Parkinson’s Disease: Improve Cell “Garbage Disposal”

Main Points: Use “Autophagy” to combat Parkinson’s:

Warning—Only begin the autophagy protocol after your health professional says you have repleted any depleted vitamins, minerals, etc.

  • Use caloric restriction twice a week to stimulate AUTOPHAGY

For the “Autophagy” protocol for Parkinson’s Disease, take your Sirt 1 activator (resveratrol), Nrf2 activator, and AMPK activators (see below) while you are on low calories—Fasting or after a very low calorie dinner so that these have time to work while you are sleeping.

  • AMPK stimulation such as exercise, ALCAR, or resveratrol (see list of “Turn on AMPK” under top menu)
  • Take a Sirt1 activator such as resveratrol
  • Take some of the listed agents (under top menu) that promote the Nrf2 pathway. Autophagy is a key step in activating the Nrf2 pathway. And Nrf2 expression can in turn regulate autophagy. (see list of “Turn on Nrf2” under top menu).
  • Hypoxia also activates autophagy via a HIF-1a pathway. This would occur with exercise if you reached your anaerobic threshold during exercise or did IHT exercise (intermittent hypoxia with exercise). See “healthy hypoxia exercises to increase HIF-1a pathway.”
  • Sunlight & Vitamin D activate autophagy – there are three ways through which UV light and Vitamin D activate autophagy via inhibiting the insulin/IGF-1 pathway
  • Caffeine activates autophagy – Caffeine can activate autophagy via an mTOR-dependent mechanism
  • Green tea activates asutophagy – ECGC can activate autophagy via an mTOR-dependent mechanism
  • Metformin activates autophagy – metformin can activate autophagy via AMPK activation – mTOR-dependent and mTOR-independent mechanisms.  Autophagy may explain as much as 50% of the benefits (mechanism of action) of Metformin. 
  • Lithium activates autophagy – lithium and other compounds can activate autophagy by inhibiting inositol monophosphate and lower IP3 levels – an mTOR-independent mechanism. Take Lithium Orotate 10 mg twice a day.

***You are on your way to promoting a very important step in stopping/reversing Parkinson’s Disease

Credit to:

Autophagy – the housekeeper in every cell that fights aging

Autophagy for Parkinson’s Disease: Stimulation & Pathways:

Experts: James P Watson and Vince Giuliano

There is a common denominator to most of the “longevity” interventions – “autophagy.”  Autophagy (“self eating”) is an old, evolutionarily conserved stress response that is present in all living cells. Like apoptosis, autophagy is a programmed response and has several sub-pathways.  Unlike apoptosis, autophagy promotes life rather than death.  Recent discoveries have shown that almost every genetic, dietary, and pharmacologic manipulation proven to extend lifespan activates autophagy as part of its mechanism of action.

 

Autophagy is the way your cells “clean house” and “recycle the trash”.  Along with the ubiquitin proteasome system, autophagy is one of the main methods that cells use to clear dysfunctional or misfolded proteins.  Autophagy can clear any kind of trash: intracellular viruses, bacteria, damaged proteins, protein aggregates and subcellular organelles.

“Autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell’s own components through the lysosomal machinery. It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more-essential processes.

There are three main pathways of Autophagy – Macroautophagy, Microautophagy, and Chaperone-mediated Autophagy (CMA).

Macroautophagy is the primary “broom” that sweeps the house. Macroautophagy is initiated when the material to be removed is tagged with ubiquitin.  This signals a complex series of molecular events that leads to the formation of a membrane around the material to be removed and recycled.  This membrane formation around the debris is called a autophagosome.  Once formed, the autophagocome fuses with a lysosome to form an autolysosome.  Once fusion occurs, the acid hydrolases found inside the lysosomes start digesting the damaged proteins and organelles.  When damaged mitochondria are digested by macroautophagy, it is called mitophagy, which is a specific type of macroautophagy.

Chaperone-mediated autophagy (CMA) is a specific mechanism of autophagy that requires protein unfolding by chaperones.   The other two mechanisms do not require protein unfolding (macroautophagy and microautophagy).  Since protein aggregates cannot be unfolded by chaperone proteins, both the ubiquitin-proteasome system and chaperone-mediated autophagy are unable to clear these protein aggregates.  For this reason, macroautophagy may be the most important pathway for preventing Alzheimer’s disease, Parkinson’s disease, Fronto-temporal dementia, and all of the other neurodegenerative diseases associated with protein aggregate accumulation.

Autophagy is the best way to get rid of bad mitochondria without killing the cell.  The process is called “mitophagy.” Since bad mitochondria produce most of the megadoses of free radicals (ROS,” this is really, really, important. The bad mitochondria are ubiquinated by the E3 ligase Parkin.  The ubiquinated bad mitochondria are then selectively destroyed by mitophagy, which is a form of macroautophagy.

Autophagy is the best way to get rid of protein aggregates like those associated with all of the neurodegenerative diseases, like amyloid beta, tau tangles, alpha synuclein aggregates, TDP-43 aggregates, SOD aggregates, and Huntington protein aggregates.  These aggregates are NOT digested via the ubiquitin-proteasome system, since they cannot be “unfolded”. For this reason, autophagy is probably the most important cellular mechanism for clearing protein aggregates found in neurodegenerative diseases.

Diminished autophagic activity may play a pivotal role in the aging process. Cellular aging is characterized by a progressive accumulation of non-functional cellular components owing to oxidative damage and a decline in turnover rate and housekeeping mechanisms. Lysosomes are key organelles in the aging process due to their involvement in both macroautophagy and other housekeeping mechanisms. Autophagosomes themselves have limited degrading capacity and rely on fusion with lysosomes.

The auto florescent protein lipofuscin is the oldest and simplest biomarker of declining autophagy and represents undigested material inside of cells.  The Lewy bodies seen in several neurodegenerative diseases (including “Parkinson’s disease with dementia”) are also biomarkers of declining autophagy and may specifically be due to “declining mitophagy”.

Declining autophagy is particularly important in post-mitotic cells such as those in the brain, heart, and skeletal muscle where very little cell regeneration via stem cells occurs.

With aging, there is a decline in energy production by the cells.  This may be one of the reasons for the decline in autophagy seen in aging.

(a) The accumulation of autophagic vacuoles with age could result from the inability of lipofuscin- loaded lysosomes to fuse with autophagic vacuoles and degrade the sequestered content.

(b) In addition, the formation of autophagosomes in old cells might be reduced because of the inability of macroautophagy enhancers (such as glucagon) to induce full activation of this pathway. The stimulatory effect of glucagon is compromised in old cells because of maintained negative signaling through the insulin receptor (IR)–Maintained insulin signaling would activate mTOR, a known repressor of macroautophagy.

 

(c) Inadequate turnover of organelles, such as mitochondria, in aging cells could increase levels of free radicals that generate protein damage and

 

(d) Aging could also potentiate the inhibitory signaling through the insulin receptor.

 

(e) An age-dependent decline in macroautophagy can also result in energetic compromise of the aging cells.

 

If you look at the mechanisms of caloric restriction, it appears that 1/2 of the benefits of caloric restriction are due to stimulating autophagy.  Caloric restriction down regulates all of the”nutrient sensing pathways that are negative regulators of autophagy” and up regulates other “ nutrient sensing pathways that are positive regulators of autophagy”.  The following interconnected “nutrient -sensing pathways” affect macroautophagy:

  1. IGF-1: two mechanisms:
  2. mTOR: three mechanisms account for the activation of autophagy by mTOR inhibition

“The (mammalian) target of rapamycin (mTOR) is a primordial negative regulator. mTOR is inhibited under starvation conditions, and this contributes to starvation-induced autophagy via activation of mTOR targets. This inhibition can be mimicked by mTOR inhibitory drugs like rapamycin (Ravikumar et al., 2010).  One of the important pathways regulating mTOR is initiated when growth factors like insulin-like growth factor bind to insulin-like growth factor receptors (IGF1R)

Sirtuin 1:  CR activates Sirtuin 1 => deacetylation of several autophagy gene products.   Sirt1 also activates AMPK, activates FOXO3a, and inhibits mTOR via TSC-1/2

AMPK: AMPK pathway (aka LKB1-AMPK) activates autophagy via two methods:

 

  1. AMPK activation => phosphorylates TSC2 and raptor => inhibits TORC1 (this requires glucose starvation).

 

  1. AMPK activation => direct phosphorylation of Atg1 (aka ULK1) => autophagy activation (this does NOT require glucose starvation).

 

  1. Less-important pathways:

 

JNK: JNK pathway – This is a MAPK that mediates starvation-induced autophagy.

Calorie Restriction works through these main pathways:

So you can see that if you are on an “Autophagy” protocol for Parkinson’s Disease, you want to take your Sirt 1 activator (resveratrol) and/or AMPK activators while you are on low calories—Fasting or after a very low calorie dinner so that these have time to work while you are sleeping.

 

  1. There are many other pathways that regulate autophagy that are not dependent on “nutrient sensing pathways.”

Although caloric restriction or fasting are clearly the most “potent” autophagy stimulators, since they can activate macroautophagy via the above “nutrient sensing pathways“, there are many other pathways that can activate autophagy.

 

JNK – JNK is a MAPK that is activated by heat shock, osmotic shock, UV light, cytokines, starvation, T-cell receptor activation, neuronal excitotoxic stimulation, and ER stress.

PKC – Protein Kinase C (PKC) is a family of kinases that were once thought to be associated mostly with apoptosis/anti-apototis.  Recent research has shown that PKCs also play a role in autophagy.  The effects of PKC depend on if the cellular stress is acute or chronic.  For instance, PKCg is an example of one of the PKCs where it stimulates autophagy with acute, short periods of hypoxia (via JNK activation) but suppresses autophagy with chronic hypoxia (via Caspace-3).   Another PKC, PKC0  is involved with ER-stress induced autophagy.  Acadesine (AICAR) induces autophagy via a PKC/Raf1/JNK pathway.  Acadesine (AICAR) in combination with GW1516 has shown to improve endurance-type exercise by converting fast-twitch muscle fibers into the more energy-efficient, fat-burning, slow-twitch muscle fibers.  These two compounds turned on 40% of the genes that were turned on when exercise + GW1516 were used together.  For this reason, acadesine (AICAR) has been termed an “exercise mimetic” and has been banned for use by athletes, since it is a performance enhancing drug, even though it is very safe.  The mechanism of action of AICAR may be in part its induction of autophagy.

Endoplasmic Reticulum Stress Kinases (i.e. the ER unfolded protein response) – Several kinases involved with the endoplasmic reticulum unfolded protein response (ER-UPR) have been found to activate autophagy. The most important is CaMKKbeta – ER stress results in calcium release from the ER.  This Ca++ release induces autophagy via the Ca dependent kinases.  The main one is called Ca/Calmodulin-dependent kinase beta (CaMKKbeta).  This is an “upstream activator” of AMPK, which in turn inhibits mTOR.  This is how calcium can induce autophagy.

 

Excess baseline ROS from bad mitochondria induces Mitophagy.

This may be the mitochondrial signal for “selective destruction” of damaged mitochondria.  Exogenous ROS can also induce autophagy, however.  For instance, there is evidence that abnormal levels of H202 in the cytoplasm will induce macroautophagy.

 

About James Watson

I am a physician with a keen interest in the molecular biology of aging. I have specific interests in the theories of antagonistic pleiotropy and hormesis as frameworks to understand cellular senescence and mechanisms for coping with cellular stress. The hormetic “stressors” that I am interested in exploiting at low doses include exercise, hypoxia, intermittent caloric restriction, radiation, etc. I also have a very strong interest in the epigenetic theory of aging and pharmacologic/dietary maintenance of histone acetylation and DNA methylation with age. I also am working on pharmacologic methods to destroy senescent cells and to reactivate quiescent endogenous stem cells. In cases where there is a “stem cell exhaustion” in the specific niche, I am very interested in stem cell therapy (Ex: OA)

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I hope autophagy is of great benifit for healthy aging and increased lifespan. I know my glucose, lipid, and IGF-1 seem to have responded favorably to years of Intermittent fasting and a recent change to an even more ketogenic diet.

I track my blood ketones and they stay in a ketogenic range 0.5 to 5 mm. Mine are usually 2 to 4 mm.

Kolaviron, a natural flavonoid from the seeds of Garcinia kola looks like it protects against lipopolysaccharide (LPS)-induced inflammatory gene expression in macrophage cell lines:

http://www.ncbi.nlm.nih.gov/pubmed/24650887

 

If I understand this correctly; Kolaviron protects Macrophages from inflammation caused by gram negative bacteria. This seems to be a good thing as there is evidence that Garcinia kola is effective against a good number of pathogens and also Malaria.

http://www.ncbi.nlm.nih.gov/pubmed/?term=Garcinia+kola

 

If the above is correct; perhaps these genetic changes in macrophages could lead to autoimmune issues and Garcinia kola may be VERY interesting!?

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