Category Archives: Neurological

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Inhibiting the Fibrillogenesis of Alpha-synuclein and Amyloid-beta by Natural Substances

Synucleinopathies

A group of neurodegenerative disorders characterized by fibrillary aggregates of alpha-synuclein protein in the cytoplasm of selective populations of neurons and glia is called Synucleinopathies or alpha-Synucleinopathies. 

Synucleinopathies include:

  • Parkinson’s disease (PD)
  • Dementia with Lewy bodies (DLB)
  • Pure autonomic failure (PAF)
  • Multiple system atrophy (MSA)

These neurological disorders are characterized by a chronic and progressive decline in the following bodily functions:

  • autonomic
  • behavioral
  • cognitive
  • motor skills

Alpha-synuclein protein

Synucleinopathies are caused by the abnormal accumulation of aggregates of alpha-synuclein protein in:

  • glial cells
  • nerve fibers
  • neurons

Alpha-synuclein is a protein that is abundant in the human brain and is predominantly expressed in the:

  • cerebellum
  • hippocampus
  • neocortex
  • substantia nigra
  • thalamus

It is also found in smaller amounts in the heart, muscles, and other tissues. 

Figure 1.  This a rendering of the Alpha-synuclein protein, based the PDB file of 1XQ8 using Rasmol.  (Source:  Hantanplan)

In the brain, alpha-synuclein is found primarily at the end of the neurons in specialized structures called the presynaptic terminal. The presynaptic terminal is a specialized area within the axon of the presynaptic cell that contains neurotransmitters enclosed in small membrane-bound spheres called synaptic vesicles.  The release of neurotransmitters from the presynaptic terminal relays signals between neurons.  Dysfunctional presynaptic terminals due to aggregation of alpha-synuclein can compromise normal brain function.

Lewy bodies

When alpha-synuclein aggregates, it forms insoluble fibrils in pathological conditions characterized by Lewy bodies.  Alpha-synuclein is the primary structural component of Lewy body fibrils, even though Lewy bodies may also contain:

  • alpha B crystallin
  • neurofilament protein
  • tau protein
  • ubiquitin

Lewy neurites are abnormal neurites in diseased neurons, containing granular material and abnormal alpha-synuclein filaments similar to those found in Lewy bodies.

Figure 2.  Microscope photograph of a Lewy body  (Source:  By Dr. Andreas Becker upload here Penarc – Own work, CC BY-SA 3.0)

Inhibiting the Fibrillogenesis of alpha-synuclein and amyloid-beta by Natural Substances

Researchers have focused on finding ways to inhibit the fibrillogenesis of alpha-synuclein in order to halt the formation of pathological conditions characterized by Lewy bodies.

Beginning in 2008, then in 2010 and 2011, researchers have been able to identify two natural substances that not only inhibits the fibrillogenesis of alpha-synuclein, but also at the same time inhibits amyloid-beta fibrillogenesis, the major cause of vascular dementia and Alzheimer’s disease.

These two natural substances include:

  • (-)-epigallocatechin gallate  (EGCG)  
  • theaflavins  

(-)-epigallocatechin gallate (EGCG) is found in high content in the dried leaves of white tea (4245 mg per 100 g), green tea (7380 mg per 100 g) and, in smaller quantities, black tea.  Smaller trace amounts can be found in apple skin, plums, onions, hazelnuts, and pecans.

Theaflavins are formed from the condensation of flavan-3-ols in tea leaves during the enzymatic oxidation of black tea.

In 2008, researchers demonstrated the redirection of amyloid fibril formation through the action of a small molecule, resulting in off-pathway, highly stable oligomers.

The polyphenol (-)-epigallocatechin gallate efficiently inhibits the fibrillogenesis of both alpha-synuclein and amyloid-beta by directly binding to the natively unfolded polypeptides and preventing their conversion into toxic, on-pathway aggregation intermediates. Instead of beta-sheet-rich amyloid, the formation of unstructured, nontoxic alpha-synuclein and amyloid-beta oligomers of a new type is promoted, suggesting a generic effect on aggregation pathways in neurodegenerative diseases.  1

Researchers in 2010 reconfirmed the fact that the polyphenol (-)-epi-gallocatechine gallate (EGCG) inhibits alpha-synuclein and amyloid-beta fibrillogenesis.  2  They showed that EGCG has the ability to convert large, mature alpha-synuclein and amyloid-beta fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells.

Finally, in 2011, researchers showed that theaflavins (TF1, TF2a, TF2b, and TF3), the main polyphenolic components found in fermented black tea, are potent inhibitors of amyloid-beta and alpha-synuclein fibrillogenesis.  3  Theaflavins stimulate the assembly of amyloid-beta and alpha-synuclein into nontoxic, spherical aggregates that are incompetent in seeding amyloid formation and remodel amyloid-beta fibrils into nontoxic aggregates.

Their conclusion suggested that theaflavins might be used to remove toxic amyloid deposits.

These three studies confirm the fact that adding green tea, white tea and/or black tea to your diet in order to obtain both EGCG and theaflavins may be a promising therapy to prevent Synucleinopathies, Dementia and Alzheimer’s disease.   

Cover photo credit: SUNY Oneonta

Delaying the Chronological Aging of the Yeast Saccharomyces cerevisiae by Six Plant Extracts

Researchers from Concordia University in Montreal, Quebec, Canada, in collaboration with the Quebec-based biotech company Idunn Technologies, published a study in the Journal Oncotarget on 29 March 2016, describing their discovery of six plant extracts that increase yeast chronological lifespan to a significantly greater extent than any of the presently known longevity-extending chemical compounds.  1

For the study, the researchers examined many plant extracts that would increase the chronological lifespan of yeast.  They finally found and used 37 plant extracts for this study.  These plant extracts are listed in the Table 1 below:

Table 1: List of plant extracts that have was used in this study

Abbreviated nameBotanical namePlant part used
PE1Echinacea purpureaWhole plant
PE2Astragalus membranaceousRoot
PE3Rhodiola rosea L.Root
PE4Cimicifuga racemosaRoot and rhizome
PE5Valeriana officinalis L.Root
PE6Passiflora incarnate L.Whole plant
PE7Polygonum cuspidatumRoot and rhizome
PE8Ginkgo bilobaLeaf
PE9Zingiber officinale RoscoeRhizome
PE10Theobroma cacao L.Cacao nibs
PE11Camellia sinensis L. KuntzeLeaf
PE12Apium graveolens L.Seed
PE13Scutellaria baicalensisRoot
PE14Euterpe oleraceaFruit
PE15Withania somniferaRoot and leaf
PE16Phyllanthus emblicaFruit
PE17Camellia sinensisLeaf
PE18Pueraria lobataRoot
PE19Silybum marianumSeed
PE20Eleutherococcus senticosusRoot and stem
PE21Salix albaBark
PE22Glycine max L.Bean
PE24Calendula officinalisFlower
PE25Salvia miltiorrhizaRoot
PE27Panax quinquefoliumRoot
PE28Harpagophytum procumbensRoot
PE29Olea europaea L.Leaf
PE30Gentiana luteaRoot
PE31Piper nigrumFruit
PE32Aesculus hippocastanumSeed
PE33Mallus pumila Mill.Fruit
PE34Fragaria spp.Fruit
PE35Ribes nigrumLeaf
PE36Dioscorea oppositaRoot
PE37Cinnamomum verumBark

Table source:  Discovery of plant extracts that greatly delay yeast chronological aging and have different effects on longevity-defining cellular processes

The means by which these six plant extracts (PEs) delays the onset and decreases the rate of yeast chronological aging is by eliciting a hormetic stress response. The budding yeast Saccharomyces cerevisiae is a beneficial model organism for the discovery of genes, signaling pathways and chemical compounds that slow cellular and organismal aging in eukaryotes across phyla.  Yeast was chosen in this study because aging progresses similarly in both yeast and humans.

The six PEs that were identified include:  2

  • Black Cohosh (Cimicifuga racemosa) (PE4)
  • Valerian  (Valeriana officinalis L.)  (PE5)
  • Passion Flower  (Passiflora incarnata L.)  (PE6)
  • Ginko Biloba  (Ginko biloba)  (PE8)
  • Celery Seed  (Apium graveolens L.)  (PE12)
  • White Willow  (Salix alba)  (PE21)

 

The six identified PEs out of the thirty-seven PEs that were examined showed the highest percentage increase of lifespan, (also known as the chronological lifespan (CLS)), in the yeast,   The researchers determined both the mean (average) CLS and the maximum CLS of the six PEs.

Table 2 below list the six PEs and their mean and max. CLS:

Table 2: Percent increase of lifespan of S. cerevisiae by 6 PEs

Plant Extract (PE)Mean CLSMax CLS
PE4 (Black Cohosh)195%100%
PE5 (Valerian)185%87%
PE6 (Passion Flower)180%80%
PE8 (Ginko Biloba)145%104%
PE12 (Celery Seed)160%107%
PE21 (White Willow)475%369%
CLS - Chronological Lifespan

(Source:  Discovery of plant extracts that greatly delay yeast chronological aging and have different effects on longevity-defining cellular processes)

The researchers noted that PE21 appears to be the most potent longevity-extending pharmacological intervention presently known. It increases the mean and maximum CLS of yeast by 475% and 369%, respectively.  PE21 or White Willow bark represents a much greater effect than rapamycin and metformin, the two best drugs known for their anti-aging effects.

These findings by the researchers imply that these extracts slow aging in the following ways:  3

  • PE4 (Black Cohosh) decreases the efficiency with which the pro-aging TORC1 pathway inhibits the anti-aging SNF1 pathway;
  • PE5 (Valerian) mitigates two different branches of the pro-aging PKA pathway;
  • PE6 (Passion Flower) coordinates processes that are not assimilated into the network of presently known signaling pathways/protein kinases;
  • PE8 (Ginko biloba) diminishes the inhibitory action of PKA on SNF1;
  • PE12 (Celery Seed) intensifies the anti-aging protein kinase Rim15; and
  • PE21 (White Willow) inhibits a form of the pro-aging protein kinase Sch9 that is activated by the pro-aging PKH1/2 pathway.

The researchers showed that each of these six PEs decelerates yeast chronological aging and has different effects on several longevity-defining cellular processes, as illustrated in Figure 1.

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Figure 1.  A model for how PE4, PE5, PE6, PE8, PE12 and PE21 delay yeast chronological aging via the longevity-defining network of signaling pathways/protein kinases.  Activation arrows and inhibition bars denote pro-aging processes (displayed in blue color) or anti-aging processes (displayed in red color). Pro-aging or anti-aging signaling pathways and protein kinases are displayed in blue or red color, respectively.  (Source: Discovery of plant extracts that greatly delay yeast chronological aging and have different effects on longevity-defining cellular processes)

Each of the six PEs have different effects on cellular processes that define longevity in organisms across phyla. These effects include the following:

  • increased mitochondrial respiration and membrane potential;
  • augmented or reduced concentrations of reactive oxygen species;
  • decreased oxidative damage to cellular proteins, membrane lipids, and mitochondrial and nuclear genomes;
  • enhanced cell resistance to oxidative and thermal stresses; and
  • accelerated degradation of neutral lipids deposited in lipid droplets.

The researchers also revealed that certain combinations of the six PEs could markedly increase aging-delaying proficiencies of each other.

In conclusion, the study stated that the obvious challenge was to assess whether any of the six PEs can delay the onset and progression of chronic diseases associated with human aging.  Idunn Technologies is collaborating with four other universities for six research programs, to go beyond yeast, and work with an animal model of aging, as well as two cancer models.  4

This study and ongoing research reveals five features of the six PEs as potential interventions for decelerating chronic diseases of old age. These five features include:  5

  • the six PEs are caloric restriction (CR) mimetics that imitate the aging-delaying effects of the CR diet in yeast under non-CR conditions;
  • they are geroprotectors that slow yeast aging by eliciting a hormetic stress response;
  • they extend yeast longevity more efficiently than any lifespan-prolonging chemical compound yet described;
  • they delay aging through signaling pathways and protein kinases implicated in such age-related pathologies as type 2 diabetes, neurodegenerative diseases, cardiac hypertrophy, cardiovascular disease, sarcopenia and cancers; and
  • they extend longevity and delay the onset of age-related diseases in other eukaryotic model organisms.

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:

  PERCENTAGE OF TOTAL LIPID BY WEIGHT
LIPID LIVER CELL PLASMA MEMBRANE RED BLOOD CELL PLASMA MEMBRANE MYELIN MITOCHONDRION (INNER AND OUTER MEMBRANES) ENDOPLASMIC RETICULUM E. COLIBACTERIUM
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

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

Phosphatidylethanolamine

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

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

Sphingomyelin

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.

Glycolipids

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

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:

Organelle

Function

Membrane Structure

Autophagosome

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

Lysosomes

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

Single membrane

Melanosome

pigment storage

Single membrane

Mitochondria

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

Double membrane

Nucleus

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

Double membrane

Peroxisome

breakdown of metabolic hydrogen peroxide

Single membrane

Vacoule

storage, transportation, helps maintain homeostasis

Single membrane

Vesicle

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

Mitochondria

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.

Autophagosome

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

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

Phosphatidylethanolamine is primarily found in lecithin.

Phosphatidylinositol

Phosphatidylinositol can be found in lecithin. 

Phosphatidylserine

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

Food

PS Content in mg/100 g

Bovine brain

713

Atlantic mackerel

480

Chicken heart

414

Atlantic herring

360

Eel

335

Offal (average value)

305

Pig‘s spleen

239

Pig’s kidney

218

Tuna

194

Chicken leg, with skin, without bone

134

Chicken liver

123

White beans

107

Soft-shell clam

87

Chicken breast, with skin

85

Mullet

76

Veal

72

Beef

69

Pork

57

Pig’s liver

50

Turkey leg, without skin or bone

50

Turkey breast without skin

45

Crayfish

40

Cuttlefish

31

Atlantic cod

28

Anchovy

25

Whole grain barley

20

European hake

17

European pilchard (sardine)

16

Trout

14

Rice (unpolished)

3

Carrot

2

Ewe‘s Milk

2

Cow‘s Milk (whole, 3.5% fat)

1

Potato

1

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

Sphingomyelin

Sphingomyelin can be obtained from eggs or bovine brain.

Cholesterol

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

Free E-Book: Enhancing the Growth of New Brain Cells

In 1998, neuroscientists undertook to investigate whether neurogenesis occurs in the adult human brain. They concluded that the human hippocampus retains its ability to generate neurons throughout life. Their results were published in the medical journal Nature Medicine.

While conducting their research, they discovered that the brain contains neural stem cells and progenitor cells which differentiate into brain neurons.

Since DNA ultimately controls the process of neurogenesis, there are specific genes that code for the production of various proteins called neurotrophins. These neurotrophins play a key role in the birth of new brain cells.

The birth of new neurons (neurogenesis) is highly related to neuroplasticity. Neuroplasticity is the ability of a particular part or region of a neuron to change in strength over time. It refers to changes in neural pathways and synapses due to changes in behavior, environment, neural processes, thinking, emotions, as well as changes resulting from bodily injury. Neuroplasticity has replaced the formerly-held position that the brain is a physiologically static organ, and explores how – and in which ways – the brain changes throughout life.

Brain atrophy is a condition in which the brain is in the process of shrinking (or a limited portion of the brain is shrinking) and that little if no neurogenesis is taking place.

If you were to look at neurogenesis as a full spectrum, you would find enhanced and optimal neurogenesis and brain atrophy as polar opposites on this spectrum.

The full spectrum would reveal that in a healthy fully optimized brain there would be enhanced neurogenesis; yet in a compromised brain there would first be neuroinflammation, then at the opposite end, brain atrophy.

The E-book on Neurogenesis will examine the natural substances that can be consumed in the form of Nootropics, Nutraceuticals, Foods, Herbs and Spices to maximize the state of enhanced neurogenesis and to enhance the three (3) main neurotrophins that facilitate neurogenesis.

In addition, the subject of Brain Atrophy will be examined and the recommended substances that can be consumed to prevent and inhibit brain atrophy.

Download Free E-book (PDF):  Enhancing the Growth of New Brain Cells

Ginkgo biloba Increases Global Cerebral Blood Flow

One of the leading factors of cognitive impairment leading to dementia and eventually Alzheimer’s disease is a condition where there is insufficient blood flow to the brain or an inadequate supply of blood to the brain. 

The condition of reduced blood flow to the brain is called cerebral ischemia or hypoperfusion of the brain.

Hypoperfusion of the brain can severely diminish neurological function and is often the first indication of changes that impact the brain and which precedes structural deterioration of the brain.  1

Researchers published a study in March 2011 that sought to determine if changes in cerebral blood flow could be detected by dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSC-MRI) in elderly human subjects taking an Extract of Ginkgo biloba (EGb).   2

Image result for ginkgo biloba

Ginko biloba leaves

The test subjects were nine healthy men with a mean age of 61±10 years.  They took 60 mg EGb twice daily for 4 weeks.

Cerebral blood flow (CBF) values were computed before and after EGb, and analyzed at three different levels of spatial resolution, using voxel-based statistical parametric mapping (SPM), and regions of interest in different lobes, and all regions combined.

Test results showed a small CBF increase in the left parietal–occipital region. CBF in individual lobar regions did not show any significant change post-EGb, but all regions combined showed a significant increase of non-normalized CBF after EGb (15% in white and 13% in gray matter, respectively, P≤0.0001).

Researchers concluded that a mild increase in CBF is found in the left parietal–occipital WM after EGb, as well as a small but statistically significant increase in global CBF.

Cover Photo credit: Radu Jianu, Brown University

7,8-dihydroxyflavone (7,8-DHF): An Flavone With Remarkable Health Benefits

7,8-Dihydroxyflavone (7,8-DHF) is a naturally-occurring flavone found in:

  • Godmania aesculifolia
  • Tridax procumbens
  • Primula tree leaves

Flavones are a class of flavonoids which are a class of plant secondary metabolites.

Natural flavones include:

  • Apigenin (4′,5,7-trihydroxyflavone)
  • Luteolin (3′,4′,5,7-tetrahydroxyflavone)
  • Tangeritin (4′,5,6,7,8-pentamethoxyflavone)
  • Chrysin (5,7-hydroxyflavone)
  • 6-hydroxyflavone
  • Baicalein (5,6,7-trihydroxyflavone)
  • Scutellarein (5,6,7,4′-tetrahydroxyflavone)
  • Wogonin (5,7-dihydroxy-8-methoxyflavone)

Synthetic flavones include:

  • Diosmin
  • Flavoxate
  • 7,8-dihydroxyflavone (7,8-DHF)

7,8-Dihydroxyflavone (7,8-DHF) has been determined and studied to be a potent and selective agonist of the TrkB receptor, which is the main signaling receptor of brain-derived neurotrophic factor (BDNF). It is able to penetrate the blood-brain-barrier after oral consumption.

7,8-DHF has been very therapeutically efficient in various central nervous system disorders including:

  • Depression [1]
  • Alzheimer’s disease [2]
  • Schizophrenia [3]
  • Parkinson’s disease [4]
  • Huntington’s disease [5]
  • Amyotrophic lateral sclerosis [6]
  • Traumatic brain injury [7]
  • Cerebral ischemia [8]

7,8-DHF has also been found to be a potent antioxidant [9] and provides neuroprotection against glutamate-induced excitotoxicity.

The authors of the study concluded that:

Our data demonstrate that 7,8-DHF protects against hydrogen peroxide and menadione-induced cell death, suggesting that 7,8-DHF has an antioxidant effect. In summary, although 7,8-DHF is considered as a selective TrkB agonist, our results demonstrate that 7,8-DHF can still confer neuroprotection against glutamate-induced toxicity in HT-22 cells via its antioxidant activity.” [10]


References:

[1] Liu X, Chan CB, Jang SW, Pradoldej S, Huang J, He K et al. (2010). “A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect”. J. Med. Chem. 53 (23): 8274–86. doi:10.1021/jm101206p. PMC 3150605. PMID 21073191

[2] Castello NA, Nguyen MH, Tran JD, Cheng D, Green KN, LaFerla FM (2014). “7,8-Dihydroxyflavone, a small molecule TrkB agonist, improves spatial memory and increases thin spine density in a mouse model of Alzheimer disease-like neuronal loss”. PLoS ONE 9 (3): e91453. doi:10.1371/journal.pone.0091453. PMC 3948846. PMID 24614170.

Chen C, Li XH, Zhang S, Tu Y, Wang YM, Sun HT (2014). “7,8-dihydroxyflavone ameliorates scopolamine-induced Alzheimer-like pathologic dysfunction”. Rejuvenation Res 17 (3): 249–54. doi:10.1089/rej.2013.1519. PMID 24325271.

Zhang Z, Liu X, Schroeder JP, Chan CB, Song M, Yu SP et al. (2014). “7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer’s disease”. Neuropsychopharmacology 39 (3): 638–50. doi:10.1038/npp.2013.243. PMID 24022672.

[3] Yang YJ, Li YK, Wang W, Wan JG, Yu B, Wang MZ et al. (2014). “Small-molecule TrkB agonist 7,8-dihydroxyflavone reverses cognitive and synaptic plasticity deficits in a rat model of schizophrenia”. Pharmacol. Biochem. Behav. 122: 30–6. doi:10.1016/j.pbb.2014.03.013. PMID 24662915.

[4] Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y et al. (2010). “A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone”. Proc. Natl. Acad. Sci. U.S.A. 107 (6): 2687–92. doi:10.1073/pnas.0913572107. PMC 2823863. PMID 20133810.

[5] Jiang M, Peng Q, Liu X, Jin J, Hou Z, Zhang J et al. (2013). “Small-molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington’s disease”. Hum. Mol. Genet. 22 (12): 2462–70. doi:10.1093/hmg/ddt098. PMC 3658168. PMID 23446639.

[6] Korkmaz OT, Aytan N, Carreras I, Choi JK, Kowall NW, Jenkins BG et al. (2014). “7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis”. Neurosci. Lett. 566: 286–91. doi:10.1016/j.neulet.2014.02.058. PMID 24637017

[7] Wu CH, Hung TH, Chen CC, Ke CH, Lee CY, Wang PY et al. (2014). “Post-injury treatment with 7,8-dihydroxyflavone, a TrkB receptor agonist, protects against experimental traumatic brain injury via PI3K/Akt signaling”. PLoS ONE 9 (11): e113397. doi:10.1371/journal.pone.0113397. PMC 4240709. PMID 25415296.

[8] Wang B, Wu N, Liang F, Zhang S, Ni W, Cao Y et al. (2014). “7,8-dihydroxyflavone, a small-molecule tropomyosin-related kinase B (TrkB) agonist, attenuates cerebral ischemia and reperfusion injury in rats”. J. Mol. Histol. 45 (2): 129–40. doi:10.1007/s10735-013-9539-y. PMID 24045895.Uluc K, Kendigelen P, Fidan E, Zhang L, Chanana V, Kintner D et al. (2013). “TrkB receptor agonist 7, 8 dihydroxyflavone triggers profound gender- dependent neuroprotection in mice after perinatal hypoxia and ischemia”. CNS Neurol Disord Drug Targets 12 (3): 360–70. PMC 3674109. PMID 23469848.

[9] Flavonoids, Coumarins, and Cinnamic Acids as Antioxidants in a Micellar System. Structure−Activity Relationship†

[10] Antioxidant activity of 7,8-dihydroxyflavone provides neuroprotection against glutamate-induced toxicity.  

In Search of Geroprotectors: The Final Four Have Been Identified

A geroprotector is one of the five different types of senotherapeutic strategies that aims to affect the root cause of aging and age-related diseases, and thus prolong the life span of animals.  Geroprotectors utilize agents and strategies which prevent or reverse the senescent state by preventing triggers of cellular senescence, including:

  • DNA damage
  • Oxidative stress
  • Proteotoxic stress
  • Telomere shortening

Senotherapeutics refers to therapeutic agents and strategies that specifically target cellular senescence and include any of the following therapies:

  • Gene therapy
  • Geroprotectors
  • Immune clearance of senescent cells
  • SASP inhibitors
  • Senolytics  (compounds capable of identifying and eliminating senescent cells)

Senescent cells enter a stage in which they no longer properly divide and function and become dysfunctional, which utlimately leads to organ failure.  Senescent cells also generate pro-inflammatory compounds which potentially damage healthy tissues.

Senolytics and geroprotectors eliminate aging and senescent cells from the tissues which then makes room for newer more active cells.

Life Extension® has partnered with Insilico Medicine to identify nutrient cocktails that function as geroprotectors by employing artificial intelligence biomedical algorithms.  These strategic uses of high-speed computer programs accelerates the research into potential geroprotectors. 

In a study published on April 23, 2016 in the Journal Aging, the authors, including Life Extension® and Insilico Medicine, among others, used GeroScope to develop a list of geroprotectors. 1

GeroScope is a computational tool that can aid prediction of novel geroprotectors from existing human gene expression data. GeroScope maps expression differences between samples from young and old subjects to aging-related signaling pathways, then profiles pathway activation strength (PAS) for each condition.

Known substances are then screened and ranked for those most likely to target differential pathways and mimic the young signalome. 

The study identified and shortlisted ten substances, all of which have lifespan-extending effects in animal models.  These ten substances include:

  • 7-Cyclopentyl-5-(4-phenoxy)phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine
  • Epigallocatechin gallate (EGCG)
  • Fasudil (HA-1077)
  • HA-1004
  • Myricetin
  • N-acetyl-L-cysteine (NAC)
  • Nordihydroguaiaretic acid (NDGA)
  • PD-98059
  • Staurosporine
  • Ursolic acid
Drug Code Model Organism Lifespan (LS) Parameter % Increase Ref.
Nordihydroguaiaretic acid A D. melanogaster Median LS 23 [47]
Mus Musculus Median LS 12 [48]
Myricetin B C. elegans Mean LS 32.9 [48,49]
HA-1004 C D. melanogaster Mean LS 18 [50]
7-Cyclopentyl-5-(4-phenoxy)phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine D C. elegans Mean LS 11 [51]
Staurosporine E D. Melanogaster Mean LS 34.8 [50]
Ursolic acid F C. elegans Mean LS 39 [52]
N-acetyl-L-cysteine G Mice Max LS 40 [53]
Fasudil (HA-1077) H D. melanogaster Mean LS 14.5 [50]
PD-98059 I D. melanogaster Mean LS 27 [50]
Epigallocatechin gallate J C. elegans Mean LS 10.1 [54]
Rattus norvegicus Median LS 13.5 [55]

Table 3. Previously reported lifespan effects of test substances in animal models (compiled from geroprotectors.org [15].)  Source:  In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state

The researchers narrowed down the list of ten substances to the final four compounds, which include:

  • Gamma tocotrienol (Vitamin E)
  • Epigallocatechin gallate (EGCG) (found in Green tea)
  • N-acetyl-L-cysteine (NAC)
  • Myricetin

These final four compounds combat numerous aging factors throughout the body by working together by influencing key anti-aging pathways. 

The researchers concluded that these four compounds reduced cellular aging and protect against the development of senescent cells by modulating a group of signaling pathways.

For a breakdown of the various pathways modulated by the final four compounds, read and review the April 2017 article from Life Extension®.

Life Extension® has combined these final four compounds into a new supplement product called GEROPROTECT™ Ageless Cell™.  Supplementing with this product may reduce the body’s burden of senescent cells.  

A Multiprong Approach to Mild Cognitive Impairment – Prong One: Nutrients that Support Brain Function

According to the Mayo Clinic, Mild Cognitive Impairment (MCI) is defined as:

“Mild cognitive impairment (MCI) is an intermediate stage between the expected cognitive decline of normal aging and the more serious decline of dementia. It can involve problems with memory, language, thinking and judgment that are greater than normal age-related changes. If you have mild cognitive impairment, you may be aware that your memory or mental function has “slipped.” Your family and close friends also may notice a change. But generally these changes aren’t severe enough to interfere with your day-to-day life and usual activities.”   (Mayo Clinic)

In evaluating whether a patient has MCI, a diagnostic tool known as the 3.0 Tesla MRI (3T MRI) scanner is often used.  A 3T MRI reveals four conditions that result in a diagnosis of MCI:

  1. Atrophy, or shrinkage, resulting from the loss of cells in the brain,
  2. Demyelination, the loss of the sheathing that surrounds neurons, which protects them as insulation does copper wiring. Myelination, or the development of the sheath around neurons, continues until age 30; thereafter, demyelination, or deterioration of the sheathing occurs,
  3. Ischemia, the restriction of blood flow, and
  4. Calcification, the hardening of tissue resulting from calcium deposits.

In order to prevent and treat MCI, a multipronged approach is often taken by health care professionals.  The first prong for the prevention and treatment of MCI is the use of specific nutraceuticals that address the four conditions of MCI. 

In addition, supporting the four main brain neurotransmitters with specific nutrients and precursors is also important in the prevention and treatment of MCI.

The four main neurotransmitters are:

  • Dopamine (Power)
  • Acetylcholine (Speed)
  • GABA (Rhythm)
  • Serotonin (Mood)

It is apparent from the Table below that the following nutraceuticals address more than one of the seven brain functions:

  • Gastrodin
  • EPA/DHA
  • Magnesium-L-Threonate
  • Tocotrienols (Vitamin E)

 Table: Nutrients that Support Brain Function

Brain Function

 

 

 

 

 

 

 

 

Category

Nutrient

Neuro-genesis

Plasticity

Blood Circula-tion

Power

Speed

 

Rhythm

 

Mood

Amino Acids

 

 

 

 

 

 

 

 

 

L-Tyrosine

 

 

 

X

 

 

 

 

Acetyl-L-Carnitine Arginate

 

 

 

X

 

 

 

 

Acetyl-L-Carnitine

 

 

X

 

 

 

 

 

GABA

 

 

 

 

 

X

 

 

Tryptophan

 

 

 

 

 

 

X

 

5-Hydroxytrypto-

phan (5-HTP)

 

 

 

 

 

 

X

Foods

 

 

 

 

 

 

 

 

 

Berry extract

X

 

 

 

 

 

 

 

Blueberry Extract

 

X

 

 

 

 

 

Herbs

 

 

 

 

 

 

 

 

 

Gastrodin

X

 

 

 

 

X

 

 

Huperzine A

 

 

 

 

X

 

 

 

Ashwagandha

 

 

 

 

 

X

 

Hormones

 

 

 

 

 

 

 

 

 

Melatonin

 

 

 

 

 

 

X

 

Pregnenolone

 

 

 

 

 

 

X

Lipids

 

 

 

 

 

 

 

 

 

EPA/DHA

 

 

X

X

X

 

 

 

PhosphatidylSerine

X

 

 

 

 

 

 

Minerals

 

 

 

 

 

 

 

 

 

Magnesium L-Threonate

 

X

 

 

X

 

 

Nootropics

 

 

 

 

 

 

 

 

 

Vinpocetine

 

 

X

 

 

 

 

Nucleic Acids

 

 

 

 

 

 

 

 

 

Uridine-5’-Monophosphate

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Polyphenols

 

 

 

 

 

 

 

 

 

Resveratrol

X

 

 

 

 

 

 

 

Green Tea

X

 

 

 

 

 

 

 

Quercetin

X

 

 

 

 

 

 

 

Curcumin

X

 

 

 

 

 

 

Quinones

 

 

 

 

 

 

 

 

 

CoQ10

 

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

Vitamins

 

 

 

 

 

 

 

 

 

Folic Acid

 

 

 

X

 

 

 

 

Alpha-Glyceryl Phosphoryl Choline

 

 

 

 

X

 

 

 

Tocotrienols (Vitamin E)

 

X

 

 

X

 

 

 

Methylcobalamin

 

 

 

 

X

 

 

 

B Complex Vitamins

 

 

 

 

 

X

 

 

Inositol

 

 

 

 

 

X

 

 

Vitamin K

 

X

 

 

 

 

 

Source:  Reverse Mild Cognitive Impairment,  By Eric Braverman, MD, and Bruce Scali  Life Extension Magazine March 2015


References:

Zhang N, Song X, Zhang Y, et al. Alzheimer’s disease neuroimaging initiative— an MRI brain atrophy and lesion index to assess the progression of structural changes in Alzheimer’s disease, mild cognitive impairment, and normal aging: a follow-up study. J Alzheimers Dis . 2011;26 Suppl 3:359-67.

Cherubini A, Péran P, Spoletini I, et al. Combined volumetry and DTI in subcortical structures of mild cognitive impairment and Alzheimer’s disease patients. J Alzheimers Dis . 2010;19(4):1273-82.

Van Dinteren R, Arns M, Jongsma M. et al. P300 development across the lifespan: a systematic review and meta-analysis. PLoS One. 2014 Feb. 9(2):e87347.

Haeusler KG , Koch L, Herm J, et al. 3 Tesla MRI-detected brain lesions after pulmonary vein isolation for atrial fibrillation: results of the MACPAF study. J Cardiovasc Electrophysiol. 2013 Jan;24(1):14-21.

Wu Z , Mittal S,Kish K,Yu Y,Hu J, Haacke EM. Identification of calcification with MRI using susceptibility-weighted imaging: a case study. J Magn Reson Imaging. 2009 Jan;29(1):177-82.


Informational References:

For more detailed information on this subject, read the Life Extension article:  Reverse Mild Cognitive Impairment,  By Eric Braverman, MD, and Bruce Scali  Life Extension Magazine March 2015


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

NF-KBPathway

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

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 

 

An external file that holds a picture, illustration, etc. Object name is ddu37105.jpg

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

SystemAcetylcholineDopamineGABASerotonin
SystemCholinergicCathecholamineGABAergicSerotonergic
TypeStimulatoryStimulatoryInhibitoryInhibitory
Lobe of the BrainParietal lobesFrontal lobesTemporal lobesOccipital lobes
BrainwaveAlphaBetaThetaDelta
Brain MeasurementSpeedVoltageBalance (Calm)Synchrony (Rest)
CharacteristicsLubricant to neuronsPowerCalmnessHealing
BalancedCreativeBlood pressureStabilityNourishment
Fast thinkingMetabolismEven moodSatisfied feelings
Feelings of wellbeingDigestionMake good decisionsSleep deeply
Voluntary movementThink rationally
Intelligence
Abstract thought
Goal setting
Long term planning
CharacteristicDecreased brain speedDecreased brain powerHeadachesDepression
DeficiencyBrain fogFatiguePalpitationsSleep disorders
DementiaAddictionSeizuresEating disorders
AlzheimersLoss of attentionAnxietySensory processing
dysfunction
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:

  • ADD/ADHD
  • 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:

Acetylcholine

Dopamine

GABA

Serotonin


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