100 replies to this topic

[Logic]

I am in the process of gathering leads for further research on autophagy and macrophage enhancing supps and thought I would post links here in case anyone else is interested in looking into this too. I am very pressed for time atm.

Effects on the immune system:Mechanism of Epimedium herb works on immume system combinatively composed of multi-ways:(1).regulating Immune related cell activity,including Macrophage,T-lymphocytes,B-lymphocytes,NK(natural killer cell) and LAK cells(lymphokine-activated killer cell),spleen antibody-forming cells (SAFC),interleukin-2 (IL-2) production;(2).promotes the phagocytic activity and stimulate lymphocyte proliferation;(3).stimulated the production of tumor necrosis factor-alpha in monocytes;(4).decrease CD25, IL-2, IL-4 and IL-10;(5).enhance the cell-mediated immunity reaction

http://www.mdidea.co...ariin/data.html


Following are a few of the vital functions acemannan and the other compounds of aloe have been found to perform:
Improves macrophage activity as much as tenfold
Enhances macrophage effectiveness in modulating the entire immune system by stimulating, producing and releasing antibodies

Oleander Leaf
It also causes apoptosis in cancerous cells (natural cell death) and increased rates of autophagic cancer cell death when tested on pancreatic cancer

http://www.naturecur...rbcureslist.htm


Thus, the isoflavonoid glabridin, from licorice
root, up-regulated manganese superoxide dismutase,
catalase and paraoxonase 2 in macrophages stimulated
by high glucose...

...Recently, Li and colleagues found that the flavonol
icariin, the major ingredient of the Chinese immunomodulatory
and antirheumatic plant Herba epimedii,
induced the expression (and its mRNA) of toll-like receptor
9 in murine macrophages (Li et al., 2011). Icariin
also modulated the levels of a number of molecules
involved in immune response such as myeloid differentiation
factor 88, tumour necrosis factor-a and interleukin-
6...

http://www.google.co....68445247,d.bGQ


the extract of [Solanum nigrum] (Solanaceae) (SNE) induced a strong cytotoxic effect toward HepG2 cells but much less to Chang liver and WRL-68 cells. High doses of SNE (2 and 5 mg/mL) induced apoptotic cell death in HepG2 cells, as evidenced by increases in the expression of p-JNK and Bax, mitochodrial release of cytochrome c, and caspase activation. On the other hand, cells treated with low concentrations of SNE (50-1000 microg/mL) revealed morphological and ultrastructural changes of autophagocytic death under electron microscopic observation. Furthermore, these cells showed increased levels of autophagic vacuoles and LC3-1 and LC3-II proteins, specific markers of autophagy. The levels of Bcl-2 and Akt that have been implicated in the down-regulation of autophagy were decreased upon SNE treatment.

Different concentrations of methanol extract of [Ipomoea batatas] (Convolvulaceae) root was subjected to study its effect on different [in vitro] methods of phagocytosis such as neutrophils locomotion and chemotaxis test, [in vitro] immunostimulant activity by slide method and qualitative nitro blue tetrazolium test using human neutrophils. The methanolic extract of [I. batatas] roots had stimulated chemotactic, phagocytic and intracellular killing potency of human neutrophils at the concentration range of 10-100 microg/ml.
 
Indukantha Ghritha (IG), prepared from 17 plants was administered at various dose levels to mice for 14 days. The results indicate that IG can stimulate hematopoietic activity as shown by an increase in the level of WBC count, hemoglobin, bone marrow cellularity, lymphocyte proliferate response and phagocytic index. The circulating level of hematopoietic growth factors like GM-CSF and MIP1 alpha also showed an increase after the oral administration of IG
 
Effects of [Saussurea lappa] (Asteraceae) root ethanol extracts prepared according to the homeopathic principles were examined in the cultures of peripheral blood mononuclear cells of goats (PBMC) [in vitro]. The results obtained demonstrated that all test dilutions (D4, D6, D8) of ethanol exerted a stimulating effect on leukocyte phagocytic activity in dose-dependent manner
 
A purified saponin mixture (PSM) of [Astragalus corniculatus] (Fabaceae) was evaluated for its immunostimulating potentials on the phagocytic cells in Graffi-tumor bearing hamsters. The number, migration and phagocytic indexes of peritoneal macrophages (pMos) and of blood polymorphonuclear leukocytes (PMNs) were evaluated in healthy and Graffi-tumor bearing hamsters (G-TBH) treated with PSM. It was established that the Graffi myeloid tumor induced suppression of the phagocytic abilities of pMos and PMNs. The number and migration of pMos was significantly decreased during the whole period of observation. All tested parameters-number, migration and phagocytic activities of pMos. as well as phagocytic ability of PMNs increased significantly in healthy and G-TBH after i.p. application of the 50 mg/kg body weight PSM.

http://www.niscair.r...logy-Dec07.html

[Centurion]

Beta 1,3 1,6 glucan also increases macrophage proliferation

Sent from my GT-I9300 using Tapatalk

[niner]

Good idea for a thread.  When evaluating the experimental work, pay attention to whether it's done in cells in a dish (in vitro) versus a live animal (in vivo).  Also consider the species.  Also look at the dose they use.  In vitro results rarely translate to humans, while there is a higher likelihood that a result from a mammal will.  Flies and worms are better than in vitro, but only marginally so.

[cgriffin]

Summary from the following site: http://www.anti-agin...fights-aging-2/

 

Not on the list but I think l-lysine helps or assists in the process.

 

AUTOPHAGY - Recap of article

• Fasting activates Autophagy -   caloric restriction affects 5 molecular pathways that activate autophagy
• Sunlight, Vitamin D and Klotho activate Autophagy - there are three ways through which UV light, Vitamin D, and the Klotho pathway activate autophagy via inhibiting the insulin/IGF-1 pathway
• Caffeine activates Autophagy - Caffeine can activate autophagy via an mTOR-dependent mechanism
• Green tea activates Autophagy - ECGC can activate autophagy via an mTOR-dependent mechanism
• Lithium activates Autophagy -  lithium and other compounds can activate autophagy by inhibiting inositol monophosphate and lower IP3 levels – an mTOR-independent mechanism
• Resveratrol activates Autophagy – there are four 4 ways through which resveratrol can activate autophagy – via mTOR-dependent and mTOR-independent mechanism

[ta5]

Cell Cycle. 2014 Apr 25;13(12).

Coffee induces autophagy in vivo.

Pietrocola F1, Malik SA2, Mariño G3, Vacchelli E1, Senovilla L4, Chaba K3, Niso-Santano M3, Maiuri MC3, Madeo F5, Kroemer G6.

Epidemiological studies and clinical trials revealed that chronic consumption coffee is associated with the inhibition of several metabolic diseases as well as reduction in overall and cause-specific mortality. We show that both natural and decaffeinated brands of coffee similarly rapidly trigger autophagy in mice. One to 4 hours after coffee consumption, we observed an increase in autophagic flux in all investigated organs (liver, muscle, heart) in vivo, as indicated by the increased lipidation of LC3B and the reduction of the abundance of the autophagic substrate sequestosome 1 (p62/STQM1). These changes were accompanied by the inhibition of the enzymatic activity of mammalian target of rapamycin complex 1 (mTORC1), leading to the reduced phosphorylation of p70S6K, as well as by the global deacetylation of cellular proteins detectable by immunoblot. Immunohistochemical analyses of transgenic mice expressing a GFP-LC3B fusion protein confirmed the coffee-induced relocation of LC3B to autophagosomes, as well as general protein deacetylation. Altogether, these results indicate that coffee triggers 2 phenomena that are also induced by nutrient depletion, namely a reduction of protein acetylation coupled to an increase in autophagy. We speculate that polyphenols contained in coffee promote health by stimulating autophagy.

PMID: 24769862

 

ACS Chem Neurosci. 2014 Apr 30.

Lithium and Autophagy.

Motoi Y1, Shimada K, Ishiguro K, Hattori N.

Lithium, a drug used to treat bipolar disorders, has a variety of neuroprotective mechanisms, including autophagy regulation, in various neuropsychiatric conditions. In neurodegenerative diseases, lithium enhances degradation of aggregate-prone proteins, including mutated huntingtin, phosphorylated tau, and α-synuclein, and causes damaged mitochondria to degrade, while in a mouse model of cerebral ischemia and Alzheimer's disease autophagy downregulation by lithium is observed. The signaling pathway of lithium as an autophagy enhancer might be associated with the mammalian target of rapamycin (mTOR)-independent pathway, which is involved in myo-inositol-1,4,5-trisphosphate (IP3) in Huntington's disease and Parkinson's disease. However, the mTOR-dependent pathway might be involved in inhibiting glycogen synthase kinase-3β (GSK3β) in other diseases. Lithium's autophagy-enhancing property may contribute to the therapeutic benefit of patients with neuropsychiatric disorders.

PMID: 24738557

 

[Logic]

Thx for your contributions everyone,  I do now remember high dose Resv,  Lithium, Spermidine  and I think Trehelose?  from an older thread?

 

Thx for the oft given good advice Niner.  I do pay much more head to In Vivo results in Mammals now-days.
My 1st post were simply leads to be followed and there may just be some In Vivo studies to be found on some of the In Vitro leads?

Sadly Lithium Orotate (or any other form) has been banned  without a prescription here.

 

Horny Goat weed is looking Interesting from many ...er... angles and worthy of a good look! 

 

Mitophagy and Xenophagy info welcome also!.

[Logic]

PABA looks interesting in that it is an interferon inducer.
An increase in interferon leads to an increase in macrophagy and immune function in general.

http://en.wikipedia....wiki/Interferon

[Para-aminobenzoic acid--an interferon inducer].
http://www.ncbi.nlm....pubmed/10483491

[Action of para-aminobenzoic acid and its combination with acyclovir in herpetic infection].
http://www.ncbi.nlm..../pubmed/8660116

http://link.springer...71219882#page-1
 

[niner]

Interesting paper about the creation and use of a high throughput screen to find small molecule activators of autophagy.  Not supplements, but most are approved drugs.  One is our good friend Rapamycin.

[tintinet]

Is anyone taking Rapamycin?

[niner]

Is anyone taking Rapamycin?

 

That one has always scared me off, but here is the list of compounds from the autophagy induction screen paper I posted above.

 

From these results, we conclude that we have identified eight compounds, fluspirilene, trifluoperazine, pimozide, niguldipine, nicardipine, amiodarone, loperamide, and penitrem A, that can truly induce autophagic degradation without causing obvious cellular damage.

 

I don't know what dose would be needed for any of these to be effective, but some have been chronically administered to a lot of people, so there could be some data out there just waiting to be measured...  If there's a way to measure the level of protein defects in an easy-to-collect tissue (e.g. blood) then it would be pretty simple to do a before / after look at patients who were taking any of these.

[krillin]

L-type calcium channel blockers, minoxidil, and clonidine. PMID: 18391949

 

[Logic]

Macrophage Wnt7b is critical for kidney repair and regeneration
"...Here we show, using the kidney as a model, that the Wnt pathway ligand Wnt7b is produced by macrophages to stimulate repair and regeneration...Here we show, using the kidney as a model, that the Wnt pathway ligand Wnt7b is produced by macrophages to stimulate repair and regeneration...The canonical Wnt pathway is known to regulate scheduled cell proliferation and death events, cell differentiation...More recently, evidence that stem cells in bone marrow and skin are regulated by Wnt canonical pathway signaling suggested to us that the Wnt pathway may play an important role in tissue regeneration..., Dkk2 functions to enhance canonical Wnt responses...Addition of the Wnt pathway inhibitor Dkk1 in recombinant form (Fig. 2C) or cotransfection of Dkk1 in STF reporter cells significantly suppressed kidney macrophage-stimulated Wnt signaling..."
http://www.ncbi.nlm....les/PMC2840080/
 
One way to upregulate WNT signalling is by supressing DKK1 with L-Throenate:
http://www.longecity...osteoarthritis/

However care should be taken when upregulatig WNT due to cancer concerns:
http://www.anti-agin...-aging-in-2013/
"...while cancer biologist have mainly focused on the Wnt signaling pathway as the primary “early driver” of cancer. there is something else going on too.. Wnt drives β-catenin into the nucleus where it activates the transcription factor TCF to “turn on” the EMT. Watson believes an “even more important villain than Wnt signaling has been virtually staring us in the face for two decades”. That “villain” is interleukin 6 (IL-6). IL-6 is the master cytokine mediator of inflammation and immunity..."

Does manipulating WNT signalling enhance macrophagy and does macrophagy play an important role in regeneration!???

[Logic]

Phytic acid as a potential treatment for Alzheimer's pathology: evidence from animal and in vitro models
http://www.ncbi.nlm....00/?tool=pubmed

"...phytic acid provided complete protection against amyloid precursor protein-C-terminal fragment-induced cytotoxicity by attenuating levels of increased intracellular calcium, hydrogen peroxide, superoxide, beta amyloid oligomers, and moderately up-regulated the expression of autophagy (beclin-1) protein..."


Autophagy in immunity against mycobacterium tuberculosis: a model system to dissect immunological roles of autophagy.
http://www.ncbi.nlm....pubmed/19802565

"...autophagy is an immune effector of Th1/Th2 T cell response polarization-autophagy is activated by Th1 cytokines (which act in defense against intracellular pathogens) and is inhibited by Th2 cytokines (which make cells accessible to intracellular pathogens)..."
 

[Aurel]

Any new leads Logic?

[niner]

Autophagy in immunity against mycobacterium tuberculosis: a model system to dissect immunological roles of autophagy.
http://www.ncbi.nlm....pubmed/19802565

"...autophagy is an immune effector of Th1/Th2 T cell response polarization-autophagy is activated by Th1 cytokines (which act in defense against intracellular pathogens) and is inhibited by Th2 cytokines (which make cells accessible to intracellular pathogens)..."

 

That's interesting.  Some fullerene analogs have been shown to cause a Th2 to Th1 shift.  I wonder if an upregulation of autophagy could be part of the explanation for the reported c60oo  life extension effect in rats?

[Logic]

Any new leads Logic?

 
I'm afraid not Aurel.

My attention is on AGE breakers (and blockers) atm. and I hope to have the Chinese study on 2,3,5,4'-tetera-hydroxystilbene soon.
Also I am trying to source a natural substance 50X stronger than ALT-711 and put together a synergistic (or at least additive) anti AGE stack with substances that have different MOA's.
Not an easy task for someone with my level of biological education.
I will post soon.

The other thing bugging me is that Nicotinamide (Riboside) may be increasing NAD+ and thus SIRT expression by down-regulating PARP.
PARP fixes DNA or initiates apoptosis if the cell is too damaged.
If its PARP gone into overdrive, due to DNA damage caused by out of control ROS as we age, that is using up all the NAD+; maybe we already have the answer to youthful levels of NAD+ and SIRT in C60oo etc....?

Soz for going off topic. AT least point 2 ties in loosely with Niner's post above. Maybe Cells stressed by ROS cause a shift toward Th2 cytokines??

[Razor444]

Trehalose.

[Logic]

Trehalose.

Is it absorbed as is?
Or is it changed into glucose in the gut?

http://metamodern.co...e-vs-trehalase/

Edited by Logic, 12 February 2015 - 08:22 PM.

[Razor444]

The post on anti-agingfirewalls.com says the following:

 

Like humans, mice have trehalase in their guts, developing its expression early in their lives (ref)(ref)(ref).  The experiments described above based on adding trehalose to mouse drinking water suggest that significant benefits are nonetheless realized via upgrading autophagy and mitigating insulin resistance(ref)(ref)(ref).  So, some trehalose must be getting into cells.  I infer this is due to a certain portion of the trehhalose evading gut trehalase breakdown and passing into the bloodstream where it is later broken down by circulating trehalase or in kidneys.  I further infer that that the same happens when humans consume trehalose.  The percentage amount entering the bloodstream is unknown.  However as identified above, it is thought that 5 gms per day is a safe amount for human consumption.

 

 

More generally, from the paper 'Effects of nutritional components on aging' (It doesn't deal with trehalase):

 

In contrast to glucose, several other carbohydrates or carbohydrate metabolites, including trehalose, pyruvate, malate, fumarate, and N-acetylglucosamine (GlcNAc), have been shown to promote longevity in C. elegans (Honda et al., 2010; Mouchiroud et al., 2011; Edwards et al., 2013; Denzel et al., 2014). In particular, it is intriguing that a disaccharide trehalose is linked to longevity in yeast and C. elegans (Honda et al., 2010; Trevisol et al., 2011), because its monomer glucose decreases lifespan as described above. Trehalose feeding also increases stress resistance in C. elegans, which is consistent with the ability of trehalose to protect invertebrates from various stresses (Honda et al., 2010). Moreover, mutations that cause accumulation of trehalose promote fermentative capacity and extend the lifespan of yeast (Trevisol et al., 2011). Thus, trehalose appears to increase lifespan by acting as a general antistress sugar in invertebrates. In addition, GlcNAc, which is generated from glucose, increases the lifespan of C. elegans by improving the homeostasis of endoplasmic reticulum (ER) proteins (Denzel et al., 2014). Thus, trehalose and GlcNAc, which are metabolites of life-shortening glucose, appear to exert beneficial effects on lifespan in C. elegans.

 

 

[normalizing]

"Thus, trehalose and GlcNAc, which are metabolites of life-shortening glucose, appear to exert beneficial effects on lifespan in C. elegans." this is getting confusing now....

[Logic]

"Thus, trehalose and GlcNAc, which are metabolites of life-shortening glucose, appear to exert beneficial effects on lifespan in C. elegans." this is getting confusing now....

 

You'r lucky! I've been confused ever since  I knew enough to realise how little I knew! 
 
Given a choice between Trehalose and normal sugars; Trehalose wins hands down.

I wonder if the same metabolic/breakdown process happens to Ribose and whether the secret to Nicotinamide Riboside is the ability to get ribose into one's system intact at a slow constant rate...?
Perhaps liposomal encapsulation is the answer here... I gotta go post elsewhere!
http://www.livonlabs...apsulation.html

[Aurel]

And yet, people which can not produce trehalase get some serious problems after ingesting trehalose? And people who can build it will break down the trehalose in the gut. Mhm...

[niner]

"Thus, trehalose and GlcNAc, which are metabolites of life-shortening glucose, appear to exert beneficial effects on lifespan in C. elegans." this is getting confusing now....

 

They make it sound kind of bizarre.  In the body, both trehalose and GlcNAc can be produced via a series of enzymatic reactions that start with glucose.  This is just a case of the body not always making as much of a particular compound as we might like it to, so we compensate by consuming the final product, and hope that it doesn't get degraded in the gut or bloodstream before it does some good.  Glucose is certainly life-shortening in excess, but most of the time our biology uses it as a form of energy currency, unless we're in ketosis.  Even in non-excess, it contributes to aging via AGE formation.  That's why we need AGE blockers and (especially) breakers.

[xEva]

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

[Kevn]

 

"Thus, trehalose and GlcNAc, which are metabolites of life-shortening glucose, appear to exert beneficial effects on lifespan in C. elegans." this is getting confusing now....

 

They make it sound kind of bizarre.  In the body, both trehalose and GlcNAc can be produced via a series of enzymatic reactions that start with glucose.  This is just a case of the body not always making as much of a particular compound as we might like it to, so we compensate by consuming the final product, and hope that it doesn't get degraded in the gut or bloodstream before it does some good.  Glucose is certainly life-shortening in excess, but most of the time our biology uses it as a form of energy currency, unless we're in ketosis.  Even in non-excess, it contributes to aging via AGE formation.  That's why we need AGE blockers and (especially) breakers.

 

 

Trehalose is unusual in that it doesn't form AGE end-products. I can find several sources to that effect if you want them, just not at 1:40 in the morning when I happen to be writing this. (Or just check http://anti-agingfirewalls.com/.)

[Razor444]

'Table 1: Functional status of autophagy induced by different natural compounds.'

 table1.png   170.71KB   11 downloads

[ClarkSims]

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.

Edited by ClarkSims, 17 August 2015 - 12:49 AM.

[ClarkSims]

I bet bitter melon would help autophagy also. There is little research on this.

 

Mechanistically, we have determined that while the extracts do not induce apoptosis, there is autophagy via the AMPK signalling pathway. In addition, the extracts modulate energy homeostasis to affect the viability of the colon cancer cells.

http://www.hindawi.c...am/2013/702869/

 

There is a fair amount of research that bitter melon upregulates AMPK:

  Activation of AMPK by bitter melon triterpenoids involves CaMKKβ.

  http://www.ncbi.nlm....ubmed/23638033 

 

  Antidiabetic activities of triterpenoids isolated from bitter melon associated with activation of the AMPK pathway.

  http://www.ncbi.nlm....pubmed/18355726

 

Bitter melon extract attenuating hepatic steatosis may be mediated by FGF21 and AMPK/Sirt1 signaling in mice.

http://www.ncbi.nlm....pubmed/24189525

 

There is a fair amount of research that AMPK upregulates autophagy. I will post only one link

AMPK and autophagy get connected

http://www.ncbi.nlm....les/PMC3041958/

 

I am convinced. I will be adding bitter melon to my intermittent fasting regimen..

 

 

 

 

 

 

[ClarkSims]

And we can;t forget that spermidine upgregulates autophagy.

Here is one such link:

http://www.ncbi.nlm....pubmed/19801973

[zorba990]

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

Edited by zorba990, 17 August 2015 - 01:59 AM.