Category Archives: Nutraceuticals


Flip Your AMPK switch to the “ON” position

Introduction to AMPK

AMPK (adenosine monophosphate-activated protein kinase) is an enzyme contained in every cell of the human body that serves as the body’s master regulating switch.

When the AMPK master switch is turned “ON” (by activating AMPK), it inhibits multiple damaging factors of aging and enables cells to become revitalized.  Scientists have found that activated AMPK promotes longevity factors that have been shown to extend life span in numerous organisms.  1  2 

There are various studies that show an increase in AMPK supports:

  • Reduced fat storage 3 
  • New mitochondria production  4 
  • Promotion of healthy blood glucose and lipids already within normal range  5 


Roles of AMPK in the control of whole-body energy metabolism. Notes: Activation of AMPK (green lines) stimulates the energy-generating pathways in several tissues while inhibiting the energy-consuming pathways (red lines). In skeletal muscle and heart, activation of AMPK increases glucose uptake and fatty acid oxidation. In the liver, AMPK activity inhibits fatty acid and cholesterol synthesis. Lipolysis and lipogenesis in adipose tissue are also reduced by AMPK activation. Activation of AMPK in pancreatic β-cells is associated with decreased insulin secretion. In the hypothalamus, activation of AMPK increases food intake.  Source: AMPK activation: a therapeutic target for type 2 diabetes? Kimberly A Coughlan, Rudy J Valentine, Neil B Ruderman, and Asish K Saha, Diabetes Metab Syndr Obes. 2014; 7: 241–253. Published online 2014 Jun 24. doi: 10.2147/DMSO.S43731

Activating AMPK:  Turning the Switch “ON”

The two major methods of activating AMPK is through:

  • exercise and
  • calorie restriction

When you exercise, you use up more ATP which generates higher AMP levels, which then activates AMPK.  6

The other method of activating AMPK is through calorie restriction by at least 30%.  This means cutting daily calorie consumption by 30%.  By reducing calorie consumption, the lower levels of available energy leads to rising AMP levels, which then activates AMPK.  7

In addition to exercise and calorie restriction, there are many other ways to activate AMPK, particularly through certain foods, herbs and nutraceuticals.  The Table below lists the many researched methods of activating AMPK:

AMPK Activators

Fasting and Intermittant Fasting2
Cold water exposure (raise AMPK in the hypothalamus)3
Calorie Restriction4
Extra Virgin Olive Oil 5
Royal Jelly (10-Hydroxy-2-decenoic acid (10H2DA)6
Dashi kombu (Laminaria japonica Areschon)7
Bitter Orange (Citrus aurantum Linn)8
Garlic and Olives (Oleanolic acid)9
Apple Cider Vinegar10
Rose Hips (Trans-Tiliroside)11
Mulberry leaves extracts12
Fish Oil – EPA , DHA 13 14
Anthocyanins 15
Bitter melon16
Herbs and Spices
Cinnamon 18
Astragalus 19 20
Marijuana (Cannabinoids)21
Green Tea/EGCG22
Danshen (Chinese Red Sage)24
Gynostemma pentaphyllum (Jiagulon)25
Baicalin26 27
Adiponectin 28 29
Thyroid hormones, especiallly T3 30
Nitric Oxide32 33
Immune System
Interleukin-6 (IL-6)34
Butyrate (Calcium/Magnesium ) or Sodium Butyrate (Short Chain Fatty-Acid)37
Co-enzyme Q1039
Glucosamine44 45
Quercetin48 49
Red yeast rice50
R-Lipoic Acid52 53
Vitamin E - gamma tocotrienol54

Informational References:

Life Extension – AMPK and Aging “A Technical Review”  (November 2015)

Enhancing and Protecting the Components of the Neurons with Nutraceuticals, Foods and Herbs

Components of a Neuron

A neuron, also known as a nerve cell, is an electrically excitable cell that processes and transmits information through electrical and chemical signals. These signals between neurons occur via specialized connections called synapses.

Neurons are major components of the :

  • brain and spinal cord of the central nervous system (CNS)
  • autonomic ganglia of the peripheral nervous system

Image result for Neuron

Figure 1.  Diagram of a neuron  (Source)

There are a number of components of a neuron that each provide a unique process in the function of the neuron.  These anatomical and physiological components of the neuron include:

  • Neurons (Whole)
  • Nerve Impulses
  • Axons
  • Myelin Sheaths
  • Presynaptic Terminal
  • Presynaptic Membrane
  • Synaptic Vesicles
  • Dendrite
  • Synaptic Cleft

The purpose of this article is to review each component of the neuron and identify the nutraceuticals, foods and herbs that may enhance and protect the function of each individual component of the neuron.

Neurons (Whole)

Neurons are very small. 

In fact, about 30,000 to 50,000 would fit on the tip of a pin.  A tiny slice of brain tissue the size of a grain of sand contains about 100,000 neurons.  They are packed so tightly that a pebble-sized chunk of tissue from the human brain contains about two miles of neuron material.  The entire brain contains about 100 billion neurons. 

Neurons are the only cells in the body that communicate directly with one another by sending messages back and forth in the form of electrochemical signals or impulses. 

The general method of communication between neurons is the same in all humans.  However, each individual is unique based on how neurons are organized in networks or patterns in the human brain.

Neurons resemble the structure of a tree, with the axon resembling the roots of the tree and the dendrites resembling the branches and twigs of the tree.  However, the neuron is not stiff like a tree.  Instead, a live neuron is very elastic and amorphous.

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Figure 2.  Structure of a neuron (Source) 

Neurons communicate via their axons and dendrites through an electrochemical messaging system.  The axon sends electrochemical information to other neurons and the dendrites receive the messages from other nerve cells. 

Even though there are over 100 billion neurons in the human brain, the amazing fact is that neurons never touch each other.  The space between neurons is called the synaptic cleft and is approximately one-millionth of a centimeter in width. 

The initiation of the neurons communication with other neurons is in the cell membrane.  The neurons cell membrane is the continuous boundary that surrounds the neuron.  The cell membrane is very thin, about 8 nanometers, or 100,000th of a meter.

The Table below lists the Nutraceuticals, Food and Herbs that May Enhance the Function of Neurons

Nutraceuticals, Foods, Herbs that Enhance the Function of the Neurons

Amino Acids
Acetyl-L-Carnitine (ALCAR)
Bee Propolis
Ginko Biloba
Bacopa Monneir
Gota Kola
Korean Ginseng
Horse Chestnut
Sanchi Ginseng
Ginsenoside Rb1
Ginsenoside Rg1
Organic Acids
Malic Acid
Coenzyme Q10
Vitamin E
Vitamin A
Vitamin B1
Vitamin B12

Nerve Impulses

Nerve Impulses are the electrical activity in the membrane of a neuron that and is the means by which information is transmitted within the nervous system. 

Nerve impulses originate in dendrites, are integrated into the soma (cell body of neurons), and are transmitted down the axon to the synapse.

Action potentials in neurons are also known as “nerve impulses” or “spikes”, and the temporal sequence of action potentials generated by a neuron is called its “spike train”.

Nearly all cell membranes in animals, plants and fungi maintain an electric potential difference (voltage)—the membrane potential. A typical voltage across an animal cell membrane is –65 mV—approximately one-fifteenth of a volt. Because the cell membrane is very thin, voltages of this magnitude give rise to very strong electric forces across the cell membrane.

The electrical properties of an animal cell are determined by the structure of the membrane that surrounds it. A cell membrane consists of a layer of lipid molecules with larger protein molecules embedded in it. The lipid layer is highly resistant to movement of electrically charged ions, so it functions mainly as an insulator.

The Table below lists the Nutraceuticals, Food and Herbs that May Improve the Transmission of Nerve Impulses

Nutraceuticals, Food and Herbs that May Improve the Transmission of Nerve Impulses

Amino Acids
Acetyl-L-Carnitine (ALCAR)
Ginko Biloba
Calcium AEP
Vitamin B6
Vitamin B1


An axon is a long, slender projection of a neuron that conducts electrical impulses away from the neuron’s cell body. Axons are also known as nerve fibers. The function of the axon is to transmit information to different neurons, muscles and glands.

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Figure 3.  Axon  (Source)

An axon is one of two types of protoplasmic protrusions that extrude from the cell body of a neuron, the other type being dendrites. Axons are distinguished from dendrites by several features, including shape (dendrites often taper while axons usually maintain a constant radius), length (dendrites are restricted to a small region around the cell body while axons can be much longer), and function (dendrites usually receive signals while axons usually transmit them).

The Table below lists the Nutraceuticals, Food and Herbs that May Enhance the Function of the Axon

Nutraceuticals, Food and Herbs that May Enhance the Function of the Axon

Amino Acids
Acetyl-L-Carnitine (ALCAR)
Nucleic Compounds
Proline Rich Peptides
Folic Acid
Vitamin D
Vitamin A
Vitamin B12
Boswellia serrata
Gota Kola
Korean Ginseng

Myelin Sheath

Acetylcholine is the building block of myelin, which acts to insulate the axon and neuron, thus providing moisture and lubricants to the nervous system.

The myelin insulation of the neuron and axon provides conductivity to the nervous system.

Image result for myelin sheath

Figure 4.  Myelin sheath  (Source)

Myelination provides:

  • neurons circuits to fire more rapidly
  • neurons to recover faster after signals have been sent
  • neurons greater processing capacity

When myelin increases in thickness, the neurons fire at a faster rate and thus you think faster.  The more the neuronal connections are used (through learning), the myelin insulation increases and becomes thicker and heavier.

Cognitive decline and memory loss occurs when the myelin decay and the neurotransmitters get disrupted as their pathways lose their lubrication.  This is when the brain starts to short-circuit due to the lack of optimal myelin and acetylcholine.

The lipid makeup of the myelin sheath is important and cholesterol is an essential constituent.  The primary lipid of myelin is a glycolipid called galactocerebroside. The intertwining hydrocarbon chains of sphingomyelin serve to strengthen the myelin sheath.

Composition of CNS Myelin and Brain

  Myelin White matter    
Substance Human Bovine Rat Human Bovine Gray matter (human) Whole brain (rat)
Protein 30.0 24.7 29.5 39.0 39.5 55.3 56.9
Lipid 70.0 75.3 70.5 54.9 55.0 32.7 37.0
Cholesterol 27.7 28.1 27.3 27.5 23.6 22.0 23.0
Cerebroside 22.7 24.0 23.7 19.8 22.5 5.4 14.6
Sulfatide 3.8 3.6 7.1 5.4 5.0 1.7 4.8
Total galactolipid 27.5 29.3 31.5 26.4 28.6 7.3 21.3
Ethanolamine phosphatides 15.6 17.4 16.7 14.9 13.6 22.7 19.8
Lecithin 11.2 10.9 11.3 12.8 12.9 26.7 22.0
Sphingomyelin 7.9 7.1 3.2 7.7 6.7 6.9 3.8
Phosphatidylserine 4.8 6.5 7.0 7.9 11.4 8.7 7.2
Phosphatidylinositol 0.6 0.8 1.2 0.9 0.9 2.7 2.4
Plasmalogensb 12.3 14.1 14.1 11.2 12.2 8.8 11.6
Total phospholipid 43.1 43.0 44.0 45.9 46.3 69.5 57.6

A  Protein and lipid figures in percent dry weight; all others in percent total lipid weight.

B  Plasmalogens are primarily ethanolamine phosphatides.

From: Characteristic Composition of Myelin, Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Siegel GJ, Agranoff BW, Albers RW, et al., editors. Philadelphia: Lippincott-Raven; 1999.

The Table below lists the Nutraceuticals, Food and Herbs that May Enhance the Function of Myelin Sheaths

Nutraceuticals, Food and Herbs that May Enhance the Function of Myelin Sheaths

Amino Acids
Acetyl-L-Carnitine (ALCAR)
Animal Organ Extracts
Mylein Sheath Extract
Lions Mane
Celastrus paniculatus seeds
Nucleic Compounds
Vitmin B6
Vitamin B12

Presynaptic Terminal

Presynaptic Terminals are the end-point or distal terminations of axons which are specialized for the release of neurotransmitters.  They are also called chemical synapses which are biological junctions through which neurons’ signals can be exchanged to each other and to non-neuronal cells such as those in muscles or glands.

There are an astonishing large number of synapses and the human brain is estimated to contain from 1014 to 5 × 1014 (100–500 trillion) synapses.  1 

Image result for presynaptic terminal

Figure 5.  Presynaptic Terminal  (Source)

The Table below lists the Nutraceuticals, Food and Herbs that May Enhance the Function of Presynaptic Terminals

Nutraceuticals, Food and Herbs that May Enhance the Function of Presynaptic Terminals

Amino Acids
N-Acetyl-Cysteine (NAC)
Vitamin B12

Presynaptic Membrane

The presynaptic membrane is that part of the plasma membrane of an axon terminal that faces the plasma membrane of the neuron or muscle fiber with which the axon terminal establishes a synaptic junction. 

It is the excitable membrane located at the end-point of the presynaptic terminal of the axons. 

Image result for presynaptic membrane

Figure 6.  Presynaptic Membrane  (Source)

Presynaptic Membranes contain very high levels of Docosahexaenoic Acid (DHA).  Presynaptic Membranes contain more DHA than almost every other type of tissue of the neuron.

The Table below lists the Nutraceuticals, Food and Herbs that May Enhance the Function of the Presynaptic Membrane

Nutraceuticals, Food and Herbs that May Enhance the Function of the Presynaptic Membrane


Synaptic Vesicles

In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell.

Image result for Synaptic Vesicles

Figure 7.  Synaptic Vesicles  (Source)

Synaptic vesicles are relatively simple because only a limited number of proteins fit into a sphere of 40 nm diameter. Purified vesicles have a protein:phospholipid ratio of 1:3 with a lipid composition of:

  • 40% phosphatidylcholine
  • 32% phosphatidylethanolamine
  • 12% phosphatidylserine
  • 5% phosphatidylinositol
  • 10% cholesterol

The Table below lists the Nutraceuticals, Food and Herbs that May Enhance the Function of Synaptic Vesicles

Nutraceuticals, Food and Herbs that May Enhance the Function of Synaptic Vesicles

Alpha-Linolenic Acid
Vitamin B1
Perilla Oil


Dendrites are the branched projections of a neuron that act to propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project.

Electrical stimulation is transmitted onto dendrites by upstream neurons (usually their axons) via synapses which are located at various points throughout the dendritic tree.

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Figure 8.  Dendrites  (Source)

Dendrites are one of two types of protoplasmic protrusions that extrude from the cell body of a neuron, the other type being an axon.

Axons can be distinguished from dendrites by several features including shape, length, and function. Dendrites often taper off in shape and are shorter, while axons tend to maintain a constant radius and be relatively long.

Typically, axons transmit electrochemical signals and dendrites receive the electrochemical signals.

The Table below lists the Nutraceuticals, Food and Herbs that May Enhance the Function of Dendrites

Nutraceuticals, Food and Herbs that May Enhance the Function of Dendrites

Huperzine A
Amino Acids
Acetyl-L-Carnitine (ALCAR)
Organic Acids
Malic Acid
Gota Kola

Synaptic Cleft

The synaptic cleft, which is a component of the chemical synapse, is the minute space (approximately 20 nanometers wide) that exists between the presynaptic membrane of axons and the postsynaptic membrane of receiving (normally) dendrites. 

When nerve impulses reach a synapse they cause the release of a neurotransmitter which diffuses across the synaptic cleft and triggers a further impulse in the postsynaptic membrane of the dendrite of the next neuron.

The small volume of the cleft allows neurotransmitter concentration to be raised and lowered rapidly.  2 

Image result for synaptic cleft

Figure 9.  Synaptic Cleft  (Source)

The Table below lists the Nutraceuticals, Food and Herbs that May Prevent Deterioration of the Synaptic Cleft

Nutraceuticals, Food and Herbs that May Prevent Deterioration of the Synaptic Cleft


Consolidation and Summary Table

The Table below is a consolidation and summary of the Nutraceuticals, Food and Herbs that enhance and protect the nine (9) components of neurons.


NEU-Neuron; NIP-Nerve Impluses; AXN-Axons; MYL-Myelin Sheath; PST-Presynaptic Terminal; PSM-Presynaptic Membrane; SNV-Synaptic Vesicles; DEN- Dendrite; SYN-Synaptic Cleft

Consolidation and Summary Table - Components of the Neurons

Huperzine AX1
Amino Acids
Acetyl-L-Carnitine (ALCAR)XXXXX5
Animal O E
Mylein Sheath ExtractX1
Perilla OilX1
Ginko BilobaXX2
American GinsengX1
Bacopa MonneriX1
Gota KolaXXX3
Korean GinsengXX2
Magnolia (Honokiol)X1
Lions ManeX1
Ginsenoside Rb1X1
Ginsenoside Rg1X1
Alpha-Lineloic AcidX1
Calcium AEPX1
Nucelic Cmd
Organic Ad
Malic AcidX1
Coenzyme Q10X1
Vitamin EX1
Vitamin AXX2
Vitamin B1XXX3
Vitamin B12XXXX4
Vitamin B6XX2
Folic AcidX1
Vitamin DX1
Vitamin DX1

Top Nine Substances for Neurons

Based on the Consolidations and Summary Table, the Chart below lists the top nine (9) nutraceuticals, foods and herbs for the enhancement and protection of neurons. 

It is of no surprise that the top three substances that enhance and protect the five (5) components of neurons include:

  • Phosphatidylserine
  • DHA
  • Acetyl-l-Carnitine

Chart:  Top 9 Substances for Neurons

Preventing Brain Atrophy and Cognitive Decline with Omega-3 Fatty Acids and B-Complex Vitamins

Brain Atrophy

Brain atrophy, or brain shrinkage, is the opposite of neurogenesis. Brain atrophy describes a loss of neurons and the connections between them.

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Figure 1.  Normal brain versus Atrophic brain  (Source)

Brain atrophy can be categorized as either general or focal. With general brain atrophy, all of the brain shrinks. With focal brain atrophy, shrinkage of the brain affects a limited area of the brain which often results in decreased functions in the area that area controls. For example, if the cerebrum atrophies, then conscious thought and voluntary processes may be impaired.

Even if you do not have a chronic disease, you may be losing as much as 0.4% of your brain mass every year.  1  The rate of brain shrinkage increases with age and is a major factor in early cognitive decline and premature death.  2  Age related cognitive decline occurs in tandem with the physical degradation of brain structure.

Image result for brain atrophy

Figure 2.  Brain atrophy in Advanced Alzheimer’s Disease  (Source)

By the age of 60, approximately .5 to 1% of brain volume is lost per year. By the time you reach age 75, your brain is on average of 15% smaller than it was when you were in your mid-20’s.

Even though brain shrinkage is progressive, a growing number of neuroscientists believe that brain shrinkage can be slowed or even reversed.  3 

Medical science has recognized a number of conditions and behaviors that cause brain atrophy:


Homocysteine is a risk factor for brain atrophy. Supplementation with B vitamins that lower levels of plasma total homocysteine can slow the rate of brain atrophy in subjects with mild cognitive impairment.  4  


Poor sleep quality was associated with reduced volume within the right superior frontal cortex in cross-sectional analyses, and an increased rate of atrophy within widespread frontal, temporal, and parietal regions in longitudinal analyses.   5


Studies have shown that both high and low blood pressure (BP) may play a role in the etiology of brain atrophy. High BP in midlife has been associated with more brain atrophy later in life.  6


Normal aging is associated with diminished blood flow to the brain. This pathology is known as hypoperfusion and causes cell injury and death. The combination of hypertension and hypoperfusion is associated with smaller brain volume.  7

Type 2 Diabetes

New research has shown that cognitive decline in people with type 2 diabetes is likely due to brain atrophy, or shrinkage, that resembles patterns seen in the early stages of Alzheimer’s disease.  8


Higher body mass index (BMI, a measure of obesity) is associated with lower brain volume in obese and overweight people.  9


Any lifetime history of smoking (even if you currently do not smoke) is associated with faster brain shrinkage in multiple brain regions, compared with people who never smoked.  10


Heavy drinkers are 80% more likely than nondrinkers to sustain frontal lobe shrinkage, compared with nondrinkers,49 and 32% more likely to have enlargement of the ventricles, indicating shrinkage from within.  11

Preventing Brain Atrophy with Omega-3 Fatty Acids and B Vitamins

A study published in July 2015 in The American Journal of Clinical Nutrition entitled “Brain atrophy in cognitively impaired elderly: the importance of long-chain ω-3 fatty acids and B vitamin status in a randomized controlled trial”, revealed some interesting new findings on brain atrophy.

The researchers investigated whether plasma omega-3 fatty acid concentrations (eicosapentaenoic acid and docosahexaenoic acid) modify the treatment effect of homocysteine-lowering B vitamins on brain atrophy rates in a placebo-controlled trial.

The study included 168 elderly people (≥70 y) with mild cognitive impairment, randomly assigned either to placebo (n = 83) or to daily high-dose B vitamin supplementation formula consisting of:

  • folic acid (800 mcg)
  • vitamin B6 (20 mg)
  • vitamin B12 (500 mcg)

The subjects underwent cranial magnetic resonance imaging scans at baseline and 2 years later. 

In the group of subjects who took the B vitamin formula and that had a high baseline omega-3 blood levels (>590 μmol/L), the mean brain atrophy rate slowed by 40% compared to the placebo group.

In the placebo group there was no slowing of brain atrophy even when this group had a high baseline of omega-3 fatty acids.

In the group receiving the B vitamin formula with a low baseline omega-3 blood levels (390μmol/L), there was no significant effect on the rate of atrophy among subjects.

The researchers conclusion demonstrates the importance to supplement with both omega-3 fatty acids and the B-complex vitamins:

“The beneficial effect of B vitamin treatment on brain atrophy was observed only in subjects with high plasma ω-3 fatty acids. It is also suggested that the beneficial effect of ω-3 fatty acids on brain atrophy may be confined to subjects with good B vitamin status.”  12

Prevention of Cognitive Decline with Omega-3 Fatty Acids and B Vitamins

A more recent study published in January 2016 in the Journal of Alzheimer’s Disease entitled “Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment”, investigated whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment slowed the rate of cognitive and clinical decline.

For this study 266 participants with MCI aged ≥70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years.

Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured.

Final scores for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations.

The results were intriguing among those with good omega-3 status.  In this group, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo.

For all three outcome measures, higher concentrations of docosahexaenoic acid (DHA) alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid  (EPA) appeared less effective.

When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline.

The concluding remarks from the researchers reinforces the necessity to consume both omega-3 fatty acids, preferably in the form of EPA and DHA (fish oil) and the B-complex vitamins:

“In conclusion, when plasma omega-3 fatty acid concentrations are low, B vitamin treatment does not slow cognitive decline in people with MCI. In contrast, when omega-3 fatty acid levels are in the upper range of normal, the slowing effects of B vitamins on both brain atrophy [27] and cognitive decline are enhanced. We suggest that the effects of this interaction between the two nutrients on brain atrophy and cognition is consistent with the view that they slow down the disease process in MCI.”  13

Probiotic Propionibacterium freudenreichii Extends the Mean Lifespan of Caenorhabditis elegans via Activation of the Innate Immune System

Propionibacterium freudenreichii is a short-chain fatty acid (SCFA)-producing bacterium which ferments lactate to:

  • acetate
  • propionate
  • carbon dioxide

The two short-chain fatty acids, acetate and propionate have been shown to enhance human gut immunity.

A study published in the Journal Scientific Reports in August 2016 evaluated the effects of Propionibacterium freudenreichii on lifespan extension and to elucidate the mechanism of Propionibacterium freudenreichii -dependent lifespan extension in Caenorhabditis elegans.  1 

Caenorhabditis elegans is a small, free-living soil nematode commonly used as a model experimental animal because it is easy to treat, has a short lifespan, can be safely used in the laboratory and propagates through self-fertilization. In particular, C. elegansis frequently used in studies on longevity, immunity, neurodegenerative diseases, fat storage, DNA damage responses and apoptosis.

The results of the study showed that Propionibacterium freudenreichii significantly (p < 0.05) extended the lifespan of C. elegans compared with Escherichia coli OP50, a standard food for the worm.

The MLS of Propionibacterium freudenreichii-fed C. elegans, compared with that of E. coliOP50-fed worms, increased by approximately 13%. The survival rates were similar in both the Propionibacterium freudenreichii- and E. coli OP50-fed C. elegans until day 13.

After day 13, the two groups showed a significant difference in the survival rate.  Analysis of age-related biomarkers showed that Propionibacterium freudenreichii retards ageing.


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Figure 1.  The effect of Propionibacterium freudenreichii on the lifespan of C. elegans (N2).  Maturing nematodes were fed E. coli OP50 until the L4 stage, and young adult worms were transferred to a fresh mNGM plate seeded with E. coli OP50 or Propionibacterium freudenreichii . Significant differences shown are relative to E. coli OP50; ***p < 0.001. (Source)

The researchers concluded that Propionibacterium freudenreichii extends the lifespan of C. elegans via the p38 MAPK pathway involved in stress response and the TGF-β pathways associated with anti-inflammation processes in the immune system.  2

Natural Rapalogs that Inhibit the mTOR Pathway

In 1975 scientists discovered the mycelial bacterium Streptomyces hygroscopicus on Rapa Nui, the native name of Easter Island.  From this bacterium they created the molecule named Rapamycin, a pharmaceutical drug which requires a doctor’s prescription.  Also known as Sirolimus, it is an immunosuppressant drug used in orthodox medicine to prevent rejection following organ transplantation.

In addition to its use as an immunosuppressant drug, Rapamycin inhibits the mTOR signalling pathway and studies show it can significantly extend lifespan in mammals, even when taken in later life, with increases in life expectancy for males and females of between 9% and 14% respectively.


mTOR Pathway  

“mTOR” or the mechanistic target of rapamycin (mTOR), (formerly mammalian target of rapamycin before it was recognized to be highly conserved among eukaryotes) refers to an enzyme from the serine/threonine protein kinase family encoded by the mTOR gene. It is found in humans as well as worms, mice, flies and yeasts. It regulates the growth, proliferation, motility and survival of cells.

Successfully inhibiting mTOR signalling pathways has been shown to produce increased lifespan in worms, flies, yeasts and even mice if accompanied by calorie restriction and the consumption of adequate protein.


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Figure 1.  mTOR Pathway  (Source)

Since Rapamycin is poorly water soluble, which effects its bioavailability, several analogs of Rapamycin have been developed and are termed rapalogs.  Some of these rapalogs have improved pharmacokinetics and include:

  • temsirolimus
  • everolimus
  • ridaforolimus
  • 32-deoxo-rapamycin
  • zotarolimus

The use of these pharamaceutical rapalogs have been generally disappointing in human trials.  One possible explanation for the disappointing results to date is that in human cancer, rapalogs predominately inhibit mTORC1, leading to increased PI3K and AKT signaling by preventing negative feedback through S6K and GRB10.  1 

Recent studies have demonstrated that a number of natural products (or nutraceuticals) isolated from plants (e.g. fruits, vegetables, spices, nuts, legumes, herbs, etc.) also inhibit the mTOR pathway, and exhibit potent anticancer activities. These particular natural products are considered “natural rapalogs”.

The Table below lists the identified natural substances that are considered natural rapalogs or mTOR inhibitors:

Natural Rapalogs (mTOR Inhibitors)

Amino Acids
β-elemene (from the traditional Chinese medicinal herb Rhizoma zedoariae)4
Butein (in the stems of Rhus verniciflua)5
Capsaicin (in chili peppers)6
Celastrol (in the traditional Chinese medicine named “Thunder of God Vine”)7
Cryptotanshinone (Salvia miltiorrhiza Bunge) (Danshen)8
Rhodiola rosea9
Indole-3-carbinol and 3,3′-diindolylmethane)10
Epigallocatechin gallate (EGCG, in green tea)15
Isoflavones (genistein and deguelin)17
R-Lipoic Acid20
Tocotrienol (Vitamin E)21

Gymnema sylvestre Improves the Function of and Regenerates Pancreatic Beta Cells

The pancreas is a glandular organ in the digestive system located in the abdominal cavity behind the stomach. It serves as an endocrine gland producing several important hormones that circulate in the blood, including:

  • insulin (important in the metabolism of glucose)
  • glucagon
  • somatostatin
  • pancreatic polypeptide

The pancreas also secretes pancreatic juice containing digestive enzymes that assist digestion and absorption of nutrients in the small intestine.

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Figure 1.  Location of the pancreas  (Source)

The region of the pancreas that contain its endocrine (hormone producing) cells is called the pancreatic islets or islets of Langerhans.  The pancreatic islets constitute 1 to 2% of the pancreas volume and receive 10–15% of its blood flow.

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Figure 2.  Islets of Langerhans  (Source)

A type of cell found in the pancreatic islets are Beta cells.  They make up 65-80% of the cells in the islets.  The primary function of a beta cell is to store and release insulin. Insulin is a hormone that brings about effects which reduce blood glucose concentration.

Image result for beta cells

Figure 3.  Beta-cells of the pancreas  (Source)

The functions of the beta cells can become compromised with insulin resistance and the pathogenesis of diabetes.  Beta cell dysfunction results from inadequate glucose sensing to stimulate insulin secretion and therefore elevated glucose concentrations prevail.

Persistently elevated glucose concentrations above the physiological range result in the manifestation of hyperglycemia. With systemic insulin resistance, insulin signaling within glucose recipient tissues is defective therefore hyperglycemia perseveres.

Image result for beta cell dysfunction

Figure 4.  Potential mechanism of beta-cell failure  (Source)

Beta cell dysfunction supersedes insulin resistance in inducing diabetes. Both pathological states influence each other and presumably synergistically exacerbate diabetes.

Preserving beta cell function and insulin signaling in beta cells and insulin signaling in the glucose recipient tissues will maintain glucose homeostasis.   1

Plant-derived Natural Compounds that Inhance the Functionality of Pancreatic Beta Cells

There is a wide selection of published data on the effects of various plant-derived natural compounds on the functionality of pancreatic beta cells. These natural compounds have been found to directly:

  • enhance insulin secretion
  • prevent pancreatic beta cell apoptosis
  • modulate pancreatic beta cell differentiation and proliferation
  • regenerate pancreatic beta cells

Certain bio-active compounds of plants have confirmed anti-diabetic properties.  Table 1 below lists these botanical plants and their active compounds:

Table 1: Biological functions of plants (bio-active compounds) with confirmed anti-diabetic properties.



Botanical name Active


Anoectochilus roxburghii Kinsenoside Increases pancreatic beta cell regeneration [98]
Biden pilosa 3-β-D-Glucopyranosyl-1-hydroxy-6(E)-tetradecene-8,10,12-triyne
Increases insulin production
Enhances insulin
Camellia sinensis Epigallocatechin-3-gallate Enhances insulin secretion
Inhibits pancreatic beta
cell apoptosis
Capsicum annuum Capsaicin Enhances insulin secretion [1719]
Carica papaya Flavonoids/alkaloids/saponin/tannins Enhances insulin secretion [20, 21]
Curcuma longa Curcumin Enhances insulin secretion [7177]
Ervatamia microphylla Conophylline Induces differentiation into insulin producing
Glycine max Genistein Enhances insulin secretion
Inhibits pancreatic beta
cell apoptosis
Gymnema sylvestre Gymnemic acids Enhances insulin secretion [2232]
Momordica charantia Momordicin Increases pancreatic beta cell regeneration [3343]
Nymphaea stellate Nymphayol Enhances insulin secretion [4446]
Panax ginseng Ginsenoside Enhances insulin secretion
Rhizoma coptidis Berberine Enhances insulin secretion [5863]
Silybum marianum Silymarin Inhibits pancreatic beta cell apoptosis [113118]
Commonly found in plants Resveratrol Inhibits pancreatic beta cell apoptosis [106112]
Commonly found in plants Quercetin Enhances insulin secretion
Inhibits pancreatic beta
cell apoptosis


Source:  Plant-Derived Compounds Targeting Pancreatic Beta Cells for the Treatment of Diabetes


Image result for Plant-Derived Compounds Targeting Pancreatic Beta Cells for the Treatment of Diabetes

Figure 5.  Biological functions of plants (bioactive compounds) with confirmed antidiabetic properties  (Source) (Click on image to enlarge)

Gymnema sylvestre increases pancreatic beta cell regeneration and insulin secretion

Gymnema sylvestre (G. sylvestre) has traditionally been used to treat diabetes in India for centuries and has been an integral part of Ayruvedic medicine.

Image result for Gymnema sylvestre

Figure 6.  Gymnema sylvestre plant and flowers

The bio-active compound of G. sylvestre are triterpenoid saponins.  The main triterpenoid saponin is gymnemic acids and are considered to be the active compounds responsible for the anti-diabetic effects of G. sylvestre.

G. sylvestre extract is known to stimulate insulin secretion in various pancreatic beta cell lines.  It also has showed hypoglycemic effects via the increase in pancreatic beta cell regeneration and insulin secretion.

The many antidiabetic effects of G. sylvestre include:

  • Decreased plasma glucose levels and significantly induced insulin secretion compared with that in control mice.  2
  • Lowered blood glucose levels through the regeneration of pancreatic beta cells.  3
  • Lowered blood glucose levels in type 2 diabetes patients by increasing insulin secretion.  4
  • Induced significant increases in circulating insulin and C-peptide concomitant with a significant reduction in blood glucose levels.  5 
  • Blood glucose homeostasis through increased serum insulin levels provided by repair/regeneration of the pancreas.  6

Repairing the Damaged Plasma Membrane of the Cell and the Membrane-Bound Organelles

Introduction to the Plasma Membrane

The human cell is enveloped in a thin, pliable, elastic structure called the cell membrane or the plasma membrane and is only 7.5 to 10 nanometers thick. It is composed almost entirely of proteins and lipids.  There are approximately 5 × 106 lipid molecules in a 1 μm × 1 μm area of lipid bilayer, or about 109 lipid molecules in the plasma membrane of a human cell.

The main purpose of the plasma membrane is to separate the inner contents of the cell from its exterior environment, much like the outer layer of the skin separates the body from its environment.  In addition to providing a protective barrier around the cell, the plasma membrane regulates which materials pass in and out of the cell.

The plasma membrane envelops the human cell and is also found inside the cell in various intracellular membranes, called organelles.  The structure and composition of the plasma membrane are the same for the plasma membrane surrounding the cell as well as for the various intracellular membranes.  The only difference among them is the proportions which vary from one type of membrane to the other.

The formation of plasma membranes is based on the structural organization of bilayers of lipids with associated proteins.  The lipid content of the plasma membrane ranges from 40 to 80% (of dried weight), which is significant.  The two main lipids that predominate quantitatively in the lipid fraction of the plasma membrane are:

  • phosphatidylcholine
  • phosphatidylethanolamine

The lipid molecules in plasma membranes are amphipathic (or amphiphilic)—that is, they have a hydrophilic (“water-loving”) or polar end and a hydrophobic (“water-fearing”) or nonpolar end.

Functions of the Plasma Membrane

In addition to the plasma membrane providing a protective barrier around the cell and the intracellular organelles, it has many essential functions:

  • transporting nutrients into the cell
  • transporting metabolic wastes out of the cell
  • preventing unwanted materials in the extracellular milieu from entering the cell
  • preventing loss of needed metabolites
  • maintaining the proper ionic composition, pH (≈7.2), and osmotic pressure of the cytosol
  • provides cell to cell communication
  • provides hormone sensitivity and utilization
  • support the many enzymatic reactions that occur along their surfaces

These various functions are carried out by specific transport proteins which restrict the passage of certain small molecules.

The plasma membrane actually has a measurable membrane differential which is the voltage across the plasma membrane.  It has been determined that healthy children has a membrane electrical potential up to 90 millivolts, whereas a healthy adult can have up to 70 millivolts.  The membrane electrical potential can decline to around 40 millivolts in an individual with a chronic disease and to as low as 15 millivolts in an individual with advanced cancer.

The Lipids Comprising the Plasma Membrane of the Human Cell

The plasma membrane of the human cell and certain intracellular organelles inside the cell are composed of three categories of lipids:

  • Phospholipids (Glycerophospholipids or Phospholycolipids or Phosphoglycerides and Phosphosphingolipids)
  • Glycolipids
  • Cholesterol

Of the three categories of  lipids, the most abundant membrane lipids are the phospholipids.

The functions of the plasma membrane determines the lipid compositions of the inner and outer monolayers of the cell plasma membrane.  Different mixtures of lipids are found in the membranes of cells of different types.  The two sides of the plasma membrane of the human cell reflect this difference:

Outer Layer (the side on the exterior of the cell)

Consists mainly of phosphatidylcholine and sphingomyelin

Inner Layer (the side on the interior of the cell)

Consists mainly of phosphatidylethanolamine and phosphatidylserine and phosphatidylinositol.  

Figure 12.2. Lipid components of the plasma membrane.

Figure 1.  Lipid components of the plasma membrane

The outer leaflet consists predominantly of phosphatidylcholine, sphingomyelin, and glycolipids, whereas the inner leaflet contains phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. Cholesterol is distributed in both leaflets. The net negative charge of the head groups of phosphatidylserine and phosphatidylinositol is indicated. (Source:  The Cell: A Molecular Approach. 2nd edition., The Molecular Composition of Cells)

The mitochondria, an intracellular organelle, contains two membranes and consists primarily of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid.  These phospholipids are asymmetrically distributed between the two halves of the membrane bilayer of the mitochondria.  The inner mitochondrial membrane contains a specific phospholipid called phosphatidylglycerol and is the precursor for cardiolipin.  Cardiolipin is predominantly found in the inner mitochondrial membrane.

Lipids constitute approximately 50% of the mass of most cell membranes, although this proportion varies depending on the type of membrane. Plasma membranes, for example, are approximately 50% lipid and 50% protein.

The lipid composition of different cell membranes also varies:

  Plasma membrane    
Lipid E. coli Erythrocyte Rough endoplasmic reticulum Outer mitochondrial membranes
Phosphatidylcholine 0 17 55 50
Phosphatidylserine 0 6 3 2
Phosphatidylethanolamine 80 16 16 23
Sphingomyelin 0 17 3 5
Glycolipids 0 2 0 0
Cholesterol 0 45 6 <5

Membrane compositions are indicated as the mole percentages of major lipid constituents.

Another source lists the lipid compositions of different cell membranes:

Cholesterol 17 23 22 3 6 0
Phosphatidylethanolamine 7 18 15 25 17 70
Phosphatidylserine 4 7 9 2 5 trace
Phosphatidylcholine 24 17 10 39 40 0
Sphingomyelin 19 18 8 0 5 0
Glycolipids 7 3 28 trace trace 0
Others 22 13 8 21 27 30
(Source: Molecular Biology of the Cell. 4th edition., The Lipid Bilayer; Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002.)
Phospholipids that Compose the Plasma Membrane

Plasma membranes contain 4 major and 1 minor phospholipids:

  • Major phospholipids
    • phosphatidylcholine
    • phosphatidylethanolamine
    • phosphatidylserine
    • sphingomyelin
  • Minor phospholipids
    • phosphatidylinositol

These major phospholipids together account for more than 50% of the lipid in most membranes. Phosphotidylinositol is present in smaller quantities in the plasma membrane but provide important functions like cell signaling.

  Figure 10-12. Four major phospholipids in mammalian plasma membranes.

Figure 2.  Four major phospholipids in mammalian plasma membranes

Note that different head groups are represented by different colors. All the lipid molecules shown are derived from glycerol except for sphingomyelin, which is derived from serine.  (Source: Molecular Biology of the Cell. 4th edition., The Lipid Bilayer; Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002.)


Phosphatidylcholine is a vital substance found in every cell of the human body.


Phosphatidylethanolamines are found in all living cells, composing 25% of all phospholipids. In humans, they are found particularly in nervous tissue such as the white matter of brain, nerves, neural tissue, and in spinal cord, where they make up 45% of all phospholipids.  1


Phosphatidylserine is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relationship to apoptosis.  


Sphingomyelin is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds nerve cell axons. It usually consists of phosphocholine and ceramide, or a phosphoethanolamine head group; therefore, sphingomyelins can also be classified as sphingophospholipids.

Phosphatidylinositol (minor phospholipid)

Phosphatidylinositol forms a minor component on the cytosolic side of eukaryotic cell membranes.

Phosphorylated forms of phosphatidylinositol are called phosphoinositides and play important roles in lipid signaling, cell signaling and membrane trafficking.

Phosphatidylglycerols  (Cardiolipin)

Phosphatidic acid reacts with CTP, producing CDP-diacylglycerol, with loss of pyrophosphate. Glycerol-3-phosphate reacts with CDP-diacylglycerol to form phosphatidylglycerol phosphate, while CMP is released. The phosphate group is hydrolysed forming phosphatidylglycerol.

Two phosphatidylglycerols form cardiolipin, the constituent molecule of the mitochondrial inner membrane.  2

Phosphatidic acid

Phosphatidic acids are the acid forms of phosphatidates, a part of common phospholipids, major constituents of cell membranes.  phosphatidic acids are the simplest diacyl-glycerophospholipids.

The role of phosphatidic acid in the cell can be divided into three categories:

  • Phosphatidic acid is the precursor for the biosynthesis of many other lipids
  • The physical properties of phosphatidic acid influence membrane curvature
  • Phosphatidic acid acts as a signaling lipid, recruiting cytosolic proteins to appropriate membranes

The conversion of phosphatidic acid into diacylglycerol (DAG) by LPPs is the commitment step for the production of phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine. In addition, DAG is also converted into CDP-DAG, which is a precursor for phosphatidylglycerol, phosphatidylinositol and phosphoinositides.

Phosphatidic acid is essential for lipid synthesis and cell survival, yet, under normal conditions, is maintained at very low levels in the cell.


The role of glycolipids is to maintain stability of the membrane and to facilitate cellular recognition.  3 

Carbohydrates are found on the outer surface of all eukaryotic cell membranes. They extend from the phospholipid bilayer into the aqueous environment outside the cell where it acts as a recognition site for specific chemicals as well as helping to maintain the stability of the membrane and attaching cells to one another to form tissues.

Figure 3.  Glycolipid attached to lipid residue

The lipid complex is most often composed of either a glycerol or sphingosine backbone, which gives rise to the two main categories of glycolipids:

  • glyceroglycolipids
  • sphingolipids

The heads of glycolipids contain a sphingosine with one or several sugar units attached to it. The hydrophobic chains belong either to:

  • two fatty acids – in the case of the phosphoglycerides, or
  • one fatty acid and the hydrocarbon tail of sphingosine – in the case of sphingomyelin and the glycolipids

Glycolipids occur in all animal cell plasma membranes, where they generally constitute about 5% of the lipid molecules in the outer monolayer. They are also found in some intracellular membranes.

The most complex of the glycolipids, the gangliosides, contain oligosaccharides with one or more sialic acid residues, which give gangliosides a net negative charge.  More than 40 different gangliosides have been identified. They are most abundant in the plasma membrane of nerve cells, where gangliosides constitute 5–10% of the total lipid mass; they are also found in much smaller quantities in other cell types.


Cholesterol is a sterol, and is biosynthesized by all animal cells, and is an essential structural component of all animal cell membranes; essential to maintain both membrane structural integrity and fluidity. Cholesterol enables animal cells to dispense with a cell wall (to protect membrane integrity and cell viability), thereby allowing animal cells to change shape and animals to move (unlike bacteria and plant cells, which are restricted by their cell walls).

Cell membranes require high levels of cholesterol – typically an average of 20% cholesterol in the whole membrane, increasing locally in raft areas up to 50% cholesterol.  4 

Within the cell membrane, cholesterol also functions in intracellular transport, cell signaling and nerve conduction. Recent studies show that cholesterol is also implicated in cell signaling processes, assisting in the formation of lipid rafts in the plasma membrane, which brings receptor proteins in close proximity with high concentrations of second messenger molecules.  5  

In multiple layers, cholesterol and phospholipids, both electrical insulators, can facilitate speed of transmission of electrical impulses along nerve tissue. For many neuron fibers, a myelin sheath, rich in cholesterol since it is derived from compacted layers of Schwann cell membrane, provides insulation for more efficient conduction of impulses.  6 

Figure 2.47. Insertion of cholesterol in a membrane.

Figure 4.  Insertion of cholesterol in a membrane

Cholesterol inserts into the membrane with its polar hydroxyl group close to the polar head groups of the phospholipids.

Organelles of the Human Cell

An organelle is a specialized sub-unit within a cell that serves a specific function.  Most organelles of the cell are covered by membranes composed primarily of lipids and proteins.

Organelles either have a single-membrane compartment or a double-membrane compartment. 

There are 10 organelles in the human cell that have either a single or double membrane.  There are 3 organelles with double membranes and 7 organelles with single membranes.  The organelles of the cell with membranes are as follows:



Membrane Structure


vesicle that sequesters cytoplasmic material and organelles for degradation

Double membrane

Endoplasmic reticulum

translation and folding of new proteins (rough endoplasmic reticulum), expression of lipids (smooth endoplasmic reticulum)

Single membrane

Golgi apparatus

sorting, packaging, processing and modification of proteins

Single membrane


breakdown of large molecules (e.g., proteins + polysaccharides)

Single membrane


pigment storage

Single membrane


energy production from the oxidation of glucose substances and the release of adenosine triphosphate

Double membrane


DNA maintenance, controls all activities of the cell, RNA transcription

Double membrane


breakdown of metabolic hydrogen peroxide

Single membrane


storage, transportation, helps maintain homeostasis

Single membrane


material transport

Single membrane

Organelles with double membranes are often critical to the function of the cell, each serveing a different purpose.  There are 3 organelles that have double membranes:

  • Mitochondria

  • Nucleus

  • Autophagosome


A mitochondrion (singular for mitochondria) contains outer and inner membranes composed of phospholipid bilayers and proteins.   Due to the double membrane structure of the mitochondrion, there are five distinct parts to a mitochondrion. They are:

  • the outer mitochondrial membrane
  • the intermembrane space (the space between the outer and inner membranes)
  • the inner mitochondrial membrane
  • the cristae space (formed by infoldings of the inner membrane)
  • the matrix (space within the inner membrane)

The mitochondrial membrane contains the major classes of phospholipids found in all cell membranes, including phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid, as well as phosphatidylglycerol, the precursor for cardiolipin; which is predominantly located in the mitochondria.

The outer mitochondrial membrane, which encloses the entire organelle, has a protein-to-phospholipid ratio similar to that of the human plasma membrane (about 1:1 by weight). It contains large numbers of integral membrane proteins called porins.

In the inner mitochondrial membrane, the protein-to-lipid ratio is 80:20, in contrast to the outer membrane, which is 50:50.  7 

The inner membrane is rich in cardiolipin.  Cardiolipin contains four fatty acids rather than two, and may help to make the inner membrane impermeable.  Unlike the outer membrane, the inner membrane doesn’t contain porins, and is highly impermeable to all molecules.

Nuclear Membrane

The nuclear envelope, otherwise known as nuclear membrane, consists of two cellular membranes, an inner and an outer membrane, arranged parallel to one another and separated by 10 to 50 nanometres (nm). The nuclear envelope completely encloses the nucleus and separates the cell’s genetic material from the surrounding cytoplasm, serving as a barrier to prevent macromolecules from diffusing freely between the nucleoplasm and the cytoplasm. 8   The outer nuclear membrane is continuous with the membrane of the rough endoplasmic reticulum.


An autophagosome is a spherical structure with double layer membranes. It is the key structure in macro autophagy, the intracellular degradation system for cytoplasmic contents (e.g., abnormal intracellular proteins, excess or damaged organelles) and also for invading microorganisms.

After formation, autophagosomes deliver cytoplasmic components to the lysosomes. The outer membrane of an autophagosome fuses with a lysosome to form an autolysosome. The lysosome’s hydrolases degrade the autophagosome-delivered contents and its inner membrane.  9

Damage and Degradation to the Cell Membrane

When cell membranes are intact their receptor surface is able to perform all necessary functions. Communication between cells, and even within the cell components, flows easily. Once the membrane is damaged this communication is disrupted, and the cell cannot function properly, due to the failure of cellular signaling. 

There are a number ways in which cell membranes can be damaged, which eventually leads to pathology and illness.  This is true of both the cell and its outer membrane barrier or cell membrane, and the membrane structures inside the cell.  Various factors can contribute to damage to the cell membrane, such as:

  • Acetaldehyde
  • Aging
  • Alcohol
  • Excessive Saturated Fatty Acids
  • Lipid peroxidation
  • Oxidization of cell membrane
  • Recreational Drugs
  • Smoking
  • Toxin exposure (toxins stored in the lipid environment)
  • Trans-fatty acids  10  11

Aging causes detrimental changes in membrane phospholipid composition. Phosphatidylcholine is one of the main types of phospholipids in the cell membrane, and its concentration within the cell membrane decreases with age, whereas sphingomyelin and cholesterol both increase with age. 

The changes in the relative amounts of phosphatidylcholine and sphingomyelin are especially great in tissues. Plasma membranes associated with the aorta and arterial wall show a 6-fold decrease in phosphatidylcholine and sphingomyelin ratio with aging. Sphingomyelin also increases in several diseases, including atherosclerosis. The sphingomyelin content can be as high as 70-80% of the total phospholipids in advanced aortic lesion.  12  

Decreased cell membrane fluidity and decomposition of cell membrane integrity, as well as break down of cell membrane repair mechanisms, are associated with various disorders, including liver disease, atherosclerosis, several cancers and ultimately cell death.

Fatty acids within the cell membrane degrade when dietary fats are either oxidized (lipid peroxides can form within the body as well) or contain trans fatty acids.

Plasma membranes are one of the preferential targets of reactive oxygen species which cause lipid peroxidation. This process modifies membrane properties such as fluidity, a very important physical feature known to modulate membrane protein localization and function.  13  

Numerous reports have established that lipid peroxidation contributes to cell injury by altering the basic physical properties and structural organization of membrane components. Oxidative modification of polyunsaturated phospholipids has been shown, in particular, to alter the intermolecular packing, thermodynamic, and phase parameters of the membrane bilayer.  14  15

Damage to the Double Membrane Structure of the Mitochondria

Damage to mitochondrial components, especially the delicate inner mitochondrial membrane, leads to the release of toxic proteins, including caspases and other enzymes. These proteins are normally confined in the mitochondria, but once released these proteins go through several steps that trigger the formation of a potent inflammatory molecular complex called an inflammasome.

New evidence has placed inflammasomes at the center stage of complex diseases like metabolic syndrome and cancer, as well as the regulation of the microbial ecology in the intestine and the production of ATP.  16 

Once the inner membrane of the mitochondria is damaged, its core ability to produce energy in the form of ATP and to maintain optimal mitochondrial nutrient uptake and utilization necessary for ATP production are impaired.

The inner mitochondrial membrane is also one of the most sensitive membranes of the cell to oxidative damage. This is because of its unique membrane structure and the presence of a very oxidation-sensitive phospholipid, cardiolipin. Cardiolipin is functionally required for the electron transport system. 

When mitochondrial cardiolipin and to a lesser degree other phosphatidyl phospholipids are damaged by oxidation, the chemical/electrical potential across the inner mitochondrial membrane is altered due to an increasingly “leaky” membrane that allows protons and ions to move across the membrane. This occurs because the oxidized membrane phospholipids no longer form a tight ionic/electrical “seal” or barrier.

Significant oxidative damage to mitochondrial membranes represents the point-of-no-return of programmed cell death pathways that culminate in apoptosis or regulated cell death leading to necrosis.  17

Repairing the Damaged Cell Membrane with Lipid Replacement Therapy®

The good news is that damaged lipids can be replaced.  In fact, a young healthy cell usually replaces damaged lipids in its membranes.  However, due to aging, eating a poor diet, exposure to environmental toxins, getting infections and certain illnesses, it becomes necessary to proactively replace the damaged lipids with new lipids. 

This can be done using Lipid Replacement Therapy (LRT®), which provides for the consumption of lipids that are the same as found in the cell membrane and organelle membranes. 

A product developed and manufactured by Nutritional Therapeutics Inc., called NTFactor®, is intended to reverse the damage done to our cells and mitochondria by oxidative stress through the process of Lipid Replacement Therapy®.

The NTFactor® formula is a unique combination that allows the healthy phospholipids to stay intact during transport through the body.

NT Factor Lipids® is based on U.S. Patent No. 8,877,239.  The lipid blend of NTFactor® includes:

  • Phosphatidic acid (PA)
  • Phosphatidyl-choline (PC)
  • Phosphatidyl-ethanolamine (PE)
  • Phosphatidyl-glycerol(PG) – (precursor for cardiolipin (CL))
  • Phosphatidyl-inositol (PI)
  • Phosphatidyl-serine (PS)
  • Digalactosyldiacylglyceride (DGDG)
  • Monoglactosyldiacylglyceride (MGDG)

NTFactor® uses a form of a stable oral supplement that emulates the amount and composition of the mitochondrial lipids assures that inappropriate oxidative membrane damage is prevented, damaged membrane phospholipids are replaced and mitochondrial membrane permeability is maintained in the optimal range.

Obtaining Phospholycolipids through Diet

Phospholycolipids can be obtained generally in the diet from meat, egg yolks, fish, turkey, chicken and beef.  Organ meats and egg yolks are among the best food sources of phosphoglycolipids, however, one would have to consume large portions of these foods at every meal to obtain the benefit of lipid replacement, which is unlikely and unhealthy.

The various lipids can be found in the following foods:


Phosphatidylcholine can be obtained from egg yolk or soybeans.  Phosphatidylcholine is a major component of egg, soy and sunflower lecithin. 

Lecithin’s are mostly phospholipids, composed of phosphoric acid with choline, glycerol or other fatty acids usually glycolipids or triglyceride. Glycerophospholipids in lecithin include phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid.


Phosphatidylethanolamine is primarily found in lecithin.


Phosphatidylinositol can be found in lecithin. 


Phosphatidylserine can be found in meat and fish. Only small amounts of phosphatidylserine can be found in dairy products or in vegetables, with the exception of white beans and soy lecithin.

Phosphatidylserine (PS) content in different foods


PS Content in mg/100 g

Bovine brain


Atlantic mackerel


Chicken heart


Atlantic herring




Offal (average value)


Pig‘s spleen


Pig’s kidney




Chicken leg, with skin, without bone


Chicken liver


White beans


Soft-shell clam


Chicken breast, with skin










Pig’s liver


Turkey leg, without skin or bone


Turkey breast without skin






Atlantic cod




Whole grain barley


European hake


European pilchard (sardine)




Rice (unpolished)




Ewe‘s Milk


Cow‘s Milk (whole, 3.5% fat)




 (Source:  Souci SW, Fachmann E, Kraut H (2008). Food Composition and Nutrition Tables. Medpharm Scientific Publishers Stuttgart)


Sphingomyelin can be obtained from eggs or bovine brain.


All animal-based foods contain cholesterol in varying amounts.  Cholesterol can be obtained from cheese, egg yolks, beef, pork, poultry, fish, and shrimp.  Cholesterol is not found in plant-based foods.   

#29 Garth Nicolson: How to Repair Mitochondria with Lipid Replacement

The Potent Compounds of Salvia militorrhiza (Danshen)

Salvia miltiorrhiza, also known as red sage, Chinese sage, tan shen, or danshen, is a perennial plant in the genus SalviaSalvia miltiorrhiza is native to China and Japan where it grows at 90 to 1,200 m (300 to 3,940 ft) elevation, preferring grassy places in forests, hillsides, and along stream banks. The specific epithet miltiorrhiza means “red ochre root” as can be seen in the photo below:


Salvia militorrhiza BUNGE (Danshen) roots

Scientist have identified over 80 compounds in Danshen, both water soluble and fat soluble:  1  2  3

  • 50 water soluble compounds
    • Salvianolic acid B
    • Danshensu (Salvianolic acid A)
    • Protocatechuic aldehyde
  • 30 fat soluble compounds
    • Tanshinones
      • Tanshinone I
      • Tanshinone IIA 
      • Cryptotanshinone

The two compounds that show the most pharmalogical significance is the Salvianolic acids, Salvianolic acid A (danshensu) and the tanshinones, Tanshinone I and Tashinone IIA.

Salvianolic acid B is a potent antioxidant and has been investigated for its ability to protect against cerebrovascular disorders.  4  5

The Tanshinones (Dihydrotanshinone, tanshinone I, and tanshinone IIA) are currently being investigated for their anti-cancer effects.  6  7

The Table below lists the active compounds that have been studied for their therapeutic benefits in human health with references to various scientific studies for each compound:

Active Compounds in Salvia miltorrhiza Bunge

Compounds in Salvia miltorrhiza Bunge Clinical ApplicationsFunctions and UsesReferences
Cryptotanshinone1. Coronary heart disease and sugar diabetes; 2. Anti-infections; 3. To treat hepatitis and lepra disease.Cryptotanshinone is a major tanshinone isolated from Salvia miltiorrhiza that uses in many different fields. It has a good effection cardiovascular disease resisting fungus, also been effective to inhibit bacterium and diminish inflammation.1 2 3
Danshensu sodium1. Anti-bacterial 2. Anti-atherosclerotic 3. Enhancing immune1. Prevention for cardiac muscle, inhibit platelet aggregation; 2. Prevention for nerve cell and hepatic fibrosis; 3. Anti-bacterial, anti-inflammatory, anti-atherosclerotic and anticoagulation. Hypolipidemic effect and enhancing immune1 2 3
Danshensu/Salvianic Acid A1. Coronary heart disease 2. Anti-platelet aggregation 3. Protection for heartDanshensu is mainly used as raw material for clearing heat, anti-inflammation, detumescence and increasing coronary flow.1 2 3
Dihydroanshinone1. Antibacterium 2. Antifungal activity 3. Anti-thromboticSome inhibitory effects on Staphylococcus aureus, human-type Mycobacterium tuberculosis, Mycobacterium, leather bacteria etc. Inhibit platelet aggregation, anti-oxidants and expansion of coronary activity. Applied in medicine, healthcare food, food additive1 2 3 4 5 6
Magnesium Lithospermate B1. Anti-oxidative junction 2. Protection for heart 3. Protection for brain 4. Prevention for hepatic fibrosis 5. Anti-aging and anti-tumorPromoting blood circulation and removing blood stasis, Stimulate the menstrual flow and activate the collaterals. It is used for apoplexy and the angina caused by coronary artery disease. Anti-fibrosis of liver. Mainly applied in Medicine, healthcare food, food additive.1 2 3 4 5 6 7 8
Protocatechuic aldehyde1. Anti-inflammation 2. anti-prostaglandin 3. anti-lipid peroxidationIt has a strong effect on antithrombotic, improving the blood circulation and anti-oxidant. Applied in medicine, healthcare food, food additive.1 2 3 4
Salvianolic Acid B1. Anti-oxidative junction 2. Protection for heart 3. Protection for brain 4. Prevention for hepatic fibrosis 5. Anti-aging and anti-tumorPromoting blood circulation and removing blood stasis, Stimulate the menstrual flow and activate the collaterals. It is used to cure apoplexy and the angina caused by coronary artery disease. Anti-fibrosis of liver. Mainly applied in Medicine, healthcare food, food additive.1 2 3 4 5 6 7 8
Sodium tanshinoneⅡA sulfonate1. To ease postpartum pain 2.To remove goreSodium tanshinoneⅡA sulfonate is used to remove blood stasis and relieve pain, promote the flow of blood and stimulate menstrual discharge, expand blood vessels. It has a good effect on abnormal menstruation.1 2 3 4 5 6
Tanshinone I1. To depress pains in bodies 2. Promote the secretion of estrogen 3. Against angina pectoris1.It has a strong inhibition on human strains of Mycobacterium and is for the treatment of acne, and angina pectoris; 2. It is effective on the treatment of hepatitis and lepra disease. Applied in medicine, healthcare food, food additive.1 2 3 4 5 6 7 8
Tanshinone IIA1. To expend vessel 2. Depress blood pressure 3. Anti-thrombotic 4 AntioxidantUsed in medicine, healthcare food, food additive.1 2 3 4 5 6 7 8
Source of Columns 1, 2 and 3 is Xi 'an Honson Biotechnology Co., Ltd.
References provided by


Oxaloacetate Reduces Neuroinflammation

Neuroinflammation is inflammation of the brain and nervous tissue. The common causes of chronic neuroinflammation include:

  • Aging
  • Air pollution
  • Autoimmunity
  • Microbes
  • Passive smoke
  • Toxic metabolites
  • Traumatic brain injury
  • Viruses

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls:

  • cell survival
  • cytokine production
  • transcription of DNA

NF-kB is an important factor in the inflammation pathway and if there is excessive or overly activated NF-kB, then this reaction can result in chronic inflammation not only in the nervous tissue but throughout the body.

NF-κB is involved in cellular responses to stimuli such as:

  • bacterial or viral antigens
  • cocaine
  • cytokines
  • free radicals
  • isoproterenol
  • oxidized LDL
  • stress
  • ultraviolet irradiation
  • tumor necrosis factor alpha (TNFα),
  • interleukin 1-beta (IL-1β)

NF-κB has been shown to have diverse functions in the nervous system.  Activated NF-κB can be transported retrogradely from activated synapses to the nucleus to translate short-term processes to long-term changes such as axon growth, which is important for long-term memory. 1

In glia, NF-κB is inducible and regulates inflammatory processes that exacerbate diseases such as autoimmune encephalomyelitis, ischemia, and Alzheimer’s disease. In summary, inhibition of NF-κB in glia might ameliorate disease. 2


Abating or lowering the NF-kB protein trans-location to the nucleus when inflammation is present is one of the strategies to reducing neuroinflammation and chronic inflammation in general.

A study from December 2014 published in the Journal Human Molecular Genetics, entitled “Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis”, found among other things, that oxaloacetate reduces neuroinflammation.

Oxaloacetic acid (also known as oxalacetic acid or oxaloacetate ) is a metabolic intermediate in many processes that occur in humans and other animals. Oxaloacetate takes part in many systems within the body, such as:

  • amino acid synthesis
  • citric acid cycle
  • fatty acid synthesis
  • gluconeogenesis
  • glyoxylate cycle
  • urea cycle

Oxaloacetic acid molecule

In the December 2014 study, the researchers assessed the effects of Oxaloacetate (OAA) administration on brain inflammation.  They measured the mRNA levels for two inflammation-related genes, tumor necrosis factor α (TNFα) and C–C motif chemokine 11 (CCL11).

While hippocampal TNFα levels were comparable across the groups, hippocampal CCL11 mRNA levels were 44% lower in the group receiving 2 g/kg/day than they were in the control group (Figure 1).

The amount of nuclear factor κB (NFκB) protein was lower in the nucleus of the combined OAA treatment group (by 50%), after two weeks of OAA supplementation, and in both OAA treatment groups the nucleus-to-cytoplasm ratio was ∼70% lower than it was in the control group.  3 


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Figure 1:  Effect on inflammation. (A) TNFα mRNA levels were comparable. (B) CCL11 mRNA was lower in the 2 g/kg/day OAA group. (C) Nuclear NFκB protein was lower in the combined OAA group. Although the ANOVA was not significant, on post hoc analysis nuclear NFκB protein was lower in the 1 g/kg/day OAA group. (D) The NFκB nucleus:cytoplasm ratio was lower in the 1 g/kg/day, 2 g/kg/day and combined OAA groups. Values shown are relative group means ± SEM. *P < 0.05; **P < 0.005; #ANOVA comparison was not significant, but the post hoc LSD test between the specified treatment group and the control group was significant at P < 0.05.  (Source:  Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis, Hum Mol Genet. 2014 Dec 15; 23(24): 6528–6541. Published online 2014 Jul 15. doi:  10.1093/hmg/ddu371)

The researchers concluded that:

When activated, NFκB’s restraint is removed and it moves to the nucleus. Since NFκB promotes the CCL11 gene, reduced NFκB may account for lower CCL11 expression. OAA, therefore, could prove useful for treating brain diseases in which neuroinflammation occurs.”  4



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Balancing Your Neurotransmitter Systems Naturally

A balanced and healthy nervous system requires a sufficient level of neurotransmitters. 

There are a number of neurotransmitters that have been identified and are typically classified as:

  • Amino acids
  • Monoamines
  • Peptides

Another classification of neurotransmitters is whether they are inhibitory or stimulatory.  For purposes of this article, four main neurotransmitters are examined:

  • Stimulatory
    • Acetylcholine
    • Dopamine
  • Inhibitory
    • GABA
    • Serotonin

The Table below lists the four major neurotransmitters and their certain characteristics:

Neurotransmitter Systems

Lobe of the BrainParietal lobesFrontal lobesTemporal lobesOccipital lobes
Brain MeasurementSpeedVoltageBalance (Calm)Synchrony (Rest)
CharacteristicsLubricant to neuronsPowerCalmnessHealing
BalancedCreativeBlood pressureStabilityNourishment
Fast thinkingMetabolismEven moodSatisfied feelings
Feelings of wellbeingDigestionMake good decisionsSleep deeply
Voluntary movementThink rationally
Abstract thought
Goal setting
Long term planning
CharacteristicDecreased brain speedDecreased brain powerHeadachesDepression
DeficiencyBrain fogFatiguePalpitationsSleep disorders
DementiaAddictionSeizuresEating disorders
AlzheimersLoss of attentionAnxietySensory processing
Dietcholine-rich: almonds; artichokes; lean beef; broccoli; Brussels sprouts; cabbage; fish; pine nuts; tomato paste; wheat bran; toasted wheat germ.high-protein: meat, poultry, cottage cheese, wheat germ; eggs; yogurt; walnuts; dark complex carbohydrates: Brown rice; broccoli; lentils; almonds; bananas; whole grain oats; oranges; spinach; walnuts; whole grain wheat..tryptophan-rich: turkey; chicken; sausage; avocados; cheese; cottage cheese; ricotta; eggs; granola; oat flakes; luncheon meats; wheat germ; whole milk; yogurt.
Supplementsphospatidylcholine powder; choline powder; huperzine A; phosphatidylserine; dopa bean; Ginkgo biloba; piracetam; omega-3 fish oil; pregnenolone. Phenylalanine; tyrosine; methionine; rhodiola; pyroxidine; B complex; DHEA; phosphatidylserine; Ginkgo biloba; green tea extract. Inositol powder; thiamine; tryptophan; passionflower; melatonin; magnesium; glutamic acid; niacinamide; pyridoxine; valerian root.tryptophan; calcium; fish oil; 5-HTP; magnesium; melatonin; passionflower; pyridoxine; SAM-e; St. John’s Wort; zinc.

To achieve a healthy nervous system, the stimulatory and inhibitory neurotransmitters should be balanced as much as possible.  Sometime this is not as easy as it sounds.  However, it is important to achieve a synergistic energy between the stimulatory and inhibitory neurotransmitters in which they work together to create balance in the nervous system.

An imbalanced neurotransmitter system can be characterized by a low level of all four neurotransmitters or a low level of a few neurotransmitters and an excess of other neurotransmitters.  Neurotransmitter imbalances can lead to a number of symptoms and pathologies.  Such imbalances are linked to:

  • Addiction or dependency
  • Adrenal dysfunction
  • Anxiety
  • Compulsive behavior
  • Cravings
  • Depression
  • Fatigue
  • Insomnia
  • Loss of appetite control
  • Loss of mental focus, or cognitive fog
  • Low libido
  • Migraines
  • Obsessive Compulsive Disorder
  • Poor sleep
  • Sexual dysfunction
  • Weight Issues

The cause of neurotransmitter imbalances can be defined by many different factors, including:

  • Alcohol
  • Caffeine usage
  • Dietary deficiencies
  • Digestive imbalances
  • Drug use (prescription and recreational)
  • Food intolerances
  • Genetic predisposition
  • Medication use, including antidepressants, anti-anxiety, sleep and migraine medications
  • Neurotoxins
  • Poor eating habits
  • Sleep disturbances
  • Stress
  • Toxic burden

Stress is often times the primary contributor to neurotransmitter imbalance. The nervous system uses up large amounts of neurotransmitters in order to cope with the ongoing stress.

A number of tests have been developed that may determine what neurotransmitters are low or imbalanced:

Dr. Braverman, M.D. of Path Medical in New York City has designed two interesting tests that can be taken quickly to determine your neurotransmitter dominance and neurotransmitter deficiency:

Another test is offered by Integrative Psychiatry and is used to determine neurotransmitter deficiency:

In addition to the written tests to determine neurotransmitter deficiencies, there are also medical lab tests that can be prescribed by a health care professional.  These medical tests include:

For a more in-depth analysis of each of the four neurotransmitters and how to enhance these neurotransmitters and create a balanced nervous system, please read the following articles below:





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