134 replies to this topic

[bkaz]

There must be a reason the vertebrates lost the capacity to produce Trehalose? Perhaps, as a chemical chaperone, it slows down functional interactions among proteins?

If that were so, we'd see such effects in experiments and tests. So far it seems pretty safe and advantageous, and is broken down just fine by the body.

Most likely vertebrates don't make it because there is no need. Doing so would be a loss of energy for too little gain. For instance, humans do not naturally make vitamin C, but goats and other vertebrates do. We, humans, have lost a lot of the metabolic capacity that even other higher vertebrates have. Vitamin C is obviously essential for us, so why don't we make it? Probably because we get enough of it in our food with our omnivore diet, so getting rid of its production saves on energy to make other things, like a big brain. That's all just my theory though, lol.

Well, there're a lot of different interaction among proteins, we can't test for them all. We don't make vit.C because we used to to get plenty from the diet, but that's not the case with trehalose, especially since "it is broken down just fine by the body..". It would be very easy for for the vertebrates to preserve the ability to synthesize trehalose from starch if it was so "safe and advantageous"?

Erm.. I think you missed my point? We can get it in our diet, considering plants, fungi, and insects make it (all sources of human food, yes, even insects haha; also why we have a metabolic enzyme specific for it). Just because we don't make it doesn't actually mean anything. It's like saying we don't need half of the 20 (actually 22) essential amino acids because we can't synthesize them anymore. Or even more relevant an example, look at bioflavanoids and how many beneficial effects they give -- only plants synthesize them, just like with trehalose, we don't synthesize them to conserve energy, not because they aren't useful.

And you can test for most every possible protein interaction that might be relevant. It's easy, just give trehalose to a rat or mouse at different concentrations and see what happens. Apparently, they do just fine, hence why it's been given GRAS (generally regarded as safe) status in the US and EU.

I suppose vertebrates did, historically, get trehalose from food (insects), but it's not nearly as ubiquitous as vit. C for primates. And, as you point out, they get rid of what they do get very thouroughly. We need to look at the results: do vertebrates have significant amounts of trehalose "in the system"? I think the answer is no, even though the metabolic expense of joining together two glucose molecules is insignificant, & they do have the enzyme to break it up. I don't question that trehlose is safe, probably even when it's "chaperoning" the proteins. But it may affect preformance, such as the speed of some enzymatic processes, especially in the brain. It's hard for me to imagine that it wouldn't: enzymes need to change shape & make physical contact to interact, & trehalose would get in the way.

[caston]

OK i'm going to drive everyone nuts here.

The cells autophagy machinery "declines with age" due to being attacked by intracelluar bacteria.

http://www.hubmed.or...i?uids=19164948

[100YearsToGo]

There must be a reason the vertebrates lost the capacity to produce Trehalose? Perhaps, as a chemical chaperone, it slows down functional interactions among proteins?

If that were so, we'd see such effects in experiments and tests. So far it seems pretty safe and advantageous, and is broken down just fine by the body.

Most likely vertebrates don't make it because there is no need. Doing so would be a loss of energy for too little gain. For instance, humans do not naturally make vitamin C, but goats and other vertebrates do. We, humans, have lost a lot of the metabolic capacity that even other higher vertebrates have. Vitamin C is obviously essential for us, so why don't we make it? Probably because we get enough of it in our food with our omnivore diet, so getting rid of its production saves on energy to make other things, like a big brain. That's all just my theory though, lol.

Well, there're a lot of different interaction among proteins, we can't test for them all. We don't make vit.C because we used to to get plenty from the diet, but that's not the case with trehalose, especially since "it is broken down just fine by the body..". It would be very easy for for the vertebrates to preserve the ability to synthesize trehalose from starch if it was so "safe and advantageous"?

Erm.. I think you missed my point? We can get it in our diet, considering plants, fungi, and insects make it (all sources of human food, yes, even insects haha; also why we have a metabolic enzyme specific for it). Just because we don't make it doesn't actually mean anything. It's like saying we don't need half of the 20 (actually 22) essential amino acids because we can't synthesize them anymore. Or even more relevant an example, look at bioflavanoids and how many beneficial effects they give -- only plants synthesize them, just like with trehalose, we don't synthesize them to conserve energy, not because they aren't useful.

And you can test for most every possible protein interaction that might be relevant. It's easy, just give trehalose to a rat or mouse at different concentrations and see what happens. Apparently, they do just fine, hence why it's been given GRAS (generally regarded as safe) status in the US and EU.

I suppose vertebrates did, historically, get trehalose from food (insects), but it's not nearly as ubiquitous as vit. C for primates. And, as you point out, they get rid of what they do get very thouroughly. We need to look at the results: do vertebrates have significant amounts of trehalose "in the system"? I think the answer is no, even though the metabolic expense of joining together two glucose molecules is insignificant, & they do have the enzyme to break it up. I don't question that trehlose is safe, probably even when it's "chaperoning" the proteins. But it may affect preformance, such as the speed of some enzymatic processes, especially in the brain. It's hard for me to imagine that it wouldn't: enzymes need to change shape & make physical contact to interact, & trehalose would get in the way.

Trehalose has the oposite effect. It does not get in the way, but stabilize the proteins and make folding faster. A cursory search on pubmed would show you this.

[FunkOdyssey]

OK i'm going to drive everyone nuts here.

The cells autophagy machinery "declines with age" due to being attacked by intracelluar bacteria.

http://www.hubmed.or...i?uids=19164948

I don't think that is the case. The example you've brought up shows how intracellular infection can actually induce autophagy as a defensive response by the cell. That's a good thing.

[caston]

OK i'm going to drive everyone nuts here.

The cells autophagy machinery "declines with age" due to being attacked by intracelluar bacteria.

http://www.hubmed.or...i?uids=19164948

I don't think that is the case. The example you've brought up shows how intracellular infection can actually induce autophagy as a defensive response by the cell. That's a good thing.

Yes, but then the bacteria that have the capability to attack the mechanisms of autophagy are more likely to survive. Over the life of an organism all its cells will slowly be taken over by bacteria as each defence mechanism is taken over or used against it. Bacteria that can shutdown or damage autophagy machinery may start off very rare but over time if this bacteria is successful is will spread to other cells.

It's like randomly mutating (or purposely written usually in this case) worms and computer viruses slowly spreading through every available means and platform exploiting every possible security hole default or misconfiguration and gradually taking over networks and computers and routers on the internet.
Sometimes the security mechanisms themselves have weaknesses like dropping in an exploit while negotiating an encrypted connection or taking over the anti-virus software.

How does your regimen affect your intracellular bacteria? I hope it's doing well for you and killing all of it.

Edited by caston, 10 March 2009 - 03:07 PM.

[FunkOdyssey]

Thanks, I hope so too.

Actually as I think about it more you may be on to something. I don't think this is typically the reason for the aging and deterioration of autophagy functions, that is a result of aging itself. But intracellular infections can play a role in making it even worse. I know with my own favorite bacteria, borrelia burgdorferi secretes proteins which can deactivate the lysozome.

Edited by FunkOdyssey, 10 March 2009 - 03:10 PM.

[caston]

Thanks, I hope so too.

Actually as I think about it more you may be on to something. I don't think this is typically the reason for the aging and deterioration of autophagy functions, that is a result of aging itself. But intracellular infections can play a role in making it even worse. I know with my own favorite bacteria, borrelia burgdorferi secretes proteins which can deactivate the lysozome and then it has been suggested that it can sometimes survive ingestion / digestion by the lysozome and basically set up shop in there. So there are at least a couple ways that this single organism can disable autophagy in a given cell.

Funk: I'd never heard of that before. I thought the lysosome would mince up anything that got into it. If a bacteria can survive inside the lysosome and really screw it up that's not good. I'll have to do some more reading on borrelia burgdorferi. I hope I don't have any !
edit:
oh it's the one that causes Lyme you were being sarcastic about it being your favorite. I'm sorry to hear about this but I'm enthusiastic and optimistic that you will beat it.

Edited by caston, 10 March 2009 - 03:13 PM.

[FunkOdyssey]

I removed that part of my reply (survival of the bacteria within the lysozome) because although I remember reading it somewhere, I can't find a reference.

[caston]

OK well I'll leave my post there.. Maybe we'll find the reference but it's bedtime for me now

edit: ok this is a little slack of me but here is the hubmed search:

http://www.hubmed.or...i...e&sort=date

Edited by caston, 11 March 2009 - 03:01 AM.

[remig]

I removed that part of my reply (survival of the bacteria within the lysozome) because although I remember reading it somewhere, I can't find a reference.

Here is a possible reference on Borrelia. I find the journal Autophagy to be the best place to find relevant articles or links on the subject of autophagy (not surprising).

Any way, the lysosome is not itself deactivated, just its ability to fuse with the particular autophageosome that is harboring the pathogen. The bacterium resides within the autophageosome and inhibits the process that leads to lysosomes fusing with the autophageosome. The bacterium initially enters the cell by inducing endocytosis at the cell surface. The resulting single-membraned endosome containing the bacterium then fuses with the double-membraned autophageosome.

The virus that causes dengue fever, and many, many other pathogens use the same mechanism. Promoting autophagy by protein or calorie cycling might then clear out the chronic infection. Cycling seems to me to be better than a chemical inducer since autophagy is then actually serving the purpose for which it is designed rather than in consequence of the cell being tricked into doing something unnecessary. With a chemical inducer, the resulting surplus of lipids and amino acids would likely suppress further autophagy. That would not, however, be the case with cycling.

[FunkOdyssey]

The virus that causes dengue fever, and many, many other pathogens use the same mechanism. Promoting autophagy by protein or calorie cycling might then clear out the chronic infection. Cycling seems to me to be better than a chemical inducer since autophagy is then actually serving the purpose for which it is designed rather than in consequence of the cell being tricked into doing something unnecessary. With a chemical inducer, the resulting surplus of lipids and amino acids would likely suppress further autophagy. That would not, however, be the case with cycling.

I'm probably going to break down and attempt some form of intermittent fasting to clear out intracellular garbage and for overall health. Protein cycling seems like a half-measure to me (no offense to the author of the excellent protein cycling diet guide). I don't think alternate day fasting would be feasible in my case, because I do not want to lose any weight and it seems improbable that I would be able to comfortably eat and digest 200% of my normal calories every other day. I think two fasting days per week would probably allow maintenance of weight.

I notice that alternate day fasting is frequently touted as curing autoimmune diseases and I suspect it is by this mechanism: elimination of the persistent intracellular infection that provokes autoimmunity.

Edited by FunkOdyssey, 11 March 2009 - 05:56 PM.

[FunkOdyssey]

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.

[remig]

I know Cuervo finds that only CMA promotion extends mice life-spans.

After a closer reading of the Cuervo paper, I see that she does not, in fact, find that only CMA is producing benefits. Her methodology directly measures a CMA substrate, and so her data is positive for CMA upregulation. But that does not rule out that the benefit is actually coming, in whole or in part, from a concomitant effect, namely non-selective autophagy. The upregulated (in effect) protein, LAMP-2a, is involved with lysosome fusion with autophagosomes as well as with CMA. She even observes that non-selective bulk autophagy is also upregulated:

In fact, analysis of several different indirect markers suggests that these mice also showed improved macroautophagic [non-selective] activity. Reduced autophagy of mitochondria is in part responsible for mitochondrial dysfunction in aged organisms16. In agreement with previous reports, we observed extensive accumulation of double-membrane vesicles with recognizable cargo (autophagosomes) in livers of aged wild-type mice (Fig. 3b), which has been attributed to problems in autophagosome clearance by lysosomes that increase with age17. In contrast, the ratio of autophagosomes (before lysosomal fusion) to autophagolysosomes (after lysosomal fusion) in the early activated aged transgenic mice was closer to that detected in young mice (Fig. 3b). Although to a lesser degree, late activation of the transgene also improved macroautophagic flow. Higher amounts of the macroautophagy effector Atg5- Atg12 and lower amounts of LC3-II, an autophagosome marker, in the aged transgenic mice livers were also indirect evidence of more efficient macroautophagy activation and autophagosome clearance, respectively, in these mice (Supplementary Fig. 8 online). Furthermore, the characteristic decrease in the amount of total liver proteins after 6 h of starvation, which is mostly due to the bulk degradation of proteins and organelles by macroautophagy, was markedly reduced in aged wild-type mice but not in transgenic littermates (Supplementary Fig. 8d). These results indirectly support preservation of appropriate starvation-induced macroautophagy in the livers of the aged transgenic mice.

[100YearsToGo]

Those trying to induce CMA autophagy to benefit from the findings of Cuervo, either through supplementation or fasting, should consider avoiding vitamin E.

At least that could be concluded based on this study and if it translates unchanged to humans.;

http://www.ncbi.nlm....ogdbfrom=pubmed

Don't know if it is related to this:

http://www.newscient...sten-death.html

Edited by 100YearsToGo, 05 April 2009 - 01:40 AM.

[100YearsToGo]

New fat fighting pathway discovered:

"In studies of liver cells in culture and in live animals, Dr. Czaja and his colleagues discovered that lysosomes do something never before observed: continuously remove portions of lipid droplets and process them for energy production."

http://www.scienceda...90401145310.htm

the study:

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

[TheFountain]

Is this a good buy for Trehalose?

http://www.swansonvi...ELAID=314643440

Edit: since trehalose is known to be used for this purpose, I thought it appropriate to post this here.

Edited by TheFountain, 05 April 2009 - 02:17 AM.

[100YearsToGo]

Is this a good buy for Trehalose?

http://www.swansonvi...ELAID=314643440

Edit: since tehalose is known to be used for this purpose, I thought it appropriate to post this here.

Looks good. but I buy mine here:

http://www.brooklynp...nd.html?b=7&p=1

[tunt01]

Don't know if it is related to this:

http://www.newscient...sten-death.html

high doses of Vitamin E produces a free radical called the Tocopheroxyl radical.

overdosing on beta carotene, selenium, Vitamin E, Vitamin C and many other antioxidants/vitamins becomes counter productive at a certain point. they end up producing more free radicals than they take out.

on the autophagy part, I don't know. I read that also though. it made me think about when the best time of the day was to skip a meal, maybe lunch.

[100YearsToGo]

Don't know if it is related to this:

http://www.newscient...sten-death.html

high doses of Vitamin E produces a free radical called the Tocopheroxyl radical.

overdosing on beta carotene, selenium, Vitamin E, Vitamin C and many other antioxidants/vitamins becomes counter productive at a certain point. they end up producing more free radicals than they take out.

on the autophagy part, I don't know. I read that also though. it made me think about when the best time of the day was to skip a meal, maybe lunch.

What works in mice is reduction of dietary intake to 40 % or every other day ad libetum. I may try one of these strategies for a month. For now I'm doing trehalose and curcumin (with piperine).

[simon007]

How do you use trehalose?
Like a supplement? How much do you take per day?

Cheers,

Simon

[simon007]

How do you use trehalose?
Like a supplement? How much do you take per day?

Cheers,

Simon

Found this, a lot of info on autophagy

http://knol.google.c...e...&locale=en#

[tunt01]

ron has posted on this forum a couple times. i bought a copy of his book.

[FunkOdyssey]

You know the author himself posted that link two pages ago, in this very thread? Way to not read the thread before posting!

[simon007]

You know the author himself posted that link two pages ago, in this very thread? Way to not read the thread before posting!

OKe, oke better over informed than not informed at all :-) Sorry...

[caston]

Check this out!

http://www.hubmed.or...i?uids=19303905

[100YearsToGo]

How do you use trehalose?
Like a supplement? How much do you take per day?

Cheers,

Simon

Read the the thread I just use it as a replacement of sugar. Perfectly safe. It tastes the same.

[rwac]

Is there a dark side to Autophagy ?

It appears that autophagy is a form of Programmed Cell Death, and "...neuronal cell loss generally occurs via autophagy" in C. elegans.
Does Autophagy promote cell senescence ?


http://ouroboros.wor...y-on-the-brain/
http://www3.intersci...398434/abstract

… Analysing major cellular changes in the ageing nematode Caenorhabditis elegans has revealed a gradual, progressive deterioration of different tissues except for the nervous system, which remarkably preserves its integrity even in advanced old age. In addition, genetic data have shown that, in C. elegans and in the fruit fly Drosophila melanogaster, lifespan is controlled by signals derived from neurons and acting throughout adulthood. Organismal death thus seems to be a consequence of the decline of specific neurons. Accumulating evidence demonstrates that late onset of neuronal cell loss generally occurs via autophagy, a process in which eukaryotic cells self-digest parts of their contents during development or to survive starvation. Here we suggest that overactivation of autophagy in the cells of the nervous system is the eventual cause of "physiological" death.

Let us for the moment accept the idea that autophagy is an anti-aging force in mid-life, per the articles cited in the intro paragraph of this posting, but a pro-death force in late life, per the neuronal death mechanism described in the paper. (Antagonistic pleiotropy, anyone?)

By the former premise, it's tempting to think that in order to decrease age-related accumulation of cellular trash, we ought to increase autophagy (by CR, CR mimetics, anti-lipolytic drugs, or some other pharmaceutical mechanism) — however, by the latter premise, broad acceleration of autophagy could have deleterious consequences on the nervous system via activation of cell death pathways. ("We have some good news and bad news: You have the heart of a sixteen-year-old, but a brain made out of swiss cheese.")

Abstract
The regulation of ageing has been extensively studied in divergent animal model systems including worms, flies and mice. However, little is known about the cellular pathways that mediate the death of these organisms. Analysing major cellular changes in the ageing nematode Caenorhabditis elegans has revealed a gradual, progressive deterioration of different tissues except for the nervous system, which remarkably preserves its integrity even in advanced old age. In addition, genetic data have shown that, in C. elegans and in the fruit fly Drosophila melanogaster, lifespan is controlled by signals derived from neurons and acting throughout adulthood. Organismal death thus seems to be a consequence of the decline of specific neurons. Accumulating evidence demonstrates that late onset of neuronal cell loss generally occurs via autophagy, a process in which eukaryotic cells self-digest parts of their contents during development or to survive starvation. Here we suggest that overactivation of autophagy in the cells of the nervous system is the eventual cause of physiological death. BioEssays 28: 1126-1131, 2006. © 2006 Wiley Periodicals, Inc.

http://www.fightagin...-senescence.php

...autophagy and cellular senescence are closely linked - which suggests that if we want to cleverly increase autophagy to obtain long-term health benefits akin to those produced by calorie restriction, we can't just run in and pull the first lever we find, otherwise we may find ourselves even more riddled with senescent cells than usual as the years advance. Here's a paper on that subject:

Here we identify autophagy as a new effector mechanism of senescence. ... A subset of autophagy-related genes are up-regulated during senescence: Overexpression of one of those genes, ULK3, induces autophagy and senescence. Furthermore, inhibition of autophagy delays the senescence phenotype, including senescence-associated secretion [of those biochemicals that harm the local cellular environment]. Our data suggest that autophagy, and its consequent protein turnover, mediate the acquisition of the senescence phenotype.

Equally, I'm fairly certain that calorie restricted people are not more riddled with senescent cells than the rest of us, so there has to be a way to usefully enhance autophagy without dragging in undesirable results.

[JLL]

If that's the case, then why does intermittent fasting (protein restriction) increase BDNF, which protects brain neurons? Maybe there's good autophagy and bad autophagy.

[tunt01]

mark this down as too much of a good thing is bad. intermittent fasting is good. starvation is bad.


Autophagy begins in as little as 2 hrs after eating a meal. if you decide to eat a meal and then starve yourself for 20 days, my bold prediction is that your brain will become swiss cheese.

Edited by prophets, 14 July 2009 - 09:55 PM.

[rwac]

If that's the case, then why does intermittent fasting (protein restriction) increase BDNF, which protects brain neurons? Maybe there's good autophagy and bad autophagy.

Oh, there's definitely good and bad autophagy. The question is whether good autophagy over the long term promotes bad autophagy ...

Autophagy begins in as little as 2 hrs after eating a meal. if you decide to eat a meal and then starve yourself for 20 days, my bold prediction is that your brain will become swiss cheese.

I assume you're talking about brucester.


Although I do wonder. How much of the cytoplasm would a 20-day fast replace ?
Maybe Ron has some idea.

Edit: ketosis and exercise have already been mentioned in this thread.

Edited by rwac, 15 July 2009 - 03:32 PM.