134 replies to this topic

[okok]

Note: I've been taking trehalose for a couple of months. During this period I've noticed better memory, brain stays alert even after a tiresome day. Can endure heavy friday drinking without colapsing the following day. Placebo?

I'm thinking ordering some. Did anyone else notice benefits?

[Athanasios]

Here's what I actually decided to try:

http://www.imminst.o...&...st&p=306801

Cliff notes: three 24 hour fasts per week (36 hour protein fasts), with 250mg micronized tween80-dissolved resveratrol 2x daily and 750mg nano-sized sesame oil-dissolved curcumin 2x daily during the fasting days.

What are your thoughts on exercise timing and IF. Resistance training before the last meal maybe?

Also, melatonin. I have been thinking of using this during fast days as well but do not know if itt will screw things up. During ramadan melatonin is lower than normal and it is also affects mtor. Thoughts?

[FunkOdyssey]

I would exercise in the middle of an eating period if possible. I have no idea how melatonin plays into this.

[Mind]

CMA isn't going to work too well when your lysosomes are clogged full of lipofuscin. Support this research and we will learn a lot more about how lipofuscin affects aging and perhaps see a new anti-aging therapy developed.

[JLL]

Does this have any relevance to oral vitamin C?

Intracellular accumulation of damaged or abnormal proteins is a common event associated with numerous neurodegenerative diseases and other age-related pathologies. Increasing the activity of the intracellular proteolytic systems normally responsible for the removal of these abnormal proteins might be beneficial in lessening the severity or development of those pathologies. In this study we have used human astrocyte glial cells to investigate the effect of vitamin C (ascorbate) on the intracellular turnover of proteins. Supplementation of the culture medium with physiological concentrations of vitamin C did not affect protein synthesis, but did increase the rate of protein degradation by lysosomes. Vitamin C accelerated the degradation of intra- and extracellular proteins targeted to the lysosomal lumen by autophagic and heterophagic pathways. At the doses analyzed, vitamin C lowered and stabilized the acidic intralysosomal pH at values that result in maximum activation of the lysosomal hydrolases

.

http://www3.intersci...l...=1&SRETRY=0

[Lufega]

Autophagy in mouse hepatocytes induced by lysine acetylsalicylate.

Aguas AP, Soares JO, Nunes JF.

I.v. administration of lysine acetylsalicylate induces autophagy in mouse liver cells. Single and multiple membrane-bounded vacuoles were found. The latter seems to be an unusual morphological form of the sequestration process. These findings could express a transitory sublethal liver cell injury induced by the drug.

The autophagy induced here was so strong it actually damaged the liver cells?

[Lufega]

Superoxide is the major reactive oxygen species regulating autophagy.

Chen Y, Azad MB, Gibson SB.
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada.

Autophagy is involved in human diseases and is regulated by reactive oxygen species (ROS) including superoxide (O(2)(*-)) and hydrogen peroxide (H(2)O(2)). However, the relative functions of O(2)(*-) and H(2)O(2) in regulating autophagy are unknown. In this study, autophagy was induced by starvation, mitochondrial electron transport inhibitors, and exogenous H(2)O(2). We found that O(2)(*-) was selectively induced by starvation of glucose, L-glutamine, pyruvate, and serum (GP) whereas starvation of amino acids and serum (AA) induced O(2)(*-) and H(2)O(2). Both types of starvation induced autophagy and autophagy was inhibited by overexpression of SOD2 (manganese superoxide dismutase, Mn-SOD), which reduced O(2)(*-) levels but increased H(2)O(2) levels. Starvation-induced autophagy was also inhibited by the addition of catalase, which reduced both O(2)(*-) and H(2)O(2) levels. Starvation of GP or AA also induced cell death that was increased following treatment with autophagy inhibitors 3-methyladenine, and wortamannin. Mitochondrial electron transport chain (mETC) inhibitors in combination with the SOD inhibitor 2-methoxyestradiol (2-ME) increased O(2)(*-) levels, lowered H(2)O(2) levels, and increased autophagy. In contrast to starvation, cell death induced by mETC inhibitors was increased by 2-ME. Finally, adding exogenous H(2)O(2) induced autophagy and increased intracellular O(2)(*-) but failed to increase intracellular H(2)O(2). Taken together, these findings indicate that O(2)(*-) is the major ROS-regulating autophagy.

[Lufega]

Glutamine increases autophagy under Basal and stressed conditions in intestinal epithelial cells.

Sakiyama T, Musch MW, Ropeleski MJ, Tsubouchi H, Chang EB.
Martin Boyer Laboratories, University of Chicago IBD Research Center, Chicago, Illinois, USA.

BACKGROUND & AIMS: Glutamine plays a protective role in intestinal cells during physiologic stress; however, the protection mechanisms are not fully understood. Autophagy functions in bulk degradation of cellular components, but has been recognized recently as an important mechanism for cell survival under conditions of stress. We therefore sought to see if glutamine's actions involve the induction of autophagy in intestinal cells and, if so, the mechanisms that underlie this action. METHODS: Formation of microtubule-associated protein light chain 3 (LC3)-phospholipid conjugates (LC3-II) in rat intestinal epithelial IEC-18 cells and human colonic epithelial Caco-2(BBE) cells was determined by Western blotting and localized by confocal microscopy. Activation of mammalian target of rapamycin (mTOR) pathway, mitogen-activated protein (MAP) kinases, caspase-3, and poly (ADP-ribose) polymerase were monitored by Western blotting. RESULTS: Glutamine increased LC3-II as well as the number of autophagosomes. Glutamine-induced LC3-II formation was paralleled by inactivation of mTOR and p38 MAP kinase pathways, and inhibition of mTOR and p38 MAP kinase allowed LC3-II induction in glutamine-deprived cells. Under glutamine starvation, LC3-II recovery after heat stress or the increase under oxidative stress was blunted significantly. Glutamine depletion increased caspase-3 and poly (ADP-ribose) polymerase activity after heat stress, which was inhibited by treatment with inhibitors of mTOR and p38 MAP kinase. CONCLUSIONS: Glutamine induces autophagy under basal and stressed conditions, and prevents apoptosis under heat stress through its regulation of the mTOR and p38 MAP kinase pathways. We propose that glutamine contributes to cell survival during physiologic stress by induction of autophagy.

But this study says glutamine upregulates mTOR and this decreases autophagy?

Bidirectional transport of amino acids regulates mTOR and autophagy.

Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO.
Respiratory Diseases Area, Novartis Institutes for BioMedical Research, Novartis Horsham Research Centre, West Sussex, UK.

Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase which regulates protein translation, cell growth, and autophagy. Cell surface transporters that allow amino acids to enter the cell and signal to mTOR are unknown. We show that cellular uptake of L-glutamine and its subsequent rapid efflux in the presence of essential amino acids (EAA) is the rate-limiting step that activates mTOR. L-glutamine uptake is regulated by SLC1A5 and loss of SLC1A5 function inhibits cell growth and activates autophagy. The molecular basis for L-glutamine sensitivity is due to SLC7A5/SLC3A2, a bidirectional transporter that regulates the simultaneous efflux of L-glutamine out of cells and transport of L-leucine/EAA into cells. Certain tumor cell lines with high basal cellular levels of L-glutamine bypass the need for L-glutamine uptake and are primed for mTOR activation. Thus, L-glutamine flux regulates mTOR, translation and autophagy to coordinate cell growth and proliferation.

An amino acid shuffle activates mTORC1.

Cohen A, Hall MN.
Biozentrum, University of Basel, Basel, Switzerland.
The mammalian target of rapamycin complex 1 (mTORC1), which promotes cell growth, is regulated by specific nutrients such as the amino acid leucine. In this issue, Nicklin et al. (2009) describe a mechanism by which glutamine facilitates the uptake of leucine, leading to mTORC1 activation.

Glutamine, arginine, and leucine signaling in the intestine.

Marc Rhoads J, Wu G.
Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX 77030, USA. J.Marc.Rhoads@uth.tmc.edu

Glutamine and leucine are abundant constituents of plant and animal proteins, whereas the content of arginine in foods and physiological fluids varies greatly. Besides their role in protein synthesis, these three amino acids individually activate signaling pathway to promote protein synthesis and possibly inhibit autophagy-mediated protein degradation in intestinal epithelial cells. In addition, glutamine and arginine stimulate the mitogen-activated protein kinase and mammalian target of rapamycin (mTOR)/p70 (s6) kinase pathways, respectively, to enhance mucosal cell migration and restitution. Moreover, through the nitric oxide-dependent cGMP signaling cascade, arginine regulates multiple physiological events in the intestine that are beneficial for cell homeostasis and survival. Available evidence from both in vitro and in vivo animal studies shows that glutamine and arginine promote cell proliferation and exert differential cytoprotective effects in response to nutrient deprivation, oxidative injury, stress, and immunological challenge. Additionally, when nitric oxide is available, leucine increases the migration of intestinal cells. Therefore, through cellular signaling mechanisms, arginine, glutamine, and leucine play crucial roles in intestinal growth, integrity, and function.

[Lufega]

Nicotinamide enhances mitochondria quality through autophagy activation in human cells.

Kang HT, Hwang ES.
Department of Life Science, University of Seoul, Dongdaemungu, Jeonnongdong, Republic of Korea.

Nicotinamide (NAM) treatment causes a decrease in mitochondrial respiration and reactive oxygen species production in primary human fibroblasts and extends their replicative lifespan. In the current study, it is reported that NAM treatment induces a decrease in mitochondrial mass and an increase in membrane potential (DeltaPsim) by accelerating autophagic degradation of mitochondria. In the NAM-treated cells, the level of LC3-II as well as the number of LC3 puncta and lysosomes co-localizing with mitochondria substantially increased. Furthermore, in the NAM-treated cells, the levels of Fis1, Drp1, and Mfn1, proteins that regulate mitochondrial fission and fusion, increased and mitochondria experienced dramatic changes in structure from filaments to dots or rings. This structural change is required for the decrease of mitochondrial mass indicating that NAM accelerates mitochondrial autophagy, at least in part, by inducing mitochondrial fragmentation. The decrease in mitochondria mass was attenuated by treatment with cyclosporine A, which prevents the loss of mitochondrial membrane potential by blocking the mitochondrial permeability transition, suggesting autophagic degradation selective for mitochondria with low DeltaPsim. All these changes were accompanied by and dependent on an increase in the levels of GAPDH, and are blocked by inhibition of the cellular conversion of NAM to NAD(+). Taken together with our previous findings, these results suggest that up-regulation of GAPDH activity may prolong healthy lifespan of human cells through autophagy-mediated mitochondria quality maintenance.

Edited by Lufega, 07 October 2009 - 04:35 AM.

[100YearsToGo]

Nicotinamide enhances mitochondria quality through autophagy activation in human cells.

Kang HT, Hwang ES.
Department of Life Science, University of Seoul, Dongdaemungu, Jeonnongdong, Republic of Korea.

Nicotinamide (NAM) treatment causes a decrease in mitochondrial respiration and reactive oxygen species production in primary human fibroblasts and extends their replicative lifespan. In the current study, it is reported that NAM treatment induces a decrease in mitochondrial mass and an increase in membrane potential (DeltaPsim) by accelerating autophagic degradation of mitochondria. In the NAM-treated cells, the level of LC3-II as well as the number of LC3 puncta and lysosomes co-localizing with mitochondria substantially increased. Furthermore, in the NAM-treated cells, the levels of Fis1, Drp1, and Mfn1, proteins that regulate mitochondrial fission and fusion, increased and mitochondria experienced dramatic changes in structure from filaments to dots or rings. This structural change is required for the decrease of mitochondrial mass indicating that NAM accelerates mitochondrial autophagy, at least in part, by inducing mitochondrial fragmentation. The decrease in mitochondria mass was attenuated by treatment with cyclosporine A, which prevents the loss of mitochondrial membrane potential by blocking the mitochondrial permeability transition, suggesting autophagic degradation selective for mitochondria with low DeltaPsim. All these changes were accompanied by and dependent on an increase in the levels of GAPDH, and are blocked by inhibition of the cellular conversion of NAM to NAD(+). Taken together with our previous findings, these results suggest that up-regulation of GAPDH activity may prolong healthy lifespan of human cells through autophagy-mediated mitochondria quality maintenance.

Thanks Lufega.

This is very nice. I'm still taking niacinamide, Trehalose and Curcumin. Nice combo in my opinion. Surprised to see this thread alive and kicking.

[Lufega]

As far as increasing Trehalose absorption, it's logical to find ways to inhibit trehalase, the enzyme that splits it into two glucose molecues. A quick search on Pubmed yielded many unfamiliar substances that can do this but none are common and readily available. Trehalase is a a glycosidase hydrolase (glycosidases). type of enzyme as is Hyaluronidase, the enzyme that degrades hyaluronic acid.

Glycoside hydrolases are typically named after the substrate that they act upon. Thus glucosidases catalyze the hydrolysis of glucosides and xylanases catalyze the cleavage of the xylose based homopolymer xylan. Other examples include lactase, amylase, chitinase, sucrase, maltase, neuraminidase, invertase, hyaluronidase and lysozyme.

I've found a few substances that can inhibit Hyaluronidase and I wonder if they will have any effect on Trehalase. Doing this would probably increase diarrhea so I wonder if anything would be absorbed. A trehalase deficiency is blamed for why some people cannot eat mushrooms, which a high in trehalose.

Effect of tannic acid on brush border disaccharidases in mammalian intestine.

Chauhan A, Gupta S, Mahmood A.
Department of Biochemistry, Panjab University, Chandigarh 160 014, India.

Tannic acid is a glucoside (penta-m-digallolyl-glucose), which exhibits a wide variety of physiological functions. Around neutral pH, 0.4 mM tannic acid produced 84% inhibition of rat brush border sucrase activity, but 35-40% enzyme inhibition was observed in the rabbit intestine at 0.08 mM concentration. In the mice, 74-77% enzyme inhibition was observed at 0.05 mM concentration of tannic acid. The observed inhibition was reversible in rat intestine. Tannic acid (0.2 mM) also inhibited lactase (18% in adult and 71% in suckling animals), maltase (76%) and trehalase (88%) activities in rat intestine. pH versus activity curves showed that 0.2 mM tannic acid inhibited enzyme activity in rat by 91% at pH 5.5 which was reduced to 14% at pH 8.5 compared to the respective controls. In the rabbit 18-60% enzyme inhibition was noticed below pH 7.0, however at pH 8.5, it was of the order of 38%. Kinetic analysis revealed that tannic acid is a competitive inhibitor of rat brush border sucrase at pH 6.8. Effect of tannic acid together with various -SH group reacting reagents revealed that the enzyme inhibition is additive in nature, suggesting the distinct nature of binding sites on the enzyme for these compounds. The results suggest that tannic acid is a potent inhibitor of intestinal brush border disaccharidases, and could modulate the intestinal functions.

Maybe taking Trehalose with say, Triphala, can increase absorption???

Edited by Lufega, 12 October 2009 - 12:55 AM.

[VespeneGas]

Nicotinamide enhances mitochondria quality through autophagy activation in human cells.

Kang HT, Hwang ES.
Department of Life Science, University of Seoul, Dongdaemungu, Jeonnongdong, Republic of Korea.

Nicotinamide (NAM) treatment causes a decrease in mitochondrial respiration and reactive oxygen species production in primary human fibroblasts and extends their replicative lifespan. In the current study, it is reported that NAM treatment induces a decrease in mitochondrial mass and an increase in membrane potential (DeltaPsim) by accelerating autophagic degradation of mitochondria. In the NAM-treated cells, the level of LC3-II as well as the number of LC3 puncta and lysosomes co-localizing with mitochondria substantially increased. Furthermore, in the NAM-treated cells, the levels of Fis1, Drp1, and Mfn1, proteins that regulate mitochondrial fission and fusion, increased and mitochondria experienced dramatic changes in structure from filaments to dots or rings. This structural change is required for the decrease of mitochondrial mass indicating that NAM accelerates mitochondrial autophagy, at least in part, by inducing mitochondrial fragmentation. The decrease in mitochondria mass was attenuated by treatment with cyclosporine A, which prevents the loss of mitochondrial membrane potential by blocking the mitochondrial permeability transition, suggesting autophagic degradation selective for mitochondria with low DeltaPsim. All these changes were accompanied by and dependent on an increase in the levels of GAPDH, and are blocked by inhibition of the cellular conversion of NAM to NAD(+). Taken together with our previous findings, these results suggest that up-regulation of GAPDH activity may prolong healthy lifespan of human cells through autophagy-mediated mitochondria quality maintenance.

I smell a promising cycle. Quercetin/resveratrol to induce mitochondrial biogenesis, followed by niacinamide to help prune defective mitochondria. Add a dash of methylene blue, and you instantly become impervious to bullets and capable of flight.

Edit: hmmm, it would appear that tannins =| tannic acid. Wow that sucker has a lot of alcohol groups!

 375px_Tannic_acid.svg.png   18.48KB   20 downloads

Edited by VespeneGas, 12 October 2009 - 03:49 AM.

[Lufega]

Superoxide is the major reactive oxygen species regulating autophagy.
Chen Y, Azad MB, Gibson SB.

Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada.

Autophagy is involved in human diseases and is regulated by reactive oxygen species (ROS) including superoxide (O(2)(*-)) and hydrogen peroxide (H(2)O(2)). However, the relative functions of O(2)(*-) and H(2)O(2) in regulating autophagy are unknown. In this study, autophagy was induced by starvation, mitochondrial electron transport inhibitors , and exogenous H(2)O(2). We found that O(2)(*-) was selectively induced by starvation of glucose, L-glutamine, pyruvate, and serum (GP) whereas starvation of amino acids and serum (AA) induced O(2)(*-) and H(2)O(2). Both types of starvation induced autophagy and autophagy was inhibited by overexpression of SOD2 (manganese superoxide dismutase, Mn-SOD), which reduced O(2)(*-) levels but increased H(2)O(2) levels. Starvation-induced autophagy was also inhibited by the addition of catalase, which reduced both O(2)(*-) and H(2)O(2) levels. Starvation of GP or AA also induced cell death that was increased following treatment with autophagy inhibitors 3-methyladenine, and wortamannin. Mitochondrial electron transport chain (mETC) inhibitors in combination with the SOD inhibitor 2-methoxyestradiol (2-ME) increased O(2)(*-) levels, lowered H(2)O(2) levels, and increased autophagy. In contrast to starvation, cell death induced by mETC inhibitors was increased by 2-ME. Finally, adding exogenous H(2)O(2) induced autophagy and increased intracellular O(2)(*-) but failed to increase intracellular H(2)O(2). Taken together, these findings indicate that O(2)(*-) is the major ROS-regulating autophagy.

From this study, it seems that manganese inhibits autophagy. Also, Methylene blue, by increasing the function of mETC will also inhibit autophagy. I've read of people using exogenous hydrogen peroxide, maybe this is one of the mechanisms why it makes people feel better. Does anyone do this?? So, adding lithium, curcumin, H2o2, nicotinamide only on fast days will enhance Autophagy further?...

[EricR]

Hello,

I was researching trehalose and found this thread. My interest is in using trehalose to treat Huntington's disease.

After reading the thread I can see that many participants are knowledgeable in chemistry and biochemistry. I am hoping that you might be able to comment on the feasibility of an idea I had about how to increase the amount of trehalose getting to parts of the body where it can do some good (specifically the brain).

The idea is to inhale the trehalose.

The reason this comes to mind is because there are many examples of substances being inhaled that affect brain: nicotine from cigarettes, paint fumes, glue fumes, cocaine, etc. Doing some research I found there is even a form of inhale-able glucose that is used to image the brain. Here's a description:

PET Scan (Positron Emission Tomography)
PET scanning (positron emission tomography) is based on the fact that the brain uses glucose for energy. By labeling a glucose molecule with a radioactive "tag," and then inhaling radioactive glucose and placing the patient's head under a large geiger counter, one can identify abnormal areas of the brain that are underutilizing glucose. Because cyclotrons are needed to generate the radioactive gas, PET scanning is not widely available.

The info above comes from this page:
http://www.braininju...diagnostic.html

From this we know that inhaled glucose can go directly to the brain. I wonder if trehalose can too? One way to know for sure would be to do a PET scan using tagged trehalose molecules. This might make a good research project for someone who has the necessary resources.

Any thoughts?

Thanks,

Eric

PS

I posted something similar on a Huntington's disease forum last week. Here's a link: http://www.hdac.org/...ead.php?5,58897

[Fred_CALICO]

The sublingual ...