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6:1 AUTOPHAGY, repair, replace, recycle, and defense systems

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6:1  Autophagy:  repair, replace, reuse, and defense systems

1, Introduction to autophagy, this is a major, major piece in puzzle of what has gone wrong, because this is the cellular tune up, parts replacement, and defective cell replacement system.  Thus with reduced autophagy (RAP) we have every cell negatively affected.  In addition, autophagy plays a major immune system function by the encasement and digesting of bacteria and other pathogens, and through apoptosis of infected cells.[1]  In the autophagic process the release of reactive chemicals are minimized and many of the complex molecules are reused.  Autophagy maintains nutrient and energy homeostasis in the face of a limited food supply; it clears intracellular proteins and damaged organelles that may lead to tissue degeneration, genomic instability, cancer, and aging; and it defends mammalian cells against microbial attack.” [2]  “Recent studies have clearly demonstrated that autophagy has a greater variety of physiological and pathophysiological roles than expected, such as starvation adaptation, intracellular protein and organelle clearance, development, anti-aging, elimination of microorganisms, cell death [apoptosis], tumor suppression, and antigen presentation” [3] While it has been argued that autophagy comes with risks, it is limited to those on the western diet, for as in Section 1, the low sugar populations lack our chronic age related conditions.  Since autophagy is about staying healthy, pharma plays a significant role in muddling its science.  For example, autophagy works to counteract the damage caused by the poisonous cocktails of chemotherapy; thus pharma blames autophagy for the ineffectiveness of chemotherapy.[4]  Evolution has finely tuned the autophagic processes, but our evolution wasn’t subjected to 180 pounds of sugars yearly (all sources), 20% of calories, and half of American’s above that average. 


There is no attempt by me to be either systematic or complete; I am stressing the major concepts which are essential in understanding why we get CAWD and LSPs don’t.  Too many details overwhelm the memory, create confusion, and burry the basic principles.   As said prior, the B-4 is causal for all bodily systems slowing down compared to LSPs.  Those systems with the greatest use of ATP are affected the most.  The reduces rate of autophagy (RRA)is one of those systems.  Their diminished performance will affect every cell, and thus every tissue.  Some ATP shortages will have a snowball upon many systems, for example, the slowed replacement of collagen (3:8).  The same happen through IR, a snow ball effect: 


High insulin or insulin resistance and low exercise levels can lead to the inhibition of mitophagy cellular regeneration.  Without regeneration, more dysfunctional mitochondria accumulate, leading to excessive reactive oxygen species (ROS) and cell damage.  Once a cell is damage beyond a certain threshold, apoptosis is inhibited.  Apoptosis is normally essential , but if almost all cells of an organ are dysfunctional, then, sadly, the outcome is degeneration and organ failure.[5]


The normal rate of regeneration by means of autophagy is essential for health.


When autophagy is downregulated (RRA) because of IR[6], MTDD and its RATP, autophagy becomes the 4th link in the chain of the B-4 for CAWD.  For this reason, I am going beyond a mere brief summary, and devoting a long chapter to autophagy.  I want you to take with you, autophagy importance.  With that goal, I start with an explanation of autophagy umbrella, which like the immune system is complex.  Under the umbrella are 1) number of transport structures each differing in function (with some overlap), 2) processes which have been given their own tag, such as mitophagy and apoptosis, 3) permanent cell structures (lysosome and Golgi apparatus) and 4) various functions and related information.  Then I will take a look at the evidence for its role in CAWD.  Sadly, evidence is limited because of the inroads of industry, and because of the barriers to monitoring in vivo organelles in cells.[7]  In section 4 the topic of pathogenic conditions is given appropriate space, here is just a survey.  Much to that survey parallels MTTD, RATP, and IR, since all are on the same pathway leading to CAWD through RAP. 


Autophagy (from the Greek, “auto” oneself, “phagy” to eat) refers to any cellular degradative pathway that involves the delivery of cytoplasmic cargo to the lysosome. At least three forms have been identified—chaperone-mediated autophagy, microautophagy, and macroautophagy—that differ with respect to their physiological functions and the mode of cargo delivery to the lysosome.


Autophagy occurs at low basal levels in virtually all cells to perform homeostatic functions such as protein and organelle turnover. It is rapidly upregulated when cells need to generate intracellular nutrients and energy, for example, during starvation, growth factor withdrawal [low HGH], or high bioenergetic demands. Autophagy is also upregulated when cells are preparing to undergo structural remodeling such as during developmental transitions or to rid themselves of damaging cytoplasmic components, for example, during oxidative stress, infection, or protein aggregate accumulation. Nutritional status, hormonal factors, and other cues like temperature, oxygen concentrations, and cell density are important in the control of autophagy.  . . . Downstream of TOR kinase, there are more than 20 genes in yeast (known as the ATG genes) that encode proteins (many of which are evolutionarily conserved) that are essential for the execution of autophagy


These approaches must be coupled with ancillary measures to discriminate between two physiologically distinct scenarios—increased autophagic flux without impairment in autophagic turnover (i.e., an increased “on-rate”) versus impaired clearance of autophagosomes (i.e., a “decreased off-rate”), which results in a functional defect in autophagic catabolism.  [This impaired functions of autophagy caused by the fructose pathway of MTDD, RAPT is they major, major cause of CAWD].  Autophagy is activated as an adaptive catabolic process in response to different forms of metabolic stress, including nutrient deprivation, growth factor depletion, and hypoxia. This bulk form of degradation generates free amino and fatty acids that can be recycled in a cell-autonomous fashion or delivered systemically to distant sites within the organism.  The repertoire of routine housekeeping functions performed by autophagy includes the elimination of defective proteins and organelles, the prevention of abnormal protein aggregate accumulation, and the removal of intracellular pathogens. Such functions are likely critical for autophagy-mediated protection against aging, cancer, neurodegenerative diseases, and infection.[8]


Another summation of autophagy with focus on science rather than consequences:[9]    


Macroautophagy (hereafter referred to as autophagy) acts as a homeostatic pathway at both the cellular and organismal levels (Mizushima and Komatsu, 2011). The finely tuned execution of this multistep process (ensured by the coordinated activity of specifically committed Atg proteins) eventually culminates in the formation of a double-membrane organelle, the autophagosome, in which bulk portions of the cytoplasm or specific organelles are engulfed prior to their lysosomal hydrolase-mediated degradation (He and Klionsky, 2009). Autophagy may be considered as one of the major anti-aging mechanisms because it assures recycling (and hence rejuvenation) of damaged cytoplasmic components, including entire organelles such as mitochondria (Pan et al., 2013, Rubinsztein et al., 2011, Sun et al., 2016). Manipulations aiming at restoring or inducing autophagy can reduce the incidence of age-related disease and extend health span and lifespan (López-Otín et al., 2016). The nature of these interventions can be nutritional (i.e., fasting or caloric restriction) (Heilbronn and Ravussin, 2003, Longo and Mattson, 2014), behavioral (i.e., physical activity) (He et al., 2012), or pharmacological. Thus, mTORC1 inhibition by rapalogs (Lamming et al., 2013), activation of sirtuin-1 (SIRT1) with resveratrol (Wood et al., 2004), and supplementation of the natural polyamine spermidine (Eisenberg et al., 2009) extend lifespan in various model organisms in an autophagy-dependent manner (López-Otín et al., 2016). Importantly, overexpression of the autophagy essential gene Atg5 is sufficient to expand lifespan in mice (Pyo et al., 2013), indicating that autophagy is not only necessary but even sufficient to enhance longevity.  Culture of cells in nutrient-free conditions, as well as fasting regimens, leads to a reduction in the global levels of protein acetylation (Eisenberg et al., 2014, Mariño et al., 2014). Reduced acetylation may be explained by the diminution in the activity of nuclear and cytoplasmic lysine-acetyltransferases (KAT) secondary to a decrease in the nucleocytosolic levels of acetyl coenzyme A (CoA), which is the sole donor of acetyl groups (Pietrocola et al., 2015a). As a consequence, blockade of acetyl CoA biosynthesis has the same functional consequence as inhibition of acetyltransferases or activation of the deacetylase activity of sirtuins (Madeo et al., 2014) insofar that it triggers autophagy (Mariño et al., 2014). Chemically unrelated agents, including anacardic acid, hydroxycitrate, resveratrol, and spermidine (Pietrocola et al., 2015b), share the capacity to reduce protein acetylation and have been classified as caloric restriction mimetics (CRMs). CRMs such as spermidine have widespread anti-aging effects (Eisenberg et al., 2016, Pietrocola et al., 2016).[10]




[1] Since much of the autophagic process involves incasing then dismantling cell parts including mitophagy of MTD, I extend under the umbrella of autophagy apoptosis.  Some writers consider apoptosis an independent process and thus not within the realm of autophagy.  Nothing changes, this is just a question of semantics. 

[2] Levine, Beth, Gkuido Kroemer, Jan 2007 Autophagy in the pathogenesis of disease.  Perhaps this is why so many cultures have empirically incorporated periodic fasting, a practice that activates autophagy, into their healing traditions.”

[3] Mizushima, Noboru, 2007 Cold Spring harbor, 2007, Autophagy: process and function

[4] “If the lysosomal clearance of autophagosomes fails, the activation of autophagy results in a cellular traffic jam that may lead to increased pathology—a scenario that may in fact occur with aging, Parkinson's disease, and other neuro- and myo-degenerative disorders.” Mizushima supra, the conclusion. 

[5] Griffiths, Ray, 2018, Mitochondria in health and disease, p. 113. 

[6] RRA stands for reduce rate of autophagy.  There are dozens of regulatory process for autophagy because there are over a dozen distinct type of autophagy (#2) thus dozens of compounds that up and down regulate the rate of autophagy.  Insulin is at the heart of the hemostatic (energy sensing) system along with the hormones that modulate insulin’s effects, and since autophagy rates are affected by the hemostatic states in that it is upregulated when the mitochondria switch primarily to fatty acid metabolism, the insulin/glucose level plays a significant regulatory role. 

[7] Mizushima, Noboru, Dec 2004, Methods for monitoring autophagy

[8] Levine, Beth, Guido Kroemer, Jan 2008, Autophagy in the Pathogenesis of Disease

[9] By going to the article on line, you can check the references and definitions for terms such as organelle.  The articled recounts their laboratory work which showed in culture, rats, and nematodes that aspirin (salicylates) that aspirin turns up autophagy.  This lies at the heart of the explanation as to why pharma who is in the business of treating illness, has turned their KOLs, guideline committees, and FDA upon the target of aspirin.  Extensive research is continuing in China, and for this article of the 23 signatures, a total of 13 are from France,  At http://healthfully.org/rc/id3.html you will find the summation of benefits, thus I take 2 uncoated 325 mgs daily.    

[10] Pietrocola, Federico, Francesca Castoldi, et al Feb 2018, Aspirin Recapitulates Features of Caloric Restriction



2. The structure and processes of autophagy:

 https://ars.els-cdn.com/content/image/1-s2.0-S0092867407016856-gr1.jpg

Figure 1. The Cellular, Molecular, and Physiological Aspects of Autophagy

The cellular events during autophagy follow distinct stages: vesicle nucleation (formation of the isolation membrane/phagophore), vesicle elongation and completion (growth and closure), fusion of the double-membraned autophagosome with the lysosome to form an autolysosome, and lysis of the autophagosome inner membrane and breakdown of its contents inside the autolysosome. This process occurs at a basal level and is regulated by numerous different signaling pathways (see text for references). Shown here are only the regulatory pathways that have been targeted pharmacologically for experimental or clinical purposes. Inhibitors and activators of autophagy are shown in red and green, respectively. At the molecular level, Atg proteins form different complexes that function in distinct stages of autophagy. Shown here are the complexes that have been identified in mammalian cells, with the exception of Atg13 and Atg17 that have only been identified in yeast. The autophagy pathway has numerous proposed physiological functions; shown here are functions revealed by in vivo studies of mice that cannot undergo autophagy (see Table 1).[1]

 

Autophagy means self-eating.  Autophagy is the orderly removal of warn out parts and the subsequent shipment to lysosomes for utilization of some of its molecules, and thus by so doing autophagy makes room for new fully functional parts and cells.  It is a cellular service and replacement system.  Autophagy is similar to apoptosis (3:2,7) and the two overlap.  “Autophagy not only recycles intracellular components to compensate for nutrient deprivation but also selectively eliminates organelles to regulate their number and maintain quality control.” [2]  It is a major catabolic pathway in eukaryotes and fungi utilizing lysosomal degradation of cytoplasmic proteins and lipids.[3]   Replacement of defective cell parts is essential of cellular health, and this must be done in a controlled way so as to limiting the escaping of reactive chemicals through autophagy, apoptosis, and related repair systems.  The system promotes optional cell functions.[4]  Autophagy principally serves an adaptive role to protect organisms against diverse pathologies, including infections, cancer, neurodegeneration, aging, and heart disease.” [5]   The downregulation of these processes is the major CC for CAWD; but how?

          AS will be developed in the subsequent chapters of this section, major contributors to CAWD are the delayed replacement of MTDD and collagen.  Other major downstream CCs includes a sensitivity to uric acid, the development of fatty liver, IR and its child LR.  Over 90% of the adult population has at least one of those just listed defects.  The norm on a blood test, such as for fasting glucose is pathogenically high because the standard should be that of LSPs.  Another sign is a malfunctioning WRS that results in a BMI above 25 or excess abdominal fat, a TOFI.  The comparison to the lean, health, and young is misleading.[6]  Under the umbrella of autophagy and apoptosis are the repair and replacement processes.  All of these require the optimal availability of ATP, which because of MTDD isn’t available.  Every cell in the body is operating at a substandard level.  Sub-optimal function of autophagy is the major CC for CAWD.  It is for these reasons that a survey of autophagy is in order.  There are six special structures and 9 processes described under the umbrella of autophagy:

          Organelle is a specialized membrane-bound subunit[7] within a cell that has a specific function, a cell compartment.  There are many types of organelles, there function.  One of them for vertebrates has DNA, the mitochondria.  They are bound to protect the reactions that occur within and to prevent the escape of reactive chemicals.  Major eukaryotic organelles include vacuole for storage and transportation; nucleus for DNA, mitochondrion for energy production, Golgi apparatus for sorting, processing and modification of proteins endoplasmic reticulum for translation and folding of new proteins.  There are at least 22 types[8] of organelle, for which 4 are described below because of relevance to autophagy. 

          Lysosome is a membrane-bound organelle found in most eukaryotic cell and most plant cells.  They contain hydrolytic enzymes that can break down many kinds of biomolecules.  Lysosomes are the repository for the items delivered to it for dismantling.  Besides the degradation of polymers, the lysosome is involved in various cell process including secretion, plasma membrane repair, cell signaling, and waste disposal—waste from both within the cell through autophagy and outside the cell through endocytosis.  “Structures targeted for destruction are sequestered into large double-membrane vesicles called autophagosomes and then delivered into the interior of the lysosome or vacuole, where they are consumed by resident hydrolases.  Autophagosome formation during selective autophagy is dependent upon the cargoes, and in all cases seems to involve expansion of the sequestering membrane.” [9]  The lysosome contains more than 60 different enzymes and 50 different membrane proteins.  Their enzymes are synthesized in the rough endoplasmic reticulum and imported therefrom by the Golgi apparatus in small vesicles.  Lysosomal enzymes can catabolize peptides, nucleic acids, carbohydrates, nucleic acids, lipids, and a number of their polymers found in larger structures such as organelles that have been transported to the lysosome.  Many components of animal cells are recycled by through the formation of protective vesicles.  Lysosomes are also part of the immune system in that pathogens are wrapped in vesicles and transported there for catabolism.          Lysosomes essential functions for autophagy consist of catabolism of wastes and providing molecules for the replacement process. 

          Phagosome is a vesicle is formed around a particle engulfed by a phagocyte.  Professional phagocytes include macrophages, neutrophils, and immature dendrite cells (but not mature dendrites).  When the phagosomes attaches to the lysosome it is called a phagolysosome.  Its contents can have included a microorganism, a senescent cell, or an apoptotic cell.  The membrane has proteins which enable fusion with lysosomes.  The lysosome can also destroy and digest a pathogen with its ROS, RNS, and hydrolytic enzymes.  The products of digestion if useful are moved into the cytoplasm, and the waste is removed by exocytosis.  In addition to professional phagocytes, there are non-professional phagocytes that have only some degree of phagocyte activity, such as thyroid, bladder, and epithelial; they lack the specific phagocytic receptors.  Phagosomes also play additional important immune functions through inflammation.  Erythrocytes are by numbers the most of all cell that undergo apoptosis by the macrophages, which occurs in the liver and spleen at their lysosomes.

 

https://upload.wikimedia.org/wikipedia/commons/thumb/4/44/Endomembrane_system_diagram_en_%28edit%29.svg/350px-Endomembrane_system_diagram_en_%28edit%29.svg.png

Endomembrane system, details of and its components

Golgi apparatus (Golgi complex, Golgi body, and Golgi): is an organelle found in eukaryotic cells.  It is part of the endomembrane system in the cytoplasm.  Golgi apparatus packages proteins into membrane-bound vesicles for transport to destinations.  It either proceeds to the lysosome or return to the Golgi apparatus.  The Golgi apparatus resides at the intersection of the secretory lysosomal and endocytic pathways.  Of particular interest is the proteins that are transported into the MTD, in that system which supplies over 90% of the MTD proteins.[10]  And there are other uses, for example, the endosomes seek out LDL that has entered the cell through LDL receptor.  The endosome is a receptor for the contents of LDL and then the endosome proceeds to the area in need of cholesterol and fatty acids.  

Autophagosome are organelles which during autophagy function as transport vehicles that deliver cytoplasmic contents to the lysosomes.  The outer membrane fuses with a lysosome to deliver the autophagosome’s contents[11] for dismantling that results in re-usage and excretion.  “The formation of autophagosomes is regulated by genes that are well-conserved from yeast to higher eukaryotes.” [12]  Despite its simplicity, recent progress has demonstrated that autophagy plays a wide variety of physiological and pathophysiological roles.  “Autophagy consists of several sequential steps—sequestration, transport to lysosomes, degradation, and utilization of degradation products—and each step may exert different function.” [13] Among autophagosome’s functions is the regulation of fat metabolism, thereby they are part of the WRS and involved in its dysfunction; just how, as far as I know, has not been adequately determined.  And there are other functions:  This degradative pathway allows cells to eliminate large portions of the cytoplasm, from aberrant protein aggregates to superfluous or damaged organelles and even entire organisms such as invading bacteria.” [14]  However, it is mainly the phagosomes that digest bacterial, and autophagosomes are used mainly to selectively degrade damaged cytosolic organelles such as MTD (mitophagy).  The complex of the autophagosomes which often varying according to tissue type, is illustrative of the advancements made that promote survival in vertebrates.

Macroautophagy, which is the main pathway used to dismantle damage organelles for recycling of and disposal of the molecular constituents, in a process that occurs in the lysosomes.  An autophagosome membrane is formed around the organelle for transport into the lysosome for degrading via acid lysosomal hydrolase.   

Microautophagy occurs with the engulfment of cytoplasmic material and transport into the lysosome and vacuole in plants, fungi and some Protista (one of the 4 types of eukaryote).  Macroautophagy and microautophagy perform nutrient recycling, which promotes survival during starvation by recycling amino acids. membrane proteins, and other membrane components which would otherwise be in short supply and cause the dismantling of proteins as a source for building materials.  Microautophagy as with macro is part of the cellular/tissue tune up process, removing the old beyond repair to make room for the new functional replacement, and there is a net conservation of energy (ATP). 

Central to the function is the autophagosome, a spherical structure with double layer membrane, used mainly for the degradation for cytoplasmic contents and also for invading microorganisms.  Eventually the autophagosome will attach to a lysosome and deliver its contents. 

https://upload.wikimedia.org/wikipedia/en/thumb/5/57/Angus_Barbieri.jpg/220px-Angus_Barbieri.jpg

          Barbieri’s 382-day fast:  A person can go for quite some time without metabolizing muscle during starvation, depending on percentage of stored fat to lean weight.   Angus Barbieri, a 456 lbs. Scotsman, starting in June 1965, went on a medically supervised water fast lasting 382 days and lost 276 lbs.  He consumed only vitamins, electrolytes, and zero-calorie beverages.[15]   The case study published 7 years later found that his average blood glucose was 30 mg/dL (1.7 mmol/L),[16] which confirmed that he wasn’t eating—as too the weight loss.  That he didn’t need an operation to remove the folds of skin is an example of his body’s efficient use of autophagy to recycle amino acids from the skin and adipose tissue.[17] Only when fat stores become low, does the body start metabolizing muscle. Not all are so fortunate, and a friend of mine, a geriatric physician, had to undergo surgery to remove the folds.  He lost nearly 200 pounds eating 1 meal a day and without medical supervision.  Note: after a half hour I gave up on trying to find Agnus’s cause of death at the age of 50 and weight at that age.  However, on an examination at after 7 year, he had gained only 16 pounds—much better than the contestants on the Biggest Looser show[18] 5:1.     EXPAND

      

https://upload.wikimedia.org/wikipedia/commons/thumb/9/9c/GroES-GroEL_top.png/250px-GroES-GroEL_top.png

A top view of the GroES/GroEL bacterial chaperone complex model

Chaperone-mediated autophagy (CMA) targets proteins with hsc70 complex, which allows the binding of the protein to the chaperone.[19]  “CMA is significantly different from other types of autophagy because it translocates protein material in a one by one manner, and it is extremely selective about what material crosses the lysosomal barrier.” [20]  There in for example the endoplasmic reticulum 4 types of chaperones. There are many different families of chaperones; each family acts to aid protein folding in a different way. Look up at the photo of a chaperone and the hundreds of amino acid placed in exact positions.  To paraphrase Darwin, there is grandeur in the complexity of chaperone system.

Mitophagy is the selective degradation of MTD by autophagy.  It thereby prevents the accumulation of dysfunctional MTD, which can lead to stress from the release of ROS, and from the diminished production of the fuel ATP, both of which are CC for cell degeneration.  Moreover, when there are sufficient MTDD or the cellular functions are downregulated are sufficient, the MTD will start the signalling pathway for apoptosis.  Mitophagy is essential for normal cell functions.      EXPAND

          Lipophagy is the degradation of lipids by autophagy, a process that also occurs in animals and fungi.  Lipid droplets store triglycerides and then supply them as needed for metabolism.  “The triglycerides are taken up by autophagosomes and delivered to lysosomes for degradation by acidic hydrolases.  . . . by the lysosomal degradative pathway.  . . .  to supply free fatty acids.  . . . Lipophagy regulates intracellular lipid content.”[21]

          Xenophagy as part of the immune system the degradation of infectious particles there are a long list of pathogens are destroyed including tuberculosis. A subset of pathogens has evolved to evade that process and promote their own replication, while others have been able to block the maturation of phagosomes. 

Peroxisome is an organelle known as a microbody[22] found in the cytoplasm of eukaryotic cell.  It is a digestive organelle, involved in catabolism of every long-chain fatty acid and branched chain fatty acids (through beta oxidation), D-amino acids, polyamines, and reduction of ROS, and also the biosynthesis of phospholipids, which are used to from myelin that is used for the myelination of nerve cells.   Peroxisomes also play a role in the synthesis of digestive biles.  Humans lack the oxidative enzyme uric acid oxidase found in most other mammals in the peroxisome, and because of this specie-wide elision some human develop gout.  Peroxisomes are found in addition to vertebrates in plants and yeast.     

          Endosome is an organelle in eukaryotic cells that are part of the transport from the Golgi membrane to the lysosome and back.  They have been shown to be involved in iron metabolism and regulation[23] as a hub for contents from lysosomes,[24] and they are involved in neural development[25] and neurodegenerative diseases.[26] 

3. Apoptosis:  There isn’t a clear separation between the 3 types of cell death, in that there often is a shift during the dismantling process between one type to another type of cell death.  “Cell death has been subdivided into the categories apoptosis (Type I), autophagic cell death (Type II), and necrosis (Type III). The boundary between Type I and II has never been completely clear and perhaps does not exist due to intrinsic factors among different cell types and the crosstalk among organelles within each type.  Apoptosis can begin with autophagy, autophagy can end with apoptosis, and blockage of caspase activity can cause a cell to default to Type II cell death from Type I. Furthermore, autophagy is a normal physiological process active in both homeostasis (organelle turnover) and atrophy.   ‘Autophagic cell death’ may be interpreted as the process of autophagy that, unlike other situations, does not terminate before the cell collapses.” [27]  The type of dismantling is highly dependent on conditions in which it occurs, needs for amino acids, cell parts, availability of ATP, and therefore on inter and intra cellular signaling.  When types I & II systems functioning at optimal level there is better tissue functions, and thus health.  The role of ATP and thus MTD is at the core of these processes.    

 

4.  Necroptosis in response to pathogens, cell death turned on in response to pathogens.  Unlike in apoptosis, necrosis and necroptosis do not involve caspase activation. Necrotic cell death culminates in leakage of cell contents into the extracellular space, in contrast to the organized disposal of cellular contents into apoptotic bodies.  [The release of reactive chemicals could be destructive to the pathogen.]  Unlike in necrosis, permeabilization of the cell membrane during necroptosis is tightly regulated.  . . . The necrosome inhibits the adenine nucleotide translocase in mitochondria to decrease cellular ATP levels.   Uncoupling of the mitochondrial electron transport chain leads to additional mitochondrial damage and opening of the mitochondrial permeability transition pore, which releases mitochondrial proteins into the cytosol. The necrosome also causes leakage of lysosomal digestive enzymes into the cytoplasm by induction of reactive oxygen species by JNK, sphingosine production, and calpain activation by calcium release.”[28]   

5. Autophagy’s role in cancer suppression:  while I wish not be sidetracked by this topic, given the fundamental flaw in the model for cancer, and this flawed model is used to explain autophagy’s role, I shall briefly go over the topic.  Simply put, a precancerous cell is normally marked by MTD for apoptosis (3:2,7); however, when certain mutations occur, the precancerous cell deforms the MTD sufficiently to turn off the MTD directed apoptosis therefor permitting the that cell line to grow vegetatively.  At this stage it might be able to invade adjacent tissues.  To become a fatal (thus metastatic cell line) certain genes are turned on which make that new cell line immortal and others to make it line invisible to the immune system.  These are the genes which make macrophages invisible permitting the macrophage to travel to distant tissues.   A seminal article argues that this occurs through a gene swap with a macrophage[29]—the validity of this swap claim I cannot now comment upon.  This event of activated genes converts a stage I, II & III cancer into a stage IV cancer.  Autophagy is essential for preventing cancer through apoptosis of the precancerous tumor, and also of the non-metastatic cancers. “In this review, we discussed the relationship between autophagy and carcinogenesis. Based on multiple studies, it has been concluded that autophagy plays an anti-neoplastic role in cells.” [30]  There are many reports that autophagy may act as a censer suppressor.” [31]Again we have pharma muddling the science to promote profits and using association to blame the bystander. 

 

6.  Aspirin and cancer:  Aspirin which upregulate genes that turns up the apoptosis process has been shown to reduce with long-term daily usage (over 5 years) cancer risk by over 50%.  Those figures are imperfectly gathered since most studies don’t exclude  low dose aspirin which are ineffective because of tolerance. Test for aspirin resistance which even at over 1,300 mgs per day, about 1/8th are resistant to its down regulation of clotting effects, and thus possible to its promotion of apoptosis.  Nor do they control of enteric coating which has two negative effects, that of reduced absorption of 50% and the removal of the acetate group for aspirin, which has additional salubrious effects (just what I don’t know).  There are other bio-mechanisms by which aspirin reduces cancer risk.  For more on those process based mostly on research in the orient, go to


[1] Levine, Beth, Gkuido Kroemer, Jan 2007 Autophagy in the pathogenesis of disease

[2] Youle, Richard, Derek Narendra, Mar 2016 Mechanisms of mitophagy

[3]  Weiberg, Hilla, Elena Shvets, et al, May 2011, Biogenesis and cargo selectivity of autophagosomes

[4] Reggiori, Fulviio, Daniel Klionsky, Aug 2005, Autophagosomes :  biogenesis from scratch?

[5]  Levine, Beth, Gkuido Kroemer, Jan 2007 Autophagy in the pathogenesis of disease

[6] A better yardstick would be the LSPs.   Even the lower standard of the lean young on the western diet are rarely used as a yard stick.  Our lean compared to the LSPs do poorly.  A comparison of sports injuries now to 70 years ago is evidence that many of our athletes stack up poorly compared to a few generations ago.  Consider baseball pitchers, tennis  and basketball players.  

[7] In prokaryotic such as bacteria cells there are unbound (without membrane) organelles; they are primitive organelles.   

[8] Wikipedia, 4/19 lists 22 of them at https://en.wikipedia.org/wiki/Organelle

[9] Reggiori, Fulvio, Daniel Klionsky, Aug 2005, Autophagosomes:  biogenesis from scratch?

[10] Thus the fructation of those proteins is contributory to MTDD.  

[11] Weiberg, Hilla, Elena Shvets, et al, May 2011, Biogenesis and cargo selectivity of autophagosomes

[13] Mizushima, Noboru, Dec. 2007 Autophagy: process and function, http://genesdev.cshlp.org/content/21/22/2861.full

[14] Reggiori, Fulvio, Daniel Klionsky, Aug 2005, Autophagosomes :  biogenesis from scratch?

[15] A case study was published 7 years later, Stewart, W. Laura Fleming, March 1973, Features of a successful therapeutic fast of 382 days' duration

[16] This level is well below that which causes symptomatic hypoglycemia and death.  During extended fasting the liver adjusts to the lack of food by producing glucose, and other adjustments occur.  Medical supervised water fasting was used to reverse obesity prior to bariatric surgery.   Drenick, Ernst, Marion, Swendseid, et al Jan, 1964, Prolonged Starvation as Treatment for Severe Obesity  

[17] Singh, Rajat, Susmita Kaushik, et al April 2009, Autophagy regulates lipid metabolism.  The article refers to the catabolism of organelles that house lipid droplets.  During starvation selective the excess organelles and skin are reprocessed to provided needed amino acids. 

[18] See Jason Fung, The complete guide to fasting, P 2014-16, who relied upon the New York Time’s article mostly, which was based upon an article in Obesity, Fothergill, Erin, Juen Guo, et al, May 2016, Persistent metabolic adaptation 6 years after “The Biggest Loser” competition. 

[19] Chaperones are proteins that assist in the covalent folding or unfolding of proteins. Chaperones also assembly or disassemble macromolecular structures.  Many of the chaperones are design to undo the damage of heat and shock stress that causes unfolding of proteins.    All of these process are in an ATP dependent. 

[21] Singh, Rajat, Susmita Kaushik, et al April 2009, Autophagy regulates lipid metabolism

[22] Microbody are tiny organelle found in the cytoplasm that have catabolic functions; they serve mainly to breakdown large molecules, alcohols, and amino acids, and detoxify smaller molecules such as hydrogen peroxide,

[23]  Lash, A, A Saleem, Jan 1995, iron metabolism and its regulation, a review

[24] Scott, Cameron, Fabizio Vaca, July 2014, Endosome maturation, transport and functions

[25]  Yap, Chan, Bettina Winkler,  May 2012,  Harnessing the Power of the Endosome to Regulate Neural Development

[26] Nixon, Ralph, Anne Cataldo, et al, Oct 2000, The Endosomal-Lysosomal System of Neurons in Alzheimer's Disease Pathogenesis: A Review

[27] Lockshin, Richard, Zahra Zakeri, Dec 2004, Apoptosis, autophagy, and more

[28] Wiki, necroptosis April 2019

[29] Allavena, P., Mantovani, Feb 2012, Immunology in the clinic review series; focus on cancer; Tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment  http://healthfully.org/rcdm/id1.html

[30] Wang, Chong, Yachen Wang. Et al, April 2011, Autophagy process is associated with anti-neoplastic function

[31] Mizushima, Noboru, 2007 Cold Spring harbor, 2007. Autophagy: process and function

6.  Aspirin and cancer:  Aspirin which upregulate genes that turns up the apoptosis process has been shown to reduce with long-term daily usage (over 5 years) cancer risk by over 50%.  Those figures are imperfectly gathered since most studies don’t exclude  low dose aspirin which are ineffective because of tolerance. Test for aspirin resistance which even at over 1,300 mgs per day, about 1/8th are resistant to its down regulation of clotting effects, and thus possible to its promotion of apoptosis.  Nor do they control of enteric coating which has two negative effects, that of reduced absorption of 50% and the removal of the acetate group for aspirin, which has additional salubrious effects (just what I don’t know).  There are other bio-mechanisms by which aspirin reduces cancer risk.  For more on those process based mostly on research in the orient, go to http://healthfully.org/rc/id18.html.  Aspirin’s ability to prevent illnesses is why pharma and the FDA stress its potential to cause ulcers and Reyes condition,[1] and to promote other NSAIDs, all of which increase the risk for myocardial infarctions and strokes.  For this and more on aspirin go to http://healthfully.org/rc/id3.html.   As Goodman and Gilman pharmacology text book state “many clinicians favor the use of other NSAIDs perceived to have better gastrointestinal tolerability, even though this perception remains unproven by convincing clinical trials[2]  

Certain substances significantly turn up genes that promote the autophagic processes and thereby lower the risk for the progress to stage I for abnormal cells, and also the progression from stage I, II, & III into stage IV.  By stimulating autophagy there are an assortment of other health benefits.  My research as of 5/19 has found 4 such substance (progesterone, estradiol, testosterone, and salicyates) and there are likely more.  Aspirin (http://healthfully.org/rc/id18.html) and (rc/id3) and sex hormones estradiol (rc/id2)and testosterone (/rc/id7) reduces the incident of cancer and fatal cancers and have many other health benefits.  Sex hormones[3] and aspirin turn up the apoptosis-autophagic system[4] and thereby increase survival of those with local cancers (stages I, II, and III) but not stage IV for which the cancer is invisible to the immune cells and to apoptotic systems, and on a cellular level autophagy.  Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate induce autophagy by virtue of their capacity to inhibit the acetyltransferase activity of EP300.[5]  For the sex hormones a chapter has been devoted as its autophagic effects have been researched, as too with aspirin.  The mutation theory of cancer which promotes chemo sales for the various types of “essential mutations” has been questioned by a small group of researcher, and I find some of them with compelling evidence, such as Thomas Seyfried.  Thus pharma is against aspirin and sex hormones, as too its lap dogs the national regulatory agencies.  I have gone over the evidence on cancer including how tumors become invisible to the immune system; it is at http://healthfully.org/rl/id4.html   Having the wrong model explains the very limited progress made since under President Nixon under whose administration was started.  Need I say more about the role of pharma and the government dole?

Like all simple models on complex processes, there are exceptions. Indolent cancer, for example, some are able to enter adjacent tissues because they are not marked as foreign by the surface proteins, or because they have been able to obtain a degree of invisibility to the immune system, but not total invisibility comparable to the macrophage.   Leukemia and lymphomas are a much different type of cancer.  It is autophagy which makes cancer rare among LSPs and wild vertebrates.

 

7. AMPK (5-AMP-actived protein kinase, 5’ adenosine monophosphate-activated protein kinase)

https://idmprogram.com/wp-content/uploads/AutophagyNEJM2.jpgSome of the systems modulating the autophagic processes

 

AMPK is an enzyme is an energy sensing protein that plays a role in cellular-energy homeostasis mainly through the uptake of glucose and fatty acids and their oxidation as needed.  As an energy sensor it functions to turn on autophagy, and is inhibited by mTOR.[6]  Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK” supra.   AMPK activation stimulates hepatic and myocyte fatty acid oxidation (ketogenesis), inhibition of cholesterol synthesis, lipogenesis, and promotes FFA conversion to triglycerides, as well as inhibition of adipocyte lipogenesis and activation of adipocyte lipolysis.  “Due to isoforms, there are 12 versions of AMPK in mammals, each of which have different tissue localizations and different functions under different conditions. . ..  AMPK is inhibited by insulin, leptin, and diacylglycerol. AMPK may be inhibited or activated by various tissue-specific ubiquitinations.” [7]   AMPK is highly conserved in eukaryotic protein family and its orthologues in yeast and plants.  AMPK can be induced by caloric restriction, exercise, and ketogenic diet.  AMPK functions as a switch.  m-TOR through insulin, leptin and diacylglycerol turn off the switch for autophagy.[8]  One of the central regulators of cellular and organismal metabolism in eukaryotes is AMP-activated protein kinase (AMPK), which is activated when intracellular ATP production decreases. AMPK has critical roles in regulating growth and reprogramming metabolism, and has recently been connected to cellular processes such as autophagy and cell polarity.” [9] And there are other mechanism regulating the functions of AMPK, such as the inhibition of protein synthesis.

 

8,  Switches, AMPK, mTOR, & insulin  Like any switch for turning on a key process, there are feedback mechanism and switches for turning down and off the system, and mTOR is off switch.  “Nutrient starvation induces autophagy in eukaryotic cells through inhibition of TOR (target of rapamycin), an evolutionarilyconserved protein kinase.  TOR, as a central regulator of cell growth, plays a key role at the interface of the pathways that coordinately regulate the balance between cell growth and autophagy in response to nutritional status, growth factor and stress signals.” [10] “Taken together, these results suggest that AMPK association with ULK1 plays an important role in autophagy induction, at least in part, by phosphorylation of raptor to lift the inhibitory effect of mTOR on the ULK1 autophagic complex.” [11]  That is the simple answer, as the diagrams below show, it is much, much more complex.  And witch switch or combination should be thrown and how much because “due to isoforms, there are 12 versions of AMPK in mammals.” [12]  And there are the isoforms for mTOR, how much of them?  It’s time to back away from mTOR and AMPK, and retain that as a team they and their isoforms are essential for heath, which is why autophagy is the last of the B-4, and first for health.  Though last it contribution to CAWD might be first.   

 

 

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Metabolic functions of AMPK. A schematic summarizing the mechanisms underlying AMPK-induced regulation of diverse metabolic pathways. Arrow indicates activation, and bar-headed line indicates inhibition (see text for details).[13]

 

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Physiological regulation of AMPK. A schematic summarizing the mechanisms underlying the regulation of AMPK activity under diverse physiological and pathological conditions. Arrow indicates activation, and bar-headed line indicates inhibition (see text for details).[14]

 

9.  DRUG FIXES?  The role of m-TOR, AMPK, and autophagy are highly regulated so as to promote survival, and we are decades away from producing road maps of the various switches and routes.   Above are cutting edge 2016 road maps.  Many studies have demonstrated that AMPK is inhibited in many pathological conditions, such as inflammation, diabetes, aging and cancer, and that activation of AMPK can be beneficial to treat such diseases.” [15]  However, merely turning on AMPK with a drug can have, given the complexity of functions, will likely have dire consequences, much like that of statins which down regulate the mevalonate pathway—especially among the elderly who have MTDD.  Drugs that intervene in autophagy given the complexity are likely a net negative, though some natural supplement are of value such as the salicylates.  With are current ownership of data and the failure to open major data banks kept by government health insurance and insurance companies, the long-term and short term harm is consistently grossly under estimated, unless the industry is doing a hatchet job.  

The body has evolved mechanism for stress.  We have recently shown that autophagy is induced by ischemia and reperfusion in the mouse heart in vivo. Ischemia stimulates autophagy through an AMP activated protein kinase (AMPK)-dependent mechanism, whereas reperfusion after ischemia stimulates autophagy through a Beclin 1-dependent, but AMPK-independent, mechanism.” [16] This and much more confirm Oliver Wendell Holmes: “Drugs are what you take while you wait for your body to heal.”  Though autophagy is the last of the B-4, given its role in healing, its down-regulation a result of our western diet places autophagy first in promoting CAWD. 

 

10.  Autophagy immune & clearing functions;

https://idmprogram.com/wp-content/uploads/AutophagyNEJM.png

         

Given autophagy’s ability to dismantle, nature has utilized autophagy as a mechanism for capturing and dismantling foreign bodies and accumulated substances.  Autophagy, as the above illustration shows is much more than a cellular repair-replacement system.   

Fill-out with examples  

 

 



[1] The evidence for Reyes condition in children is another example of a hatchet job, a way to reduce the usage of aspirin in future generations.  Using a lab test instead of symptoms its frequency went from about 500 cases per year to 2.  That part of the article in Wikipedia on aspirin has long since been replaced.  For much more on aspirin, go to rc/id3. I have been taking one a day since 1992 on an empty stomach and since 2008 uncoated aspirin, since the coated form is only half absorb with peak serum level at 8 hours. 

[2] Goodman & Gilman’s The Pharmacological Basis of Therapeutics 11th Edition, p. 690. And at 690, “It is the standard against which all rheumatoid arthritis medication should be measured

[3] The evidence for the benefit of sex hormones reducing the rate of stage 1-III becoming a stage IV is far less researched as too the progression of precancerous tumor progressing to cancer.   But worth mentioning, since pharma makes billions suppressing these hormones for breast, ovarian, uterine, cervical and prostate cancers--another marketing myth supported by marketing science.  The complexity of this topic would take chapters to develop.  The links to testosterone and estradiol have sufficient evidence to support the obvious:  that nature is promoting survival for species in the reproductive years—not the opposite implied by pharma.  The evidence for aspirin preventing cancer and metastatic cancer is of the highest level. 

[4] Din, Farhat, Asta Valanciute, et al, June 2012, Aspirin Inhibits mTOR Signaling, Activates AMP-Activated Protein Kinase, and Induces Autophagy in Colorectal Cancer Cells

[5] Pietrocola, Frederico, Francesca Castoldi, et al, Feb 2018, Aspirin Recapitulates Features of Caloric Restriction

[6] Kim, Joungmok, Mondira Kundu, et al Jan 2011, AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1

[7] Wiki April 2019 https://en.wikipedia.org/wiki/AMP-activated_protein_kinase Again I must grumble about how KOLs stonewall subjects, in this case the failure of Wiki to have in its autophagy reference in the AMPK, and only one line on AMPK in its autophagy article.  Not surprising, I almost missed its importance, because they frame autophagy because it gives a much different explanation of pathologies. Business should be barred from science expect for to fund at arms-length research.  I finally took notice of AMPK when watching a lecture on Autophagy which stated that AMPK is a switch for turning on autophagy and which is turned on by fasting, and turned off by leptin and insulin.  All 3 are missing in the autophagy article; they don’t promote drug sales.     

[8] To repeat myself over KOLs, “I finally took notice of AMPK when watching a lecture on Autophagy which stated that AMPK is a switch for turning on autophagy and which is turned on by fasting, and turned off by leptin and insulin.  All 3 are missing in the autophagy article; they don’t promote drug sales.”  We have gone into a medical dark ages.  I had been puzzling in Jan of 2018 over the role of mTOR, but failed to understand it because I didn’t have the other piece of AMPK.   This rant is over the time I spent sorting out what should have been clearly presented, and thoroughly researched.      

[9]  Mihaylova, Maria, Reuben Shaw, Sept. 2011, The AMPK signalling pathway coordinates cell growth, autophagy and metabolism

[10] Jung, Chang, Seung-Hyun Ro et al Jan 2010, mTOR regulation of autophagy  seminal article, full

[11] Woo-Lee, Jong, Sungman Park et all, Nov 2010. The Association of AMPK with ULK1 Regulates Autophagy

[13] Jeon, San-Min, July 2016, Regulation and function of AMPK in physiology and disease

[14] Jeon, San-Min, July 2016, Regulation and function of AMPK in physiology and disease 

[15] Jeon, San-Min, July 2016, Regulation and function of AMPK in physiology and disease

[16] Takagi, Hiromitsu, Yutaka Matsui, et al, April 2007, AMPK Mediates Autophagy during Myocardial Ischemia in Vivo.  It is held that autophagy hinders reperfusion following an MI, but is protective during ischemia.

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On how daily excessive fructose damages the mitochondria and thus is the main cause for the conditions associated with the Western diet--much, much, more than insulin resistance, type-2 diabetes, and weight gain