More General Science 

• Study statistics, confidence interval and p-value,
• DOSAGE MATTERS
• Placebo effect and study biases
• Meta analyses -what does it mean?
• How does Omega3 turn rancid?
• How is omega3 made in Algae? Delta15 desaturase – the reason we exist
• Macrophages, Cytokine storm, Netosis
• NSAIDS
• Cortisol and other hormones
• Can your body make DHA?
• DHA science and π-electrons
• Fiber
• Lipid-peroxidation and the resolution of inflammation
• Triglycerides, Adiponectin, Diabetes and Neuropathy
• What are lipids? 
• How much Cholesterol is in your body?
• What happens during starvation and ketosis?
• WHAT DO WE OWE OUR LIFE TO?
• More inflammatory blood markers
• Protein-food-science and veganism
• Stomach Acid and reflux
• Do your own research
• FOOD TABLES of omega6/3 

Eicosanoids and DHA conversion

The age-related reduction in PUFA composition was inversely correlated with SCD (desaturase) expression and activity resulting in elevations in monounsaturated fatty acid. This means that even if you have alpha linoleic acid in your diet (eg from flax seed oil) you cannot convert it to necessary DHA when you get older because you don’t have a functional desaturase enzyme activity anymore. We can see this blockage in the enzymatic activity in our balance tests. source: As you can see the EPA has a special role. That is why the body can make small amounts from ALA but also reconvert DHA: The “EPA shunt” or “EPA-to-EPA conversion” likely refers to the metabolic pathway involving the conversion of EPA (eicosapentaenoic acid) to other metabolites. However, without more context or specific details, it’s challenging to provide a more accurate or comprehensive explanation. Additionally, I am unable to provide real-time or the most up-to-date information or developments that might have occurred after my last training data in September 2021. EPA, along with DHA (docosahexaenoic acid), is one of the omega-3 fatty acids, crucial for human health. They are found primarily in fatty fish and algae oil, and they play essential roles in inflammatory response, cardiovascular health, and neural development. If the reference is to a specific concept, pathway, or mechanism proposed or described by a researcher or author named Sprecher, it would be helpful to have more information or a more detailed reference to the specific work or publication in question. Please note that to give precise, accurate, and responsible information regarding scientific concepts, details, and context are crucial, especially if the information is to be used for educational or health-related decision-making.   Dihomo-gamma-linolenic acid (DGLA) is a fatty acid that has several roles in the body.

1. Prostaglandin Production: One of DGLA’s most significant roles is as a precursor in the production of a type of eicosanoids called series-1 prostaglandins. These molecules have a variety of effects throughout the body, many of which are anti-inflammatory. For example, prostaglandin E1 (PGE1), which is produced from DGLA, has a variety of beneficial effects. It can inhibit platelet aggregation (which helps prevent blood clots), dilate blood vessels (which can help lower blood pressure), and has anti-inflammatory effects. 
2. Competes with Arachidonic Acid: DGLA competes with arachidonic acid (AA) for the enzyme that converts these fatty acids into their respective series of prostaglandins. In doing so, it can help reduce the production of series-2 prostaglandins, which are typically pro-inflammatory. This can have a modulating effect on inflammation in the body.
3. Direct Anti-Inflammatory Effects: Some research has suggested that DGLA itself, even before it is converted into prostaglandins, has anti-inflammatory effects. This is believed to occur through a variety of mechanisms, including suppressing the production of inflammatory cytokines and chemokines.

However, it’s important to note that much of our understanding of DGLA’s roles in the body comes from in vitro (test tube) studies and animal models. For most people tests show that the body has even established a negative feedback mechanism where the AA precursor, DGLA , accumulates because the body has already reached its limit. Gamma-linolenic acid (GLA) is an omega-6 fatty acid that is found in various plant seed oils such as evening primrose oil, borage oil, and blackcurrant seed oil. GLA levels in humans are typically very low <0.3%! GLA is mainly an intermediate step in the body’s inflammation response. After it’s consumed or converted from LA, GLA is converted into dihomo-gamma-linolenic acid (DGLA), which is one of the body’s three omega-6 derived anti-inflammatory molecules. Some research suggests that GLA and its derivatives might help reduce symptoms of conditions like rheumatoid arthritis, eczema, and premenstrual syndrome (PMS), though more research is needed in these areas. In addition to its potential anti-inflammatory properties, GLA also helps maintain the integrity of the skin barrier, regulate water loss, and protect the skin from injury and inflammation. Please note that while omega-6 fats are essential for good health, they must be balanced with omega-3 fats in your diet. Most people consume too many omega-6 fats and not enough omega-3s, leading to inflammation. However, because GLA is metabolized differently than other omega-6 fats and has anti-inflammatory properties, it doesn’t contribute to this imbalance. Gamma-linolenic acid (GLA) is metabolized in the body through a series of enzymatic reactions. Here’s an overview of this process:

1. Desaturation: Once consumed, GLA, which is an 18-carbon omega-6 fatty acid, is acted upon by the enzyme delta-5-desaturase to produce dihomo-γ-linolenic acid (DGLA).
2. Elongation: DGLA is then elongated by the enzyme elongase to form a 20-carbon omega-6 fatty acid known as arachidonic acid (AA).
3. Conversion to Eicosanoids: Both DGLA and AA can be further metabolized by cyclooxygenase or lipoxygenase enzymes to form various eicosanoids. These are biologically active compounds that have diverse functions in inflammation, immune responses, and other physiological functions.

Notably, while AA-derived eicosanoids are generally pro-inflammatory, DGLA can give rise to anti-inflammatory compounds. This makes GLA unique among omega-6 fatty acids, as it can potentially lead to both pro- and anti-inflammatory compounds, depending on its metabolic pathway.

4. Conversion to Prostaglandins: AA can also be converted into various types of prostaglandins, thromboxanes, and leukotrienes, which have wide-ranging effects on inflammation, blood clotting, and other physiological processes.

It’s important to note that the process of GLA metabolism is complex and influenced by many factors, including the presence of other dietary fats, individual genetic factors, overall health status, and more. For example, the activity of delta-5-desaturase can be inhibited by factors such as aging, stress, alcohol, and certain medical conditions, which can affect the efficiency of GLA metabolism.

As a side note, below you see how omega6 and omega3 molecules are made. Nomenclature can get confusing here. Typically but not always, first the chain gets elongated at the carboxyl end then a new double bond is introduced at the carboxyl end (not at the terminal methyl end). So delta Δ refers to the carboxyl end and omega ω to the methyl end. Omega6 is missing the last double bond at the methyl end and therefore requires delata15 desaturase (in algae only) to make omega3.

Delta15 Desaturase – the reason we exist

Only Algae can make Omega3 in chloroplasts. Here is why animal mitochondria cannot perform this step.

Only Chloroplasts in Algae can make Omega3 from Omega6 with the help of photosynthesis!

The requirement for chloroplasts (or similar plastid organelles in non-photosynthetic organisms) rather than mitochondria for fatty acid desaturation, including the synthesis of polyunsaturated fatty acids (PUFAs) like alpha-linolenic acid (ALA), is due to several specialized features of chloroplasts that make them uniquely suited for this process. Here’s why desaturation primarily occurs in chloroplasts:

1. Fatty Acid Biosynthesis Occurs in Plastids

• Site of Fatty Acid Synthesis:

  • In plants, the initial steps of fatty acid biosynthesis occur exclusively in the stroma of chloroplasts, where acetyl-CoA is converted into saturated fatty acids like palmitic acid (C16:0) and stearic acid (C18:0).
  • These saturated fatty acids are the substrates for desaturation, making chloroplasts the natural location for subsequent modifications, such as introducing double bonds.

• Seamless Processing:

  • Chloroplasts contain the full suite of enzymes required for elongation and desaturation of fatty acids, allowing for efficient synthesis of PUFAs.

2. Specialized Enzymes and Membrane Environment

• Chloroplast Desaturases:

  • Fatty acid desaturases in chloroplasts are specifically adapted to work on acyl-lipid substrates embedded in chloroplast membranes.
  • These enzymes often require a highly fluid lipid bilayer environment enriched with glycolipids and PUFAs, which chloroplast membranes provide.

• Mitochondrial Limitations:

  • Mitochondrial membranes are optimized for oxidative phosphorylation, with a lipid composition and protein density that are not ideal for hosting desaturase enzymes.
  • Unlike chloroplasts, mitochondria lack the enzymatic machinery needed for advanced desaturation steps, such as the insertion of a double bond at the 15th position.

3. Oxygen Activation and Reducing Power

• Oxygen Activation in Chloroplasts:

  • Chloroplasts produce a local abundance of molecular oxygen (O2O_2O2​) during photosynthesis. This oxygen is directly available for use by desaturase enzymes.

• Reductant Source:

  • Chloroplast desaturation depends on NADPH or reduced ferredoxin as electron donors, which are readily generated during the light reactions of photosynthesis.
  • Mitochondria, in contrast, prioritize their reducing equivalents (e.g., NADH, FADH₂) for ATP production rather than biosynthetic pathways.

4. Photosynthetic Integration

• Coordinated Lipid Biosynthesis:
  • Chloroplasts integrate fatty acid synthesis with photosynthesis, ensuring that lipid production aligns with the energy and carbon availability from light-driven processes.
  • The need for polyunsaturated fatty acids (like ALA) in chloroplast membranes is directly tied to maintaining membrane fluidity and enabling efficient photosynthetic function.

5. Functional Specialization

• Chloroplasts vs. Mitochondria:
  • Chloroplasts:
    • Specialized for biosynthesis of lipids, including saturated and polyunsaturated fatty acids.
    • Provide the ideal lipid environment, enzyme machinery, and oxygen supply for desaturation.
  • Mitochondria:
    • Specialized for energy metabolism (oxidative phosphorylation).
    • Focused on lipid oxidation (e.g., beta-oxidation of fatty acids) rather than synthesis or desaturation.

6. Evolutionary Adaptations

• Plastids as Centers for PUFA Synthesis:
  • In plants and algae, chloroplasts evolved as the central hub for PUFA synthesis to support membrane fluidity and signaling needs.
  • Animals, which lack chloroplasts, obtain PUFAs like omega-3 fatty acids from the diet, relying on dietary sources or limited elongation/desaturation in the endoplasmic reticulum (ER).

7. Exceptions: Fatty Acid Modifications Outside Chloroplasts

• While mitochondria are not the primary site for desaturation, they can:
  • Perform beta-oxidation (fatty acid breakdown for energy).
  • Contribute to limited lipid remodeling, such as in cardiolipin, a mitochondrial membrane lipid.
• In animals, some desaturation steps occur in the endoplasmic reticulum (ER) rather than mitochondria. But mitochondria cannot make omega3 only convert it!

Desaturation of fatty acids, including the synthesis of alpha-linolenic acid (ALA), occurs in chloroplasts rather than mitochondria because chloroplasts are equipped with the necessary enzymes, oxygen, and reducing power to perform these reactions. Additionally, the chloroplast’s role in fatty acid biosynthesis, coupled with its membrane environment, makes it the ideal organelle for PUFA production. Mitochondria, specialized for energy production, lack the machinery and lipid environment required for these biosynthetic processes.’

In summary, The last step in ALA synthesis, catalyzed by delta-15 desaturase, introduces a double bond at the 15th carbon of linoleic acid, converting it into alpha-linolenic acid. This step is vital in organisms capable of endogenous omega-3 synthesis, but in humans, the absence of this enzyme makes dietary ALA essential. Humans can only covert essential omega3 ALA from their diet into EPA.

Dosage Matters

There is a minimal threashold of omega3 intake. In other words if you are 70-90% omega3 deficient, 1 g of supplementation will never get you over the required 8% omega3 index.

Omega3 Dosage Matters! Many studies are meaningless since they do not really look at the omega6/3 index and establish a therapeutic baseline!

Elagizi 2021: Interestingly, the trial that used a higher dose (4 g/day highly purified eicosapentaenoic acid (EPA)) found a remarkable, statistically significant reduction in CVD events. It was proposed that insufficient Ω-3 dosing (<1 g/day EPA and docosahexaenoic acid (DHA)), as well as patients aggressively treated with multiple other effective medical therapies, may explain the conflicting results of Ω-3 therapy in controlled trials.

Here you can see how 1g/day supplementation will not get you above the required 8% index, unless you already start out at 6% which is very very unlikely, most people have less than 3% omega3 in their membrane.

Standard Pathway for EPA Synthesis:

1. Starting with Alpha-Linolenic Acid (ALA): This is an omega-3 fatty acid which undergoes a series of elongations and desaturations:

   • Delta-6 Desaturase converts ALA to stearidonic acid (SDA).
   • Elongation of SDA produces eicosatetraenoic acid (ETA).
   • Delta-5 Desaturase converts ETA to eicosapentaenoic acid (EPA).

2. Role of Desaturases: In these pathways, desaturases typically referred to include delta-6, delta-5, and sometimes delta-4, depending on the specific fatty acid and organism.

Desaturation in Microorganisms and Plants:

• Some microalgae and phytoplankton can synthesize EPA and DHA more directly due to their unique sets of enzymes, which can include desaturases and elongases not found in terrestrial plants or higher animals. These organisms can be crucial sources of EPA and DHA in marine ecosystems, which then get concentrated up the food chain through fish and other marine animals.

Genetic Modification:

• In biotechnological contexts, organisms have been genetically modified to produce EPA more efficiently. For example, transgenic plants or yeast may be engineered to express specific desaturases (such as those from microalgae) that allow them to convert fatty acids to EPA more directly than in natural plant or animal pathways.

Implications and Uses:

• Understanding and manipulating these pathways is crucial for enhancing the nutritional content of crops (such as creating EPA-rich plants) and for industrial biosynthesis of these important fatty acids, reducing dependency on fish and marine sources.

In summary, while the term “delta 17 desaturase” is not standard, the ability of certain organisms, particularly marine organisms like microalgae, to synthesize EPA efficiently is well-documented. These pathways involve a combination of desaturation and elongation steps, which can vary somewhat depending on the organism. Advances in biotechnology may further expand these capabilities in other organisms through genetic engineering.

The bodies efforts to downregulate inflammation!

Arachidonic acid (AA) is a polyunsaturated omega-6 fatty acid that plays a vital role in the body and is generally highly inflammatory as discussed. In the order of eicosanoid conversion AA is made from dihomo-gamma-linolenic acid (DGLA), but it’s one of the pathways. Here’s a brief overview of how AA can be synthesized:

1. From Linoleic Acid (LA): The most common pathway for the synthesis of arachidonic acid in the human body starts with linoleic acid (LA), an essential omega-6 fatty acid. LA is first converted to gamma-linolenic acid (GLA) by the enzyme delta-6-desaturase.
2. Conversion to DGLA: GLA is then elongated to form dihomo-gamma-linolenic acid (DGLA). This step is catalyzed by an elongase enzyme.
3. Formation of Arachidonic Acid: Finally, DGLA can be converted to arachidonic acid by the enzyme delta-5-desaturase. This conversion adds a double bond to DGLA, producing AA.

However, it’s important to note that not all DGLA is destined to become arachidonic acid. DGLA can also be a substrate for the production of anti-inflammatory eicosanoids. The balance between DGLA and AA, and the metabolic pathways they enter, can be influenced by various factors, including diet, the presence of other fatty acids, and the activity of specific enzymes. In summary, DGLA is a precursor for the synthesis of arachidonic acid, it’s part of a sequence of metabolic transformations that begin with linoleic acid. So very often AA can appear balanced but DGLA is very high trying to downregulate inflammation.  

How can I increase my desaturase activity?

The activity of desaturase enzymes is influenced by a variety of factors, including age, diet, and overall health. While it’s true that aging can affect enzyme activity, certain strategies can potentially optimize the function of these enzymes.

1. Nutrient-dense diet: Essential fatty acids, vitamins, and minerals support various bodily functions, including enzyme activity. For example, a diet rich in zinc, magnesium, and B vitamins can potentially boost desaturase activity.
2. Limit Alcohol and Unhealthy Fats: Excessive alcohol and consumption of unhealthy fats (trans fats, for instance) can impair the activity of desaturase enzymes.
3. Regular exercise: Regular physical activity is associated with better overall health and may support enzyme function.
4. Adequate Sleep: Poor sleep can impact various bodily functions, including enzyme activity. Prioritizing good sleep hygiene may contribute to optimal enzyme function.
5. Manage Stress: Chronic stress can negatively affect body’s biochemical processes, including enzymatic reactions. Implementing stress management strategies like meditation, yoga, or other relaxation techniques could be beneficial.

Remember, the ability to convert ALA to EPA and DHA decreases with age, and it’s typically not efficient even in young individuals. Therefore, for most people, especially as they age, it’s advisable to obtain EPA and DHA directly from dietary sources like fatty fish or from high-quality supplements if necessary. Always consult a healthcare professional or a dietitian before making significant changes to your diet or starting a supplement regimen.

What do we owe our lives to?

Only Algae can convert omega6 to omega3 and then to EPA. Plants can make only ALA which is not useful to humans. In essence, omega3 production requires the use of chloroplasts and energy from light to produce the high energy omega3 double bond.

1. Photosystem II and light Absorption
Photosystem II (PSII) plays a critical role in the light reactions of photosynthesis. It absorbs light and uses that energy to extract electrons from water, release oxygen, and transfer the high-energy electrons to the electron transport chain, ultimately helping to generate ATP and NADPH.

Absorption Spectrum: PSII absorbs light primarily through pigments like chlorophyll a, which has absorption peaks around 430 nm (blue spectrum) and 662 nm (red spectrum).

Energy for Electron Transfer: The energy absorbed from light at these wavelengths excites electrons in the chlorophyll molecules, enabling them to be transferred to the primary electron acceptor of PSII. This process initiates the electron transport chain that ultimately contributes to the formation of NADPH in the light-dependent reactions of photosynthesis.

2. Plant Fatty Acid Synthesis and Limitations
Alpha-linolenic acid (ALA) is a plant-derived omega-3 fatty acid, and as you noted, while plants can synthesize ALA, they typically do not produce long-chain omega-3 fatty acids like EPA (eicosapentaenoic acid).

Fatty Acid Elongation and Desaturation: Plants lack the necessary enzymes (elongases and desaturases) to efficiently convert ALA to EPA. In contrast, marine algae and some microorganisms possess these enzymes, which enable them to produce EPA and DHA directly. These marine organisms are key sources of EPA and DHA for higher trophic levels in the food chain, including fish and subsequently humans.

Dietary Implications: For humans, dietary intake of EPA and DHA is crucial since humans can convert only a small percentage of ALA to EPA and even less to DHA. This conversion is inefficient and influenced by various factors, including genetics, diet, and overall health.

The role of delta-15 desaturase enzymes in algae and their broader implications for life on Earth are profound, particularly through their contribution to the biosynthesis of omega-3 fatty acids. Delta-15 desaturase, also known as omega-3 desaturase, is crucial for converting omega-6 fatty acids into omega-3 fatty acids, a process essential for maintaining the balance of these vital nutrients in the ecosystem. Here’s a deeper look into how delta-15 desaturases in algae are pivotal:

source researchgate

What are lipids?

Lipids are your building blocks of your cellular membrane. But they also include fats, waxes, oils, hormones, and certain components of membranes and function as energy-storage molecules and chemical messengers. There are a vast amount of over 1000 species involved in many different tissue variations. Lipids contain fatty acids, saturated and omega-6 and -3 chains. That is what alters and varies their function. For example cardiolipin is prevalent to up to in heart muscle containing large amounts of omega-3! Omega3 is a fatty acid and part of a lipid – incorporated into membrane lipids and are most stable in that form!

Lipid Panels

The term lipid panel is used because the test measures substances commonly associated with lipid metabolism and their roles in the body, even though not all the substances tested fit the strict chemical definition of a lipid. Here’s a detailed explanation:

Chemical Definition of Lipids

Lipids are a broad group of hydrophobic or amphipathic molecules that are:

• Insoluble in water.
• Soluble in organic solvents.
• Typically include fats, oils, waxes, sterols, phospholipids, and others.

Triglycerides and Cholesterol: Are They Lipids?

1. Triglycerides:

   • Yes, they are lipids.
   • Triglycerides consist of three fatty acids attached to a glycerol backbone. These are classic lipids and serve as a major energy storage form in the body.

2. Cholesterol:

   • Technically, cholesterol is a sterol, not a lipid.
   • However, cholesterol is lipophilic (fat-loving) and behaves like a lipid in the body.
   • It plays a role in lipid metabolism, forming the structural basis of cell membranes and acting as a precursor for bile acids, steroid hormones, and vitamin D.

Why the Term “Lipid Panel” is Used

1. Historical and Practical Reasons:

   • The term “lipid panel” evolved because the test primarily measures substances involved in lipoprotein complexes, which transport fats and cholesterol through the bloodstream.

2. Focus on Lipid-Related Functions:

   • Even though cholesterol is a sterol, it’s tightly integrated into the body’s lipid transport system, carried by lipoproteins (HDL, LDL, VLDL), which consist of triglycerides, cholesterol, phospholipids, and proteins.

3. Clinical Use:

   • The lipid panel is used to assess cardiovascular risk, focusing on substances that contribute to plaque formation (e.g., LDL cholesterol) and overall fat metabolism.

Components of a Lipid Panel

1. Total Cholesterol:
   • Measures all cholesterol (HDL, LDL, and VLDL).
2. HDL (High-Density Lipoprotein):
   • Often called “good cholesterol,” as it helps remove cholesterol from arteries.
3. LDL (Low-Density Lipoprotein):
   • Often called “bad cholesterol,” as it contributes to plaque buildup.
4. Triglycerides:
   • Measures the most common type of fat in the bloodstream, stored in fat cells for energy.

The term lipid panel is more of a clinical shorthand to describe a test that evaluates fat-like substances and their carriers in the blood, which are integral to lipid metabolism and cardiovascular health. While not all components measured are strictly lipids in a chemical sense, their roles in lipid-related physiology justify the term.

A lipid raft index or related metric is used in biophysical and biochemical studies to evaluate the composition and properties of lipid rafts, which are specialized microdomains within cellular membranes. These lipid rafts are rich in cholesterol, sphingolipids, and certain proteins, and they play crucial roles in cellular signaling, trafficking, and membrane organization.

What is a Lipid Raft Index?

The lipid raft index is not a standardized single metric but rather a conceptual framework or experimental readout used to quantify:

1. Lipid Composition:
   • Proportion of raft-associated lipids (e.g., cholesterol, sphingomyelin, glycosphingolipids) relative to non-raft lipids (e.g., phosphatidylcholine or phosphatidylethanolamine).
2. Biophysical Properties:
   • Membrane fluidity, order, and phase separation into raft (ordered) and non-raft (disordered) domains.
3. Protein Association:
   • Enrichment of raft-associated proteins (e.g., GPI-anchored proteins or certain signaling receptors).

Experimental Approaches to Calculate a Lipid Raft Index

1. Lipidomics:

   • Using mass spectrometry, lipid composition is analyzed, focusing on cholesterol, sphingolipids, and other raft-enriched lipids.
   • A lipid raft index might be expressed as: Lipid Raft Index=Concentration of raft lipidsTotal lipid concentration\text{Lipid Raft Index} = \frac{\text{Concentration of raft lipids}}{\text{Total lipid concentration}}Lipid Raft Index=Total lipid concentrationConcentration of raft lipids​

2. Cholesterol/Sphingomyelin Ratio:

   • Cholesterol and sphingomyelin are hallmark raft components. A high ratio suggests a more prominent lipid raft population.

3. Fluorescent Probes:

   • Laurdan fluorescence or fluorescent-tagged cholesterol analogs can assess membrane order and fluidity. Lipid raft domains typically exhibit lower fluidity and greater order, reflected in their fluorescence intensity or shifts.

4. Detergent Resistance:

   • Lipid rafts are often defined as detergent-resistant membrane fractions (DRMs).
   • Fractionation via ultracentrifugation can quantify raft-associated lipids and proteins, indirectly giving a “raft index.”

5. Atomic Force Microscopy (AFM):

   • AFM can visualize membrane domains and measure physical properties such as stiffness and phase separation indicative of raft formation.

6. Simulation Studies:

   • Molecular dynamics simulations calculate the clustering of raft-associated lipids and their interactions.

Applications of a Lipid Raft Index

1. Biological Research:

   • To study the role of lipid rafts in signal transduction, virus entry, or immune receptor clustering.
   • Example: Lipid rafts are critical for T-cell receptor signaling.

2. Drug Development:

   • Drugs targeting membrane microdomains may be designed to disrupt or stabilize lipid rafts in diseases like cancer or neurodegenerative disorders.

3. Metabolic Studies:

   • Changes in lipid raft composition (e.g., altered cholesterol or sphingolipid levels) are associated with conditions like insulin resistance or cardiovascular disease.

4. Virology:

   • Viruses like HIV and Influenza exploit lipid rafts for entry and assembly, making the lipid raft index a potential therapeutic target.

Limitations

• Dynamic Nature: Lipid rafts are transient and dynamic, making it challenging to define a fixed “index.”
• Context-Specific: The composition and prevalence of lipid rafts vary across cell types, membrane regions, and physiological states.

While a universal “lipid raft index” does not exist, researchers use various lipidomics, biophysical, and imaging approaches to characterize and quantify lipid rafts. These metrics serve as proxies for understanding the role of lipid rafts in cellular function and disease.

Vitas labs does independent anonymous fatty acid testing!

Other Zinzino supplements and their Science

Not your average Multi-Vitamin!

Xtend+

All ingredients are derived from natural sources. – Vitamin C from acerola, B-vitamins from buckwheat, Magnesium from seawater The B vitamins (B₁-B₁₂) and also a number of minerals in Xtend+ such as copper, magnesium, iodine and manganese have health claims stating that they are important for normal energy-yielding metabolism. Xtend+ contains several vitamins and minerals with approved health claims related to bones and muscles. These are Vitamin D, C, K and magnesium, manganese and zinc. Xtend+ contains 1-3, 1-6 beta glucans. These nutrients, derived from the cell walls of highly purified, proprietary strains of baker’s yeast, have been proven to enhance the immune system. Several of the compounds (for example folate, iron, B₆, copper) also con­tribute to this crucial health benefit. In addition to the vitamins and minerals, Xtend+ also contains carotenoids, xanthophylls and a group of polyphenols from a basket of fruits, spices and vegetables. To get the same amount of all these nutrients from foods, you would have to eat more than 3 000 calories of the most nutrient-dense foods every day. All the ingredients combined in Xtend+ offer over a hundred health benefits as confirmed by EFSA (the European Food Safety Authority). These affect every cell, organ and tissue in the body. Xtend+ is the perfect complement to BalanceOil products, providing you with a complete nutritional support program.  

Zinzinogen+

Curcumin extract With its bright yellow color, curcumin is the cornerstone in the ZinoGene+ formulation. As a member of the ginger family, curcumin is produced by plants of the Curcuma longa species. Historically, curcumin has been used in India for thousands of years, both as a spice and as part of their Ayurvedic traditions. Today, it is widely used all around the globe in supplements, cosmetics, food flavoring, and food coloring. There are many different curcumin extracts on the market, but there is a considerable variance when it comes to their bioavailability, and as such they differ a lot when it comes to how much of the ingredient wields an active effect. The curcumin extract that makes it into our products is very carefully selected and provides a full spectrum of curcuminoids. We have chosen the global award-winning ingredient HydroCurc®, which is the world´s most bioavailable curcumin. This means enhanced absorption, and consequently improved efficacy and functionality.

Data shows evidence for curcumin-mediated DNA methylation alterations as a potential mechanism of colon cancer chemoprevention. In contrast to non-specific global hypomethylation induced by 5-aza-CdR, curcumin-induced methylation changes occurred only in a subset of partially-methylated genes, which provides additional mechanistic insights into the potent chemopreventive effect of this dietary nutraceutical.

Quercetin Quercetin is a natural pigment present in many fruits, vegetables and grains. It has antioxidant properties and belongs to a subgroup of polyphenols called flavonoids. It is estimated that the average person consumes 10–100 mg of it daily through food sources such as onions, apples, capers, berries, broccoli, citrus fruits, cherries, coffee, grapes, green tea, and red wine. Important to note, is that the amount of quercetin in foods may depend on the conditions in which the food was grown. As such, in order to optimize bioavailability and functionality, we have made our own proprietary blend of quercetin using three different ingredients from two different plant sources: the pagoda tree, and onions. As always, the quality of our ingredients is every bit as important as the quantity, and this has remained our priority when it comes to the sources of quercetin we have selected for this formulation.

Fucoidans Fucoidan-containing seaweeds have a rich history of medicinal and therapeutic use. Brown seaweed contains an element called fucoidan. Fucoidans from seaweed are non-stick compounds (think of them as the biological equivalent of Teflon). They are found in various species of brown algae and are located in the cell walls of the seaweed plant serving to protect it from external stress. The nutritional properties of fucoidans are nothing new. Historically, fucoidan-containing seaweed have been used in ancient traditions for thousands of years. In fact, the earliest records of its use are dated back to 12000BC, where archaeological digs at Monte Verde in Chile have uncovered evidence of their use. Today, fucoidans are being incorporated as high value ingredients in nutritional products. We know that quality and price vary considerably among the different suppliers and have chosen to apply an exclusive fucoidan ingredient in our ZinoGene+.

Active research into the health benefits of fucoidan continues across a range of health indications including anti-cancer, immune modulation, anti-viral, digestive health, anti-inflammation, wound healing and anti-ageing applications.

Orally administered Synergy and DPF, but not intraperitoneal DPF treatment, significantly ameliorated symptoms of colitis based on retention of body weight, as well as reduced diarrhoea and faecal blood loss, compared to the untreated colitis group.

Fucoidans can stimulate multi potent stem-like cells. We found that fucoidan induced hABM-MSC proliferation. It also significantly increased ALP activity, calcium accumulation and the expression of osteoblast-specific genes

Treatment of senescent MSCs with fucoidan significantly reversed this cellular senescence.

  Bowel Health: Dietary fucoidans provide small but constant amounts of FCSPs to the intestinal tract, which can reorganize the composition of commensal microbiota altered by FCSPs, and consequently control inflammation symptoms in the intestine.  Source: Yang 2021 Order Zinogen+ here

Zinoshine+ Vitamin D and Magnesium – Deficiency

Immunity: patients who turn critical with viral infections including ‘covid‘ are very low on Vitamin D levels typically below 35ng/l. Above the 36th parallel north you do not get sufficient sunshine to make your own D. Most people do not realize that you really need to spend 20min+ in full sun exposure on your back skin to make proper levels of D. To the contrary, we choose to spend most of our day indoors because we are afraid of the sun and also use sun blockers. The result is that we are all testing low in Vitamin D levels! Recommended Vitamin D levels: Your Vitamin D demands fluctuate and depend on injury, stress, immune response, pollution, toxicity and your ability to absorb and make natural D!  30 ng/mL (75 nmol/L) is now defined as sufficiency in western medicine standards; ->however levels of 20ng/mL have been show to have many detrimental effects on health, so 30ng/mL are clearly set too low. We like to see levels between 40-80ng/ml (above 90 there maybe a danger of overdose).   Order your at home VITAMIN D TEST HERE What is Vitamin D?

“Vitamin D3 (cholecalciferol)” is actually a steroid-like hormone not a ‘cofactor’ to enzymes, as most other vitamins. Vitamin D3 is fat soluble and gets converted to its active form calcitriol and can pass into the cell to dock onto a receptor to control nuclear DNA transcription of eg. calcium transport proteins. This has great implications for Muscle and Bone health but also the immune system: Vitamin D has many effects on the immune system as vitamin D receptors are present in many cell types including various immune cells such as antigen-presenting-cells, T cells, B cells and monocytes.  You should be aware that this mechanism cannot be functional if your omega3 levels are low and the membrane fluidity and functionality is not properly established. In addition you need large amounts of Magnesium for Vitamin D3 to be absorbed. Humans can synthesize D3 with the help of UV radiation in the skin. It is generally accepted that above the 36th degree latitude people become Vitamin D deficient quickly. But even below 36 degrees most people avoid the sun nowadays and are deficient. Bone Health: Daylight outdoor exposure showed a significant negative association with combined relative risk against rickets and osteomalacia (RR 0·33 (95 % CI 0·17, 0·66), P<0·001). 167 Studies revealed: There was fair evidence from studies of an association between circulating 25(OH)D concentrations with some bone health outcomes (established rickets, PTH, falls, BMD).      Vitamin D analyses of covid severity MaryamVasheghani 2021

  Zinzino balance oil already contains some Vitamin D, however as discussed above your demands for Vitamin D fluctuate and we recommend that a supplementation of simultaneous Vitamin D and Magnesium. Magnesium is a necessary cofactor for enzyme function in fat and steroid metabolism!

Vitamin D and Magnesium deficiency go together and symptoms may include:

• Fatigue.
• Bone pain.
• Muscle weakness, muscle aches, or muscle cramps.
• Mood changes, like depression.

Vitamin D is actually a hormone involved in important functions within the body, helping to regulate the absorption of calcium and phosphorus, but perhaps the most vital is that it assist with facilitating normal immune system function. Further, getting a sufficient amount of vitamin D is important for normal growth and development of bones and teeth*. Like most nutritional and health factors, there is a significant amount of individuality when it comes to addressing our vitamin D needs. Many social and behavioral influences affect our ability to get sufficient amounts of vitamin D through sunshine alone. Factors such as being in an area with high pollution, using sunscreen, the amount of time spent indoors, living and working in big cities where buildings block sunlight, all play a part in how our bodies respond to the sun and produce this essential ‘sunshine vitamin’. In addition, your body weight needs to be taken into consideration. Vitamin D is a fat-soluble vitamin and as such the more excess body weight we have, the more we need to produce and consume in order for us to reach and maintain sufficient levels in our blood*. About 1 billion people have vitamin D deficiency worldwide. That is why it is important to both monitor your vitamin D levels and adjust with extra sources of vitamin D besides sunlight whenever necessary.

The source of vitamin D we use is lichen. It is a small unique plant species consisting of a symbiotic association of algae and fungus. It is found on mountainsides, rocks, and trees, in an abundance, and this natural source of Vitamin D3 is a conscious choice made for the sake of our environment. Magnesium is very important in this enzymatic immune function metabolism. It is very important in the process of D3 absorption! However even Magnesium absorption depends on the quality of the supplement, its chemical form and most of all on omega3! So omega3, D3 and Magnesium go together. It is now recommended that you supplement with >250mg Magnesium per day. There are many sources to vitamins and minerals out there. Zinzino strives to find the best and most efficient sources available on the market. ZinoShine+ features 4 different magnesium salts: magnesium hydroxide from seawater, magnesium citrate, magnesium malate and magnesium bisglycinate. Together, these four sources provides a broad spectrum approach for enhanced absorption and utilization in our body*.

Vitamin K note: Vitamin K is only needed for Vitamin D absorption in very high dosages. That is why Zinzino does not include it. We always recommend to get your Vitamin K levels tested as well to ensure that you have adequate levels.

Fiber Science

Fiber and omega3 work closely together. Beta-glucan is a vital fiber and assists omega3 in gut health. Zinzino+ products contain natural fiber such as beta-glucans. The best sources of beta-glucan are traditionally grains like wheat, oats, and rye however many people are restricting their grain diet nowadays because of anti-gluten diets. The cholesterol lowering effect of oats is attributed to beta-gulcans. They are also implemented in diabetes and hypertension. Overall, fiber was found to reduce systolic and diastolic blood pressure. However, it should be noted that they looked at several types of fiber, not just beta-glucan. Psyllium lowered systolic blood pressure stronger in this study. Beta Glucan is one of 6 fiber source ingredients in Zinobiotic+ (Inulin, fructo-oligo, psyllium, corn starch, glucan, guar). Fibers act as an important immune modulator by interacting with omega3 and other lipids.   Beta-gulcans can activate M2 macrophages and are involved in tumor necrosis. They are also known for naturally lowering cholesterol levels. Fiber is essential in the health of your probiotic microbiome! The ability to favorably alter the intestinal microflora has been demonstrated by a number of fiber containing plant food sources! eg Acacia gum was shown to produce a greater increase in bifidobacteria and lactobacilli than an equal dose of inulin, and resulted in fewer gastrointestinal side effects, such as gas and bloating    https://aspenjournals.onlinelibrary.wiley.com/doi/abs/10.1177/0115426506021004323  

DHA Science

DHA is crucial for all membrane function and human evolution: below you will find some information on the importance of DHA. In summary DHA is needed for 4 very important processes:

1.Membrane function and fluidity: This is obvious because the omega-3 chain is curved and bent and creates a bigger more fluid volume. This is important if you want the create a concave membrane structure for cell division. Essentially DHA is incorporated into the bottom hemi layer of the membrane and the other hemi layer contains more saturated fatty acid. That will assist in cellular budding event necessary in cell division. This of course plays a role in intra and extra cellular exo- and endosome formation and many cellular interactions.

2.Anti-inflammatory Eicosanoids; This is a very complex topic but it can be summed up into inflammatory omega 6 fatty acids and anti-inflammatory omega-3s. That is why the ratio of 6/3 omegas is so important. A stop is placed on making too much arachidonic acid (negative feedback). This in turn will also stop the production of DHA, EPA, DPA for ALA (if available).

3.Redox potential: A well overlooked factor is that omega-3 oxidized easily and is thus an important acceptor of electrons within the cell membrane. As much as omega-3 is susceptible to oxidation it also protects the cell membrane and transmembrane proteins directly.

4.Trans-Membrane protein function. This includes cytochrome C in the mitochondria. Almost 50% of cardiolipin is responsible in the heart muscle lipids to keep up with the high demand of energy. Nerves and brain cells rely on the potassium channel function. Without DHA channels cannot undergo a conformation change and cannot open properly.

5. The Quantum Brain. The extreme conservation in electrical signalling membranes despite great genomic change suggests it was DHA dictating to DNA rather than the generally accepted other way around. 

The Cellular  and mitochondrial membrane is what sources life and is vital to all functions. Without DHA the cell cannot properly sort what goes in or out or maintain an electric potential.

First of all let us shine some light on the importance of lipids in general.

How much lipid fat is in a typical cell (not adipose)?

As you can see fat molecules far outnumber proteins or sugars in the cell. They are responsible for the function of all metabolism and keep the cell intact and selective. DHA keeps a vital role in keeping lipid rafts within the membrane fluid and functional!

Molecular structures of AA and EPA

AA and EPA have the same length of 20 carbons but EPA has an additional double bond in the 3rd position from the end (which gives it the name omega3). This position is chemically ‘fragile’ as it is subject to oxidation! That is why omega-3 turn rancid faster than omega-6 fatty acids.

Eicosanoids and DHA conversion

Eicosanoids: AA gets converted to so called pro-inflammatory prostaglandin series 2 ; PGE2; whereas EPA gets converted to anti-inflammatory PGE series 3s. This process is highly complex involving many other messengers such as leukotrienes, HETE, Thromboxane’s Here is a detailed review on this process and their implications on inflammatory disease.   Source, researchgate   For more information on how Eicosanoids work click here.  Here is an overview of the eicosanoids that are produced from AA. They are generally considered of inflammatory nature. On the right you see COX enzymes producing prostaglandins. This enzyme gets blocked by NSAIDS.

Inflammatory omega-6 eicosanoids, Wang et al 2021

Omega-3 Polyunsaturated Fatty Acids and Their Health Benefits- STRUCTURAL FEATURES AND PROPERTIES OF OMEGA-3 FATTY ACIDS Source Researchgate : Here you can see again how Omega3s choose the anti-inflammatory pathway and Omega6 pro-inflammatory (right side). What is important to note here is the same enzymes “desaturase and elongase” convert both LA and ALA simultaneously. In other words they dont know the difference and use whatever is there.

Crawford MA 2017: A theory on the role of π-electrons of docosahexaenoic acid in brain function!

How does Omega3 turn rancid?

Omega-3 fatty acids, particularly the long-chain polyunsaturated types like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have multiple double bonds in their structure. This makes them especially susceptible to oxidation by reactive oxygen species (ROS). This is not the same as lipid peroxidation in the cell membrane discussed below. Here’s how ROS can oxidize omega-3 fatty acids:

1. Initiation: ROS, such as the hydroxyl radical (•OH) or other free radicals, can attack the methylene group (-CH2-) situated between the double bonds of the omega-3 fatty acid. This attack removes a hydrogen atom from the fatty acid, generating a lipid radical (L•).
2. Propagation: The lipid radical (L•) is unstable and reacts with molecular oxygen (O₂) to form a lipid peroxyl radical (LOO•). This lipid peroxyl radical can then react with another lipid molecule, abstracting a hydrogen atom and creating a new lipid radical (L•) and a lipid hydroperoxide (LOOH). This chain reaction can continue, resulting in the oxidation of multiple lipid molecules.
3. Termination: The propagation phase can end when two free radicals react together to form a non-radical species or when they are neutralized by antioxidants. For instance, vitamin E is a lipid-soluble antioxidant that can donate an electron to the lipid peroxyl radical, converting it into a non-radical species and terminating the chain reaction.

The end products of lipid oxidation include lipid hydroperoxides (which can further decompose to form secondary products like aldehydes, ketones, and more) and other compounds that can adversely affect the taste, smell, and nutritional value of the lipid. Additionally, some of these oxidation products are potentially toxic or pro-inflammatory when ingested. This process of omega-3 fatty acid oxidation by ROS is a concern because it reduces the nutritional value and beneficial effects of omega-3s. It also has implications for the shelf-life and quality of omega-3-rich foods and supplements. As a result, storage conditions, the presence of antioxidants, and exposure to light, heat, and air can significantly impact the rate of omega-3 oxidation. Lipid-peroxidation and the resolution of inflammation

Lipid-peroxidation

The topic of Reactive oxygen species (ROS) is complex. Below you will find a more detailed scientific discussion. In effect you will see that both omega3 and omega6 PUFA are buffers for ROS. PUFA do not propagate or multiply ROS!

Some journalists are talking about Omega-3 causing ROS (reactive oxygen species). This is an unscientific claim and the discussion below will clear this up. Omega-3 levels average far below 4% for average people (most are below 2.5%) even with supplementation it takes years to achieve the required levels above 8%. At the same time combined omega-6 levels average above 30%!

claim by Al-Gubory 2012:
“Dietary intake of omega-3 polyunsaturated fatty acids (ω3PUFAs) and consequently the increase in ω3PUFA content of membrane lipids may be disadvantageous to the health because ROS-induced oxidative peroxidation of ω3PUFAs within membrane phospholipids can lead to the formation of toxic products.”

However it appears that this article is just an unsupported opinion and not research based.

The question: “Oxidative Stress: High levels of ω3PUFAs in cell membranes could potentially increase the risk of lipid peroxidation if there is an imbalance between pro-oxidants and antioxidants, leading to oxidative stress.”

This would potentially lead to toxic Oxidation Products: The peroxidation of ω3PUFAs can result in the formation of various oxidation products, some of which are aldehydes like malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), which can be toxic to cells and tissues.

Inflammation and Cell Damage: These toxic products can form adducts with proteins and DNA, impairing their function and potentially leading to inflammation, cell damage, and even cell death.

Disease Associations: Chronic oxidative stress and lipid peroxidation are associated with the development and progression of several diseases, including atherosclerosis, Alzheimer’s disease, and other conditions linked to inflammation and aging.

However, the opposite is the truth when you look at the cellular defense mechanisms against oxidative damage:

Antioxidant Systems: The body possesses endogenous antioxidant systems, including enzymes like superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase, as well as non-enzymatic antioxidants like vitamin E and C, which protect lipids from peroxidation.

Repair Mechanisms: Cells quickly repairs or removes oxidized phospholipids from membranes through the action of specific enzymes and pathways.

Dietary Antioxidants: Consuming antioxidants with ω3PUFAs, either through the diet or supplementation, can help protect against oxidative damage.

Specialized Pro-resolving Mediators (SPMs)

It is important to understand that the formation of omega-3 oxidation products leads to the production of compounds with biological activity, including certain types of resolvins and protectins, which can help to resolve inflammation and are part of the body’s natural healing response.

The process by which omega-3 fatty acids, such as EPA and DHA, are converted into bioactive molecules like resolvins, maresins, and protectins is indeed an oxidative process, but it’s a tightly regulated one that doesn’t indiscriminately produce reactive oxygen species (ROS) in the way that uncontrolled lipid peroxidation does. Here’s how the two processes differ:

Controlled Oxidation to Form Specialized Pro-resolving Mediators (SPMs):
Enzymatic Catalysis: The conversion of EPA and DHA into SPMs like resolvins, protectins, and maresins is catalyzed by specific enzymes, including lipoxygenases (LOX). This is a controlled and beneficial type of oxidation.

Resolution of Inflammation: SPMs play key roles in resolving inflammation. They help to bring the inflammatory process to a close and promote healing, rather than contributing to ongoing inflammation.

No Excessive ROS: The enzymatic conversion to SPMs does not generate excessive amounts of ROS. It’s a controlled oxidation that specifically targets the omega-3 fatty acids to produce these molecules with potent anti-inflammatory and pro-resolving actions.

In contrast Uncontrolled Oxidative Peroxidation:
In contrast to the controlled production of SPMs, uncontrolled oxidative peroxidation of lipids in cell membranes is typically non-enzymatic and can be triggered by already excessive ROS. This can lead to damaged to Cell Structures. Uncontrolled lipid peroxidation leads to the formation of a variety of reactive aldehydes and other products that can damage proteins, DNA, and other cellular structures.

Contribution to Disease: If unchecked, such oxidative damage can contribute to the pathogenesis of a variety of diseases, particularly those associated with chronic inflammation and oxidative stress. This prevalent in Lipid peroxidation outside the cell, eg. within low-density lipoprotein (LDL) particles oxidation is indeed a key factor in the formation of foam cells, which are an integral part of the development of atherosclerosis and the underlying process of cardiovascular diseases. However, this problem once again is a result of the large deficiency of omega-3 anti-inflammatory action that is to be expected at omega6/3 inflammatory indices above 20:1 !

Cholesterol and lipids

A very large portion of Fat/lipids are cholesterol.

Cellular Cholesterol Content

• Cholesterol constitutes about 30 mol% of lipids, and lipids make up about 40% of a cell’s dry weight. Using these, you estimate cholesterol’s weight contribution to cells as 6% of dry weight. This calculation is valid: $$30\%\times 40\%=6\%\text{ of the dry weight.}$$

Assumption of Body Composition

• You estimate the non-water (dry) weight of an 80kg male as 45kg. This aligns with the general assumption that about 55–60% of body weight is water. Hence, 40–45kg represents the remaining solid matter (proteins, fats, minerals, etc.).
• Based on the 6% figure, you calculate: 6%×45 kg=0.6  This is a reasonable estimate for total cholesterol content in the human body, although it’s an approximation and depends on assumptions about tissue composition.

Blood Serum Cholesterol Misinterpretation

• You correctly point out that blood cholesterol (e.g., 200 mg/dL) underestimates total cholesterol in the body. Blood cholesterol is primarily found in lipoproteins and represents a small fraction of total body cholesterol.
• For an average 80kg male with 5L of blood: $$\text{ (or 10g)}.$$ While this figure is accurate for circulating cholesterol, the majority of cholesterol resides in cellular membranes and lipoprotein storage within tissues.

Importance of Cholesterol

• Cholesterol’s biological roles :
  • Membrane fluidity and integrity.
  • Precursor for vital molecules like steroid hormones, bile acids, and vitamin D.
  • Role in immunity and other critical functions.

These points underscore cholesterol’s indispensability in cellular and systemic physiology.

1. Dry Weight Assumption:

   • State explicitly that the 45kg dry weight includes proteins, lipids, and other biomolecules, and cholesterol is part of the lipid fraction.

2. Variability:

   • Keep in mind variability due to age, sex, health, and diet. For instance, muscle tissue has less cholesterol than the brain, which is lipid-rich.

3. “Total Cholesterol” Language:

   • One has to Differentiate between blood cholesterol (as measured clinically) and total body cholesterol, which resides predominantly in cell membranes.

“Cholesterol is a critical biomolecule, constituting approximately 6% of the dry weight of a mammalian cell. For an average 80kg male, this translates to about 0.6kg (600g) of cholesterol distributed throughout the body. This far exceeds the circulating cholesterol measured in the blood, emphasizing its role beyond cardiovascular health. Cholesterol is essential for maintaining cell membrane structure and fluidity, as well as serving as a precursor for steroid hormones, bile acids, and vitamin D. It also plays a significant role in the immune system, digestion, and hormonal balance. Clearly, cholesterol is indispensable for life and health.”

A detail discussion of the “cholesterol problem” can be found here. Here’s a step-by-step narrative of how lipid peroxidation in LDL contributes to foam cell formation:

1. Oxidation of LDL: LDL particles can undergo oxidative modifications, particularly lipid peroxidation, when exposed to oxidative stress in the vascular wall. Reactive oxygen species (ROS) can react with the polyunsaturated fatty acids in the LDL particles, leading to the formation of lipid peroxides.

2. Endothelial Dysfunction: The oxidized LDL (oxLDL) is no longer recognized by the normal LDL receptor. Instead, it contributes to endothelial dysfunction and the recruitment of inflammatory cells.

3. Inflammatory Response: The presence of oxLDL in the endothelium attracts immune cells such as monocytes. These monocytes migrate into the intima, the inner layer of the arterial wall, where they differentiate into macrophages.

4. Scavenger Receptor Uptake: Macrophages express scavenger receptors that recognize and bind to oxLDL. Unlike regular LDL receptors, scavenger receptors do not have a negative feedback mechanism; they can continue to take up large amounts of oxLDL.

5. Foam Cell Formation: As the macrophages engulf more and more oxLDL, they become engorged with lipids and transform into foam cells. These foam cells are characterized by their lipid-laden appearance when viewed under a microscope.

6. Plaque Development? this is where it all goes wrong: “The accumulation of foam cells within the arterial wall contributes to the formation of fatty streaks, which are the earliest visible lesions in the development of atherosclerotic plaques. Over time, continued accumulation of foam cells, along with other substances like calcium and fibrous tissue, leads to the development of a mature atherosclerotic plaque. These plaques can narrow the arteries and restrict blood flow or rupture, leading to heart attacks or strokes.”

Yes, the peroxidation of lipids within LDL takes part in the formation of foam cells and the development of atherosclerotic plaques. However is this mechanism the cause or just part of the collateral damage?

Are “foam cells” really the bad guys or just part of the cholesterol narrative? “Based on our analysis, we were surprised to find that, instead of increasing the amount of cholesterol uptake and accumulation in the macrophage foam cells, mildly oxidized LDL almost completely prevents increases in cholesterol,” 

Cholesterol is coincidental in the formation of plaques. It is the persistent inflammasome that leads to problems. As such inflammatory markers are increased such as CRP.

Experimental work has elucidated molecular and cellular pathways of inflammation that promote atherosclerosis.

Omega-3 prevents inflammation and LDL oxidation

For decades now we know that omega-3 proves instrumental in prevention of LDL oxidation, and addition of dietary antioxidants is controlling risk factors for oxidative stress. Omega-3 is considered an important strategy for reducing the risk of cardiovascular diseases.

Please see the discussion on Triglycerides and Cholesterol here.

In summary, while both processes involve the oxidation of omega-3 fatty acids, the controlled production of SPMs is a normal and beneficial aspect of the resolution of inflammation, whereas uncontrolled lipid peroxidation (as in rancidity) can lead to cell damage and disease. It’s the balance between antioxidants and pro-oxidants in the body that helps to regulate these processes. The body has evolved complex mechanisms to ensure that the production of SPMs occurs without causing the collateral damage associated with uncontrolled oxidative stress.

In conclusion, while there is little to no potential risk of oxidative damage due to the peroxidation of ω3PUFAs in a cell membrane that contains adequate amounts of omega-3 (more than 8%). A balanced diet rich in antioxidants, combined with the body’s own protective mechanisms, generally supports the health benefits of ω3PUFAs. It is important to consume these fats as well as saturated fats as part of a diet that includes adequate antioxidants to help mitigate the risks. As always, it’s best to consult with healthcare professionals before making significant changes to dietary habits, especially for individuals with specific health concerns or conditions.

Below you can see a summary of how Omega-3 deficiency leads to never ending inflammation through the lack of SPMs.

High levels of Omega-6 can cause ROS?

The potential for omega-6 fatty acids to undergo lipid peroxidation and contribute to reactive oxygen species (ROS) production is a similar concern as with omega-3 fatty acids. Both omega-6 and omega-3 fatty acids are polyunsaturated and have multiple double bonds, which are points of vulnerability where oxidation can occur. The point made here is that you will see modern high levels of inflammatory Omega6 either result in inflammatory HETE or prostaglandin or when unchecked result in ROS.  Here’s how this problem relates to omega-6 fatty acids:

1. Susceptibility to Oxidation: Like omega-3s, omega-6 fatty acids (such as linoleic acid and arachidonic acid) are susceptible to peroxidation due to their polyunsaturated structure. The more double bonds a fatty acid has, the more susceptible it is to being attacked by ROS.

2. Lipid Peroxidation: When omega-6 fatty acids are integrated into cell membranes or lipoproteins like LDL, they can be oxidized by ROS, leading to the formation of lipid peroxides and other oxidative products.

3. Inflammation: Some of the oxidative products derived from the peroxidation of omega-6 fatty acids are pro-inflammatory and can contribute to the inflammatory process within the body.

4. Atherosclerosis: Just as with omega-3 fatty acids, the oxidation of omega-6 fatty acids in LDL can contribute to the formation of oxLDL, which is a key player in the development of atherosclerosis, including the formation of foam cells and atheromatous plaques.

5. Balance of Omega-6 to Omega-3: The balance of omega-6 to omega-3 fatty acids in the diet is important for health. High levels of omega-6 fatty acids, especially in the absence of sufficient omega-3 fatty acids, can promote an environment more conducive to inflammation and oxidative stress.

6. Antioxidants: Adequate intake of antioxidants is essential to protect against the peroxidation of both omega-6 and omega-3 fatty acids. Antioxidants can neutralize ROS, reducing the risk of lipid peroxidation.

In conclusion, both omega-6 and omega-3 fatty acids can undergo lipid peroxidation and contribute to ROS production, which has potential implications for inflammation and diseases such as atherosclerosis. Only a diet that maintains a proper balance between omega-6 and omega-3 fatty acids, alongside adequate antioxidant intake, can help mitigate these risks. 

The High omega6/3 balance risk!

Following a typical Western diet, the levels of arachidonic acid (AA) can be quite high relative to the anti-inflammatory omega-3 fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). This imbalance can potentially increase the risk of oxidative stress and ROS formation for several reasons:

1. High Omega-6 Intake: Diets high in omega-6 fatty acids, which include linoleic acid (LA) and its derivative AA, can elevate the omega-6/3 index. A higher intake of LA, which is abundant in many processed foods and vegetable oils, contributes to higher levels of AA in cell membranes due to the body’s metabolic pathways.

2. Pro-inflammatory Eicosanoids: AA is the precursor to a number of eicosanoids that have pro-inflammatory and pro-thrombotic actions, which can contribute to chronic inflammation and diseases like atherosclerosis.

3. Oxidative Susceptibility: Both AA and LA are susceptible to peroxidation due to their unsaturated bonds. High levels of these fatty acids increase the substrate available for ROS attack, leading to the production of pro-inflammatory oxidized metabolites.

4. Low Omega-3 Intake: The typical Western diet often provides inadequate amounts of omega-3 fatty acids, which are vital for producing anti-inflammatory eicosanoids and for competing with AA for incorporation into cell membranes and enzymatic pathways.

5. Risk of Oxidative Stress: Given the high prevalence of AA and the relative deficiency of EPA and DHA, there’s a greater chance that lipid peroxidation will result in pro-inflammatory mediators rather than the production of protective compounds like resolvins and protectins derived from omega-3 fatty acids.

6. Inflammatory Balance: A high omega-6/3 index is often associated with a state of increased systemic inflammation and can be a marker for chronic diseases, where oxidative stress plays a key role.

The average arachidonic acid level is over 10% not even counting LA or DGLA… EPA and DHA never even reach 5% for 99% of people. –

Significant increases in several omega-6 derived oxylipins and reductions in omega-3 derived oxylipins were observed in the high LA dietary group compared to the low LA group. Our findings suggest that dietary oxidized LA metabolites (OXLAMs) do not accumulate in liver, and likely exert pro-inflammatory and pro-apoptotic effects via downstream secondary metabolites.

In summary, the entire discussion of Omega3 and ROS is rendered nonsensical since the combined levels of PUFA (both omega6+omega3) typically stay the same. As omega3 goes up omega6 gets replaced as the cells always prefers omega3.

In addition LA (omega6) levels average over 20% contributing to the ROS. 

Linoleic acid (LA), an omega-6 polyunsaturated fatty acid (PUFA), is abundantly consumed in modern diets through vegetable oils like corn, soybean, safflower, and sunflower oil, as well as processed foods that contain these oils. High dietary intake of LA can influence health and disease risk, particularly in relation to inflammation and oxidative stress. Here’s how high levels of LA play a role in the context of inflammation, oxidative stress, and omega fatty acid balance:

1. Arachidonic Acid (AA) Precursor: LA is a precursor to AA. While AA is essential for certain physiological functions, an excessive amount can lead to the production of pro-inflammatory eicosanoids, which can exacerbate inflammatory processes.

2. Omega-6 to Omega-3 Ratio: A high intake of LA relate to high levels of AA and can skew the balance of omega-6 to omega-3 fatty acids in the body, leading to a high omega-6/3 ratio. A higher ratio has been associated with an increased risk of chronic inflammatory diseases.

3. Oxidative Stress: Polyunsaturated fats like LA are prone to oxidative damage due to their double bonds. Excessive levels of LA in the diet can lead to increased lipid peroxidation, contributing to the formation of ROS and oxidative stress.

4. Endothelial Function: Some research suggests that high levels of LA can affect endothelial function and may influence atherogenesis, the formation of atherosclerotic plaques in arteries.

5. Chronic Diseases: There are associations between high dietary LA and certain chronic conditions, such as cardiovascular disease, though the evidence is not fully consistent. The role of LA in these conditions is complex and influenced by various dietary and genetic factors.

6. Role of Diet Composition: The effects of LA cannot be considered in isolation. The overall dietary pattern, including the types of fats consumed and the presence of antioxidants, fibers, and other nutrients, plays a significant role in how LA affects health.

In light of these considerations, the role of LA in the diet is an area of active research and debate. While it’s essential to have some omega-6 fatty acids like LA for normal cell function and health, the key seems to be maintaining a balanced intake of omega-6 and omega-3 fatty acids and consuming them as part of a varied and nutrient-dense diet. 

Conclusions

To mitigate the risk of ROS, a balanced intake of omega-6 to omega-3 fatty acids is recommended. Since that is very difficult – Strategies to improve this balance is necessary to increase levels of  EPA and DHA through consumption of fatty fish or supplementation (non-rancid omega3), reducing intake of LA-rich oils, and ensuring adequate intake of antioxidants through a diet rich in fruits, vegetables, nuts, and seeds.

In summary the entire discussion around omega3 causing ROS is futile due the to the high amounts of omega6 and the anti-inflammatory action of omega-3!

ROS mechanism

Here’s a breakdown and continuation of the process of ROS propagation in detail. Keep in mind that only from a theoretical perspective, lipid peroxidation manifests as a complex chain radical process. This is only observed outside the cell or eg. in food that is exposed to oxygen.

1. Lipid Peroxidation Initiation: When polyunsaturated fatty acids (PUFAs) in cell membranes, such as omega-3 and omega-6 fatty acids, are attacked by reactive oxygen species (ROS), it can lead to the removal of a hydrogen atom from the fatty acid, creating a lipid radical. This radical can then react with molecular oxygen (O2) forming a lipid peroxyl radical (LOO•).

2. Propagation: The lipid peroxyl radical can further react with another fatty acid, stealing a hydrogen atom and creating another lipid radical, thus propagating the chain reaction of lipid peroxidation. This can continue unless interrupted by antioxidants.

3. Termination by Antioxidants: Antioxidants like Vitamin E (α-tocopherol) can donate a hydrogen atom to the lipid peroxyl radical, effectively stopping the chain reaction and forming a lipid hydroxide (LOH) and a tocopheroxyl radical. This radical is relatively stable but can be reduced back to α-tocopherol by vitamin C or glutathione (GSH).

4. Role of Glutathione (GSH): GSH, a major cellular antioxidant, can reduce lipid hydroperoxides (LOOH) to lipid alcohols (LOH) and water, preventing further radical formation. If GSH is depleted, lipid hydroperoxides may decompose to form more radicals, perpetuating oxidative stress.

5. Electron Shuttling to NADP+: In the broader context of cellular metabolism, the electrons from various cellular reactions, including those involving ROS, ultimately need to be shuttled to electron acceptors to maintain redox balance. NADP+ (nicotinamide adenine dinucleotide phosphate) is reduced to NADPH in such processes. NADPH is crucial for biosynthetic reactions, for regenerating reduced glutathione, and for operating in the pentose phosphate pathway, which helps in managing oxidative stress by supplying reducing equivalents.

6. NADPH in Antioxidant Defense: NADPH provides the necessary reducing power for glutathione reductase to convert oxidized glutathione (GSSG) back to its reduced form (GSH), maintaining the cellular antioxidant capacity.

In summary, while the initial interaction of PUFAs with ROS can create a lipid radical, the presence of antioxidants and the glutathione system are crucial to prevent a runaway lipid peroxidation process. Proper functioning of these systems ensures that ROS are neutralized and that electrons are eventually transferred to molecules like NADP+, contributing to cellular redox balance and preventing oxidative damage.

Once again articles like these are just opinions without data: Hisatomi 2021 “These aberrant molecules aggregate and cause apoptotic and non-apoptotic cell death, leading to various protein aggregation diseases. Thus, we investigated the cell-death cross-linking between lipid peroxidation and protein aggregation.

The article cited even properly explain how omega3 deficiency is linked to the neurodegnerative disease not the lipid peroxidation: “DHA levels did not differ in patients with Alzheimer’s disease across age quartiles: all were consistently lower than in control subjects.”

Yes, in theory the propagation of lipid peroxidation can lead to continuous membrane damage, ultimately causing cell apoptosis through endless membrane rupture. Here’s a closer look at how the process would enfold and its potential consequences for the cell, however that is not reality:

Propagation and Cellular Damage?

1. Propagation Mechanics: During lipid peroxidation, once a lipid peroxy radical (LOO•) is formed, it can abstract a hydrogen atom from a neighboring lipid, resulting in the formation of a new lipid radical (L•). This new radical can then react with oxygen, perpetuating the cycle. This chain reaction can propagate as long as there are susceptible lipids and sufficient oxygen, generating new lipid radicals and hydroperoxides.

2. Membrane Integrity: The oxidation of membrane lipids changes the physical and chemical properties of the cell membrane. This can include increased membrane fluidity, altered membrane permeability, and the loss of essential fatty acids. Over time, these changes can impair the membrane’s function, potentially leading to disruptions in ion gradients and cellular homeostasis.

3. Endless Propagation?: The propagation of lipid peroxidation is not truly endless. It can be terminated by various mechanisms:

   • Antioxidant Intervention: Antioxidants like vitamin E, glutathione, and others can intercept and neutralize radicals, forming non-radical products and stopping the chain reaction.
   • Radical-Radical Reactions: Lipid radicals can also terminate by reacting with each other or with other types of radicals, forming non-reactive compounds.

4. Rupture and Apoptosis: While lipid peroxidation could significantly damage cell membranes, it does not necessarily lead to membrane rupture in the traditional sense of a physical breach. However, extensive lipid peroxidation can result in functional impairment of the membrane, potentially triggering programmed cell death (apoptosis) through pathways that involve mitochondrial damage, release of cytochrome c, or activation of specific caspases.

Apoptosis Triggering

• Signal Mediation: Extensive lipid peroxidation can generate specific oxidation products that act as signaling molecules. For example, certain aldehydes produced during lipid peroxidation can modify proteins and DNA, triggering pathways that lead to cell death.
• Mitochondrial Involvement: Lipid peroxidation products can impair mitochondrial function, leading to the release of pro-apoptotic factors and the initiation of the apoptotic cascade.

These claims are just theories based on few experimental designs.

In conclusion, in theory lipid peroxidation, if unchecked, can contribute to cell damage and death, but it does not cause endless membrane rupture leading directly to apoptosis. Instead, it leads to functional impairments and may initiate signaling pathways that result in apoptosis. This is further exasperated by the very high unnatural omega6/3 ratio.

The cell has multiple defense and repair mechanisms to cope with oxidative stress and to prevent the irreversible damage that leads to cell death. This includes enzymatic systems to repair oxidized lipids and mechanisms to clear damaged cells and maintain tissue health. Thus, while lipid peroxidation is a damaging process, cells are equipped with robust systems to limit and respond to this damage. 

Once again, the supplementation with Omega-3 does not change the total amount of PUFA. Given the fact that large amounts of omega6 levels of over 30% are prevalent in modern humans, the entire ROS problem comes down to proper levels of anti-inflammatory omega3 and proper anti-oxidants as explained above.

Tables – Omega6/3 ratios in Foods

Note: these tables are approximations and amounts can vary in actual food sources. Also, pay close attention to absolute amounts of inflammatory omega6! EG. generally flax and chia seeds are considered good sources of omega3 but the reality is that they deliver far more absolute omega6! In addition you need to consider that these plant sources are rancid, eg. prepared nuts (not in a shell). 

Plant sourced

Keep in mind that plants only contain ALA-omega3 which does not typically convert to necessary EPA in the body. At the same time however inflammatory omega6 is resulting in high amounts of inflammatory arachidonic acid.

Here you can see that Flaxseed and Chia have a low omega6/3 index but they also contain high absolute amounts of omega6. In general all plant sources are high in inflammatory omega6.

Note: plants only contain ALA and no EPA or DHA and look at the high absolute amounts of omega6. EG. Yes Flax contains 22g/100g of omega3 but also 5.7g of omega6.

In general nuts are rich in inflammatory omega6. The omega6/3 ratio is even worse if the nuts are prepackaged and not freshly cracked out of their shells.

Animal sources

Only grass-fed-grass-finished beef, lamb and venison as well as cold water fish contain a low omega6/3 ratio index! In addition they contain ready made EPA from the algae they eat.

You can see that coconut is favorable since it contains mostly saturated fat and the only plant food that delivers stearic acid. 

Fat Content by Tofu Type

Soy is inflammatory but Tofu has much less omega6 due to processing. Still extra firm tofu can contain up to 8g of omega6/100g. Tofu is rich in protein but delivers very little saturated fat!

• Unsaturated Fats:
  • The majority of the fat in tofu is unsaturated, primarily polyunsaturated fats like omega-6 and a smaller amount of omega-3 fatty acids.
• Saturated Fats:
  • Tofu has only low levels of saturated fat compared to many animal-based protein sources.

Please also see reactive oxygen species in athletic performance.

Protein-food-science and veganism

Essentially humans rely on Ruminants which are herbivorous grazing or browsing artiodactyls belonging to the suborder Ruminantia that are able to acquire nutrients from plant-based food by fermentation.

Humans can synthesize Nonessential amino acids from oxaloacetate and ketoglutarate out of the Krebs cycle : alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine.

But humans cannot make essential amino acids: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine—these are not synthesized by mammals and are therefore dietarily essential or indispensable nutrients that have to be obtained from food sources.

Here is how that works:

Cows obtain protein from grass through a complex and efficient digestive process that involves their specialized stomach system, which has four compartments: the rumen, reticulum, omasum, and abomasum. Here’s how it works:

1. Rumen Fermentation: When a cow eats grass, it enters the rumen, the largest compartment, where it is mixed with saliva and broken down by a vast population of microorganisms, including bacteria, protozoa, and fungi. These microbes ferment the cellulose and other complex carbohydrates in the grass, breaking them down into simpler compounds.

2. Microbial Protein Synthesis: During fermentation, the microbes themselves grow and multiply, creating microbial protein. The microbes also break down the plant proteins and non-protein nitrogen (such as urea) in the grass to form amino acids and ammonia, which they then use to synthesize their own proteins.

3. Digestion of Microbes: The partially digested food, along with the microbes, passes into the reticulum and then to the omasum, where water and many of the volatile fatty acids are absorbed. The food and microbes then move to the abomasum, which functions similarly to a monogastric stomach (like humans). Here, the acidic environment and digestive enzymes break down the microbial cells, releasing the microbial protein.

4. Absorption in the Small Intestine: The digested microbial protein, along with any undigested food proteins, moves into the small intestine, where it is further broken down into amino acids. These amino acids are then absorbed through the intestinal wall into the bloodstream.

5. Protein Utilization: The absorbed amino acids are transported to various tissues in the cow’s body, where they are used for growth, maintenance, and milk production. They are also used to produce keratin, which is essential for healthy skin and hair (coat).

Through this highly efficient process, cows can convert low-protein grass into high-quality protein, supporting their nutritional needs and overall health.

The microbes in a cow’s rumen play a crucial role in synthesizing essential amino acids. Here’s a more detailed look at how this process works:

1. Microbial Fermentation: The microbes in the rumen ferment the carbohydrates in the grass, producing volatile fatty acids, gases, and microbial biomass. This fermentation process breaks down the plant cell walls and makes the nutrients more accessible.

2. Protein Breakdown and Synthesis: The microbes also break down the proteins and non-protein nitrogen (such as urea) in the grass into their constituent amino acids and ammonia. Using these basic building blocks, the microbes synthesize their own proteins, including all the essential amino acids that the cow cannot produce on its own.

3. Microbial Growth: As the microbes grow and multiply, they incorporate the synthesized amino acids into their own cellular proteins.

4. Digestion of Microbial Protein: When the microbial population is washed out of the rumen into the lower digestive tract, these microbial cells are broken down by the cow’s digestive enzymes in the abomasum and small intestine. This process releases the amino acids from the microbial proteins.

5. Absorption: The free amino acids are then absorbed through the wall of the small intestine into the cow’s bloodstream, where they are available to be used for the cow’s own protein synthesis needs.

Through this symbiotic relationship, the cow benefits from the ability of the rumen microbes to convert low-quality plant proteins and non-protein nitrogen into high-quality microbial protein, which includes all the essential amino acids necessary for the cow’s growth, maintenance, and production. This is a key factor in the efficiency of ruminant digestion and their ability to thrive on diets primarily composed of fibrous plant material.

Common ruminant animals include:

1. Cattle (e.g., cows, bulls, oxen)
2. Sheep
3. Goats
4. Deer
5. Elk
6. Moose
7. Giraffes
8. Bison
9. Antelope
10. Buffalo (e.g., water buffalo, African buffalo)

These animals rely on their rumen and the microbial population within it to break down cellulose and other complex carbohydrates in their plant-based diet, converting it into nutrients they can absorb and utilize. This adaptation allows ruminants to thrive on diets that are high in fibrous plant material.

The “odd” Odds Ratio

In Short, the odds ratio OR does not mean your odds are eg. 0.55 for a particular risk… it only means 0.55 compared to the control group… Consider a study investigating the relationship between regular exercise and the risk of developing heart disease. The relative risk (RR) is found to be 0.6 (those who regularly exercise are 60% as likely to develop heart disease as those who don’t exercise), and the probability of heart disease in the non-exercising population (p) is 0.2 (20% of non-exercisers develop heart disease). Using these values in the formula: OR = ((1 – 0.2) * 0.6) / (1 – 0.6 * 0.2) = 0.8 * 0.6 / 0.88 = 0.48 / 0.88 = 0.55 The odds ratio would be 0.55, suggesting that those who exercise regularly are less likely to develop heart disease compared to those who don’t exercise. However the risk is not reduced by 45% here. An odds ratio less than 1 indicates a reduction in risk, but it does not directly translate to a percentage decrease in risk. An odds ratio of 0.5, for example, would mean that the exposed group (in our example, those who exercise regularly) have half the odds of developing the outcome (heart disease) compared to the unexposed group (those who don’t exercise). So, in the second example, the people who exercise regularly have 55% of the odds of developing heart disease compared to those who don’t exercise. This doesn’t mean their risk is reduced by 45%, but rather that their odds are 45% less compared to the non-exercising group. To put it another way, if you were to say their risk is reduced, you could say their odds of getting the disease are 45% lower than those who don’t exercise, not that their risk is reduced by 45%. It’s a subtle but important distinction in epidemiological studies. Eg this study  shows: Reduced risk of hyperactivity of kids in fish eating mothers was OR 0.34. “OR .34, 95% CI .15 to .78” is a way of reporting the results of a study that used odds ratio (OR) and confidence interval (CI) to measure the strength of the association between a particular exposure or risk factor and a specific outcome. An OR is a measure of the odds of an event occurring in one group compared to another group. In this case, the OR of .34 means that the odds of the event occurring in the group exposed to the risk factor are  0.34 times the odds or 1/3 of the event occurring in the group not exposed to the risk factor. A 95% CI is a range of values that are likely to include the true value of the OR with a probability of 95%. In this case, the 95% CI of .15 to .78 means that there is a 95% chance that the true value of the OR falls within the range of .15 and .78. So the statement OR .34, 95% CI .15 to .78, indicates that there is a statistically significant association between the risk factor and the outcome, with a odds ratio of 0.34, and the true odds ratio is likely to fall between 0.15 and 0.78.

>The smaller the OR, the lower the likelihood of the outcome, and the lower the CI, the more precise the estimate of the OR.

An odds ratio (OR) of 0.1 means that the odds of an event occurring in the exposed group (i.e. those who were exposed to a particular factor, such as a treatment or a risk factor) are 0.1 times the odds of the event occurring in the unexposed group (i.e. those who were not exposed to the factor). In other words, an OR of 0.1 indicates a strong protective effect of the exposure, meaning that the odds of the event occurring are much lower in the exposed group compared to the unexposed group. For example, if the odds of developing a particular disease in a group of people exposed to a certain treatment are 0.1 times the odds of developing the disease in a group of people who did not receive the treatment, this suggests that the treatment is highly effective at reducing the risk of the disease. It is important to note that an OR of 0.1 on its own does not provide information about the statistical significance or clinical relevance of the effect. The significance and relevance of the effect depend on a variety of factors, such as the sample size, the study design, and the clinical context. Therefore, it is always important to interpret the OR in the context of the specific study and the question being asked. So and OR of 0.1 does not necessarily mean that only 10% of the exposed group experience the effect compared to the control group. The odds ratio is a measure of association between an exposure and an outcome, and it does not directly provide information on the proportion of individuals who experience the outcome in each group. To calculate the proportion of individuals who experience the outcome in each group, you would need to look at the raw data, such as the number of individuals with the outcome in each group, and calculate the proportions or percentages. An odds ratio of 0.1 means that the odds of the outcome occurring in the exposed group are one-tenth (or 10%) of the odds of the outcome occurring in the unexposed group. So, if the odds of the outcome in the unexposed group were 20%, then the odds of the outcome in the exposed group would be 2% (i.e. 10% of 20%). It’s important to note that the odds ratio is not the same as a risk ratio or a risk difference, which are measures that directly compare the risk of an outcome between two groups. The interpretation of the odds ratio depends on the specific study design and the characteristics of the population being studied. Statistical regression analysis determine whether the difference in the outcome variable between the two groups is statistically significant, and whether the relationship between the two variables is getting weaker or disappearing over time. Some examples of numbers that may be used to measure statistical regression include the p-value, which represents the probability that the difference in the outcome variable between the two groups is due to chance, and the coefficient of determination (R²) which represents the proportion of the variance in the outcome variable that is explained by the predictor variable. Again, A common threshold for statistical significance is p < 0.05, which means that there is less than a 5% chance that the difference in the outcome variable is due to chance. A low R² value, like less than 0.3, indicates a weak relationship between the predictor and outcome variables. Study design: Always look at the study design and the methods. EG. Arthritis score is very complex but well defined = WOMAC  But when measuring mental clarity or depression results can be difficult to put into numbers! However most studies that are peer reviewed undergo a rigorous process of making sure that numbers they get are meaningful. Also take time to look at the plots and figures: Eg lower blood pressure readings vs time on DHA index.  Again: This is not a true statement: “the odds of developing DM were reduced by 28% (OR 0.72, 95% CI 0.63 to 0.84, p<0.001)” = it should be: the odds of developing DM were reduced by 28% compared to the risk of the control group (not specified here)>..    

Placebo

  The famous Placebo effect was coined when it was recognized in the 18th and 19th centuries that drugs or remedies often worked best while they were still new. So the belief system of the study participant plays an important role. Or in other words a doctor telling take this you will get better already has a significant effect. A placebo is a substance that has no therapeutic effect or it is a sham replacement procedure such as placing a surgical probe but not performing the actual procedure. But how big is the placebo effect and how do we make sure a treatment is actually working? It is almost impossible to estimate the effect due to the study design or circumstances. Average estimates are around 50% for any treatment (even surgery) ; In this study KIrsch analyzing data from the FDA, concluded that 82% of the response to antidepressants was accounted for by placebos. The placebo effect makes it more difficult to evaluate new treatments. For that reason clinical trials supposed to control for this effect by including a group of subjects that receives a sham treatment. The subjects in such trials are blinded as to whether they receive the treatment or a placebo.  For more information look here. However, simply the knowledge of the participant of being on a trial for a certain condition is a bias: Placebo effects across trials were highly correlated (r=.60 and .77) when placebos bore the same name but were not significantly correlated when placebos had different names. Placebo effects were significantly associated with response expectancy but not with acquiescence or absorption. Clinical trials are often double-blinded so that the researchers or doctors also do not know which test subjects are receiving the active or placebo treatment. The placebo effect in such clinical trials is weaker than in normal therapy since the subjects are not sure whether the treatment they are receiving is active. Very often treatment are staggered, eg 1st group half receive placebo and then much later receive treatment.  Many trials such as vaccine or chemotherapy trials do not require placebos because that would be considered unethical.  In this example there was an effect reported for patients with HER2-positive early breast cancer that taking this drug -significantly improves long-term disease-free survival  (HR 0·76, 95% CI 0·68-0·86)??.  Then the “observation groups” were crossed over so in the end only 813 out of 5100 participants were in the ‘observer group’. This renders the results non-conclusive in our opinion. However an effectivness: “Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab” – so in effect 6% more survived by taking the drug, yet the drug caused 7.3% heart failure (vs 0.9% in the observation group). So in summary, this 10 year cancer treatment ‘study’ is an example of a ‘pretend’ placebo random controlled study. The study did not use a blinded group that received a placebo, nor was the ‘observation’ group in a comparable size, nor did they get treated by a placebo. So in other words the observer group was not given the ‘healing effect’ of knowing they are getting treated within the study. Yes Fig. 2 shows a small effect: after 10 years eg. 472 women survived vs 388 in the observation group subset F which this paper accounted for a the HR of 0.76. However are the results statistically meaningful with a CI that goes up to HR 0.86?   Here is a discussion on the ethics of using the placebo effect. To evade this issue or to convolute the outcome results, trials use another “drug” that is already FDA approved as a placebo (but still call this a placebo controlled study). EG. a vaccine study uses the Meningococcal vaccine as placebo or chemo-agent is replaced by a “more benign long term supplemental treatment” such as “trastuzumab only” as the control or in this case radiation. Obviously these are ‘fake studies’ or in other words you cannot compare the side effects or outcome of your new drug to the side effects of another drug or compare ‘apples to oranges’. A placebo is a substance that has no therapeutic effect such as saline or sometimes a diluted sugar pill. In addition many of these studies show very marginal effects. In conclusion,  we argue that If the outcome of a treatment in anything less than 80-90% effective on the condition, that simply means that 8-9 out of 10 treated persons report significant improvement the treatment is questionable. So if a study is not properly placebo controlled the results have to show at least 80% effective. If you subtract the placebo estimate of 50% this makes the treatment “30% more effective than placebo”.   NOCEBO: A nocebo effect is said to occur when negative expectations of the patient regarding a treatment cause the treatment to have a more negative effect than it otherwise would have. Many of these ‘not placebo controlled’ or fake-placebo controlled studies show outcome effects of less than 50%. EG the flu vaccine can be effective as low as 19% which means ~30% could be below the placebo, which means that the treatment was harmful. Here is a history of the yearly flu effectiveness of the vaccines on the CDC website. By its own words the CDC distinguishes ‘RCT efficacy trials’ and ‘effectiveness studies’: Vaccine effectiveness is a measure of how well flu vaccines work among different groups of people, in different settings, and in different real-world conditions (as opposed to RCTs or “clinical trials”). However we argue here these effectiveness studies or often called ‘meta analyses’ are in-fact a large placebo control study but without subtraction of the actual effect. We have great difficult time finding any placebo RCTs. Instead another term of ‘non-inferiority’ is coined: a comparator quadrivalent inactivated influenza vaccine in a pediatric population: A phase 3, randomized noninferiority study  Scientists in the US examined data from 12 clinical trials of Covid vaccines and found that the “nocebo effect” accounted for about 76% of all common adverse reactions after the first dose and nearly 52% after the second dose. However just as it is difficult to “measure and absolute average of placebo” it is difficult to measure ‘nocebo’. Many times the rate of trial-dropouts is very high. These withdrawals maybe  mentioned but not taken into effective ‘placebo control data’. Data were extracted from 20 RCTs fulfilling our search criteria. Of 3049 placebo-treated patients, 57.8% (95% CI: 50.1%-66.7%) reported at least one AE and 6.6% (95% CI: 5.3%-8.4%) discontinued placebo treatment because of AEs.  Demicheli 2018 finds: We included 52 clinical trials of over 80,000 people assessing the safety and effectiveness of influenza vaccines: Inactivated influenza vaccines probably reduce influenza in healthy adults from 2.3% without vaccination to 0.9% (risk ratio (RR) 0.41, 95% confidence interval (CI) 0.36 to 0.47; 71,221 participants; moderate-certainty evidence), and they probably reduce ILI from 21.5% to 18.1% (RR 0.84, 95% CI 0.75 to 0.95; 25,795 participants; moderate-certainty evidence; Vaccination may lead to a small reduction in the risk of hospitalisation in healthy adults, from 14.7% to 14.1% This is also call the NNT (number of necessary targets): In other words 71 healthy adults need to be vaccinated to prevent one of them experiencing influenza! 

Summary: the flu vaccine is far from being 30-70% effective and there are no proper RCT studies, plus treatment often shows a nocebo effect instead. Use natural nutraceuticals like omega3 and vitaminD to strengthen your immunity.

Studies need to be repeated, analyzed in meta studies and independently verified!

Many new recent studies are biased. They claim results based on rancid omega3 supplementation and improper or non-existent placebo controls (eg. vegetable oil capsules)!

For this reason it is recommended:

1. always look for the inflammatory omega6/3 index. If there is no mention of its improvement – how would you know your omega3 actually works
2. many studies need to be combined but also normalized to proper statistical measures, such as WOMAC for OA (not just a subjective pain scale)
3. duration of studies: eg. you cannot claim to show an effect on chronic conditions in 24 week that took decades to develop.
4. Look at absolute numbers eg. 30 people are helped out of 10,000 participants. One cannot conclude proper statistics from those low number.

Paxlovid is a prescription medication used for the treatment of mild to moderate COVID-19 in adults and pediatric patients aged 12 years or older weighing at least 40 kg. It is a combination of two drugs: nirmatrelvir and ritonavir. Nirmatrelvir is a protease inhibitor that works by inhibiting an enzyme called the main protease (Mpro) of the SARS-CoV-2 virus, which is responsible for the replication of the virus. Ritonavir is another protease inhibitor that works by inhibiting an enzyme called cytochrome P450 3A4 (CYP3A4), which breaks down nirmatrelvir in the body, allowing it to remain effective for a longer period of time. The development of Paxlovid was a collaboration between Pfizer and the US government’s Operation Warp Speed program, which was established in 2020 to accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics. Clinical trials for Paxlovid began in 2020, and the drug was granted emergency use authorization (EUA) by the US Food and Drug Administration (FDA) in November 2021 (normally this process involves years of rigorous phase3 trials). 2021 study: The EUA was based on the results of a phase 2/3 clinical trial that showed Paxlovid reduced the risk of hospitalization or death by 89% in high-risk adults with mild to moderate COVID-19. The trial included more than 1,200 patients and was conducted in the US, Mexico, Brazil, and Argentina.   2022: However recent studies show NO EFFECT: There was no significant difference in the duration of SARS-CoV-2 RNA clearance among the two groups (mean days, 10 in Paxlovid plus standard treatment group and 10.50 in the standard treatment group; ARD, −0.62; 95% CI −2.29 to 1.05, P = 0.42). The incidence of adverse events that occurred during the treatment period was similar in the two groups (any adverse event, 10.61% with Paxlovid plus standard treatment vs. 7.58% with the standard, P = 0.39; serious adverse events, 4.55% vs. 3.788%, P = 0.76).   It is important to look at the absolute changes:  Rosenberg 2023: Hospitalization or death occurred in 0.55% (n = 69) of patients who received nirmatrelvir plus ritonavir compared with 0.97% (n = 310) of patients who did not receive the treatment. Evaluating the absolute changes of “treated vs placebo” helps you to draw conclusions if small effects of a drug treatment are worth side effects. In addition possible long term safety data is often not available. In addition, always verify if the placebo used in the study was actually saline.   ODDs Ratio: This meta analyses shows an effect however they are using OR: Three RCTs involving 4241 patients were included. Overall, anti-viral agents were associated with a significantly lower risk of COVID-19 related hospitalization or death compared with the placebo (OR, 0.23; 95% CI: 0.06-0.96; p = 0.04)  So treating people with paxlovid does not mean they have only a “23% chance” of eg not getting hospitalized. OD 0.23 means that the odds of the outcome occurring in the exposed group are about a quarter (or 23%) of the odds of the outcome occurring in the control group. So, if the odds of the outcome in the untreated group were 20%, then the odds of the outcome in the treated group would be 5% (i.e. 25% of 20%). Now it is important to know what are the odds or better the relative risk of the control group to evaluate this data. This number is not easily obtainable and fluctuates!   Lai 2022: If you look at the absolute numbers of treated vs ‘placebo’ you can see the effect is very small. 585 (treated) events vs 628 (placebo)! So out of 3 large studies 43 people had less events when treated or roughly 1%. This does not correspond to 23% reduction in events! In addition 177 vs 126 = 51 more treated people had adverse effects. To be fair, the analyses shows 69 vs 160 people had serious adverse effects and it is not full clear to the author how 160 people ~3% receiving a placebo ended up with severe effects in these studies. Generally “adverse effects” are defined as any new symptoms, clinical or laboratory abnormalities, or complications that occurred after the start of treatment.

Stomach acid

So the term = low stomach acid is not quite accurate . Proton pump inhibitors (PPIs) do not directly eliminate stomach acid but significantly reduce its production by blocking the proton pumps (H+/K+ ATPase enzymes) in the parietal cells of the stomach lining. This leads to low levels of gastric acid while on PPIs, and in some cases, extended use can result in a longer-term reduction in stomach acid production. Here’s a detailed explanation:

Absolute Stomach Acid Levels While on PPIs:

PPIs do not eliminate all stomach acid, but they reduce it by 70–90%. The stomach’s pH may rise to 3.5–5.0 or higher (less acidic), depending on the dose and individual response.
After Stopping PPIs:

In most cases, acid production resumes within a few days to weeks as new proton pumps are synthesized.
However, some individuals may experience a rebound acid hypersecretion, where acid production temporarily increases above baseline levels after stopping PPIs.
Long-Term Use and Absolute Acid Levels
Potential for Chronic Low Acid (Hypochlorhydria):

• Prolonged PPI use (e.g., months to years) may lead to persistent low stomach acid levels (hypochlorhydria) in some people, even after discontinuation. This is more likely in older adults or individuals with predisposing conditions.
• Chronic low acid levels can impair digestion and nutrient absorption, particularly for:
  Vitamin B12 (requires stomach acid for release from food).
  Calcium, iron, and magnesium (require acidic conditions for optimal solubility and absorption).
•  

Parietal Cell Atrophy:

Long-term PPI use may lead to parietal cell downregulation or mild atrophy in some cases, contributing to lower baseline acid production.
H. pylori Infection:

Chronic PPI use may mask or worsen Helicobacter pylori infections, which can damage the stomach lining and contribute to hypochlorhydria.
Effects of Low Stomach Acid
Impaired Digestion:

Reduced protein digestion (less activation of pepsinogen into pepsin).
Slower gastric emptying and possible bloating.
Increased Risk of Infections:

Low acidity can allow pathogenic bacteria to survive in the stomach and intestines, increasing the risk of infections like Clostridium difficile or small intestinal bacterial overgrowth (SIBO).
Nutrient Deficiencies:

Chronic hypochlorhydria can lead to deficiencies in vitamins and minerals.

IN Conclusion PPIs cause low stomach acid levels while being used by inhibiting acid production at the source (proton pumps). In some cases, prolonged use may lead to chronic hypochlorhydria or impair the ability of the stomach to return to normal acid production. Regular monitoring and dietary adjustments may help mitigate the risks associated with long-term PPI use. If concerns arise, consult a healthcare provider for personalized management.

Examples of pH Levels

Macrophages – Their balance in the innate immune system

Macrophages are a type of white blood cell that plays an important role in the immune system. They are involved in both innate and adaptive immune responses and can polarize into different functional subtypes, depending on the cytokine environment they are exposed to. M1 and M2 macrophages represent two different functional phenotypes of macrophages with distinct roles in the immune response. M1 macrophages are classically activated macrophages that are induced by interferon-gamma (IFN-γ) and lipopolysaccharide (LPS), which are primarily produced during bacterial and viral infections. M1 macrophages produce pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, and reactive oxygen species (ROS) to promote pathogen clearance and tissue damage. M2 macrophages, on the other hand, are alternatively activated macrophages that are induced by cytokines such as IL-4, IL-13, and IL-10, which are produced during parasitic infections, allergies, and tissue repair processes. M2 macrophages produce anti-inflammatory cytokines, such as IL-10 and TGF-β, and promote tissue remodeling and repair. The balance between M1 and M2 macrophages is crucial for maintaining immune homeostasis and preventing chronic inflammation. Excessive M1 polarization can lead to tissue damage and autoimmune diseases, while excessive M2 polarization can lead to impaired pathogen clearance and increased susceptibility to infections. Therefore, the appropriate balance between M1 and M2 macrophages is essential for a healthy immune response. A cytokine storm is an exaggerated and uncontrolled immune response characterized by the overproduction of pro-inflammatory cytokines, which are signaling molecules that help to regulate the immune response. Cytokine storms are most commonly associated with viral infections, such as severe cases of COVID-19, influenza, and Ebola. However, they can also occur in response to other types of infections, autoimmune diseases, and immunotherapies. In a cytokine storm, immune cells produce large amounts of cytokines, which can lead to systemic inflammation, tissue damage, and multiple organ failure. This can result in severe and potentially life-threatening symptoms, such as high fever, respiratory distress, low blood pressure, and organ dysfunction. The severity of a cytokine storm depends on several factors, including the type of pathogen or trigger, the individual’s immune system response, and the presence of underlying health conditions. Treatment for cytokine storms may include immunosuppressive drugs, anti-cytokine therapy, and other supportive care measures to manage symptoms and prevent complications. Chinese Medicine herbal treatments can also control the inflammatory process.    

Netosis

Neutrophils are primarily responsible for the process of NETosis. NETosis is a form of programmed cell death in which neutrophils release extracellular traps (NETs) made of DNA, histones, and granule proteins to trap and kill pathogens. This process is an important part of the immune response and is triggered by various stimuli, such as microbial pathogens, inflammatory cytokines, and other inflammatory mediators. While other cell types, such as eosinophils, mast cells, and macrophages, can also undergo NETosis, neutrophils are the primary cells involved in this process.     Normal Immune response has a balance between M1 and M2 macrophages, if this balance is disturbed serious blood clots and other cardiovascular events can occur. 

Triglycerides, Diabetes and Neuropathy

Diabetes 2 is initially a liver disease and it is largely controlled by fat metabolism. High Triglycerides are a result of metabolic disease which are all integrally linked to omega3 deficiency. 

High triglycerides are often associated with diabetes due to the interrelated processes of metabolism and insulin regulation. Here’s a detailed look at why high triglyceride levels are commonly seen in individuals with diabetes, particularly type 2 diabetes:

Insulin Resistance
Key Role of Insulin: Insulin plays a crucial role in helping cells absorb glucose from the bloodstream and also in managing lipid metabolism. It helps inhibit the breakdown of fat and facilitates the uptake of triglycerides from the blood into adipose tissue.
Impact of Insulin Resistance: In the context of type 2 diabetes, insulin resistance is a condition in which the body’s cells do not respond effectively to insulin. When insulin does not function properly, it cannot adequately suppress fat breakdown nor promote triglyceride storage, leading to increased levels of free fatty acids and triglycerides in the bloodstream.
Impaired Lipid Metabolism
Overproduction of VLDL: The liver synthesizes and secretes very-low-density lipoprotein (VLDL), which is rich in triglycerides. Insulin resistance often leads to increased production of VLDL by the liver, contributing to higher circulating levels of triglycerides.
Decreased Clearance of Triglycerides: Normally, enzymes such as lipoprotein lipase help break down triglycerides in the lipoproteins for use or storage by the body’s tissues. Insulin supports the activity of these enzymes. However, in the state of insulin resistance, the activity of lipoprotein lipase can be diminished, leading to a slower clearance of triglycerides from the blood.
Associated Conditions
Obesity and Metabolic Syndrome: Both conditions are common in individuals with type 2 diabetes. Obesity, especially increased visceral fat, is linked to insulin resistance and dyslipidemia, including elevated triglyceride levels.
Inflammatory Markers: High triglycerides are also associated with increased inflammatory markers, which are often elevated in diabetes. Chronic inflammation can exacerbate insulin resistance and contribute further to metabolic dysregulation.
Complications
Cardiovascular Disease: Elevated triglycerides are a risk factor for cardiovascular disease, which is a major complication of diabetes. The presence of high triglycerides can contribute to the development of atherosclerosis, particularly when combined with other lipid abnormalities commonly seen in diabetes, such as low HDL (good) cholesterol and small, dense LDL particles.
In summary, high triglycerides in diabetes are primarily a consequence of insulin resistance affecting lipid metabolism. This results in increased production and decreased clearance of triglycerides. Managing triglyceride levels is crucial for people with diabetes as part of a broader strategy to reduce the risk of cardiovascular disease and improve overall metabolic health. Strategies may include lifestyle changes such as diet and exercise, along with medications to improve insulin sensitivity and directly lower triglyceride levels.

Diabetes is a complex metabolic disorder that significantly impacts multiple organ systems, with particular detriment to vascular health and nerve function. The relationship between diabetes, vascular damage, and neuropathy is crucial in understanding many of the complications associated with the disease. Here’s an overview of how these elements are interconnected:

Vascular Damage in Diabetes

1. Hyperglycemia: Chronic high blood glucose levels in diabetes can damage blood vessels over time. This damage is primarily due to the glycation of proteins and lipids, which leads to the formation of advanced glycation end products (AGEs). AGEs can cause structural and functional changes in the vascular walls.

2. Microvascular Complications: Diabetes primarily affects small vessels (microvasculature), leading to complications such as diabetic retinopathy (eye damage), nephropathy (kidney damage), and neuropathy (nerve damage). These microvascular changes are often due to endothelial dysfunction, reduced nitric oxide availability, and increased oxidative stress.

3. Macrovascular Complications: Diabetes also affects larger blood vessels (macrovasculature), increasing the risk of atherosclerosis. This condition can lead to major cardiovascular events such as heart attacks and strokes.

Diabetic Neuropathy

1. Mechanisms: Neuropathy in diabetes is believed to result from a combination of direct glucose toxicity, microvascular damage which impairs blood flow to nerves, and metabolic changes that injure nerve tissues. Chronic hyperglycemia facilitates these processes, leading to nerve fiber loss and dysfunction.

2. Types of Neuropathy:

   • Peripheral Neuropathy: The most common type, affecting the feet and hands first. It can cause numbness, tingling, pain, and weakness in the affected areas.
   • Autonomic Neuropathy: Affects the autonomic nerves controlling internal organs, potentially leading to digestive issues, cardiovascular problems, and urinary tract functions.
   • Focal Neuropathies: Involves sudden weakness of one nerve or a group of nerves, causing muscle weakness or pain.

The Link Between Vascular Damage and Neuropathy

1. Blood Supply: The health of nerves is critically dependent on their blood supply. Microvascular damage reduces blood flow to nerves, depriving them of oxygen and nutrients, which exacerbates nerve damage and dysfunction.

2. Oxidative Stress and Inflammation: Both vascular damage and neuropathy are exacerbated by increased oxidative stress and inflammatory responses in diabetes, contributing to the progression of both conditions.

3. Ischemia and Hypoxia: Poor blood circulation due to damaged vessels can lead to ischemia (reduced blood flow) and hypoxia (low oxygen levels) in nerve tissues, further impairing nerve function and leading to symptoms of neuropathy.

Managing Vascular Damage and Neuropathy in Diabetes

• Glucose Control: Maintaining blood glucose levels within a normal range is crucial for preventing or slowing the progression of both vascular damage and neuropathy.
• Lifestyle Modifications: Diet, exercise, and smoking cessation are important to improve blood flow and reduce the risk of vascular complications.
• Medications: Drugs that improve blood flow, reduce blood pressure, and lower cholesterol levels can also help manage these complications. Additionally, specific treatments for neuropathy symptoms, such as pain relievers and medications that enhance nerve function, can be beneficial.

In summary, the relationship between diabetes, vascular damage, and neuropathy is characterized by a cycle of mutual exacerbation where damage to blood vessels compounds nerve damage, and vice versa. Effective management of diabetes and its vascular effects is essential for preventing or mitigating neuropathy and other related complications.

Adiponectin, a hormone secreted by adipose (fat) tissue, plays a critical role in regulating glucose levels and fatty acid breakdown. It is known for its anti-inflammatory and insulin-sensitizing properties, making it beneficial in the context of metabolic diseases such as diabetes and obesity. Omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are well-known for their cardiovascular and anti-inflammatory benefits. The relationship between adiponectin and omega-3 fatty acids is an area of interest due to their overlapping and potentially synergistic effects on metabolic health. Here’s how they are connected:

Effects of Omega-3 Fatty Acids on Adiponectin Levels

1. Increase in Adiponectin Secretion: Research suggests that omega-3 fatty acids can increase the secretion of adiponectin from adipose tissue. This effect is beneficial because higher levels of adiponectin are associated with a reduced risk of type 2 diabetes and coronary heart disease. Omega-3 fatty acids may enhance adiponectin’s effects on insulin sensitivity and lipid oxidation.

2. Anti-inflammatory Actions: Both adiponectin and omega-3 fatty acids have potent anti-inflammatory properties. Adiponectin can modulate inflammatory responses by interfering with the pathways that activate inflammatory cytokines. Omega-3 fatty acids contribute similarly by reducing the production of eicosanoids derived from omega-6 fatty acids, which are typically pro-inflammatory. This shared pathway can be particularly beneficial in reducing systemic inflammation seen in conditions like obesity, metabolic syndrome, and type 2 diabetes.

3. Improved Lipid Profile: Adiponectin helps regulate lipid metabolism by enhancing fatty acid oxidation, which can lead to improved lipid profiles. Omega-3 fatty acids also directly improve lipid profiles by lowering triglycerides and potentially increasing HDL cholesterol levels. Together, they can synergistically improve lipid metabolism, reducing the risk of cardiovascular disease.

Clinical Implications and Research

• Cardiometabolic Health: The combination of increased adiponectin levels and omega-3 fatty acid intake may help mitigate the risk factors associated with cardiovascular diseases and metabolic disorders. This synergy could be particularly useful in therapeutic strategies aimed at improving cardiometabolic health.

• Anti-atherosclerotic Potential: Both adiponectin and omega-3 fatty acids have properties that may reduce the progression of atherosclerosis. Adiponectin’s ability to enhance endothelial function and reduce arterial inflammation, combined with omega-3’s effects on lipid lowering and plaque stabilization, underscores their potential in preventing atherosclerotic diseases.

• Dietary Sources and Supplementation: Including omega-3-rich foods, such as fatty fish (salmon, mackerel, sardines), or considering omega-3 supplements could be beneficial for increasing adiponectin levels. However, dietary interventions should be tailored to individual health needs and conditions, often in consultation with a healthcare provider.

In conclusion, the interplay between adiponectin and omega-3 fatty acids highlights a promising area of research with potential implications for dietary and pharmacological interventions aimed at improving metabolic health and reducing the risk of chronic diseases. Further studies are needed to fully understand the mechanisms and to define the optimal strategies for using omega-3 fatty acids to modulate adiponectin levels and function in various populations.

ω3-PUFA’s act to soften inflammation through an increase in adiponectin secretion.  Functional foods contribute to reduced food intake by promoting satiety, less weight gain via metabolic uncoupling and improved insulin sensitivity via several distinct mechanisms.

What happens during starvation and Ketosis?

Beta-oxidation is the metabolic process where fatty acid molecules are broken down in the mitochondria and/or in peroxisomes to generate acetyl-CoA, which then enters the citric acid cycle (Krebs cycle), ultimately leading to the production of ATP through oxidative phosphorylation. This process indeed requires oxygen because the electrons removed from the fatty acids are passed down the electron transport chain and eventually combined with oxygen to form water. In conditions of starvation, the body prioritizes the use of fats for energy through beta-oxidation because glycogen stores are limited and are depleted within about 24 hours. The liver converts some of the acetyl-CoA into ketone bodies, which can be used as an energy source by the brain and other tissues when glucose levels are low. However, if tissue becomes anaerobic, such as during intense exercise when oxygen delivery to muscles may be insufficient, or in pathological conditions like ischemia, the following can occur:

1. Beta-Oxidation Decreases: Since beta-oxidation requires oxygen, it cannot proceed at its normal rate without adequate oxygen supply. Instead, cells must rely more on glycolysis, the process of breaking down glucose for energy in the absence of oxygen.
2. Lactic Acid Production: Anaerobic glycolysis results in the production of lactic acid. While muscles and other tissues can tolerate some level of lactic acid, excessive accumulation can lead to muscle fatigue and discomfort, commonly known as lactic acidosis.
3. Ketone Body Utilization: During starvation, ketone bodies are an alternative fuel source, particularly for the brain. Ketones do not require oxygen to be used for energy, but their production through ketogenesis in the liver is initially dependent on the oxygen-requiring beta-oxidation process. Thus, if a state of anaerobiosis persists, the production of ketone bodies might be affected.
4. Protein Catabolism: In prolonged starvation combined with anaerobic conditions, the body may increase the breakdown of proteins into amino acids, which can be used for gluconeogenesis (the generation of glucose from non-carbohydrate sources), although this is not an anaerobic process and primarily takes place in the liver and kidneys which typically remain aerobic.

In summary, beta-oxidation of fats does indeed require oxygen. If a tissue becomes anaerobic, beta-oxidation is hampered, and the cell must rely on anaerobic glycolysis for energy, which is less efficient and has byproducts like lactic acid. However, during starvation, the body can use ketone bodies that have been generated during prior aerobic conditions as an alternative energy source that does not require oxygen. Omega-3 fatty acids, particularly EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), have several roles in cellular metabolism and cardiovascular health that could theoretically enhance beta-oxidation:

1. Cardiovascular Health: Omega-3 fatty acids are known for their cardiovascular benefits. They can improve endothelial function, reduce triglyceride levels, lower blood pressure, and have anti-inflammatory and antithrombotic properties. By improving overall cardiovascular health, omega-3s can enhance blood flow, thereby potentially increasing oxygen delivery to tissues. Enhanced oxygen delivery could support aerobic processes, including beta-oxidation.
2. Membrane Fluidity: DHA is an important component of cell membranes and can affect their fluidity. This can influence membrane-bound proteins, including those involved in the electron transport chain. Improved membrane fluidity can facilitate the activity of enzymes involved in beta-oxidation and oxidative phosphorylation.
3. Regulation of Gene Expression: Omega-3 fatty acids can regulate the expression of certain genes involved in fatty acid metabolism. They can act on nuclear receptors such as PPARs (peroxisome proliferator-activated receptors), which play a role in the expression of genes involved in fatty acid transport and oxidation.
4. Anti-inflammatory Effects: Omega-3 fatty acids have anti-inflammatory properties. Inflammation can impair endothelial function and reduce tissue oxygenation, so by reducing inflammation, omega-3s might indirectly support beta-oxidation.
5. Cytochrome c Function: While omega-3 fatty acids are not direct activators of cytochrome c, their role in maintaining cell membrane integrity and fluidity might affect the overall function of the electron transport chain, in which cytochrome c is involved.

In summary, omega-3 fatty acids can influence these aspects of metabolism and cardiovascular function. The direct effect of omega-3 on beta-oxidation rates in humans needs to be understood in the context of a myriad of other regulatory mechanisms. It’s not solely the presence of omega-3 that dictates the rate of beta-oxidation; rather, it is a combination of nutritional status, energy demands, hormonal regulation, and the availability of substrates and oxygen. However it has become clear that without proper Omega3 levels fat metabolism and ketosis is impaired.