134 replies to this topic

[FunkOdyssey]

My bad lithium.

I was hoping for maybe a citation or an excerpt of a study to back that up. If trehalose does reduce inositol levels that has some implications for your mental state, possible effects on mood, since you are now dabbling in the realm of the mood stabilizers.

Edited by FunkOdyssey, 18 December 2008 - 05:20 PM.

[100YearsToGo]

My bad lithium.

I was hoping for maybe a citation or an excerpt of a study to back that up. If trehalose does reduce inositol levels that has some implications for your mental state, possible effects on mood, since you are now dabbling in the realm of the mood stabilizers.

I'll back that up. I'll pm you the complete study when I'm at home. Don't have it at the office. It's not public.

[Mind]

Just a couple of notes I wrote about CMA from Cuervo's talk at UABBA

[100YearsToGo]

Just a couple of notes I wrote about CMA from Cuervo's talk at UABBA

Thanks Mind,

The following is a nice review on autophagy and aging. Hope everyone interested in autophagy reads it and enjoy it:

http://www.nature.co...cdd2008126a.pdf

"In nature, different animal species are characterised by markedly different lifespans. For example, mice have relatively short (around 2-year) mean lifespans, whereas humans live for many decades. In these organisms, autophagic activity, which is tightly regulated during development and the reproductive period so that it is maintained at basal levels and induced only when needed, declines during the postreproductive period with a rate specific to a given species. Uncovering the molecular mechanisms underlying the developmental regulation of autophagy will certainly help to understand why and how humans have evolved to a maximum over 70 years. To date, E2F-1, a component of the retinoblastoma complex involved in chromatin-mediated transcriptional regulation, has been identified to promote the activity of Atg1, Atg8 and DRAM in mammals.83 Thus, the mechanisms underlying chromatin structure may contribute to the progressive decline in autophagy during ageing."

and

"Starvation or treatment with rapamycin (a specific inhibitor of the nutrient sensor TOR) also rapidly induces an increase in autophagic activity."

I dont like rapamycin and I don't like Lithium. brrrrr...I'l stick to trehalose.

[FunkOdyssey]

Is there nothing that inhibits mTOR besides rapamycin? rapamycin is such an ugly drug.

I wonder if this provides some justification for the idea of periodic fasting as healthful (starvation -> autophagy).

Edited by FunkOdyssey, 19 December 2008 - 04:19 AM.

[Shepard]

Is there nothing that inhibits mTOR besides rapamycin? rapamycin is such an ugly drug.

I wonder if this provides some justification for the idea of periodic fasting as healthful (starvation -> autophagy).

Yeah, AMPK does.

[FunkOdyssey]

So AMPK could be activated with something like AICAR and then inhibit mTOR and you get your autophagy?

[Shepard]

AICAR, metformin, glycogen depletion, caloric restriction, exercise, lots of approaches could be used.

And other stuff like GTE/resveratrol activate AMPK in some tissues (don't recall any in vivo human studies off the top of my head, though).

[FunkOdyssey]

AICAR, metformin, glycogen depletion, caloric restriction, exercise, lots of approaches could be used.

And other stuff like GTE/resveratrol activate AMPK in some tissues (don't recall any in vivo human studies off the top of my head, though).

As I investigate this further it seems that all or most of those approaches reduce testosterone production. :( And here I thought we could have some free lunch with this.

Edited by FunkOdyssey, 19 December 2008 - 05:26 AM.

[Shepard]

As far as I know, the effect on testosterone would be due to higher SHBG levels from lowered insulin. It's been a couple of years since I really looked into any of it, though.

Regardless, AMPK is activated when the cell senses energy deprivation, and that can't be good for anabolic hormones.

[100YearsToGo]

FYI:

http://www.ncbi.nlm....Pubmed_RVDocSum

http://myhealthspan....nemarrhena.shtm

[caston]

This may sound like a stupid question but if autophagy is breaking down the cellular components what is the process called when *building* them up again.

[FunkOdyssey]

FYI:

http://www.ncbi.nlm....Pubmed_RVDocSum

http://myhealthspan....nemarrhena.shtm

Eek, the method Anemarrhena uses to induce autophagy is "totally F up the cell", not one of the two friendly pathways we've been looking at. They want to use it for chemotherapy.

[100YearsToGo]

FYI:

http://www.ncbi.nlm....Pubmed_RVDocSum

http://myhealthspan....nemarrhena.shtm

Eek, the method Anemarrhena uses to induce autophagy is "totally F up the cell", not one of the two friendly pathways we've been looking at. They want to use it for chemotherapy.

Cytoxicity can be usefull. A "friendlier" mTor inhibitor would be curcumin.

http://www.ncbi.nlm....pubmed/17395690

[geddarkstorm]

This may sound like a stupid question but if autophagy is breaking down the cellular components what is the process called when *building* them up again.

Biogenesis and anabolism, I guess.

[100YearsToGo]

Some more info on curcumin and autophagy;

"Among the targets of curcumin there is also the mammalian target of rapamycin (mTOR), an important regulator of autophagic cell death (80). At physiological concentrations (2.5 µM), curcumin rapidly inhibits phosphorylation of mTOR and its downstream effector molecules, p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), in a panel of cell lines (Rh1, Rh30, DU145, MCF-7 and HeLa). Curcumin also inhibits phosphorylation of Akt in these cells, but only at high concentrations (>40 µM) (80). Since mTOR is a pivotal player of autophagy, we speculate that curcumin may execute its cell death activity also through the induction of such a mechanism."




http://ecam.oxfordjo...nt/full/4/2/181

I surmise a mix of Curcumin and trehalose could target both mTor dependent and mTor independent autophagy.

Edited by 100YearsToGo, 20 December 2008 - 04:33 PM.

[FunkOdyssey]

At physiological concentrations (2.5 µM), curcumin rapidly inhibits phosphorylation of mTOR and its downstream effector molecules

You would need to do some research to determine what doses are needed to reach this concentration. Curcumin is notoriously poorly absorbed, and while some strategies for improving absorption exist, one of them messes with too many enzymes in possibly dangerous ways (bioperine) and the other is proprietary and unproven (bio-curcumin).

Some people taking curcumin at high doses for therapy of autoimmune disease mix it with olive oil, chocolate, and other fats and seem to think this makes a difference.

And would the concentration of curcumin need to be consistently at or above that level or do you simply need to "trip" it occasionally for the effect on mTOR to persist? Its been my understanding that resveratrol activates SIRT1 in this periodic "flipping the switch" manner with briefly spiked concentrations.

Edited by FunkOdyssey, 20 December 2008 - 07:24 PM.

[rwac]

I'm not sure curcumin is the best thing for everybody, anymore.

Curcumin inhibits Th1 cytokine profile

Perhaps it's good for auto-immune issues, but for Lyme, not so much.

At physiological concentrations (2.5 µM), curcumin rapidly inhibits phosphorylation of mTOR and its downstream effector molecules

You would need to do some research to determine what doses are needed to reach this concentration. Curcumin is notoriously poorly absorbed, and while some strategies for improving absorption exist, one of them messes with too many enzymes in possibly dangerous ways (bioperine) and the other is proprietary and unproven (bio-curcumin).

Some people taking curcumin at high doses for therapy of autoimmune disease mix it with olive oil, chocolate, and other fats and seem to think this makes a difference.

And would the concentration of curcumin need to be consistently at or above that level or do you simply need to "trip" it occasionally for the effect on mTOR to persist? Its been my understanding that resveratrol activates SIRT1 in this periodic "flipping the switch" manner with briefly spiked concentrations.

[FunkOdyssey]

I'm not sure curcumin is the best thing for everybody, anymore.

Curcumin inhibits Th1 cytokine profile

Perhaps it's good for auto-immune issues, but for Lyme, not so much.

There is some evidence to suggest Lyme in the chronic stage prefers and acts to induce a Th1-dominant immune response at the expense of Th2. A high initial Th1 response is effective at preventing infection, but once the infection is well-established and widely disseminated, innate immunity poses less danger to the spirochete than the uber heat-seeking IgG antibodies. A strong IgG antibody response correlates with better clinical outcomes in Lyme patients.

Anecdotally, a large percentage of chronic-late Lyme patients report that they never get sick with the common cold despite overall depressed immune function and this may be the reason (constantly primed Th1 response).

Edited by FunkOdyssey, 20 December 2008 - 07:50 PM.

[100YearsToGo]

At physiological concentrations (2.5 µM), curcumin rapidly inhibits phosphorylation of mTOR and its downstream effector molecules

You would need to do some research to determine what doses are needed to reach this concentration. Curcumin is notoriously poorly absorbed, and while some strategies for improving absorption exist, one of them messes with too many enzymes in possibly dangerous ways (bioperine) and the other is proprietary and unproven (bio-curcumin).

Some people taking curcumin at high doses for therapy of autoimmune disease mix it with olive oil, chocolate, and other fats and seem to think this makes a difference.

And would the concentration of curcumin need to be consistently at or above that level or do you simply need to "trip" it occasionally for the effect on mTOR to persist? Its been my understanding that resveratrol activates SIRT1 in this periodic "flipping the switch" manner with briefly spiked concentrations.

According to this indian study piperine increased bioavailability by 2000%

http://www.ncbi.nlm....0?dopt=Abstract

according to this study

http://www.sciencedi...c110109751f9fe3

4 grams of plain curcumin raises blood levels to 490 nmol/L = 0,490 uM/L


Our target is 2.5 uM/L blood level.

Calculation:
Asuming the relation between dose and molar level in blood is linear you would need:

(2.5/0.4)*4 = 25 grams per day of plain curcumin

OR

25/20 = 1.25 gram of curcumin with piperine per day.


If you don't like piperine, Quercetin can also be used. Maybe Gedarkstorm has some data on that baby.

Edited by 100YearsToGo, 20 December 2008 - 08:58 PM.

[geddarkstorm]

Sadly, I'm having trouble finding information on quercetin with curcumin, other than the two working together to kill cancer and protect the renal system. But, here's a paper that seems like it may have a lot of such info PMID: 16557604. I can't get it right now, being at home, but it looks at the different effects the flavonoids have on eachother, including stability and absorption, so it may have such data for quercetin with curcumin.

If I had more time, I might be able to find a bit more, but.. alas.. I must be off for a week on vacation back home. Hope everyone has a Merry Christmas!

[rwac]

I'm not sure curcumin is the best thing for everybody, anymore.

Curcumin inhibits Th1 cytokine profile

Perhaps it's good for auto-immune issues, but for Lyme, not so much.

There is some evidence to suggest Lyme in the chronic stage prefers and acts to induce a Th1-dominant immune response at the expense of Th2. A high initial Th1 response is effective at preventing infection, but once the infection is well-established and widely disseminated, innate immunity poses less danger to the spirochete than the uber heat-seeking IgG antibodies. A strong IgG antibody response correlates with better clinical outcomes in Lyme patients.

Anecdotally, a large percentage of chronic-late Lyme patients report that they never get sick with the common cold despite overall depressed immune function and this may be the reason (constantly primed Th1 response).

You just threw my entire plan into disarray.

"no battle plan survives first contact with the enemy"
(Lyme's the enemy here ...)

More links on IgG would be much appreciated.

[caston]

Does water fasting induce CMA?

And perhaps we should be looking to repair damage to autophagy machinery rather than just trying to make the machinery work harder.

Edited by caston, 02 January 2009 - 04:00 PM.

[100YearsToGo]

Does water fasting induce CMA?

And perhaps we should be looking to repair damage to autophagy machinery rather than just trying to make the machinery work harder.

The problem is the machinery (autophagy) slows down with age. For instance LAMP-2A just keeps going down the hill with advancing age, making chaperone mediated autophagy slow down.

To answer you first question: Both Macro and Chaperone mediated autophagy is activated during short term and long term starvation.

http://www.ncbi.nlm....pubmed/16874031

But...fasting induces autophagy through the activation of FoxO3 transcript factors. This induces wasting of skeletal muscle.

mTor dependant (macro) autophagy (rapamycin, curcumin) does not cause muscle wasting, but only activates macro autophagy.

http://www.ncbi.nlm....Pubmed_RVDocSum

Lithium has the same effect, macro autophagy, but through an mTor independent pathway.

The thing we have not discovered yet is a decent activator of chaperone mediated autophagy.

http://www.scribd.co...epatic-Function

6-aminonicotinamide, geldanamycin are both too ugly for my taste.

I have found no evidence that trehalose activates chaperone mediated autophagy, but it certainly has autophagic function and acts differently than fasting on skeletal mouse muscle:

"Furthermore, oral administration of trehalose attenuated muscle weakness, reduced aggregate formation and decreased the number of TUNEL-labelled nuclei in skeletal muscle in an OPMD transgenic mouse model. Thus, anti-aggregation therapy may prove effective in the treatment of human OPMD. "

http://hmg.oxfordjou...nt/full/15/1/23

Edited by 100YearsToGo, 03 January 2009 - 02:51 AM.

[FunkOdyssey]

The strategies discussed in this thread for stimulating autophagy (lithium, trehalose, curcumin) should result in improved immunity because autophagy is used to destroy pathogenic material and to process antigens:

Annu Rev Immunol. 2008 Dec 23. [Epub ahead of print]
Enhancing Immunity Through Autophagy.
Münz C.

Viral Immunobiology, Institute of Experimental Immunology, University Hospital of Zürich, CH-8057 Zürich, Switzerland; email: christian.muenz@usz.ch.

Next to the proteasome, autophagy is the main catabolic pathway for the degradation of cytoplasmic constituents. The immune system uses it both as an effector mechanism to clear intracellular pathogens and as a mechanism to monitor its products for evidence of pathogen invasion and cellular transformation. Because autophagy delivers intracellular material for lysosomal degradation, its products are primarily loaded onto MHC class II molecules and are able to stimulate CD4(+) T cells. This process might shape the self-tolerance of the CD4(+) T cell repertoire and stimulate CD4(+) T cell responses against pathogens and tumors. Beyond antigen processing, autophagy's role in cell survival is to assist the clonal expansion of B and T cells for efficient adaptive immune responses. These immune-enhancing functions make autophagy an attractive target for therapeutic manipulation in human disease. Expected final online publication date for the Annual Review of Immunology Volume 27 is March 19, 2009. Please see http://www.annualrev...g/pubdates.aspx for revised estimates.

PMID: 19105657

[niner]

Along these lines, I stumbled across this paper about oleuropein, a constituent of olive oil, found in significant quantity in olive leaf extract.

Rejuvenation Res. 2007 Jun;10(2):157-72.
The olive constituent oleuropein exhibits proteasome stimulatory properties in vitro and confers life span extension of human embryonic fibroblasts.

Katsiki M, Chondrogianni N, Chinou I, Rivett AJ, Gonos ES.
Institute of Biological Research and Biotechnology, Laboratory of Molecular and Cellular Aging, National Hellenic Research Foundation, Athens, Greece.

Normal human fibroblasts undergo replicative senescence due to both genetic and environmental factors. Senescence and aging can be further accelerated by exposure of cells to a variety of oxidative agents that contribute among other effects to the accumulation of damaged proteins. The proteasome, a multicatalytic nonlysosomal protease, has impaired function during aging, while its increased expression delays senescence in human fibroblasts. The aim of this study was to identify natural compounds that enhance proteasome activity and exhibit antiaging properties. We demonstrate that oleuropein, the major constituent of Olea europea leaf extract, olive oil and olives, enhances the proteasome activities in vitro stronger than other known chemical activators, possibly through conformational changes of the proteasome. Moreover, continuous treatment of early passage human embryonic fibroblasts with oleuropein decreases the intracellular levels of reactive oxygen species (ROS), reduces the amount of oxidized proteins through increased proteasome-mediated degradation rates and retains proteasome function during replicative senescence. Importantly, oleuropein-treated cultures exhibit a delay in the appearance of senescence morphology and their life span is extended by approximately 15%. In summary, these data demonstrate the beneficial effect of oleuropein on human fibroblasts undergoing replicative senescence and provide new insights towards enhancement of cellular antioxidant mechanisms by natural compounds that can be easily up-taken through normal diet.
PMID: 17518699

And, speaking of the relationship between autophagy and immune function...

Traffic. 2009 Jan 24. [Epub ahead of print]
Macroautophagy in immunity and tolerance.
Gannagé M, Münz C.
Viral Immunobiology, Institute of Experimental Immunology, University Hospital of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Autophagy and proteasomal degradation constitute the two main catabolic pathways in cells. While the proteasome degrades primarily short-lived soluble proteins, macroautophagy, the main constitutive autophagic pathway, deliver cell organelles and protein aggregates for lysosomal degradation. Both the proteasome and macroautophagy are attractive effector mechanisms for the immune system, because they can be used to degrade foreign substances, including pathogenic proteins, within cells. Therefore, both innate and adaptive immune responses use these pathways, for intracellular clearance of pathogens as well as presentation of pathogen fragments to the adaptive immune system. Since, however, the same mechanisms are used for the steady-state turnover of cellular self-components, the immune system has to be desensitized in order not to recognize these. Therefore, proteasomal degradation and macroautophagy are also involved in tolerizing the immune system prior to pathogen encounter. We will discuss recent advances in our understanding how macroautophagy selects self-structures in the steady-state, how presentation of these on MHC class II molecules leads to tolerance, and how macroautophagy assists both innate and adaptive immunity. This new knowledge on the specialized functions of the metabolic process macroautophagy in higher eukaryotes, should allow us to target it for therapy development against immunopathologies and to improve vaccinations.
PMID: 19192248

[FunkOdyssey]

That's funny you mention oleuropein because I was looking at that same study today too (I'm taking olive leaf extract and reading up on it). However, I don't know if works this way in vivo, because oleuropein does not seem to make it into circulation. Oleuropein is metabolized to hydroxytyrosol in the gut, and when oleurpein is administered to humans, it is recovered as hydroxytyrosol in urine:

Free Radic Res. 2006 Jun;40(6):647-58.Click here to read Links
The fate of olive oil polyphenols in the gastrointestinal tract: implications of gastric and colonic microflora-dependent biotransformation.
Corona G, Tzounis X, Assunta Dessì M, Deiana M, Debnam ES, Visioli F, Spencer JP.

Molecular Nutrition Group, School of Food Biosciences, University of Reading, UK.

We have conducted a detailed investigation into the absorption, metabolism and microflora-dependent transformation of hydroxytyrosol (HT), tyrosol (TYR) and their conjugated forms, such as oleuropein (OL). Conjugated forms underwent rapid hydrolysis under gastric conditions, resulting in significant increases in the amount of free HT and TYR entering the small intestine. Both HT and TYR transferred across human Caco-2 cell monolayers and rat segments of jejunum and ileum and were subject to classic phase I/II biotransformation. The major metabolites identified were an O-methylated derivative of HT, glucuronides of HT and TYR and a novel glutathionylated conjugate of HT. In contrast, there was no absorption of OL in either model. However, OL was rapidly degraded by the colonic microflora resulting in the formation of HT. Our study provides additional information regarding the breakdown of complex olive oil polyphenols in the GI tract, in particular the stomach and the large intestine.

PMID: 16753843

J Nutr. 2002 Mar;132(3):409-17.Click here to read Links
Olive oil phenols are absorbed in humans.
Vissers MN, Zock PL, Roodenburg AJ, Leenen R, Katan MB.

Division of Human Nutrition and Epidemiology, Wageningen University, Wageningen, The Netherlands.

Animal and in vitro studies suggest that olive oil phenols are effective antioxidants. The most abundant phenols in olive oil are the nonpolar oleuropein- and ligstroside-aglycones and the polar hydroxytyrosol and tyrosol. The aim of this study was to gain more insight into the metabolism of those phenols in humans. We measured their absorption in eight healthy ileostomy subjects. We also measured urinary excretion in the ileostomy subjects and in 12 volunteers with a colon. Subjects consumed three different supplements containing 100 mg of olive oil phenols on separate days in random order. Ileostomy subjects consumed a supplement with mainly nonpolar phenols, one with mainly polar phenols and one with the parent compound oleuropein-glycoside. Subjects with a colon consumed a supplement without phenols (placebo) instead of the supplement with oleuropein-glycoside. Ileostomy effluent and urine were collected for 24 h after supplement intake. Tyrosol and hydroxytyrosol concentrations were low (< 4 mol/100 mol of intake) in the ileostomy effluent, and no aglycones were detected. We estimated that the apparent absorption of phenols was at least 55-66% of the ingested dose. Absorption was confirmed by the excretion of tyrosol and hydroxytyrosol in urine. In ileostomy subjects, 12 mol/100 mol and in subjects with a colon, 6 mol/100 mol of the phenols from the nonpolar supplement were recovered in urine as tyrosol or hydroxytyrosol. In both subject groups, 5--6 mol/100 mol of the phenols was recovered from the polar supplement. When ileostomy subjects were given oleuropein-glycoside, 16 mol/100 mol was recovered in 24-h urine, mainly in the form of hydroxytyrosol. Thus, humans absorb a large part of ingested olive oil phenols and absorbed olive oil phenols are extensively modified in the body.

PMID: 11880564

But that's alright, because hydroxytyrosol is an awesome compound in its own right and a legitimate challenger of resveratrol in its health benefits.

[100YearsToGo]

Along these lines, I stumbled across this paper about oleuropein, a constituent of olive oil, found in significant quantity in olive leaf extract.

Rejuvenation Res. 2007 Jun;10(2):157-72.
The olive constituent oleuropein exhibits proteasome stimulatory properties in vitro and confers life span extension of human embryonic fibroblasts.

Katsiki M, Chondrogianni N, Chinou I, Rivett AJ, Gonos ES.
Institute of Biological Research and Biotechnology, Laboratory of Molecular and Cellular Aging, National Hellenic Research Foundation, Athens, Greece.

Normal human fibroblasts undergo replicative senescence due to both genetic and environmental factors. Senescence and aging can be further accelerated by exposure of cells to a variety of oxidative agents that contribute among other effects to the accumulation of damaged proteins. The proteasome, a multicatalytic nonlysosomal protease, has impaired function during aging, while its increased expression delays senescence in human fibroblasts. The aim of this study was to identify natural compounds that enhance proteasome activity and exhibit antiaging properties. We demonstrate that oleuropein, the major constituent of Olea europea leaf extract, olive oil and olives, enhances the proteasome activities in vitro stronger than other known chemical activators, possibly through conformational changes of the proteasome. Moreover, continuous treatment of early passage human embryonic fibroblasts with oleuropein decreases the intracellular levels of reactive oxygen species (ROS), reduces the amount of oxidized proteins through increased proteasome-mediated degradation rates and retains proteasome function during replicative senescence. Importantly, oleuropein-treated cultures exhibit a delay in the appearance of senescence morphology and their life span is extended by approximately 15%. In summary, these data demonstrate the beneficial effect of oleuropein on human fibroblasts undergoing replicative senescence and provide new insights towards enhancement of cellular antioxidant mechanisms by natural compounds that can be easily up-taken through normal diet.
PMID: 17518699

And, speaking of the relationship between autophagy and immune function...

Traffic. 2009 Jan 24. [Epub ahead of print]
Macroautophagy in immunity and tolerance.
Gannagé M, Münz C.
Viral Immunobiology, Institute of Experimental Immunology, University Hospital of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Autophagy and proteasomal degradation constitute the two main catabolic pathways in cells. While the proteasome degrades primarily short-lived soluble proteins, macroautophagy, the main constitutive autophagic pathway, deliver cell organelles and protein aggregates for lysosomal degradation. Both the proteasome and macroautophagy are attractive effector mechanisms for the immune system, because they can be used to degrade foreign substances, including pathogenic proteins, within cells. Therefore, both innate and adaptive immune responses use these pathways, for intracellular clearance of pathogens as well as presentation of pathogen fragments to the adaptive immune system. Since, however, the same mechanisms are used for the steady-state turnover of cellular self-components, the immune system has to be desensitized in order not to recognize these. Therefore, proteasomal degradation and macroautophagy are also involved in tolerizing the immune system prior to pathogen encounter. We will discuss recent advances in our understanding how macroautophagy selects self-structures in the steady-state, how presentation of these on MHC class II molecules leads to tolerance, and how macroautophagy assists both innate and adaptive immunity. This new knowledge on the specialized functions of the metabolic process macroautophagy in higher eukaryotes, should allow us to target it for therapy development against immunopathologies and to improve vaccinations.
PMID: 19192248

Helathy autophagic function is definitely important to fight deseases including cancers.

"Mounting evidence indicates that alterations of autophagy processes are directly involved in the development of many human diseases, including cancers. Autophagy-related gene (ATG) products are main players in the autophagy process"

http://www.ncbi.nlm....8?dopt=Abstract

[100YearsToGo]

Just some F.Y.I. stuff.

Chaperone Mediated Autophagy:

It appear the thing functions as follows:

Protein substrates* are delivered to the surface of lysosomes** by a chaperone, the 70 kDa heat shock cognate protein (hsc70). hsc70. promotes the interaction of the substrates with a receptor protein at the lysosomal membrane, the lysosome-associated membrane protein type 2A (LAMP-2A) . Then the protein gets unfolded and is translocated to the lumen*** with the help of a luminal-resident chaperone (lys-hsc70). (1)

This is the form of autophagy that renewed the old mouse liver and with all probability will extend life if fixed.

The rate limiting factor here is Lamp-2A, that is a protein transcripted through the gene Lamp2. However the decreased levels of LAMP-2A with age is not a consequence of transcriptional downregulation. The transcription power remains the same in old age (2).

What appear to be going on in aged individuals is:

a) While Lamp-2A is present in the lumen, it is not retreived in sufficient numbers to the lysomal membrane making the whole CMA process to bog down (2). This appears to be because of some defect in the membrane that stop Lamp-2A to associate with the membrane.
b) Apparantly because Lamp-2A can not associate, an abnormal accelerated degradation of LAMP-2A sets in in the lumen. reducing overall Lamp-2A levels in the cell. making the situation even worse.

This could be solved by a supplement as follows:

- The supplement fixing this must work either directly or indirectly on the lysomal membrane to fix the defect. What would be good for the lysomal membrane?
- The supplement could increase the Lamp-2A protein in cells. A Lamp-2A increase appears to have worked for the Lamp2A mouse (2), as it kept Lamp-2A level up through old age.


1 http://www.ncbi.nlm....Pubmed_RVDocSum

2 http://jcs.biologist.../full/120/5/782


* Substrate: junk protein, ** Lysosome: organelle that contain digestive enzymes ,*** lumen: (space inside the lysosome)

[remig]

Non-selective macro and micro autophagy is used by cells when the supply of nutrients by the body is inadequate. The body must supply calories, essential fatty acids, and the essential amino acids required for protein synthesis. Whenever the supply is inadequate, the cell must then acquire the missing nutrients by recycling some portion of itself.

In non-selective autophagy (not CMA), some portion of the cell's cytoplasm is enclosed in a membrane. The membrane may be the lysosome's own membrane (in which case it is termed microautophagy) or another membrane generated for just that purpose (in which case it is call macroautophagy.) In macroautophagy, the vesicle so formed then merges with lysosomes and the end result of the two forms of autophagy is the same, some portion of the cytoplasm, including even entire organelles such as mitochondria, is digested and the constituent molecules made available for the anabolic processes of the cell.

A shortage of any essential structural nutrient induces autophagy. Creating a shortage of essential amino acids (leucine in particular) is a standard way to induce to induce autophagy in free cell culture (nitrogen starvation). Anybody can do the same by restricting protein in the diet for some period of time. I have an on-line monograph on just this subject if anyone is interested.

By alternating periods of protein restriction with periods of protein abundance, repeated induction of autophagy could clear the aggregates associated with AD, PD, HD and ALS and maybe even clear cryptic infections. A protein cycling diet is much easier to follow than a calories restriction diet.