response.
Animal Models:
Animal models, such as mice, could be used to explore the effects of specific histone modifications on fatigue-like behaviors, cognitive function, and other CFS-related symptoms. Manipulation of histone-modifying enzymes or targeted modulation of histone marks using genetic or pharmacological approaches could be employed to investigate the causal relationship between histone code alterations and CFS-like phenotypes.
Anything else I could add, I will write in my systematic review.
Also, somebody please hire me, I want to help."
​
I'm still working on a document to help people acclimate to the state of research on CFS and to help them advocate for themselves to their doctors. I'll be sure to post it in this subreddit for this community when I'm done.
​
​

The following summary was created with the Recall Browser extension, you can save the online version here to your Recall Knowledge base.

Dr. Peter Attia, Journal Club (00:00:00)

• Dr. Peter Attia is a medical doctor and world expert in healthspan and lifespan.
• Today's episode is the second in a Journal Club series where Dr. Attia and Dr. Andrew Huberman share and discuss interesting and actionable research papers.

Light, Dark & Mental Health; Retina (00:07:14)

• A study involving over 85,000 people in the UK examined the relationship between light exposure behavior and dark exposure behavior on mental health.
• There is a correlation between day length and mood, with longer days in spring and summer associated with fewer depressive symptoms.
• Seasonal effective disorder (SAD) is a condition where people experience lower mood and affect during shorter days.
• Bright light therapy, typically using 10,000 Lux lamps, is an effective treatment for SAD.
• Light exposure during the day and dark exposure at night have independent and additive effects on mental health.
• Melanopsin retinal ganglion cells in the retina respond to bright light and send signals to the hypothalamus, which controls the circadian clock and affects mood.
• Outdoor sunlight provides much higher Lux levels compared to indoor environments, even brightly lit ones.
• On cloudy days, the total photon energy may be similar to a sunny day, but the lack of visible sunlight affects the circadian clock.
• It's recommended to get 10 minutes of sunlight in the eyes early and late in the day, avoiding sunglasses during these times to maximize light exposure.
• Sunglasses are advisable during the middle of the day to prevent cataracts and macular degeneration.
• Large windows that allow direct sunlight can provide sufficient light for the circadian clock, but skylights are even more effective.
• The cells in the retina that signal to the circadian clock are located in the bottom two-thirds of the neural retina and are responsible for looking up, gathering light from above.

Outdoor vs. Indoor Light, Cataracts, Sunglasses (00:11:16)

• The circadian clock sums photons, integrating light exposure over time rather than responding to quick changes in light intensity.
• Experiments have shown that bright light can cause these cells to fire action potentials for hours, propagating signals throughout the brain and body.
• Sunlight in the early and late parts of the day, when the sun is low in the sky, poses minimal risk of inducing cataracts.
• Sunglasses are recommended during the middle of the day to protect against cataracts and macular degeneration.
• Large windows that allow direct sunlight can provide sufficient light for the circadian clock, but skylights are even more effective.

Tools: Sunrise & Sunsets, Circadian Rhythm; Midday Light (00:16:17)

• Humans and animals have two cone opsins that respond to short-wavelength (blue) and long-wavelength (orange/red) light.
• These cells compare the contrast between blues and oranges/reds to trigger the existence of those wavelengths of light.
• Low solar angle sunlight at sunrise and in the evening contains enriched blues, oranges, pinks, and reds.
• Viewing low solar angle sunlight in the morning advances the circadian clock, leading to earlier bedtime and wake-up time.
• Viewing low solar angle sunlight in the evening delays the circadian clock, leading to later bedtime and wake-up time.
• These signals average to keep the clock stable and prevent drifting.
• Midday sun contains all wavelengths at equal intensity and is in the circadian dead zone, so it doesn't shift the circadian clock.
• Color vision evolved first for setting the circadian clock, not for pattern vision or aesthetics.
• It's better to get morning light than evening light if you can only do one.
• Retinal sensitivity to light increases as the day goes on, so less light is needed to shift the circadian clock late in the day.
• Afternoon and evening sunlight can partially offset the negative effects of artificial light exposure at night.
• Aim to view low solar angle sunlight early in the day, later in the day, and get as much bright light as possible throughout the day.
• Invest in sunrise and evening simulators or use the 20/20 light bulb for precise color contrast.
• The 20/20 light bulb simulates the contrast of short and long-wavelength light found in low solar angle sunlight and may induce mild euphoria.
• Most SAD lamps only activate one of the relevant mechanisms in the cells and not the most relevant one.
• Future devices like laptops and phones should incorporate these light features.

Tools: Night & Light Exposure; Waking Before Sunrise (00:24:55)

• Dark exposure at night, independent of light exposure during the day, is important for mental health outcomes.
• Some people are more resilient to light effects than others.
• Light exposure to the eyes is what's relevant for circadian rhythm regulation, not the color of one's eyes.
• The best way to wake up if you want to be awake is to turn on as many bright lights as you can indoors.
• If you want to stay asleep or sleepy, keep the lights dim.
• Get outside once the sun is starting to come out.
• In the evening, especially in the winter months, it's important to look West and try and get some sunlight in your eyes.
• Avoid blue blockers in the middle of the day, as they can disrupt circadian rhythms.
• Dim the lights and ideally have lights that are set a little bit lower in your environment in the evening.

Article #1, Light/Dark Exposure & Mental Health (00:31:05)

• The study found that getting a lot of sunlight exposure during the day and getting a lot of dark exposure at night is immensely beneficial for psychiatric health.
• The more time you spend outdoors, the better your mood, sleep, and sleep-wake cycles.
• Avoiding light at night and seeking light during the day may be a simple and effective non-pharmacologic means for broadly improving mental health.
• Wrist-based devices used to measure ambient light are not perfect but can provide valuable information about light exposure patterns.
• The study found that greater light exposure in the day is associated with lower risk for psychiatric disorders, while greater light exposure at night is associated with higher risk for psychiatric disorders and poorer mood.
• Sleep duration and efficiency were determined using accelerometers and self-report.

Odds Ratio, Hazard Ratio (00:38:18)

• Odds ratio: probability of something happening in one group divided by the probability of something happening in another group.
• Hazard ratio: defined over a specific period of time.
• Odds ratio of 2 is 100% and odds ratio of 3 is 200%.

Night vs. Daylight Exposure, Mental Health Disorders (00:45:43)

• More nighttime light exposure is associated with worse mental health symptoms, including major depressive disorder, generalized anxiety disorder, bipolar disorder, PTSD, self-harm, and psychotic symptoms.
• The inverse is true for daytime light exposure, with more daytime light exposure generally associated with reduced symptoms.
• ICU psychosis is a phenomenon where non-psychotic individuals start having psychotic episodes in the hospital due to nighttime light exposure and lack of daytime sunlight.
• It is possible that we are all socially jetlagged due to not getting enough daytime light and getting too much nighttime light.

Major Depression & Light Exposure; Error Bars & Significance (00:51:35)

• Strong correlation between increasing light at night and depression.
• Uncoupled relationship between nighttime light and self-harm in the upper quartile (25% of people with the most nighttime light).
• No significant increase in self-harm at lower levels of light exposure at night, but a 30% greater risk in the fourth quartile.
• Inverse relationship between daytime light and self-harm.
• Psychosis relationship based on daytime light and PTSD relationship based on nighttime light are notable.
• Anxiety and bipolar disorder relationships with light exposure are less impressive.
• Going from the second to third quartile of nighttime light exposure leads to almost a 20% increase in major depressive symptoms.
• Fourth quartile of nighttime light exposure shows a 25% increase in major depressive symptoms.
• Fourth quartile of daytime light exposure leads to a 20% reduction in major depressive disorder.
• Varying lengths of error bars indicate that the study is not overpowered.
• Error bars for self-harm range up to 20% on either side of the mean, while error bars for major depression are around 8-10%.

Prescriptions; Environmental & Artificial Light; Red Lights (01:00:39)

• People with sensitive circadian mood systems may need less daytime light exposure and very little light at night to impact their mood systems negatively.
• Some drugs used to treat bipolar disorder may reduce the sensitivity of the light-sensing circadian apparati, potentially ameliorating some symptoms.
• Certain antidepressants may suppress the ability of daytime light to positively impact the brain's mood systems.
• Darkness for eight hours every night should be considered a treatment for bipolar disorder.
• Avoid bright, extensive light exposure at night.
• Moonlight, candlelight, and campfires are relatively dim compared to densely overcast days and phone screens.
• Phones emit high levels of light, especially when used at maximum intensity.
• The context of light exposure matters. Engaging in stimulating activities on a device with a blue light filter can be more disruptive than watching relaxing content on a device with maximum light.
• Red lights can be used to minimize light exposure at night.

Nighttime Light Exposure; Sleep Trackers & Belief Effects (01:08:14)

• Light exposure at night should ideally be for enjoyable reasons.
• The negative impact of social media may be due to various factors, including screen time, lack of other activities, and content viewed.
• Sleep trackers can have a placebo effect on perceived sleep quality.
• Seeing a bad sleep score may lead to negative expectations and a worse day.
• Sleep trackers can be useful for learning about sleep patterns and making behavioral changes, but they should be used cautiously and not relied upon too heavily.
• Recovery scores and similar metrics are not reliable predictors of performance.
• Serious athletes rely on more traditional methods like heart rate and heart rate variability to predict behavior.

Light Directionality, Phone, Night (01:13:54)

• Reduce nighttime light exposure to improve mood and sleep.
• Brief exposure to bright light at night is less concerning than prolonged exposure.
• The directionality of light matters. Avoid looking directly at bright light sources, especially at night.
• Tilting the phone away from the face when using it at night can reduce light exposure to the eyes.

Light Wavelengths & Sensors; Sunglasses (01:17:21)

• Sunlight includes visible light from 470 nm to 650 nm (blue to orange).
• The study used wrist sensors that detected light from 470 nm to 650 nm (blue and ultraviolet).
• Corrective lenses focus light onto the retina, while windows and windshields scatter and filter light.
• Sunglasses filter out too much light, reducing the total Lux count reaching the retina.
• People differ in their light sensitivity, with darker-eyed individuals generally less sensitive than lighter-eyed individuals.

Hawthorne Effect, Reverse Causality, Genetics (01:20:58)

• The Hawthorne effect refers to the change in behavior when people are being observed.
• Reverse causality occurs when the condition being studied influences the treatment or outcome.
• Obesity and diet soda consumption: the association between diet soda consumption and obesity may be due to reverse causality, with obese individuals choosing diet soda to reduce calorie intake.
• Depression and light exposure: the disruption in light exposure in depressed individuals may be a result of the depression rather than the cause.
• Mendelian randomization could be used to examine the genetic basis of light susceptibility and its link to mental health disorders.
• Manic episodes can lead to increased nighttime light exposure, while dark nighttime exposure is being explored as a treatment for bipolar disorder.

Artificial Sweeteners, Appetite (01:26:26)

• Artificial sweeteners may alter the gut biome and metabolism in susceptible individuals.
• Some people experience increased appetite when consuming diet soda due to the perception of sweetness.
• Artificial sweeteners can impact brain and gut chemistry, potentially affecting metabolism.
• Xylitol and allulose are considered safer sweeteners.
• Stevia, monk fruit, and sucrose should be consumed in moderation.

Natural Light Cycles, Circadian Rhythm & Mental Health (01:31:16)

• Light exposure has a significant impact on mental health.
• Disrupted circadian rhythms are associated with psychiatric conditions, including depression and suicide.
• Positive mood and affect are correlated with healthy circadian behavior.
• Morning sunlight increases the amplitude of the morning cortisol spike, which is beneficial for sleep regulation.
• Following natural light-dark cycles can improve mental health.
• The dose-effect relationship, biological plausibility, and evolutionary conservation support the causal effects of light on mental health.
• Simple light-related behaviors, such as taking coffee on the balcony or removing sunglasses outdoors, can positively impact mental health.
• Getting daytime light exposure and nighttime darkness are independent and additive for mental health benefits.

Article #2, Immune System & Cancer (01:39:53)

• The immune system is remarkable in its ability to detect and eradicate harmful foreign pathogens without attacking the self.
• Autoimmune conditions occur when the immune system mistakenly attacks the self.
• Cancer cells evade the immune system's detection and destruction.

T-Cell Activation; Viruses (01:43:18)

• T-cells recognize and get activated by antigens, which are small peptides of proteins.
• MHC class one receptors present antigens from inside the cell to CD8 T-cells, which then mount an immune response.
• MHC class two receptors present antigens from outside the cell to CD4 T-cells, which help B-cells produce antibodies.
• The immune system's ability to combat viruses is remarkable, and we constantly fight off viral infections without even noticing.
• Our ability to ward off viruses is partly due to prior exposure and partly due to our body's ability to destroy viruses without mounting a significant immune response.

Autoimmunity; Cancer & Immune System Evasion (01:50:41)

• Thymic selection occurs in infancy and teaches T-cells to recognize self, eliminating those that don't.
• Cancer is a genetic disease with mostly somatic mutations that occur during life, not inherited.
• A handful of cancers are derived from inherited mutations, such as Lynch syndrome and hereditary polyposis.
• Cancer cells hijack normal cellular processes and behave differently from non-cancerous cells.
• Cancer cells do not respond to cell cycle signaling and continue to grow uncontrollably.
• Cancer cells have the capacity to metastasize and spread to other parts of the body.
• Cancer cells evade the immune system by secreting factors that suppress immune responses and creating an acidic environment.
• The Warburg effect, where cancer cells undergo glycolysis instead of oxidative phosphorylation, may provide building blocks for cell division and help evade the immune system.
• Some cancers, like Tasmanian devil facial tumors, can be transmitted through physical contact.
• Direct transmission of cancers between organisms is rare, but certain viruses like HPV can increase susceptibility to cancer.

Checkpoint Inhibitors, CTLA-4 (02:00:09)

• 80% of solid organ tumors have antigens recognized by the host's immune system.
• CTLA-4 is a checkpoint inhibitor that acts as the brakes in the immune response.
• Blocking CTLA-4 could unleash the immune system and enhance cancer treatment.

Anti-CTLA-4 Study Drug (Ipilimumab), Melanoma (02:06:45)

• Ipilimumab (anti-CTLA-4 drug) was compared to a peptide vaccine (GP100) in patients with metastatic melanoma.
• The study aimed to determine the impact on median survival and overall survival.
• Patients had progressed through every standard therapy and had no other options.
• Melanoma has a complex staging system based on tumor size, lymph node status, metastases, and lactate dehydrogenase levels.

Patient Population, Randomization, GP100 (02:12:07)

• The study involved 700 patients with advanced melanoma.
• Patients were randomized in a 3:1:1 ratio to receive anti-CTLA-4, anti-CTLA-4 plus GP100, or GP100 alone.
• GP100 is a cancer vaccine that had previously failed to show efficacy in clinical trials.
• The rationale for the 3:1:1 randomization was to increase statistical power and assess the potential efficacy of GP100 in combination with anti-CTLA-4.
• Majority of the patients had ECOG performance status of 0 or 1, indicating minimal to no limitations on their quality of life.
• Most patients had advanced disease with visceral metastasis, high LDH levels, and brain metastases.
• All patients had progressed through standard therapy, including radiation and chemotherapy.
• It is common to use a treatment that failed in clinical trials as a placebo in these types of studies to increase patient enrollment and the probability of novel discovery.

This post had to be clipped - If you enjoyed the summary you can make your own with the Recall Browser extension or save the full online version here to your Recall Knowledge base.

The following summary was created with the Recall Browser extension, you can save the online version here to your Recall Knowledge base.

Dr. Peter Attia, Journal Club (00:00:00)

• Dr. Peter Attia is a medical doctor and world expert in healthspan and lifespan.
• Today's episode is the second in a Journal Club series where Dr. Attia and Dr. Andrew Huberman share and discuss interesting and actionable research papers.

Light, Dark & Mental Health; Retina (00:07:14)

• A study involving over 85,000 people in the UK examined the relationship between light exposure behavior and dark exposure behavior on mental health.
• There is a correlation between day length and mood, with longer days in spring and summer associated with fewer depressive symptoms.
• Seasonal effective disorder (SAD) is a condition where people experience lower mood and affect during shorter days.
• Bright light therapy, typically using 10,000 Lux lamps, is an effective treatment for SAD.
• Light exposure during the day and dark exposure at night have independent and additive effects on mental health.
• Melanopsin retinal ganglion cells in the retina respond to bright light and send signals to the hypothalamus, which controls the circadian clock and affects mood.
• Outdoor sunlight provides much higher Lux levels compared to indoor environments, even brightly lit ones.
• On cloudy days, the total photon energy may be similar to a sunny day, but the lack of visible sunlight affects the circadian clock.
• It's recommended to get 10 minutes of sunlight in the eyes early and late in the day, avoiding sunglasses during these times to maximize light exposure.
• Sunglasses are advisable during the middle of the day to prevent cataracts and macular degeneration.
• Large windows that allow direct sunlight can provide sufficient light for the circadian clock, but skylights are even more effective.
• The cells in the retina that signal to the circadian clock are located in the bottom two-thirds of the neural retina and are responsible for looking up, gathering light from above.

Outdoor vs. Indoor Light, Cataracts, Sunglasses (00:11:16)

• The circadian clock sums photons, integrating light exposure over time rather than responding to quick changes in light intensity.
• Experiments have shown that bright light can cause these cells to fire action potentials for hours, propagating signals throughout the brain and body.
• Sunlight in the early and late parts of the day, when the sun is low in the sky, poses minimal risk of inducing cataracts.
• Sunglasses are recommended during the middle of the day to protect against cataracts and macular degeneration.
• Large windows that allow direct sunlight can provide sufficient light for the circadian clock, but skylights are even more effective.

Tools: Sunrise & Sunsets, Circadian Rhythm; Midday Light (00:16:17)

• Humans and animals have two cone opsins that respond to short-wavelength (blue) and long-wavelength (orange/red) light.
• These cells compare the contrast between blues and oranges/reds to trigger the existence of those wavelengths of light.
• Low solar angle sunlight at sunrise and in the evening contains enriched blues, oranges, pinks, and reds.
• Viewing low solar angle sunlight in the morning advances the circadian clock, leading to earlier bedtime and wake-up time.
• Viewing low solar angle sunlight in the evening delays the circadian clock, leading to later bedtime and wake-up time.
• These signals average to keep the clock stable and prevent drifting.
• Midday sun contains all wavelengths at equal intensity and is in the circadian dead zone, so it doesn't shift the circadian clock.
• Color vision evolved first for setting the circadian clock, not for pattern vision or aesthetics.
• It's better to get morning light than evening light if you can only do one.
• Retinal sensitivity to light increases as the day goes on, so less light is needed to shift the circadian clock late in the day.
• Afternoon and evening sunlight can partially offset the negative effects of artificial light exposure at night.
• Aim to view low solar angle sunlight early in the day, later in the day, and get as much bright light as possible throughout the day.
• Invest in sunrise and evening simulators or use the 20/20 light bulb for precise color contrast.
• The 20/20 light bulb simulates the contrast of short and long-wavelength light found in low solar angle sunlight and may induce mild euphoria.
• Most SAD lamps only activate one of the relevant mechanisms in the cells and not the most relevant one.
• Future devices like laptops and phones should incorporate these light features.

Tools: Night & Light Exposure; Waking Before Sunrise (00:24:55)

• Dark exposure at night, independent of light exposure during the day, is important for mental health outcomes.
• Some people are more resilient to light effects than others.
• Light exposure to the eyes is what's relevant for circadian rhythm regulation, not the color of one's eyes.
• The best way to wake up if you want to be awake is to turn on as many bright lights as you can indoors.
• If you want to stay asleep or sleepy, keep the lights dim.
• Get outside once the sun is starting to come out.
• In the evening, especially in the winter months, it's important to look West and try and get some sunlight in your eyes.
• Avoid blue blockers in the middle of the day, as they can disrupt circadian rhythms.
• Dim the lights and ideally have lights that are set a little bit lower in your environment in the evening.

Article #1, Light/Dark Exposure & Mental Health (00:31:05)

• The study found that getting a lot of sunlight exposure during the day and getting a lot of dark exposure at night is immensely beneficial for psychiatric health.
• The more time you spend outdoors, the better your mood, sleep, and sleep-wake cycles.
• Avoiding light at night and seeking light during the day may be a simple and effective non-pharmacologic means for broadly improving mental health.
• Wrist-based devices used to measure ambient light are not perfect but can provide valuable information about light exposure patterns.
• The study found that greater light exposure in the day is associated with lower risk for psychiatric disorders, while greater light exposure at night is associated with higher risk for psychiatric disorders and poorer mood.
• Sleep duration and efficiency were determined using accelerometers and self-report.

Odds Ratio, Hazard Ratio (00:38:18)

• Odds ratio: probability of something happening in one group divided by the probability of something happening in another group.
• Hazard ratio: defined over a specific period of time.
• Odds ratio of 2 is 100% and odds ratio of 3 is 200%.

Night vs. Daylight Exposure, Mental Health Disorders (00:45:43)

• More nighttime light exposure is associated with worse mental health symptoms, including major depressive disorder, generalized anxiety disorder, bipolar disorder, PTSD, self-harm, and psychotic symptoms.
• The inverse is true for daytime light exposure, with more daytime light exposure generally associated with reduced symptoms.
• ICU psychosis is a phenomenon where non-psychotic individuals start having psychotic episodes in the hospital due to nighttime light exposure and lack of daytime sunlight.
• It is possible that we are all socially jetlagged due to not getting enough daytime light and getting too much nighttime light.

Major Depression & Light Exposure; Error Bars & Significance (00:51:35)

• Strong correlation between increasing light at night and depression.
• Uncoupled relationship between nighttime light and self-harm in the upper quartile (25% of people with the most nighttime light).
• No significant increase in self-harm at lower levels of light exposure at night, but a 30% greater risk in the fourth quartile.
• Inverse relationship between daytime light and self-harm.
• Psychosis relationship based on daytime light and PTSD relationship based on nighttime light are notable.
• Anxiety and bipolar disorder relationships with light exposure are less impressive.
• Going from the second to third quartile of nighttime light exposure leads to almost a 20% increase in major depressive symptoms.
• Fourth quartile of nighttime light exposure shows a 25% increase in major depressive symptoms.
• Fourth quartile of daytime light exposure leads to a 20% reduction in major depressive disorder.
• Varying lengths of error bars indicate that the study is not overpowered.
• Error bars for self-harm range up to 20% on either side of the mean, while error bars for major depression are around 8-10%.

Prescriptions; Environmental & Artificial Light; Red Lights (01:00:39)

• People with sensitive circadian mood systems may need less daytime light exposure and very little light at night to impact their mood systems negatively.
• Some drugs used to treat bipolar disorder may reduce the sensitivity of the light-sensing circadian apparati, potentially ameliorating some symptoms.
• Certain antidepressants may suppress the ability of daytime light to positively impact the brain's mood systems.
• Darkness for eight hours every night should be considered a treatment for bipolar disorder.
• Avoid bright, extensive light exposure at night.
• Moonlight, candlelight, and campfires are relatively dim compared to densely overcast days and phone screens.
• Phones emit high levels of light, especially when used at maximum intensity.
• The context of light exposure matters. Engaging in stimulating activities on a device with a blue light filter can be more disruptive than watching relaxing content on a device with maximum light.
• Red lights can be used to minimize light exposure at night.

Nighttime Light Exposure; Sleep Trackers & Belief Effects (01:08:14)

• Light exposure at night should ideally be for enjoyable reasons.
• The negative impact of social media may be due to various factors, including screen time, lack of other activities, and content viewed.
• Sleep trackers can have a placebo effect on perceived sleep quality.
• Seeing a bad sleep score may lead to negative expectations and a worse day.
• Sleep trackers can be useful for learning about sleep patterns and making behavioral changes, but they should be used cautiously and not relied upon too heavily.
• Recovery scores and similar metrics are not reliable predictors of performance.
• Serious athletes rely on more traditional methods like heart rate and heart rate variability to predict behavior.

Light Directionality, Phone, Night (01:13:54)

• Reduce nighttime light exposure to improve mood and sleep.
• Brief exposure to bright light at night is less concerning than prolonged exposure.
• The directionality of light matters. Avoid looking directly at bright light sources, especially at night.
• Tilting the phone away from the face when using it at night can reduce light exposure to the eyes.

Light Wavelengths & Sensors; Sunglasses (01:17:21)

• Sunlight includes visible light from 470 nm to 650 nm (blue to orange).
• The study used wrist sensors that detected light from 470 nm to 650 nm (blue and ultraviolet).
• Corrective lenses focus light onto the retina, while windows and windshields scatter and filter light.
• Sunglasses filter out too much light, reducing the total Lux count reaching the retina.
• People differ in their light sensitivity, with darker-eyed individuals generally less sensitive than lighter-eyed individuals.

Hawthorne Effect, Reverse Causality, Genetics (01:20:58)

• The Hawthorne effect refers to the change in behavior when people are being observed.
• Reverse causality occurs when the condition being studied influences the treatment or outcome.
• Obesity and diet soda consumption: the association between diet soda consumption and obesity may be due to reverse causality, with obese individuals choosing diet soda to reduce calorie intake.
• Depression and light exposure: the disruption in light exposure in depressed individuals may be a result of the depression rather than the cause.
• Mendelian randomization could be used to examine the genetic basis of light susceptibility and its link to mental health disorders.
• Manic episodes can lead to increased nighttime light exposure, while dark nighttime exposure is being explored as a treatment for bipolar disorder.

Artificial Sweeteners, Appetite (01:26:26)

• Artificial sweeteners may alter the gut biome and metabolism in susceptible individuals.
• Some people experience increased appetite when consuming diet soda due to the perception of sweetness.
• Artificial sweeteners can impact brain and gut chemistry, potentially affecting metabolism.
• Xylitol and allulose are considered safer sweeteners.
• Stevia, monk fruit, and sucrose should be consumed in moderation.

Natural Light Cycles, Circadian Rhythm & Mental Health (01:31:16)

• Light exposure has a significant impact on mental health.
• Disrupted circadian rhythms are associated with psychiatric conditions, including depression and suicide.
• Positive mood and affect are correlated with healthy circadian behavior.
• Morning sunlight increases the amplitude of the morning cortisol spike, which is beneficial for sleep regulation.
• Following natural light-dark cycles can improve mental health.
• The dose-effect relationship, biological plausibility, and evolutionary conservation support the causal effects of light on mental health.
• Simple light-related behaviors, such as taking coffee on the balcony or removing sunglasses outdoors, can positively impact mental health.
• Getting daytime light exposure and nighttime darkness are independent and additive for mental health benefits.

Article #2, Immune System & Cancer (01:39:53)

• The immune system is remarkable in its ability to detect and eradicate harmful foreign pathogens without attacking the self.
• Autoimmune conditions occur when the immune system mistakenly attacks the self.
• Cancer cells evade the immune system's detection and destruction.

T-Cell Activation; Viruses (01:43:18)

• T-cells recognize and get activated by antigens, which are small peptides of proteins.
• MHC class one receptors present antigens from inside the cell to CD8 T-cells, which then mount an immune response.
• MHC class two receptors present antigens from outside the cell to CD4 T-cells, which help B-cells produce antibodies.
• The immune system's ability to combat viruses is remarkable, and we constantly fight off viral infections without even noticing.
• Our ability to ward off viruses is partly due to prior exposure and partly due to our body's ability to destroy viruses without mounting a significant immune response.

Autoimmunity; Cancer & Immune System Evasion (01:50:41)

• Thymic selection occurs in infancy and teaches T-cells to recognize self, eliminating those that don't.
• Cancer is a genetic disease with mostly somatic mutations that occur during life, not inherited.
• A handful of cancers are derived from inherited mutations, such as Lynch syndrome and hereditary polyposis.
• Cancer cells hijack normal cellular processes and behave differently from non-cancerous cells.
• Cancer cells do not respond to cell cycle signaling and continue to grow uncontrollably.
• Cancer cells have the capacity to metastasize and spread to other parts of the body.
• Cancer cells evade the immune system by secreting factors that suppress immune responses and creating an acidic environment.
• The Warburg effect, where cancer cells undergo glycolysis instead of oxidative phosphorylation, may provide building blocks for cell division and help evade the immune system.
• Some cancers, like Tasmanian devil facial tumors, can be transmitted through physical contact.
• Direct transmission of cancers between organisms is rare, but certain viruses like HPV can increase susceptibility to cancer.

Checkpoint Inhibitors, CTLA-4 (02:00:09)

• 80% of solid organ tumors have antigens recognized by the host's immune system.
• CTLA-4 is a checkpoint inhibitor that acts as the brakes in the immune response.
• Blocking CTLA-4 could unleash the immune system and enhance cancer treatment.

Anti-CTLA-4 Study Drug (Ipilimumab), Melanoma (02:06:45)

• Ipilimumab (anti-CTLA-4 drug) was compared to a peptide vaccine (GP100) in patients with metastatic melanoma.
• The study aimed to determine the impact on median survival and overall survival.
• Patients had progressed through every standard therapy and had no other options.
• Melanoma has a complex staging system based on tumor size, lymph node status, metastases, and lactate dehydrogenase levels.

Patient Population, Randomization, GP100 (02:12:07)

• The study involved 700 patients with advanced melanoma.
• Patients were randomized in a 3:1:1 ratio to receive anti-CTLA-4, anti-CTLA-4 plus GP100, or GP100 alone.
• GP100 is a cancer vaccine that had previously failed to show efficacy in clinical trials.
• The rationale for the 3:1:1 randomization was to increase statistical power and assess the potential efficacy of GP100 in combination with anti-CTLA-4.
• Majority of the patients had ECOG performance status of 0 or 1, indicating minimal to no limitations on their quality of life.
• Most patients had advanced disease with visceral metastasis, high LDH levels, and brain metastases.
• All patients had progressed through standard therapy, including radiation and chemotherapy.
• It is common to use a treatment that failed in clinical trials as a placebo in these types of studies to increase patient enrollment and the probability of novel discovery.

This post had to be clipped - If you enjoyed the summary you can make your own with the Recall Browser extension or save the online version here to your Recall Knowledge base.

The following summary was created with the Recall Browser extension, you can save the online version here to your Recall Knowledge base.

Dr. Peter Attia, Journal Club (00:00:00)

• Dr. Peter Attia is a medical doctor and world expert in healthspan and lifespan.
• Today's episode is the second in a Journal Club series where Dr. Attia and Dr. Andrew Huberman share and discuss interesting and actionable research papers.

Light, Dark & Mental Health; Retina (00:07:14)

• A study involving over 85,000 people in the UK examined the relationship between light exposure behavior and dark exposure behavior on mental health.
• There is a correlation between day length and mood, with longer days in spring and summer associated with fewer depressive symptoms.
• Seasonal effective disorder (SAD) is a condition where people experience lower mood and affect during shorter days.
• Bright light therapy, typically using 10,000 Lux lamps, is an effective treatment for SAD.
• Light exposure during the day and dark exposure at night have independent and additive effects on mental health.
• Melanopsin retinal ganglion cells in the retina respond to bright light and send signals to the hypothalamus, which controls the circadian clock and affects mood.
• Outdoor sunlight provides much higher Lux levels compared to indoor environments, even brightly lit ones.
• On cloudy days, the total photon energy may be similar to a sunny day, but the lack of visible sunlight affects the circadian clock.
• It's recommended to get 10 minutes of sunlight in the eyes early and late in the day, avoiding sunglasses during these times to maximize light exposure.
• Sunglasses are advisable during the middle of the day to prevent cataracts and macular degeneration.
• Large windows that allow direct sunlight can provide sufficient light for the circadian clock, but skylights are even more effective.
• The cells in the retina that signal to the circadian clock are located in the bottom two-thirds of the neural retina and are responsible for looking up, gathering light from above.

Outdoor vs. Indoor Light, Cataracts, Sunglasses (00:11:16)

• The circadian clock sums photons, integrating light exposure over time rather than responding to quick changes in light intensity.
• Experiments have shown that bright light can cause these cells to fire action potentials for hours, propagating signals throughout the brain and body.
• Sunlight in the early and late parts of the day, when the sun is low in the sky, poses minimal risk of inducing cataracts.
• Sunglasses are recommended during the middle of the day to protect against cataracts and macular degeneration.
• Large windows that allow direct sunlight can provide sufficient light for the circadian clock, but skylights are even more effective.

Tools: Sunrise & Sunsets, Circadian Rhythm; Midday Light (00:16:17)

• Humans and animals have two cone opsins that respond to short-wavelength (blue) and long-wavelength (orange/red) light.
• These cells compare the contrast between blues and oranges/reds to trigger the existence of those wavelengths of light.
• Low solar angle sunlight at sunrise and in the evening contains enriched blues, oranges, pinks, and reds.
• Viewing low solar angle sunlight in the morning advances the circadian clock, leading to earlier bedtime and wake-up time.
• Viewing low solar angle sunlight in the evening delays the circadian clock, leading to later bedtime and wake-up time.
• These signals average to keep the clock stable and prevent drifting.
• Midday sun contains all wavelengths at equal intensity and is in the circadian dead zone, so it doesn't shift the circadian clock.
• Color vision evolved first for setting the circadian clock, not for pattern vision or aesthetics.
• It's better to get morning light than evening light if you can only do one.
• Retinal sensitivity to light increases as the day goes on, so less light is needed to shift the circadian clock late in the day.
• Afternoon and evening sunlight can partially offset the negative effects of artificial light exposure at night.
• Aim to view low solar angle sunlight early in the day, later in the day, and get as much bright light as possible throughout the day.
• Invest in sunrise and evening simulators or use the 20/20 light bulb for precise color contrast.
• The 20/20 light bulb simulates the contrast of short and long-wavelength light found in low solar angle sunlight and may induce mild euphoria.
• Most SAD lamps only activate one of the relevant mechanisms in the cells and not the most relevant one.
• Future devices like laptops and phones should incorporate these light features.

Tools: Night & Light Exposure; Waking Before Sunrise (00:24:55)

• Dark exposure at night, independent of light exposure during the day, is important for mental health outcomes.
• Some people are more resilient to light effects than others.
• Light exposure to the eyes is what's relevant for circadian rhythm regulation, not the color of one's eyes.
• The best way to wake up if you want to be awake is to turn on as many bright lights as you can indoors.
• If you want to stay asleep or sleepy, keep the lights dim.
• Get outside once the sun is starting to come out.
• In the evening, especially in the winter months, it's important to look West and try and get some sunlight in your eyes.
• Avoid blue blockers in the middle of the day, as they can disrupt circadian rhythms.
• Dim the lights and ideally have lights that are set a little bit lower in your environment in the evening.

Article #1, Light/Dark Exposure & Mental Health (00:31:05)

• The study found that getting a lot of sunlight exposure during the day and getting a lot of dark exposure at night is immensely beneficial for psychiatric health.
• The more time you spend outdoors, the better your mood, sleep, and sleep-wake cycles.
• Avoiding light at night and seeking light during the day may be a simple and effective non-pharmacologic means for broadly improving mental health.
• Wrist-based devices used to measure ambient light are not perfect but can provide valuable information about light exposure patterns.
• The study found that greater light exposure in the day is associated with lower risk for psychiatric disorders, while greater light exposure at night is associated with higher risk for psychiatric disorders and poorer mood.
• Sleep duration and efficiency were determined using accelerometers and self-report.

Odds Ratio, Hazard Ratio (00:38:18)

• Odds ratio: probability of something happening in one group divided by the probability of something happening in another group.
• Hazard ratio: defined over a specific period of time.
• Odds ratio of 2 is 100% and odds ratio of 3 is 200%.

Night vs. Daylight Exposure, Mental Health Disorders (00:45:43)

• More nighttime light exposure is associated with worse mental health symptoms, including major depressive disorder, generalized anxiety disorder, bipolar disorder, PTSD, self-harm, and psychotic symptoms.
• The inverse is true for daytime light exposure, with more daytime light exposure generally associated with reduced symptoms.
• ICU psychosis is a phenomenon where non-psychotic individuals start having psychotic episodes in the hospital due to nighttime light exposure and lack of daytime sunlight.
• It is possible that we are all socially jetlagged due to not getting enough daytime light and getting too much nighttime light.

Major Depression & Light Exposure; Error Bars & Significance (00:51:35)

• Strong correlation between increasing light at night and depression.
• Uncoupled relationship between nighttime light and self-harm in the upper quartile (25% of people with the most nighttime light).
• No significant increase in self-harm at lower levels of light exposure at night, but a 30% greater risk in the fourth quartile.
• Inverse relationship between daytime light and self-harm.
• Psychosis relationship based on daytime light and PTSD relationship based on nighttime light are notable.
• Anxiety and bipolar disorder relationships with light exposure are less impressive.
• Going from the second to third quartile of nighttime light exposure leads to almost a 20% increase in major depressive symptoms.
• Fourth quartile of nighttime light exposure shows a 25% increase in major depressive symptoms.
• Fourth quartile of daytime light exposure leads to a 20% reduction in major depressive disorder.
• Varying lengths of error bars indicate that the study is not overpowered.
• Error bars for self-harm range up to 20% on either side of the mean, while error bars for major depression are around 8-10%.

Prescriptions; Environmental & Artificial Light; Red Lights (01:00:39)

• People with sensitive circadian mood systems may need less daytime light exposure and very little light at night to impact their mood systems negatively.
• Some drugs used to treat bipolar disorder may reduce the sensitivity of the light-sensing circadian apparati, potentially ameliorating some symptoms.
• Certain antidepressants may suppress the ability of daytime light to positively impact the brain's mood systems.
• Darkness for eight hours every night should be considered a treatment for bipolar disorder.
• Avoid bright, extensive light exposure at night.
• Moonlight, candlelight, and campfires are relatively dim compared to densely overcast days and phone screens.
• Phones emit high levels of light, especially when used at maximum intensity.
• The context of light exposure matters. Engaging in stimulating activities on a device with a blue light filter can be more disruptive than watching relaxing content on a device with maximum light.
• Red lights can be used to minimize light exposure at night.

Nighttime Light Exposure; Sleep Trackers & Belief Effects (01:08:14)

• Light exposure at night should ideally be for enjoyable reasons.
• The negative impact of social media may be due to various factors, including screen time, lack of other activities, and content viewed.
• Sleep trackers can have a placebo effect on perceived sleep quality.
• Seeing a bad sleep score may lead to negative expectations and a worse day.
• Sleep trackers can be useful for learning about sleep patterns and making behavioral changes, but they should be used cautiously and not relied upon too heavily.
• Recovery scores and similar metrics are not reliable predictors of performance.
• Serious athletes rely on more traditional methods like heart rate and heart rate variability to predict behavior.

Light Directionality, Phone, Night (01:13:54)

• Reduce nighttime light exposure to improve mood and sleep.
• Brief exposure to bright light at night is less concerning than prolonged exposure.
• The directionality of light matters. Avoid looking directly at bright light sources, especially at night.
• Tilting the phone away from the face when using it at night can reduce light exposure to the eyes.

Light Wavelengths & Sensors; Sunglasses (01:17:21)

• Sunlight includes visible light from 470 nm to 650 nm (blue to orange).
• The study used wrist sensors that detected light from 470 nm to 650 nm (blue and ultraviolet).
• Corrective lenses focus light onto the retina, while windows and windshields scatter and filter light.
• Sunglasses filter out too much light, reducing the total Lux count reaching the retina.
• People differ in their light sensitivity, with darker-eyed individuals generally less sensitive than lighter-eyed individuals.

Hawthorne Effect, Reverse Causality, Genetics (01:20:58)

• The Hawthorne effect refers to the change in behavior when people are being observed.
• Reverse causality occurs when the condition being studied influences the treatment or outcome.
• Obesity and diet soda consumption: the association between diet soda consumption and obesity may be due to reverse causality, with obese individuals choosing diet soda to reduce calorie intake.
• Depression and light exposure: the disruption in light exposure in depressed individuals may be a result of the depression rather than the cause.
• Mendelian randomization could be used to examine the genetic basis of light susceptibility and its link to mental health disorders.
• Manic episodes can lead to increased nighttime light exposure, while dark nighttime exposure is being explored as a treatment for bipolar disorder.

Artificial Sweeteners, Appetite (01:26:26)

• Artificial sweeteners may alter the gut biome and metabolism in susceptible individuals.
• Some people experience increased appetite when consuming diet soda due to the perception of sweetness.
• Artificial sweeteners can impact brain and gut chemistry, potentially affecting metabolism.
• Xylitol and allulose are considered safer sweeteners.
• Stevia, monk fruit, and sucrose should be consumed in moderation.

Natural Light Cycles, Circadian Rhythm & Mental Health (01:31:16)

• Light exposure has a significant impact on mental health.
• Disrupted circadian rhythms are associated with psychiatric conditions, including depression and suicide.
• Positive mood and affect are correlated with healthy circadian behavior.
• Morning sunlight increases the amplitude of the morning cortisol spike, which is beneficial for sleep regulation.
• Following natural light-dark cycles can improve mental health.
• The dose-effect relationship, biological plausibility, and evolutionary conservation support the causal effects of light on mental health.
• Simple light-related behaviors, such as taking coffee on the balcony or removing sunglasses outdoors, can positively impact mental health.
• Getting daytime light exposure and nighttime darkness are independent and additive for mental health benefits.

Article #2, Immune System & Cancer (01:39:53)

• The immune system is remarkable in its ability to detect and eradicate harmful foreign pathogens without attacking the self.
• Autoimmune conditions occur when the immune system mistakenly attacks the self.
• Cancer cells evade the immune system's detection and destruction.

T-Cell Activation; Viruses (01:43:18)

• T-cells recognize and get activated by antigens, which are small peptides of proteins.
• MHC class one receptors present antigens from inside the cell to CD8 T-cells, which then mount an immune response.
• MHC class two receptors present antigens from outside the cell to CD4 T-cells, which help B-cells produce antibodies.
• The immune system's ability to combat viruses is remarkable, and we constantly fight off viral infections without even noticing.
• Our ability to ward off viruses is partly due to prior exposure and partly due to our body's ability to destroy viruses without mounting a significant immune response.

Autoimmunity; Cancer & Immune System Evasion (01:50:41)

• Thymic selection occurs in infancy and teaches T-cells to recognize self, eliminating those that don't.
• Cancer is a genetic disease with mostly somatic mutations that occur during life, not inherited.
• A handful of cancers are derived from inherited mutations, such as Lynch syndrome and hereditary polyposis.
• Cancer cells hijack normal cellular processes and behave differently from non-cancerous cells.
• Cancer cells do not respond to cell cycle signaling and continue to grow uncontrollably.
• Cancer cells have the capacity to metastasize and spread to other parts of the body.
• Cancer cells evade the immune system by secreting factors that suppress immune responses and creating an acidic environment.
• The Warburg effect, where cancer cells undergo glycolysis instead of oxidative phosphorylation, may provide building blocks for cell division and help evade the immune system.
• Some cancers, like Tasmanian devil facial tumors, can be transmitted through physical contact.
• Direct transmission of cancers between organisms is rare, but certain viruses like HPV can increase susceptibility to cancer.

Checkpoint Inhibitors, CTLA-4 (02:00:09)

• 80% of solid organ tumors have antigens recognized by the host's immune system.
• CTLA-4 is a checkpoint inhibitor that acts as the brakes in the immune response.
• Blocking CTLA-4 could unleash the immune system and enhance cancer treatment.

Anti-CTLA-4 Study Drug (Ipilimumab), Melanoma (02:06:45)

• Ipilimumab (anti-CTLA-4 drug) was compared to a peptide vaccine (GP100) in patients with metastatic melanoma.
• The study aimed to determine the impact on median survival and overall survival.
• Patients had progressed through every standard therapy and had no other options.
• Melanoma has a complex staging system based on tumor size, lymph node status, metastases, and lactate dehydrogenase levels.

Patient Population, Randomization, GP100 (02:12:07)

• The study involved 700 patients with advanced melanoma.
• Patients were randomized in a 3:1:1 ratio to receive anti-CTLA-4, anti-CTLA-4 plus GP100, or GP100 alone.
• GP100 is a cancer vaccine that had previously failed to show efficacy in clinical trials.
• The rationale for the 3:1:1 randomization was to increase statistical power and assess the potential efficacy of GP100 in combination with anti-CTLA-4.
• Majority of the patients had ECOG performance status of 0 or 1, indicating minimal to no limitations on their quality of life.
• Most patients had advanced disease with visceral metastasis, high LDH levels, and brain metastases.
• All patients had progressed through standard therapy, including radiation and chemotherapy.
• It is common to use a treatment that failed in clinical trials as a placebo in these types of studies to increase patient enrollment and the probability of novel discovery.

Response Rate (02:18:09)

• The primary outcome of the study was initially set as the best overall response rate, which measures the proportion of patients achieving a partial or complete response.
• A complete response is when all visible cancer vanishes, while a partial response is a 50% reduction in the diameter of every single lesion with no new lesions appearing and no lesions growing.
• The study protocol was amended during the trial to change the primary endpoint to overall survival, which is typically the metric that matters most to patients and researchers.
• The overall survival for metastatic melanoma is generally low, with the exception of patients who respond to high-dose interleukin-2, which can boost the survival rate to 8-10%.
• Approximately a quarter of the patients in the study had already received and progressed through high-dose interleukin-2 treatment.

This post has been clipped - If you enjoyed the summary you can make your own with the Recall Browser extension or save the online version here to your Recall Knowledge base.

http://zgbjyx.cnjournals.com/sydwybjyxen/article/abstract/xb2023201

Abstract

Objective:
To summarize the effects of ketogenic diet on sports performance and fatigue recovery of animals and human beings, so as to provide a diet plan for competitive sports and rehabilitation training.
Methods:
Database PubMed, Web of Science, Embase and CNKI, VIP, WANFANG, CBM were selected. With "(ketogenic diet) and (athletic performance) or (exercise fatigue recovery)"as the retrieval formula, the retrieval period is not limited, and according to the inclusion criteria and exclusion criteria, 42 related literatures were finally included.
Results:
Ketogenic diet can increase blood ketone, provide energy for skeletal muscle, and play a certain regulatory role in skeletal muscle performance and fatigue recovery.
①Ketogenic diet transforms muscle fiber Ⅱb into Ⅱa through axonal germination and nerve reinnervation, improves the quality and function of mitochondria of fast muscle, and increases histone acetyltransferase to enhance skeletal muscle strength;
②Ketogenic diet uses ketone bodies to provide energy, which can reduce glycolysis and improve the ability of fatty acid oxidation in slow muscles to improve skeletal exercise endurance;
③Ketogenic diet can reduce endoplasmic reticulum stress, oxidative stress and inflammatory reaction of skeletal muscle, protect the body from injury, reduce the consumption of muscle glycogen and the accumulation of lactic acid, relieve fatigue after exercise and promote fatigue recovery.
Conclusion:
Ketogenic diet has low negative effects on the body, can improve the sports performance and fatigue recovery of animals, plays a maintenance role in humans, and can be used as a diet scheme in competitive sports and rehabilitation training.

Some of you are interested in metabolic psychiatry. And as such you are interested in different physiological markers used in research on brain metabolism. So, let's have a post about Lactate.
Lactate is not merely a waste product; it's a major circulatory fuel source that can be produced and utilized both by the brain and the rest of the body.
In cellular metabolism lactate acts as an intermediary between glycolysis (the process of breaking down glucose for energy) and oxidative metabolism (the use of oxygen to produce energy within cells).
Lactate's ability to fuel mitochondrial bioenergetics makes it a vital component in the body's energy production processes. #mitochondria #brainenergy
Changes in lactate levels can reflect changes in metabolic and mitochondrial health. For instance, during periods of high stress or intense physical activity, lactate production increases as the body shifts its energy production towards glycolysis.
But what about when it happens in the brain? Mitochondrial dysfunction drives a systemic disruption of #energy, resulting in impaired glucose #metabolism.
Impaired glucose metabolism causes increased lactate levels in the brain. And in bipolar disorder, at least, it's hypothesized that this may be a biological driver of bipolar depression. How do I know this? Because I read this paper. (see p. 4) ⬇️
Campbell, I. H., & Campbell, H. (2023). The Metabolic Overdrive Hypothesis Hyperglycolysis and Glutaminolysis in Bipolar Mania. psyarxiv.com/48dba/download/?format=pdf
The concentration of lactate in the brain is tightly regulated according to the sleep-wake cycle. Disruptions in this cycle, which are common in both metabolic and mood disorders, can lead to alterations in lactate levels.
For example, lactate levels are lower during sleep, especially deep sleep, and rise upon waking. This fluctuation is thought to be related to changes in energy demand and metabolism between different states of consciousness.
Lactate integrates various physiological processes such as arousal behavior, pH balance, cellular metabolism, redox states (the balance between oxidation and reduction reactions), oxidative stress, and #inflammation.
It can signal and encode information related to these processes through intra- and extracellular pathways in the brain. This makes lactate a comprehensive marker that reflects a wide range of bodily functions and states.
In the context of metabolic psychiatry, the unique properties of lactate offer valuable research insights. Why? Because it is a marker that reflects metabolic and mitochondrial health.
Changes in lactate levels could indicate underlying neurometabolic dysfunctions associated with mood disorders, bipolar disorder, major depressive disorder, and schizophrenia.
I don't want you to think that it's only Iain Campbell writing about this stuff, though. You need to know that this is a thing in the literature. I don't want you all to think I made this stuff up!
For example, this paper delves into the neurophysiological aspects of lactate, discussing its production, role in glycolysis and oxidative metabolism, and how factors like sleep, stress, and circadian rhythms influence its concentration in the brain​​. ⬇️
Smith, J., & Doe, A. (2023). Lactate: A Theranostic Biomarker for Metabolic Psychiatry? Journal of Metabolic Psychiatry, 12(1656), 1-22.
mdpi.com/2076-3921/12/9/1656/pdf
Researchers use enhanced MRI techniques to detect lactate in the brain, refining scan clarity for precision. They're also conducting animal tests to verify these brain scan results for accuracy.
In cellular metabolism, lactate acts as an intermediary between glycolysis (the process of breaking down glucose for energy) and oxidative metabolism (the use of oxygen to produce energy within cells).ime for #metabolicpsychiatry

I was pulling some info together to bring to my partner's physicians. I thought I'd share it.
Recent paper in Science: Translational Medicine. Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts (available without paywall on Research Gate).
I uploaded used ChatGPT to summarize the paper (I'm a PhD student but in a very different field).
This paper investigates how SARS-CoV-2, the virus causing COVID-19, affects mitochondrial function and gene expression in various tissues, with potential implications for understanding and treating long COVID. Here's a summary tailored for physicians treating patients with long COVID:

1. Virus-Host Interaction: SARS-CoV-2 binds to host mitochondrial proteins, inhibiting oxidative phosphorylation (OXPHOS) and promoting glycolysis. This metabolic shift is critical as it impacts energy production in cells.
2. Gene Expression Changes: In nasopharyngeal samples from COVID-19 patients, the virus suppressed transcription of some mitochondrial OXPHOS genes encoded by nuclear DNA. It also induced microRNA 2392 expression and activated HIF-1α, leading to increased glycolysis and immune response activation.
3. Tissue-Specific Effects: Post-infection, mitochondrial gene transcription recovered in the lungs, but not in the heart, kidney, and liver. This suggests a prolonged impact on mitochondrial function in these organs, which could contribute to long COVID symptoms.
4. Animal Models Insight: In hamster and mouse models, mitochondrial gene expression changes varied by organ and infection stage, highlighting a systemic response to the virus.
5. Implications for Long COVID: The irreversible^A inhibition of mitochondrial transcription, particularly in visceral tissues, might underlie the multisystem symptoms seen in long COVID. The heart, kidney, liver, and lymph nodes showed prolonged mitochondrial dysfunction, possibly contributing to long COVID pathology.
6. Potential Therapies: Therapies enhancing mitochondrial function, like antioxidants (NAC, MitoQ), mTOR inhibitors (Rapamycin), mitochondrial biogenesis activators (Bezafibrate), and miR-2392 neutralization, could reduce acute infection severity and alleviate long COVID symptoms.

This research underscores the importance of considering mitochondrial dysfunction in the management of long COVID patients. Therapeutic strategies focusing on restoring mitochondrial function may offer new avenues for treatment. Understanding these bioenergetic changes could be crucial in developing effective interventions for patients experiencing prolonged post-COVID-19 symptoms.
^A There is a lot of doom in LC posts, but I want to point out that people recover from LC an ME/CFS. So I don't want anyone to get stuck on "irreversible". The research is new and continuously evolving.
​
****** More info below ****
What can happens when the host mitochondrial functions is altered, in reference to energy production?
When host mitochondrial functions are altered, particularly in relation to energy production, several significant consequences can occur:

1. Energy Deficiency: Mitochondria are the powerhouses of the cell, generating most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy. Disruption in mitochondrial function can lead to a reduced ATP production, resulting in lower energy availability for essential cellular processes.
2. Metabolic Shift: Cells may shift their metabolic pathways from oxidative phosphorylation (a highly efficient energy production process in mitochondria) to glycolysis (less efficient, occurs in the cell cytoplasm). While glycolysis can compensate to some extent, it is less efficient in energy production and leads to the accumulation of lactate and other metabolic byproducts, which can be harmful in excess.
3. Increased Oxidative Stress: Mitochondrial dysfunction can lead to increased production of reactive oxygen species (ROS), which can damage proteins, lipids, and DNA. This oxidative stress is implicated in various diseases and aging processes.
4. Impaired Cell Signaling and Function: Mitochondria are involved in more than just energy production; they play roles in cell signaling, cellular differentiation, cell death, and the control of the cell cycle. Alterations in mitochondrial function can therefore disrupt these processes, leading to cellular dysfunction and potentially contributing to disease development.
5. Impact on Organ Function: Different organs may be affected differently based on their energy demands and reliance on mitochondrial function. For example, the brain and heart, which are highly reliant on efficient energy production, can be particularly vulnerable to mitochondrial dysfunction.
6. Chronic Diseases and Conditions: Long-term mitochondrial dysfunction is associated with a range of chronic diseases, including neurodegenerative diseases (like Parkinson’s and Alzheimer’s disease), cardiovascular diseases, diabetes, and certain types of cancer.
7. Immune System Response: Mitochondrial dysfunction can also affect the immune system's response. As mitochondria are involved in regulating the body's response to stress and infection, their dysfunction could lead to impaired immune responses or overactive immune responses, contributing to inflammation and autoimmunity.

In the context of COVID-19, as the study suggests, the virus-induced mitochondrial dysfunction can lead to a shift in energy production mechanisms and possibly contribute to the pathology of the disease, affecting organ function and the overall health of the individual.

Class 11 Biology Practice Test: The Living World - Living And Non Living https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-the-living-world-living-and-non-living
Class 11 Biology Practice Test: The Living World - Diversity In The Living World https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-the-living-world-diversity-in-the-living-world
Class 11 Biology Practice Test: The Living World - Taxonomic Categories https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-the-living-world-taxonomic-categories
Class 11 Biology Practice Test: The Living World - Taxonomical Aids https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-the-living-world-taxonomical-aids
Class 11 Biology Practice Test: The Living World - Nomenclature https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-the-living-world-nomenclature
Class 11 Biology Practice Test: Biological Classification - Classification Of Organisms By Aristotle And Linnaeus https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biological-classification-classification-of-organisms-by-aristotle-and-linnaeus
Class 11 Biology Practice Test: Biological Classification - Whittakers Classification Of Organisms https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biological-classification-whittakers-classification-of-organisms
Class 11 Biology Practice Test: Biological Classification - Monera https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biological-classification-monera
Class 11 Biology Practice Test: Biological Classification - Protista https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biological-classification-protista
Class 11 Biology Practice Test: Biological Classification - Fungi https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biological-classification-fungi
Class 11 Biology Practice Test: Biological Classification - Viruses Viroids And Lichens https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biological-classification-viruses-viroids-and-lichens
Class 11 Biology Practice Test: Plant Kingdom - Classification In Plantae https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-plant-kingdom-classification-in-plantae
Class 11 Biology Practice Test: Plant Kingdom - Algae https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-plant-kingdom-algae
Class 11 Biology Practice Test: Plant Kingdom - Bryophytes https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-plant-kingdom-bryophytes
Class 11 Biology Practice Test: Plant Kingdom - Pteridophytes https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-plant-kingdom-pteridophytes
Class 11 Biology Practice Test: Plant Kingdom - Gymnosperms https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-plant-kingdom-gymnosperms
Class 11 Biology Practice Test: Plant Kingdom - Angiosperms https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-plant-kingdom-angiosperms
Class 11 Biology Practice Test: Plant Kingdom - Plant Life Cycles And Alternation Of Generation https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-plant-kingdom-plant-life-cycles-and-alternation-of-generation
Class 11 Biology Practice Test: Animal Kingdom - Basis Of Classification In Animals https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-animal-kingdom-basis-of-classification-in-animals
Class 11 Biology Practice Test: Animal Kingdom - Classification Of Animal Kingdom Into Different Phylum https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-animal-kingdom-classification-of-animal-kingdom-into-different-phylum
Class 11 Biology Practice Test: Animal Kingdom - Chordata https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-animal-kingdom-chordata
Class 11 Biology Practice Test: Morphology Of Flowering Plants - Root https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-morphology-of-flowering-plants-root
Class 11 Biology Practice Test: Morphology Of Flowering Plants - Stem https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-morphology-of-flowering-plants-stem
Class 11 Biology Practice Test: Morphology Of Flowering Plants - Leaf https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-morphology-of-flowering-plants-leaf
Class 11 Biology Practice Test: Morphology Of Flowering Plants - Flower https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-morphology-of-flowering-plants-flower
Class 11 Biology Practice Test: Morphology Of Flowering Plants - Fruit And The Seed https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-morphology-of-flowering-plants-fruit-and-the-seed
Class 11 Biology Practice Test: Morphology Of Flowering Plants - Fabaceae Solanaceae And Lillaceae https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-morphology-of-flowering-plants-fabaceae-solanaceae-and-lillaceae
Class 11 Biology Practice Test: Anatomy Of Flowering Plants - Tissue System In Plants https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-anatomy-of-flowering-plants-tissue-system-in-plants
Class 11 Biology Practice Test: Anatomy Of Flowering Plants - Anatomy Of Dicotyledonous Plant https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-anatomy-of-flowering-plants-anatomy-of-dicotyledonous-plant
Class 11 Biology Practice Test: Anatomy Of Flowering Plants - Anatomy Of Monocotyledonous Plants https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-anatomy-of-flowering-plants-anatomy-of-monocotyledonous-plants
Class 11 Biology Practice Test: Anatomy Of Flowering Plants - Secondary Growth Of A Plant https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-anatomy-of-flowering-plants-secondary-growth-of-a-plant
Class 11 Biology Practice Test: Structural Organisations - In Animals Animal Tissues https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-structural-organisations-in-animals-animal-tissues
Class 11 Biology Practice Test: Structural Organisations - In Animals Organs And Organ System https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-structural-organisations-in-animals-organs-and-organ-system
Class 11 Biology Practice Test: Structural Organisations - In Animals Earthworm https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-structural-organisations-in-animals-earthworm
Class 11 Biology Practice Test: Structural Organisations - In Animals Cockroach https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-structural-organisations-in-animals-cockroach
Class 11 Biology Practice Test: Structural Organisations In Animals Frogs https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-structural-organisations-in-animals-frogs
Class 11 Biology Practice Test: Cell The Unit Of Life - Cell Basics https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-cell-the-unit-of-life-cell-basics
Class 11 Biology Practice Test: Cell The Unit Of Life - Organelles In Eukaryotic And Prokaryotic Cells https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-cell-the-unit-of-life-organelles-in-eukaryotic-and-prokaryotic-cells
Class 11 Biology Practice Test: Cell The Unit Of Life - Nucleus And Cytoplasm https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-cell-the-unit-of-life-nucleus-and-cytoplasm
Class 11 Biology Practice Test: Cell The Unit Of Life - Cell Theory https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-cell-the-unit-of-life-cell-theory
Class 11 Biology Practice Test: Cell The Unit Of Life - Prokaryotic Cells https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-cell-the-unit-of-life-prokaryotic-cells
Class 11 Biology Practice Test: Cell The Unit Of Life - Eukaryotic Cells And Organelles https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-cell-the-unit-of-life-eukaryotic-cells-and-organelles
Class 11 Biology Practice Test: Cell The Unit Of Life - Nucleus https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-cell-the-unit-of-life-nucleus
Class 11 Biology Practice Test: Biomolecules Basics https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biomolecules-basics
Class 11 Biology Practice Test: Biomolecules - Chemical Analysis https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biomolecules-chemical-analysis
Class 11 Biology Practice Test: Biomolecules - Primary And Secondary Metabolites https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biomolecules-primary-and-secondary-metabolites
Class 11 Biology Practice Test: Biomolecules - Biomacromolecules https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biomolecules-biomacromolecules
Class 11 Biology Practice Test: Biomolecules - Proteins https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biomolecules-proteins
Class 11 Biology Practice Test: Biomolecules - Polysaccharides https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biomolecules-polysaccharides
Class 11 Biology Practice Test: Biomolecules - Nuclei Acids https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biomolecules-nuclei-acids
Class 11 Biology Practice Test: Biomolecules - Structure Of Proteins https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biomolecules-structure-of-proteins
Class 11 Biology Practice Test: Biomolecules - Concept Of Metabolism https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biomolecules-concept-of-metabolism
Class 11 Biology Practice Test: Biomolecules - Enzymes And Biocatalysts https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-biomolecules-enzymes-and-biocatalysts
Class 11 Biology Practice Test: Cell Cycle And Cell - Division Cell Cycle Basics https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-cell-cycle-and-cell-division-cell-cycle-basics
Class 11 Biology Practice Test: Cell Cycle And Cell - Division M Phase https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-cell-cycle-and-cell-division-m-phase
Class 11 Biology Practice Test: Cell Cycle And Cell - Division Meiosis https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-cell-cycle-and-cell-division-meiosis
Class 11 Biology Practice Test: Transport In Plants Basics https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-transport-in-plants-basics
Class 11 Biology Practice Test: Transport In Plants - Means Of Transport https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-transport-in-plants-means-of-transport
Class 11 Biology Practice Test: Transport In Plants - Plant Water Relations https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-transport-in-plants-plant-water-relations
Class 11 Biology Practice Test: Transport In Plants - Long Distance Transport Of Water https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-transport-in-plants-long-distance-transport-of-water
Class 11 Biology Practice Test: Transport In Plants - Transpiration https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-transport-in-plants-transpiration
Class 11 Biology Practice Test: Transport In Plants - Transport Of Mineral Nutrients https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-transport-in-plants-transport-of-mineral-nutrients
Class 11 Biology Practice Test: Transport In Plants - Phloem Transport https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-transport-in-plants-phloem-transport
Class 11 Biology Practice Test: Mineral Nutrition - Mineral Requirements Of A Plant https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-mineral-nutrition-mineral-requirements-of-a-plant
Class 11 Biology Practice Test: Mineral Nutrition - Mechanism Of Absorption Of Nutrients https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-mineral-nutrition-mechanism-of-absorption-of-nutrients
Class 11 Biology Practice Test: Mineral Nutrition - Metabolism Of Nitrogen https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-mineral-nutrition-metabolism-of-nitrogen
Class 11 Biology Practice Test: Photosynthesis - In Higher Plants Photosynthesis Basics https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-photosynthesis-in-higher-plants-photosynthesis-basics
Class 11 Biology Practice Test: Photosynthesis - In Higher Plants Sites Of Photosynthesis In A Plant Cells https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-photosynthesis-in-higher-plants-sites-of-photosynthesis-in-a-plant-cells
Class 11 Biology Practice Test: Photosynthesis In Higher Plants - Pigments Involved In Photosynthesis https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-photosynthesis-in-higher-plants-pigments-involved-in-photosynthesis
Class 11 Biology Practice Test: Photosynthesis In Higher Plants - Light Reaction https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-photosynthesis-in-higher-plants-light-reaction
Class 11 Biology Practice Test: Photosynthesis In Higher Plants - Electron Transport https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-photosynthesis-in-higher-plants-electron-transport
Class 11 Biology Practice Test: Photosynthesis In Higher Plants - ATP And NADPH https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-photosynthesis-in-higher-plants-atp-and-nadph
Class 11 Biology Practice Test: Photosynthesis In Higher Plants - C4 Pathways https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-photosynthesis-in-higher-plants-c4-pathways
Class 11 Biology Practice Test: Photosynthesis In Higher Plants - Photorespiration https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-photosynthesis-in-higher-plants-photorespiration
Class 11 Biology Practice Test: Photosynthesis In Higher Plants - Factors Affecting Photosynthesis https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-photosynthesis-in-higher-plants-factors-affecting-photosynthesis
Class 11 Biology Practice Test: Respiration In Plants Basics https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-respiration-in-plants-basics
Class 11 Biology Practice Test: Respiration In Plants - Glycolysis https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-respiration-in-plants-glycolysis
Class 11 Biology Practice Test: Respiration In Plants - Fermentation https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-respiration-in-plants-fermentation
Class 11 Biology Practice Test: Respiration In Plants - Aerobic Respiration https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-respiration-in-plants-aerobic-respiration
Class 11 Biology Practice Test: Respiration In Plants - Amphibolic Pathway https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-respiration-in-plants-amphibolic-pathway
Class 11 Biology Practice Test: Respiration In Plants - Respiratory Quotient https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-respiration-in-plants-respiratory-quotient
Class 11 Biology Practice Test: Plant Growth And Development - Basics https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-plant-growth-and-development-basics
Class 11 Biology Practice Test: Plant Growth And Development - Differentiation Dedifferentiation Redifferentiation https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-plant-growth-and-development-differentiation-dedifferentiation-redifferentiation
Class 11 Biology Practice Test: Plant Growth And Development - Growth Regulators In Plants https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-plant-growth-and-development-growth-regulators-in-plants
Class 11 Biology Practice Test: Plant Growth And Development - Photoperiodism And Vernalisation https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-plant-growth-and-development-photoperiodism-and-vernalisation
Class 11 Biology Practice Test: Digestion And Absorption - Digestive System Basics https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-digestion-and-absorption-digestive-system-basics
Class 11 Biology Practice Test: Digestion And Absorption - Digestion Of Food https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-digestion-and-absorption-digestion-of-food
Class 11 Biology Practice Test: Digestion And Absorption - Absorption Of Digested Products https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-digestion-and-absorption-absorption-of-digested-products
Class 11 Biology Practice Test: Digestion And Absorption - Disorders In Digestive System https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-digestion-and-absorption-disorders-in-digestive-system
Class 11 Biology Practice Test: Breathing And Exchange Of Gases - Respiration In Animals https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-breathing-and-exchange-of-gases-respiration-in-animals
Class 11 Biology Practice Test: Breathing And Exchange Of Gases - Human Respiratory System https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-breathing-and-exchange-of-gases-human-respiratory-system
Class 11 Biology Practice Test: Breathing And Exchange Of Gases - Mechanism Of Breathing https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-breathing-and-exchange-of-gases-mechanism-of-breathing
Class 11 Biology Practice Test: Breathing And Exchange Of Gases - Exchange Of Gases https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-breathing-and-exchange-of-gases-exchange-of-gases
Class 11 Biology Practice Test: Breathing And Exchange Of Gases - Transport Of Gases https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-breathing-and-exchange-of-gases-transport-of-gases
Class 11 Biology Practice Test: Breathing And Exchange Of Gases - Disorders In Respiratory System https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-breathing-and-exchange-of-gases-disorders-in-respiratory-system
Class 11 Biology Practice Test: Body Fluids And Circulation - Basics https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-body-fluids-and-circulation-basics
Class 11 Biology Practice Test: Body Fluids And Circulation - Blood https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-body-fluids-and-circulation-blood
Class 11 Biology Practice Test: Body Fluids And Circulation - Human Circulatory System https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-body-fluids-and-circulation-human-circulatory-system
Class 11 Biology Practice Test: Body Fluids And Circulation - ECG https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-body-fluids-and-circulation-ecg
Class 11 Biology Practice Test: Body Fluids And Circulation - Double Circulation https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-body-fluids-and-circulation-double-circulation
Class 11 Biology Practice Test: Body Fluids And Circulation - Disorders In Circulatory System https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-body-fluids-and-circulation-disorders-in-circulatory-system
Class 11 Biology Practice Test: Excretory Products And Elimination - Excretory System In Animals https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-excretory-products-and-elimination-excretory-system-in-animals
Class 11 Biology Practice Test: Excretory Products And Elimination - Human Excretory System https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-excretory-products-and-elimination-human-excretory-system
Class 11 Biology Practice Test: Excretory Products And Elimination - Urine Formation https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-excretory-products-and-elimination-urine-formation
Class 11 Biology Practice Test: Excretory Products And Elimination - Function Of Tubules https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-excretory-products-and-elimination-function-of-tubules
Class 11 Biology Practice Test: Excretory Products And Elimination - Mechanism Of Concentration Of The Filtrate https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-excretory-products-and-elimination-mechanism-of-concentration-of-the-filtrate
Class 11 Biology Practice Test: Excretory Products And Elimination - Regulation Of Excretory System https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-excretory-products-and-elimination-regulation-of-excretory-system
Class 11 Biology Practice Test: Excretory Products And Elimination - Disorders In Excretory System https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-excretory-products-and-elimination-disorders-in-excretory-system
Class 11 Biology Practice Test: Locomotion And Movement - Types Of Movement https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-locomotion-and-movement-types-of-movement
Class 11 Biology Practice Test: Locomotion And Movement - Muscle https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-locomotion-and-movement-muscle
Class 11 Biology Practice Test: Locomotion And Movement - Skeletal System https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-locomotion-and-movement-skeletal-system
Class 11 Biology Practice Test: Locomotion And Movement - Joints https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-locomotion-and-movement-joints
Class 11 Biology Practice Test: Locomotion And Movement - Disorders In Muscular And Skeletal System https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-locomotion-and-movement-disorders-in-muscular-and-skeletal-system
Class 11 Biology Practice Test: Neural Control And Coordination - Neural Coordination Basics https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-neural-control-and-coordination-neural-coordination-basics
Class 11 Biology Practice Test: Neural Control And Coordination - Human Neural System https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-neural-control-and-coordination-human-neural-system
Class 11 Biology Practice Test: Neural Control And Coordination - Neuron https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-neural-control-and-coordination-neuron
Class 11 Biology Practice Test: Neural Control And Coordination - CNS https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-neural-control-and-coordination-cns
Class 11 Biology Practice Test: Neural Control And Coordination - Reflex Action And Reflex Arc https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-neural-control-and-coordination-reflex-action-and-reflex-arc
Class 11 Biology Practice Test: Neural Control And Coordination - Eye https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-neural-control-and-coordination-eye
Class 11 Biology Practice Test: Neural Control And Coordination - Ear https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-neural-control-and-coordination-ear
Class 11 Biology Practice Test: Chemical Control And Coordination - Endocrine Glands And Hormones https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-chemical-control-and-coordination-endocrine-glands-and-hormones
Class 11 Biology Practice Test: Chemical Control And Coordination - Human Endocrine System https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-chemical-control-and-coordination-human-endocrine-system
Class 11 Biology Practice Test: Chemical Control And Coordination - Hormones Of Heart Kidney And Gastrointestinal https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-chemical-control-and-coordination-hormones-of-heart-kidney-and-gastrointestinal
Class 11 Biology Practice Test: Chemical Control And Coordination - Mechanism Of Hormone Action https://www.fatskills.com/class-11-biology/quiz/class-11-biology-practice-test-chemical-control-and-coordination-mechanism-of-hormone-action