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Supps to enhance autophagy and macrophagy

macrophage autophagy

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#31 ClarkSims

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Posted 18 August 2015 - 12:41 AM

Would like to see more research on allantoin in this regard, since it seems to operate like metformin
http://www.sigmaaldr...papers/22147657

Allantoin activates AMPK in similar manner to metformin
http://bvsalud.org/p...pt/mdl-22147657

and improves memory
http://www.ncbi.nlm....pubmed/24296131

 

This is great information,

Thanks

Clark



#32 geo12the

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Posted 18 August 2015 - 04:55 PM

I have been looking for trehalose in humans studies. This one should be done in September of this year. I look forward to seeing the results: https://clinicaltria...how/NCT01575288

 

This one says yyou can take high doses via an IV with no ill effects.

http://www.neurology...pplement/P7.068

 

Here are two ideas for increasing bioavailability of oral trehalose:

mix it with dmso and water. The DMSO should take the solution through the stomach walls. Then the liver will get a chance to digest it into sucrose, but at least the intestines are skipped.

 

Mix some polar and oil soluble solvent in olive oil, then add trehalose. For example, MSM or DMSO should do the trick. Then add in the trehalose. The olive oil will be taken into the lymph system, thus bypassing both the liver and trehalase in the small intestine.

 

One could also take a trehalase inhibitor, with the trehalose. Or perhaps package them together in a liposome.  One such drug is triamcinolone. I can't find any research on this, other than as an insecticide for locust. In humans it is used as a nasal decongestant. It can't be too toxic, since it is used in paediatrics.

 

There have been some mouse studies that suggest that if ingested orally a small percentage (I forget how much, maybe 1%) of trehalose will remain intact and make it into the bloodstream. It could be that a small amount in the bloodstream is all you need for the beneficial effects (enhanced autophagy and helping solubilize missfolded proteins). I use it as a sugar substitute. Only drawbacks are that its expensive, half as sweet as sucrose so you have to use more, is less soluble than other sugars and doesn't have the same properties as sucrose when used in cooking so you need to tinker around a bit if using it in a recipe.  



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#33 stefan_001

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Posted 18 August 2015 - 08:22 PM

Hello,

Perhaps a silly question but how would one know if it is beneficial to try to increase macrophage, autophagy? Are you simply assuming that it must be too low in any person growing older?
Stefan



#34 geo12the

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Posted 18 August 2015 - 09:55 PM

Hello,

Perhaps a silly question but how would one know if it is beneficial to try to increase macrophage, autophagy? Are you simply assuming that it must be too low in any person growing older?
Stefan

 

Autophagy linked to aging:

 

Cell. 2011 Sep 2;146(5):682-95. doi: 10.1016/j.cell.2011.07.030.
Autophagy and aging.
Abstract

Genetic inhibition of autophagy induces degenerative changes in mammalian tissues that resemble those associated with aging, and normal and pathological aging are often associated with a reduced autophagic potential. Pharmacological or genetic manipulations that increase life span in model organisms often stimulate autophagy, and its inhibition compromises the longevity-promoting effects of caloric restriction, Sirtuin 1 activation, inhibition of insulin/insulin growth factor signaling, or the administration of rapamycin, resveratrol, or spermidine. Here, we discuss the probable cause and effect relationship between perturbed autophagy and aging, as well as possible molecular mechanisms that may mediate the anti-agingeffects of autophagy.

 

Clin Calcium. 2013 Jan;23(1):39-44. doi: CliCa13013944.
[Aging and autophagy].
[Article in Japanese]
Abstract

Autophagy, a major intracellular degradation system which is conserved from yeast to mammals, is essential for the cellular clearance and the maintenance of homeostasis inside the cell. The autophagic activity is reported to decrease in almost all cells and tissues following aging, and genetic inhibition of autophagy in mice leads to degenerative changes and diseases that are highly associated with aging. On the other hand, various intervention strategies that delay senescence or increase life span in model organisms often stimulate autophagy, and autophagy inhibition compromises these anti-aging effects. Here, we review recent evidences in support of tight connections between autophagy and aging.

 

J Clin Invest. 2015 Jan;125(1):85-93. doi: 10.1172/JCI73946. Epub 2015 Jan 2.
Essential role for autophagy in life span extension.
Abstract

Life and health span can be prolonged by calorie limitation or by pharmacologic agents that mimic the effects of caloric restriction. Both starvation and the genetic inactivation of nutrient signaling converge on the induction of autophagy, a cytoplasmic recycling process that counteracts the age-associated accumulation of damaged organelles and proteins as it improves the metabolic fitness of cells. Here we review experimental findings indicating that inhibition of the major nutrient and growth-related signaling pathways as well as the upregulation of anti-aging pathways mediate life span extension via the induction of autophagy. Furthermore, we discuss mounting evidence suggesting that autophagy is not only necessary but, at least in some cases, also sufficient for increasing longevity.

     


#35 Darryl

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Posted 18 August 2015 - 10:22 PM

The notes I kept on this from two years ago. I was particularly intrigued by rilmenidine, a centrally acting antihypertensive (ie, crosses the blood brain barrier) with few side effects.

 

Autophagy inducers
• 1,25-dihydroxyvitamin D3 - via (CaMKK)-b, AMPK, cathelicidin activated transcription of Beclin-1 and Atg5
• spermidine: soybeans, green peas, pear, lentil soup, mushroom, red beans, broccoli, cauliflower
• soy saponins
• resveratrol: postulated to affect expression of ATG genes
• Rx: rilmenidine
• AMPK induction
     • caloric restriction, fasting
     • exercise
     • salicylate: Rx – salsalate, magnesium salicylate, aspirin
     • α-lipoic acid (but not in hypothalamus)
     • berberine
     • Rx: metformin
     • Rx: telmisartan
     • Also: caffeic acid, resveratrol, anthocyanins, genestein, capsaicin, curcumin, CAPE, EGCG, garlic oil, hispidulin (Snow Lotus). glabridin (from deglycyrrhizinated licorice), gelegine (goats rue)

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#36 Phoenicis

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Posted 19 August 2015 - 07:55 AM

 

• Rx: rilmenidine

That's an interesting one, I think I read it actually inhibits cAMP to induce autophagy and I suspect Clonidine might work like that too. Any thoughts on the latter, it seems to have a wide variety of applications?

 

Reminds me of this study:

One thing about metformin; as opposed to resveratrol and rapamycin, it does not enhance stem cell regeration:

I'd like to add pterostilbene:

 


Edited by Phoenicis, 19 August 2015 - 08:09 AM.

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#37 Skyguy2005

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Posted 20 August 2015 - 02:30 AM

Ginkgo Biloba. I am surprised how little this gets mentioned. It has enhanced Autophagy in various studies, and even enhanced mutant Huntingtin clearance by a non-autophagy mechanism.

 

Ginkgo Biloba contains Ginkgolic acid. Ginkgolic acid induces autophagy in cancer cells. Ginkgolic acid also inhibits EP300, which has been implicated as an autophagy repressor. Ginkgo Biloba also is extreeeemely long lived, as well as evolutionarily closer to humans than most long lived plants (it even has sperm, in the males, and eggs in the girls).



#38 Gerrans

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Posted 24 August 2015 - 06:01 PM

Stimulatory effect of Eucalyptus essential oil on innate cell-mediated immune response

Annalucia Serafino et al  BMC Immunology 2008

 

http://www.biomedcen.../1471-2172/9/17

 

Here we investigated whether EO extract is able to affect the phagocytic ability of human monocyte derived macrophages (MDMs) in vitro and of rat peripheral blood monocytes/granulocytes in vivo in absence or in presence of immuno-suppression induced by the chemotherapeutic agent 5-fluorouracil (5-FU).

 

Results

 

EO is able to induce activation of MDMs, dramatically stimulating their phagocytic response. EO-stimulated internalization is coupled to low release of pro-inflammatory cytokines and requires integrity of the microtubule network, suggesting that EO may act by means of complement receptor-mediated phagocytosis. Implementation of innate cell-mediated immune response was also observed in vivo after EO administration, mainly involving the peripheral blood monocytes/granulocytes. The 5-FU/EO combined treatment inhibited the 5-FU induced myelotoxicity and raised the phagocytic activity of the granulocytic/monocytic system, significantly decreased by the chemotherapic.

 

 

 

 


Edited by Gerrans, 24 August 2015 - 06:01 PM.

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#39 geo12the

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Posted 28 August 2015 - 04:42 PM

Regarding Trehalose, there are Trehalose eye drops available (a treatment for dry eyes). I wonder if using the drops would be an effective way to get some trehalose into your bloodstream. 



#40 normalizing

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Posted 29 August 2015 - 07:49 AM

how is trehalose good for dry eyes? wow people will come up with all kinds of bullshit for everything out there proven or non proven, none shit given


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#41 Turnbuckle

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Posted 29 August 2015 - 01:33 PM

how is trehalose good for dry eyes? wow people will come up with all kinds of bullshit for everything out there proven or non proven, none shit given

 

Next time, rather than just calling bullshit, try looking on Pubmed--

 

 

http://www.ncbi.nlm....pubmed/25926736


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#42 theobroma

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Posted 31 August 2015 - 05:42 AM

Olive polyphenols (best source olive leaf extract):

 

PLoS One. 2013 Aug 8;8(8):e71702. doi: 10.1371/journal.pone.0071702. eCollection 2013.

The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology.

Abstract

The claimed beneficial effects of the Mediterranean diet include prevention of several age-related dysfunctions including neurodegenerative diseases and Alzheimer-like pathology. These effects have been related to the protection against cognitive decline associated with aging and disease by a number of polyphenols found in red wine and extra virgin olive oil. The double transgenic TgCRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein), aged 1.5 and 4, and age-matched wild type control mice were used to examine in vivo the effects of 8 weeks dietary supplementation of oleuropein aglycone (50 mg/kg of diet), the main polyphenol found in extra virgin olive oil. We report here that dietary supplementation of oleuropein aglycone strongly improves the cognitive performance of young/middle-aged TgCRND8 mice, a model of amyloid-ß deposition, respect to age-matched littermates with un-supplemented diet. Immunofluorescence analysis of cerebral tissue in oleuropein aglycone-fed transgenic mice showed remarkably reduced ß-amyloid levels and plaque deposits, which appeared less compact and "fluffy"; moreover, microglia migration to the plaques for phagocytosis and a remarkable reduction of the astrocyte reaction were evident. Finally, oleuropein aglycone-fed mice brain displayed an astonishingly intense autophagic reaction, as shown by the increase of autophagic markers expression and of lysosomal activity. Data obtained with cultured cells confirmed the latter evidence, suggesting mTOR regulation by oleuropein aglycone. Our results support, and provide mechanistic insights into, the beneficial effects against Alzheimer-associated neurodegeneration of a polyphenol enriched in the extra virgin olive oil, a major component of the Mediterranean diet.

 

 

Also have mTOR and AMPK effects, so I'm surprised olive leaf extract doesn't garner more attention (or high quality extra virgin olive oil), e.g.:

 

 

Cell Cycle. 2013 Feb 15;12(4):555-78. doi: 10.4161/cc.23756. Epub 2013 Jan 31.

Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil: a new family of gerosuppressant agents.
Abstract

Aging can be viewed as a quasi-programmed phenomenon driven by the overactivation of the nutrient-sensing mTOR gerogene. mTOR-driven aging can be triggered or accelerated by a decline or loss of responsiveness to activation of the energy-sensing protein AMPK, a critical gerosuppressor of mTOR. The occurrence of age-related diseases, therefore, reflects the synergistic interaction between our evolutionary path to sedentarism, which chronically increases a number of mTOR activating gero-promoters (e.g., food, growth factors, cytokines and insulin) and the "defective design" of central metabolic integrators such as mTOR and AMPK. Our laboratories at the Bioactive Food Component Platform in Spain have initiated a systematic approach to molecularly elucidate and clinically explore whether the "xenohormesis hypothesis," which states that stress-induced synthesis of plant polyphenols and many other phytochemicals provides an environmental chemical signature that upregulates stress-resistance pathways in plant consumers, can be explained in terms of the reactivity of the AMPK/mTOR-axis to so-called xenohormetins. Here, we explore the AMPK/mTOR-xenohormetic nature of complex polyphenols naturally present in extra virgin olive oil (EVOO), a pivotal component of the Mediterranean style diet that has been repeatedly associated with a reduction in age-related morbid conditions and longer life expectancy. Using crude EVOO phenolic extracts highly enriched in the secoiridoids oleuropein aglycon and decarboxymethyl oleuropein aglycon, we show for the first time that (1) the anticancer activity of EVOO secoiridoids is related to the activation of anti-aging/cellular stress-like gene signatures, including endoplasmic reticulum (ER) stress and the unfolded protein response, spermidine and polyamine metabolism, sirtuin-1 (SIRT1) and NRF2 signaling; (2) EVOO secoiridoids activate AMPK and suppress crucial genes involved in the Warburg effect and the self-renewal capacity of "immortal" cancer stem cells; (3) EVOO secoiridoids prevent age-related changes in the cell size, morphological heterogeneity, arrayed cell arrangement and senescence-associated β-galactosidase staining of normal diploid human fibroblasts at the end of their proliferative lifespans. EVOO secoiridoids, which provide an effective defense against plant attack by herbivores and pathogens, are bona fide xenohormetins that are able to activate the gerosuppressor AMPK and trigger numerous resveratrol-like anti-aging transcriptomic signatures. As such, EVOO secoiridoids constitute a new family of plant-produced gerosuppressant agents that molecularly "repair" the aimless (and harmful) AMPK/mTOR-driven quasi-program that leads to aging and aging-related diseases, including cancer.

 


Edited by theobroma, 31 August 2015 - 05:43 AM.


#43 geo12the

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Posted 31 August 2015 - 04:56 PM

Trehalose has been shown to help dry eye in lots of published studies. An older review paper:

 

Clin Ophthalmol. 2011;5:577-81. doi: 10.2147/OPTH.S18827. Epub 2011 May 10.
Trehalose: an intriguing disaccharide with potential for medical application in ophthalmology.
Abstract

Trehalose is a naturally occurring disaccharide comprised of two molecules of glucose. The sugar is widespread in many species of plants and animals, where its function appears to be to protect cells against desiccation, but is not found in mammals. Trehalose has the ability to protect cellular membranes and labile proteins against damage and denaturation as a result of desiccation and oxidative stress. Trehalose appears to be the most effective sugar for protection against desiccation. Although the exact mechanism by which trehalose protects labile macromolecules and lipid membranes is unknown, credible hypotheses do exist. As well as being used in large quantities in the food industry, trehalose is used in the biopharmaceutical preservation of labile protein drugs and in the cryopreservation of human cells. Trehalose is under investigation for a number of medical applications, including the treatment of Huntington's chorea and Alzheimer's disease. Recent studies have shown that trehalose can also prevent damage to mammalian eyes caused by desiccation and oxidative insult. These unique properties of trehalose have thus prompted its investigation as a component in treatment for dry eye syndrome. This interesting and unique disaccharide appears to have properties which may be exploited in ophthalmology and other disease states.

 



#44 Logic

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Posted 10 September 2015 - 05:30 PM

Gc macrophage activating factor (Gc-MAF)

http://www.longecity...r-magic-bullet/



#45 ClarkSims

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Posted 14 September 2015 - 09:47 AM

Gc macrophage activating factor (Gc-MAF)

http://www.longecity...r-magic-bullet/

 

gc-maf looks very promising. Thanks


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#46 albedo

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Posted 19 September 2015 - 11:16 PM

Would you agree that also ibuprofen could be considered, next to aspirin and the other substances mentioned in this thread, as an inducer of autophagy? By the same activation of AMPK? E.g. see:

 

COX-Independent Mechanisms of Cancer Chemoprevention by Anti-Inflammatory Drugs

“..Taken together, these studies provide a strong case that mechanisms independent of COX-1 and/or COX-2 inhibition fully or partially contribute to the chemopreventive activity of traditional NSAIDs and selective COX-2 inhibitors. The anticancer effects of this class of compounds have been proposed to consist of multiple cellular mechanisms, which include induction of apoptosis, inhibition of proliferation and angiogenesis, and more recently, induction of autophagy..”

http://www.ncbi.nlm....les/PMC3708159/


Edited by albedo, 19 September 2015 - 11:26 PM.

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#47 Logic

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Posted 25 September 2015 - 07:51 PM

TFEB-Induced Autophagy to Increase Clearance of α-synuclein

http://www.longecity...ndpost&p=745540



#48 normalizing

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Posted 24 February 2016 - 08:05 PM

I have been looking for trehalose in humans studies. This one should be done in September of this year. I look forward to seeing the results: https://clinicaltria...how/NCT01575288

 

This one says yyou can take high doses via an IV with no ill effects.

http://www.neurology...pplement/P7.068

 

Here are two ideas for increasing bioavailability of oral trehalose:

mix it with dmso and water. The DMSO should take the solution through the stomach walls. Then the liver will get a chance to digest it into sucrose, but at least the intestines are skipped.

 

Mix some polar and oil soluble solvent in olive oil, then add trehalose. For example, MSM or DMSO should do the trick. Then add in the trehalose. The olive oil will be taken into the lymph system, thus bypassing both the liver and trehalase in the small intestine.

 

One could also take a trehalase inhibitor, with the trehalose. Or perhaps package them together in a liposome.  One such drug is triamcinolone. I can't find any research on this, other than as an insecticide for locust. In humans it is used as a nasal decongestant. It can't be too toxic, since it is used in paediatrics.

 

 

that trehalose study is completed but i cant find the results anywhere. anyone care to help

 



#49 Logic

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Posted 27 February 2016 - 07:42 AM

I saw this linked somewhere around recently, but maybe not in this thread -? Chemical Inducers of Autophagy That Enhance the Clearance of Mutant Proteins in Neurodegenerative Diseases, 2010

 
I know the thread is called Supps to enhance autophagy and macrophagy, but whoever marked post off topic didn't bother to take a look at the linked study.
And it contains a lot of interesting, practical info:
 

"...The first hint that there may be mTOR-independent pathways controlling autophagy was the discovery that intracellular IP3 levels negatively regulate autophagy (41). We have shown that autophagy can be induced by lowering intracellular inositol or IP3 levels independently of mTOR..."

 
Now inositol is in almost every multi vitamin!  :|?
https://examine.com/...ments/inositol/
 

"...Lithium ... and sodium valproate, enhances the clearance of autophagy substrates by reducing intracellular inositol levels...due to inhibition of IMPase, which prevents inositol recycling, leading to depletion of cellular inositol and inhibition of the phosphoinositol cycle...
 
...Lithium and sodium valproate reduced mutant huntingtin aggregation/toxicity in HD cell models and protected against neurodegeneration... lithium treatment in ALS patients... for 15 months survived, but ∼30% of the control patients...died (19). Apart from the neuroprotective effects of lithium (49), this fascinating but preliminary result was attributed partly to autophagy up-regulation...
 
...Additive Effects of mTOR-dependent and mTOR-independent Autophagy Pathways
 
The existence of mTOR-dependent and mTOR-independent pathways regulating autophagy allows the combined use of different perturbations to increase the autophagic clearance of aggregate-prone proteins. For instance, although lithium induces autophagy in an mTOR-independent manner by inhibiting IMPase, it also inhibits GSK-3β, which activates mTOR (47, 61). This mTOR activation acts to partially inhibit the autophagy-inducing effects of lithium action via IMPase inhibition (47). We have shown that treatment with rapamycin impedes the GSK-3β-dependent activation of mTOR that occurs with the simultaneous treatment with lithium, thereby eliminating the undesirable effects on autophagy resulting from mTOR activation. Combinatorial treatment with rapamycin and lithium enables greater autophagic clearance ...Moreover, this strategy may also benefit from the cytoprotective effects of GSK-3β inhibition occurring as a result of lithium treatment due to activation of the β-catenin-T-cell factor pathway, which may serve as an additional protective effect in the context of neurodegenerative diseases in which there are secondary apoptotic insults (47, 62).
We have further shown that simultaneous treatment with rapamycin and other mTOR-independent autophagy inducers, such as trehalose, calpastatin, and the SMERs, results in a greater up-regulation of autophagy than the single treatments alone (48, 50, 60). The combined therapy approach may minimize the side effects arising from these treatments by lowering the required doses of each compound, thereby providing a safer strategy for long-term treatments. Therefore, the use of combination treatment with lower doses not only provides additive mechanisms for enhancing autophagy but also may abrogate undesirable effects resulting from the perturbations of these signaling pathways on their own..."

http://www.jbc.org/c...11061.full.pdf3


Now Rapamycin is an immunosuppressant increasing the risk of cancer and also causes glucose tolerance and insensitivity to insulin and can cause lung toxicity etc.
 

"...In separate studies conducted by Zhang et al., pterostilbene was shown to inhibit apoptosis and induce autophagy in VECs counteracting the proatherosclerosis effect of oxidized low-density lipoprotein (oxLDL) [34, 35]. The cytoprotective mechanism of autophagy involves removal of abnormal proteins that results from oxLDL accumulation [36]. Zhang and colleagues have demonstrated that pterostilbene treatment induces autophagy in oxLDL-stimulated VECs through activation of AMP-activated protein kinase (AMPK), intracellular calcium (Ca2+), and mammalian target of rapamycin (mTOR) signaling..."
http://www.hindawi.c...cl/2013/575482/

 
Off topic, but interesting as everything is connected and avoiding the oxidation of LDL in the 1st place and all the below downstream effects seems like a bloody good idea.  Especially as LDL is used in the building of telomeres: 
 

"... Treatment with pterostilbene was shown to inhibit oxLDL-induced apoptosis, suppress oxLDL-induced OS, and reduce expression of the pro-apoptosis proteins Bax and p53. Pterostilbene treatment also inhibited NF-κB activation, an instrumental mediator of OS in VECs [34]. Furthermore, pterostilbene treatment suppressed oxLDL-induced expression of MMP, caspase-3/9, and attenuation of LOX-1 signaling [34]. Previous studies have shown that OS leads to LOX-1 activation that further stimulates production of OS creating a positive feedback loop that is pathogenic to vascular cells [38].
Pterostilbene’s modulation of LOX-1, NF-κB, and the antioxidant enzymes SOD and catalase indicate strong antioxidant and anti-atherosclerosis effects that may be clinically significant..." 
 
"...The objective of the present study was to assess various antioxidative activities of Rosmarinic Acid (RA) and its effect on oxidation of Low Density Lipoprotein (LDL)...
 
...The antioxidant activity of RA was evaluated by the DPPH radical scavenging capacity. Fig. 1 shows the percentage of DPPH radicals scavenging capacity with BHT as reference. In the DPPH scavenging assay, the IC50 (the concentration required to scavenge 50% of radical) values of RA and BHT were 0.5±0.03 and 0.06±0.004 μM, respectively. The data obtained show that RA is a free radical scavenger and may act as a primary antioxidant which can react with free radicals by donating hydrogen.
 
fig1-2k12-301-307.gif
Free radical scavenging capacities of the RA and BHT
 
http://scialert.net/...bs.2012.301.307


Note that BHT also has lipid disrupting effects on the virii that use lipid layers to disguise themselves from the immune system etc, such as CMV (the immune sys killer), HSV, EBV, HIV, IFV etc. and that the study designed to discredit it by showing pro cancer activity used the HED of 30 grams a day chronically IIRC..!


Edited by Logic, 27 February 2016 - 07:50 AM.

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#50 Harkijn

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Posted 27 February 2016 - 10:14 AM

If I understand you right,  inositol is not the stuff we want to supplement. Have been taking 50mg of Inositol in my B-complex for years :sad: ....


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#51 Logic

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Posted 27 February 2016 - 10:46 AM

If I understand you right,  inositol is not the stuff we want to supplement. Have been taking 50mg of Inositol in my B-complex for years :sad: ....

 

So have I and probably most others.
This needs to be investigated more.

My point was that upregulating autophagy by mTOR dependant and independant means has an additive effect.  In this case the additive effect of Lithium and Rapamycin was demonstrated.
I hypophyse that the immunosuppressant Rapamycin could probably be replaced with Pterostilbene.

 

I then head off topic to point out the other positive effects of pterostilbene.
Then too hint that the oxidation of LDL is what is actually bad, not LDL and that rosmarinic acid and BHT are effective at countering this.

Then that BHT also counters many chronic low level infections common in humans and has an unjustified bad reputation IHO.

 

The connection is that chronic low level infections are a large part of chronic low level inflammation which has downstream effects on most of the markers of biological age, all the way up to short telomere length and its often overlooked 'epigenetic effect'.
Increased autophagy helps  clear these infections and other causes of inflammation like senescent cells, misfolded proteins, etc.
 


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#52 albedo

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Posted 27 February 2016 - 11:22 AM

 

I saw this linked somewhere around recently, but maybe not in this thread -? Chemical Inducers of Autophagy That Enhance the Clearance of Mutant Proteins in Neurodegenerative Diseases, 2010

 
I know the thread is called Supps to enhance autophagy and macrophagy, but whoever marked post off topic didn't bother to take a look at the linked study.
And it contains a lot of interesting, practical info:
 

"...The first hint that there may be mTOR-independent pathways controlling autophagy was the discovery that intracellular IP3 levels negatively regulate autophagy (41). We have shown that autophagy can be induced by lowering intracellular inositol or IP3 levels independently of mTOR..."

 
Now inositol is in almost every multi vitamin!  :|?
https://examine.com/...ments/inositol/
 

....

 

Wow, thank you for having pointed this out Logic! Something new to me I need now to research. I am using IP6 since long time, probably, summing over all supplements, inositol in the 300mg range!!

 

So and pardon my ignorance, how IP3 possibly behaves differently than IP6 and inositol in most B complex supplements?

 

On the positive side:

 

Inositol-6-Phosphate (IP6) induces autophagy mediated cell death in HT-29 colon cancer cells (Conference paper, found at ResearchGate, I am looking for publication) From the abstract: “Colorectal cancer (CRC) is common, with a worldwide incidence estimated at more than 1 million cases annually. Therefore, the search for chemotherapeutic agents for the treatment of CRC is highly warranted. Inositol-6 Phosphate (IP6), is enriched in rice bran, possess many beneficial effects. Autophagy is a physiologic process that allows degradation of the cytoplasmic contents including unfolded proteins and membranous organelles under certain stress conditions. This serves as a temporary survival mechanism. However, recent studies have shown that autophagy is also a cell death mechanism and is a response to various anticancer therapies in many kinds of cancer cells. Hence we aimed to study the effect of IP6 on autophagy mediated cell death in HT-29 colon cancer cells. We found IP6 (10, 15µg/mL, 24 and 48h) induced autophagic vesicles confirmed by acridine orange staining and Transmission electron that was microscopy analysis. We found increased confocal microscopic expression of LC3 as time dependent manner after incubation with IP6. IP6 also induce apoptosis that was confirmed by Annexin V expression. Further study is warranted to study the indetail mechanism of IP6 induced autophagy mediated cell death.”

 


 



#53 xEva

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Posted 27 February 2016 - 07:08 PM

When considering various supplements that may enhance autphagy, I think it's important to also know what stage of this multistep process a given substance affects. 'Cause, for example, just about any intracellular pathogen initiates autophagy (that's just a normal cellular response to it) but all pathogens that persist jam autophagy at some specific step, be it autophagosome maturation or its fusion with lysosome.

On the other hand, for a number of particularly nasty already established infections, autophagy can trigger their activation from latency and with some, like HCV or P. gingivalis, even drive their rapid proliferation.

So, when you say that a substance A enhances autophagy, at what point exactly does it contribute to the process? Simply triggering autophagy may not be such a great idea. Maybe a given substance damages some cellular component hence autophagy response to fix it. On the other hand, if a substance can nudge autophagy that has been already initiated but stalled at some step, that would be great.

But simply to know that substance A "enhances autophagy" and nothing else is not very valuable, I don't think.
 
 
--
 
The other point I wanted to make is in regard to some recent posts that show that you guys sorta think that you should always take something for something. Looks like some of you are just about ready to drop IP6 from you regimens. But I don't think it's wise. Autophagy is not something that goes on continuously. Nothing goes on continuously. A cell cannot feed on exogenous nutrients and do autophagy at the same time.  
 
These things are done in cycles. There is a cycle to feed and there is a cycle for autophagy. In 24h that usually happens at night. Then there are longer cycles and it's a good idea to fast once in a while. Then autophagy will be naturally enhanced and knowledge of some of the substances discussed here may come handy. .though so far I did not see anything useful.  ..xcept IP6 -- sometimes it's good to block autophagy without having to eat a lot. -? ...I hope you do realize that any food that triggers insulin release will also block autophagy, don't you?
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#54 Logic

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Posted 28 February 2016 - 05:33 AM

xEva

 

I am aware of your knowledge on fasting and now more aware that it extends to autophagy and its cyclic nature and also which pathogens halt autophagy and at which point they do so.

That is valuable practical knowledge IMHO and I'm surprised people have not asked you more on the subject in the past.
So I will!  :)

I, for one, would appreciate your sharing your knowledge on the above if you would be so kind plz?

 

So far we have: Take Inositol in the morning, but avoid it before bed?  

A good start. I assume the half life of Inositol is short enough for this to work?  I know IP6 has a very long half life..?  IP3??

 

A list of pathogens that stall autophagy and how to get the better of them etc, would be great!  :)

Also substances that cause autophagy by causing damage and in which situations to use them etc.

There is most likely a good amount of other questions/info I am not aware off?

 


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#55 xEva

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Posted 28 February 2016 - 11:55 PM

why, this is flattering :) yes I studied autophagy extensively but I rarely keep refs, so I'll just give you the headlines.

Re: list of pathogens that stall autophagy

You must be referring to when, years ago, I was working on such a list. In the process I realized that it must include all the pathogens that persists. This is because a successful run of autophagy spells the end of an intracellular pathogen (when, in the final step, the lysosomal enzymes take it apart, right?) So, naturally, to survive, the bugs interfere with some step along the way. Usually they set up shop in a autophagosome that forms around them and then they either block its maturation or its fusion with lysosome (some also mess with lysosomal enzymes).

Viruses are also known to interfere with the final step, even if they don't 'live' in autophagosomes. This is because the antigen presentation, essential in adaptive immunity, depends on lysosomes producing the necessary peptide. No antigen displayed on the cell surface means that the immune patrol will not recognize that something is wrong with that cell.

So, if you consider the image of a typical dysfunctional cell (whether it is infected or not), its cytoplasm is packed with autophagosomes and/or lysosomes and its mitochondria leak ROS. Such a cell does not need to initiate more autophagy. What it needs is to complete what has already started but stalled.

That's why I think it's good to know how exactly a substance "enhances" autophagy. Surely the most valuable are not the ones that initiate it but the ones that help overcome blocks on its way, no?



Re: "substances that cause autophagy by causing damage", I believe they are called poisons and so fall under the 'hormesis' category.



Re inositol, I'm a wrong person to ask this, 'cause I don't take anything day in and day out and rely on my instincts when deciding what to eat or take. When it comes to new supps, I mostly read what you guys write here -- many thanks for that! :)


PS
oh yes, re viruses that reactivate from latency and such: I am about to start a topic on herpes viruses and autophagy.

Edited by xEva, 29 February 2016 - 12:03 AM.

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#56 Logic

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Posted 02 March 2016 - 08:30 PM

Lithium and Autophagy

...Lithium affects this pathway by inhibiting IMPase, leading to free inositol depletion, which in turn decreases myo-inositol-1,4,5-trisphosphate (IP3) levels (Figure ​(Figure2).2). Increased inositol or IP3 levels inhibit autophagy, which reverse lithium’s effect.2 IP3 and the stimulation of its receptor have been seen to suppress autophagy...

http://www.ncbi.nlm....les/PMC4063500/

 



#57 normalizing

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Posted 02 March 2016 - 09:19 PM

its hard to find good source of water containing lithium, any clues?



#58 geo12the

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Posted 02 March 2016 - 11:15 PM

its hard to find good source of water containing lithium, any clues?

 

I remember reading, I think in a NYT article last year, that Pellegrino mineral water is relatively high in Lithium.

 

https://en.wikipedia.../San_Pellegrino

 

Or you can take a supplement. They are very inexpensive. 



#59 pamojja

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Posted 02 March 2016 - 11:35 PM

its hard to find good source of water containing lithium, any clues?

 

Rogaska Donat Mg contains 3.3 mg per liter, beside a whooping gram of Mg.
 


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#60 normalizing

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Posted 03 March 2016 - 09:25 AM

good leads thanks. i read san pallegrino contains a bit of a high amount of uranium too which is a turn off. not sure if rogaska contains much uranium as of yet but from what i know, mineral waters in general tend to have uranium sadly :S







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