Monthly Archives: April 2017

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High-mobility group protein 1 (HMG-1): A Marker of Chronic Inflammation

High-mobility group protein 1 (HMG-1) is a protein that in humans is encoded by the HMGB1 gene.

HMGB1 turns on the release of chemical signals called cytokines that generate inflammation in your body.

The molecule HMGB1 is responsible for initiating acute inflammation, which is a helpful reaction when your body is under attack by germs, or following an injury. Unfortunately, when a cell is damaged, its contents of HMGB1 leak out, leading to chronic inflammation.

When HMGB1 leaks out, it acts as a “danger signal” that triggers the release of chemical signaling molecules (called cytokines) that call in more white blood cells, which release still more cytokines, in a vicious cycle.

Inhibiting HMGB1 is a powerful means of slowing and reversing the processes involved in inflammation.

HMGB1 serves as a risk factor for memory impairment, chronic neuro-degeneration, and progression of neuro-inflammation. 1

The Table below lists the recognized and researched substances that may inhibit High-mobility group protein 1 (HMG-1):

Substances that Inhibit HMGB1

HMGB1  
CategoryNutraceuticals/Foods/HerbsReference(s)
Foods
Mung Bean Coat Extract1 2 vitexin, isovitexin
Herbs
Green Tea4 5 6 7
Angelica sinensis (Dong Quai)8
Lipids
Glycyrrhizin (Licorce)9


Resources:

Life Extension Cytokine Suppress with EGCG


 

Increasing Nrf2: A Master Regulator of the Aging Process

Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a transcription factor. The Nrf2 pathway is “the primary cellular defense against the cytotoxic effects of oxidative stress.”

Activation of Nrf2 results in the induction of many cytoprotective proteins. These include, but are not limited to, the following:

  • NAD(P)H quinone oxidoreductase 1 (Nqo1)
  • Glutamate-cysteine ligase, catalytic (Gclc) and glutamate-cysteine ligase, modifier (GCLM)
  • Heme oxygenase-1 (HMOX1, HO-1)
  • The glutathione S-transferase (GST) family
  • The UDP-glucuronosyltransferase (UGT) family
  • Multidrug resistance-associated proteins (Mrps)

A wide variety of dietary components have been shown in vitro or cell culture to activate Nrf2 and directly increase activity of phase II enzymes; these include:

  • epigallocatechin gallate (EGCG)
  • resveratrol
  • curcumin and its metabolite tetrahydrocurcumin, which has greater phase II activity
  • cinnamaldehyde
  • caffeic acid phenyethyl ester
  • alpha lipoic acid
  • alpha tocopherol
  • lycopene
  • apple polyphenols (chlorogenic acid and phloridzin)
  • gingko biloba
  • chalcone
  • capsaicin
  • hydroxytyrosol from olives
  • allyl sulfides from garlic
  • chlorophyllin
  • xanthohumols from hops

The beneficial effects of these phytochemicals have been demonstrated in numerous animal and human studies, particularly their chemopreventative and antioxidant abilities; these effects may be explained by their indirect stimulation of antioxidant enzyme production and phase II detoxification through Nrf2 signaling. (Source: Life Extension)


References:

Yuan JH, Li YQ, Yang XY. Inhibition of epigallocatechin gallate on or- thotopic colon cancer by upregulating the Nrf2-UGT1A signal path- way in nude mice. Pharmacology 2007; 80: 269 – 78

Hsieh TC, Lu X, Wang Z, Wu JM. Induction of quinone reductase NQO1 by resveratrol in human K562 cells involves the antioxidant response element ARE and is accompanied by nuclear translocation of tran-scription factor Nrf2. Med Chem 2006; 2: 275 – 85

Nayak S and Sashidhar RB. Metabolic intervention of aflatoxin B1 toxicity by curcumin. J Ethnopharmacol 2010;127 (3) : 641-4

Osawa T. Nephroprotective and hepatoprotective effects of curcuminoids. Adv Exp Med Biol 2007;595 : 407-23

Liao BC, Hsieh CW, Liu YC, Tzeng TT, Sun YW, Wung BS. Cinnamaldehyde inhibits the tumor necrosis factor-alpha-induced expression of cell adhesion molecules in endothelial cells by suppressing NF-kap- paB activation: Effects upon IkappaB and Nrf2. Toxicol Appl Pharmacol 2008; 229: 161 – 71

Lii CK, Liu KL, Cheng YP et al. Sulforaphane and alpha-lipoic acid upregulate the expression of the pi class of glutathione S-transferase through c-jun and Nrf2 activation. J Nutrition 2010;140 (5) : 885-92

Feng Z, Liu Z, Li X, et al. α-Tocopherol is an effective Phase II enzyme inducer: protective effects on acrolein-induced oxidative stress and mitochondrial dysfunction in human retinal pigment epithelial cells. J Nutr Biochem 2010;21 (12) : 1222-31

Wang H and Leung LK. The carotenoid lycopene differentially regulates phase I and II enzymes in dimethylbenz[a]anthracene-induced MCF-7 cells. Nutrition 2010;26 (11-12) : 1181-7

Veeriah S, Miene C, Habermann N et al. Apple polyphenols modulate expression of selected genes related to toxicological defence and stress response in human colon adenoma cells. Int J Cancer 2008;122 (12) : 2647-55

Liu XP, Goldring CE, Wang HY, Copple IM, Kitteringham NR, Park BK. Extract of Ginkgo biloba induces glutathione-S-transferase subunit-P1 in vitro. Phytomedicine 2009; 16(5):451–455

Liu YC, Hsieh CW, Wu CC, Wung BS. Chalcone inhibits the activation of NF-kappaB and STAT3 in endothelial cells via endogenous electrophile. Life Sci 2007; 80: 1420 – 30

Joung EJ, Li MH, Lee HG, Somparn N, Jung YS, Na HK et al. Capsaicin in- duces heme oxygenase-1 expression in HepG2 cells via activation of PI3K-Nrf2 signaling: NAD(P)H:quinone oxidoreductase as a potential target. Antioxid Redox Signal 2007; 9: 2087 – 98

Zhu L, Liu Z, Feng Z et al. Hydroxytyrosol protects against oxidative damage by simultaneous activation of mitochondrial biogenesis and phase II detoxifying enzyme systems in retinal pigment epithelial cells. J Nutr Biochem 2010;21 (11) : 1089-98

Gong P, Hu B, Cederbaum AI. Diallyl sulfide induces heme oxygenase-1 through MAPK pathway. Arch Biochem Biophys 2004; 432: 252 – 60

Zhang Y, Guan L, Wang X, Wen T, Xing J, Zhao J. Protection of chloro- phyllin against oxidative damage by inducing HO-1 and NQO1 ex- pression mediated by PI3K/Akt and Nrf2. Free Radic Res 2008; 42: 362–71

Dietz BM, Kang YH, Liu G et al. Xanthohumol isolated from Humulus lupulus Inhibits menadione-induced DNA damage through induction of quinone reductase. Chem Res Toxicol 2005;18 (8) : 1296-305

Surh YJ, Kundu JK, Na HK. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med 2008;74 (13) : 1526-39


Informational Reference:

Nrf2.com  

The Proposed Nine Hallmarks of Aging

Scientist and researchers have attempted to identify and categorize the cellular and molecular hallmarks of aging in a published paper in the research journal Cell on 6th June 2013.  1 

In this paper, researchers proposed nine candidate hallmarks that are generally considered to contribute to the aging process and together determine the aging phenotype.

These nine hallmarks include:

  • altered intercellular communication
  • cellular senescence
  • deregulated nutrient-sensing
  • epigenetic alterations
  • genomic instability
  • loss of proteostasis
  • mitochondrial dysfunction
  • stem cell exhaustion
  • telomere attrition

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The 9 Hallmarks of Aging  (Source: The Hallmarks of Aging)

Researchers set three criteria for each ‘hallmark’:  2

  • it should manifest during normal aging;
  • its experimental aggravation should accelerate aging; and
  • its experimental amelioration should retard the normal aging process and, hence, increase healthy lifespan.

The challenge that the researchers encountered was to show the interconnectedness between the candidate hallmarks and their relative contribution to aging.  The ultimate goal of the research was to “identifying pharmaceutical targets to improve human health during aging with minimal side-effects.”  3

A clear and easy to understand article on the nine Hallmarks of Aging was published by Geroscience.com on 23rd February 2017.  This article, written by Alexandra Bause, PhD, examines each of the nine hallmarks in plain English and provides a better understanding beyond the original publication in the journal Cell.   

Despite the fact that these hallmarks can be complex and complicated and the understanding of them are still limited, there is hope that new medical strategies will emerge that will ameliorate the the normal aging process.

Geroscience.com is the premier site for news, discussion, and scientific insight related to the basic biology of aging and the development of new medicines with the ability to cure or prevent the diseases of aging.

Geroscience.com is committed to bringing its readers the most interesting developments in the science of aging and will: 4

  • Feature a wide range of multimedia content including interviews with experts, looks behind the scenes of everyday lab life, and the latest trends from longevity conferences
  • Capture the perspectives of leading researchers, entrepreneurs, and other experts to act as a platform to share ideas about aging and longevity
  • Cover the emerging biotechnology business of geroscience, including investment coverage, clinical trial data, and insight into the regulatory world
  • Aid collaboration between cross-functional scientific communities, connecting researchers, investors, and industry heads from around the globe

  

Read the article at Geroscience.com:

The hallmarks of aging, in plain English, by Alexandra Bause, PhD at Geroscience.com

 

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

Inhibiting the Destructive Effects of arNOX (ENOX3)

The Aging-Related Cell Surface NADH Oxidase (arNOX) enzyme is one in a class of newly-identified ECTO-NOX (external NADH oxidase or ENOX (Ectos is Greek for outside) ) proteins that are located on external cell membranes.  arNOX is also known as ENOX3.

As the cells mitochondria age and produce less energy, arNOX becomes increasingly active.  arNOX is present in all cells tested, and in particular in the serum and saliva as well as the dermis and epidermis of the skin. 

ArNOX activity increases with age between 30 and 50–65 years and generates the destructive superoxide free radical.  arNOX transmits cell surface oxidative changes to surrounding cells and circulating lipoproteins. 

arNOX promotes tissue aging, especially in the vascular walls and the skin and the structural components of the skin’s extracellular matrix, such as collagen and elastin. arNOX is shed from the cell surface and is found in saliva, urine, perspiration, and interstitial fluids that surround the collagen and elastin matrix underlying dermis.

There is a strong correlation with the level of arNOX in the blood or saliva and a persons age.  The older one looks, apparently the more arNOX is in the blood and saliva.  arNOX is inactive in youth and can vary among individuals after age 30.  arNOX activity correlates with age and reaches a maximum at about age 65 in males and 55 in females.

Inhibiting arNOX by exogenous (dietary) natural substances is the only way to lessen and mitigate the destrucitve effects of arNOX.

Inhibiting arNOX activity

There are a number of natural substances that have been shown to inhibit arNOX activity and reduce oxidative damage caused by the superoxide free radical.  The following natural substances are able to inhibit arNOX:

Co-enzyme Q10 (CoQ10)

Co-enzyme Q, especially CoQ10 is capable of inhibiting arNOX.  1  The generation of superoxide by arNOX proteins is inhibited by Coenzyme Q10 as one basis for an anti-aging benefit of CoQ10 supplementation in human subjects.  arNOX activity was reduced between 25 and 30% by a 3 x 60 mg daily dose Coenzyme Q10 supplementation. Inhibition was the result of Coenzyme Q10 presence. 2

Tyrosol and Hydroxytyrosol

Tyrosol and Hydroxytyrosol are capable of inhibit arNOX activity.  3

Herbes de Provence

Based on the scientific research of James and Dorothy M. Morré, they demonstrated that natural compounds from French culinary seasonings – “Herbes de Provence” inhibit arNOX activity.  4

Herbes de Provence typically comprise:

  • basil (Ocimum basilicum)
  • fennel seed (Foeniculum vulgare)
  • marjoram (Origanum majorana)
  • oregano (Oreganum vulgare)
  • rosemary (Rosmarinus officinalis)
  • sage (Salvia officinalis)
  • summer savory (Satureja hortensis)
  • tarragon (or estragon, dragon’s-wort, Artemisia dracunculus)
  • thyme (Thymus vulgaris)

The ratio of these herbs that make up Herbes de Provence vary with personal or regional choice.

Of the herbs listed, the following are particularly active as arNOX inhibitors:

  • basil
  • tarragon (especially French tarragon)
  • rosemary
  • marjoram
  • sage
  • savory (especially summer savory)

Figure 1.  Summer Savory

Summer savory was the herb that had the highest arNOX activity inhibition at 89%.

Figure 2:  arNOX activity % inhibition.  (Source:  U.S. Patent 20120207862 A1)

According to U.S. Patent 20120207862 A1 entitled ORAL INHIBITORS OF AGE-RELATED NADH OXIDASE (arNOX), COMPOSITIONS AND NATURAL SOURCES, by the inventors, D. James Morré, Dorothy M. Morré, Thomas Shelton, components can be incorporated in the following proportions:

  • basil, 0-95%
  • thyme, 0-50%
  • oregano, 0-90%
  • tarragon, 0-95%
  • rosemary, 0-95%
  • lavender, 0-50%
  • sage, 0-95%
  • savory, 0-95%
  • marjoram, 0-95%

The U.S. Patent recommends the following dosages.  By formulating the herbal preparations as sustained-release preparations, 24 h of protection were attained with just two 400-mg capsules/day (one in the morning and one before bedtime) A preferred total daily dose is from about 200 mg to about 600 mg of a combination of herbs and/or natural products as described herein.

Free E-Book: The Health and Medicinal Benefits of Ashitaba

Ashitaba, which is the common name used in Japan, is botanically known as Angelica keiskei or Angelica Keiskei Koidzumi. The English translation of the Japanese word “Ashitaba” (アシタバ or 明日葉) is “Tomorrow’s Leaf”. Ashita means ‘tomorrow and ba means ‘leaf.’ The name stems from the plant’s ability to quickly regenerate new leaves after taking cuttings. This give an indication of its potential for longevity of life.

asitab_5

Ashitaba plant

There are two separate substances (products) that are derived from the Ashitaba plant.

The first is the hot-air dried powder of Ashitaba from the leaves and stems. The color of this powder is bright green. The leaves of the Ashitaba plant contain approximately 0.25% to 0.35% chalcones.

The second is the powder made from the unique yellow sap which is collected from the Ashitaba’s stem. It is commonly called Ashitaba Chalcone Powder which consists up to 8% chalcones. The color of Ashitaba Chalcone Powder is bright yellow and is a fat-soluble substance.

Although the green Ashitaba powder from the leaves and stems provide nutritional and health benefits, it is the Ashitaba Chalcone Powder (bright yellow powder from the sap of the stem) that is the Chalconoids are natural phenols related to chalcone. They form the central core for a variety of important biological compounds.

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Chalcone sap from Ashitaba stem

Chalcones are the active factors in Angelica Keiskei Koidzumi. At least 20 chalcones have been identified in Angelica Keiskei.

Ashitaba contains a thick, sticky yellow sap, which is not found in other celery plants, and are unique to this strain of angelica. This yellowish element in Ashitaba contain the chalconoids.

 

Download the Free E-Book (PDF): The Health and Medicinal Benefits of Ashitaba

Left-click to download into new window, then right-click (in new window) to save as PDF file.

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

Astaxanthin and Other Natural Substances Increase the Activity of the FOXO3 Longevity Gene

The gene FOXO3a codes for a human protein called Forkhead box O3, also known as FOXO3.

FOXO3 belongs to the family of transcription factors which are characterized by a distinct fork head DNA-binding domain. There are three other FoxO family members in humans:

  • FOXO1
  • FOXO4
  • FOXO6

Protein FOXO3 PDB 2K86.png

Structure of protein FOXO3. Based on PyMOL rendering of PDB 2K86  (Source: Pleiotrope – Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=15989699)

This important protein has many vital functions in the human body and is primarily associated with human longevity, which is why it is often referred to as the “longevity gene”.  1  2 

Among the many functions and roles that this protein plays in the human body, the most important have been identified:

  • functions as a trigger for apoptosis through upregulation of genes necessary for cell death  3
  • upregulates antioxidants such as catalase and MnSOD  4
  • suppresses tumorgenesis in cancer  5
  • functions in DNA repair mechanisms  6  7
  • promotes resistance to oxidative stress  8

These important functions of the FOXO3 protein will only happen when the FOXO3 gene is activated and increased to encode the protein. 

Researchers have identified certain natural substances that activate and increase the FOXO3 gene:  These natural substances include:

  • Astaxanthin 9
  • Baicalein (from the Scutellaria baicalensis root or Baikal skullcap)  10
  • Butyrate (as Calcium Magnesium Butyrate) 11
  • R-Lipoic Acid 12
  • Selenium 13
  • Vitamin D  14

A Closer Look at Astaxanthin

Astaxanthin is a keto-carotenoid which belongs to a larger class of chemical compounds known as terpenes.  Astaxanthin is usually classified as a xanthophyll.

Astaxanthin can be found in:

  • microalgae
  • yeast
  • salmon
  • trout
  • krill
  • shrimp
  • crayfish
  • crustaceans
  • feathers of some birds (e.g., flamingos)

A recent study published in 2017 and co-authored by the The University of Hawaii John A. Burns School of Medicine (“JABSOM”) and Cardax, Inc. (“Cardax”), a Honolulu based life sciences company, demonstrated that the Astaxanthin compound (CDX-085 (developed by Cardax)) is able to switch on the FOX03 ‘longevity gene’ in mice.  15

Researchers of the study stated that all humans have the FOXO3 gene, which protects against aging in humans, but about one in three persons carry a version of the FOXO3 gene that is associated with longevity. By activating the FOXO3 gene common in all humans, researchers stated that they can make it act like the “longevity” version. This important study has shown that Astaxanthin “activates” the FOXO3 gene.

The study used mice which were fed either normal food or food containing a low or high dose of the Astaxanthin compound CDX-085 provided by Cardax. They witnessed a significant increase in the activation of the FOXO3 gene in the heart tissue of those mice that were fed the higher amount of the Astaxanthin compound.  In fact, they found a nearly 90% increase in the activation of the FOXO3 gene in the mice fed the higher dose of the Astaxanthin compound CDX-085. 

The researchers concluded that their hope is that these findings will lead to a highly effective anti-aging therapy that extends the lifespan of human beings.  

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