49 replies to this topic

[eighthman]

http://groups.google...1ca023c8748580e#

As far as I know, this is a confirmed first. Lipofuscin safely removed from cells. Could be very significant.

[niner]

Neurobiol Aging. 2012 Jan 12. [Epub ahead of print]
Lipofuscin can be eliminated from the retinal pigment epithelium of monkeys.
Julien S, Schraermeyer U.
SourceSection of Experimental Vitreoretinal Surgery, Centre for
Ophthalmology, Tübingen, Germany.

Lipofuscin is a cytologic hallmark of aging in metabolically active postmitotic cells including neurons, cardiac muscle cells, and the retinal pigment epithelium (RPE). High levels of lipofuscin are involved in the pathogenesis of age-related macular degeneration (AMD), the main cause of blindness in the elderly population in the western world. Degradation and exocytosis of lipofuscin by RPE cells have not been observed in vivo until now, and no drug is known to eliminate the intracellular amount of lipofuscin. Here, we show that in monkeys treated with a small molecule belonging to the tetrahydropyridoethers class (n = 36 of 48 monkeys), RPE cells significantly release lipofuscin. In 4 eyes, macrophages were detected which had taken up lipofuscin. They were located between the Bruch's membrane and the RPE, and in the choroid. The quantification of pigment granules was performed by transmission electron microscopy. Our findings open the way to develop therapeutic strategies to remove lipofuscin from RPE cells, which may have implications for the treatment of age-related macular degeneration in which lipofuscin accumulation in cells is a causative factor.

PMID:22244091

This sounds like a big deal. Like they say in the abstract, it could be important in AMD, but if it turns out to be a general phenomenon, and not just limited to RPE cells, that would be huge. I didn't know sci.life-extension was so active these days.

Edited by Michael, 08 May 2012 - 07:58 PM.

[Elus]

Fascinating. How would this drug induce endocytosis for just one specific cellular material (lipofuscin)? If the mechanism were found, we could go about activating this in numerous cell types, at least in theory...

[okok]

http://abstracts.iov...tract/51/5/2786
<br>

Tetrahydropyridoethers Eliminate Lipofuscin From Retinal Pigment Epithelium of Monkeys

<nobr>U. Schraermeyer</nobr>, <nobr>S. Schultheiss</nobr>, <nobr>S. Hofmeister</nobr> and <nobr>S. Julien</nobr>
Experimental Vitreoretinal Surgery, Institute for Ophthalmic Research, Tubingen, Germany

Commercial Relationships: U. Schraermeyer, None; S. Schultheiss, None; S. Hofmeister, None; S. Julien, None.
Support: None.
Abstract
Purpose:To test the effect of tetrahydropyridoethers (THPE) on pigment granules of the retinal pigment epithelium (RPE), monkeys (Macaca fascicularis) were orally treated with this drug for up to one year.
Methods:54 monkeys were daily treated with different concentrations of (7R, 8R, 9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imi-dazo [1,2-h] [1,7] naphthyridine between 4 weeks and one year by oral administration. 12 monkeys served as controls. Right eyes were investigated by electron microscopy, left eyes were used for immunocytochemistry and fluorescence light microscopy.
Results:After exposure to THPE, focal depigmentation of RPE cells was observed. These sites were about 100 - 1000 µm long and their numbers were dose-dependent. Lipofuscin granules, melanosomes as well as melanolipofuscin granules disintegrated within the RPE cells and/or were released to macrophages. Different stages of pigment lysis were detected under the electron microscope. There were areas of 1000 µm² or more in which the RPE was completely free of melanin and lipofuscin granules. Close to such depigmented RPE cells, highly pigmented macrophages identified by CD68 staining were located between Bruch’s membrane and the RPE and in the subretinal space or within the choroid.The total number of lipofuscin granules was counted in the cytoplasm of RPE cells from untreated and treated monkeys. Per 10 µm of RPE length, 7.2 ± 3.6 versus 0.07 ± 0.26 lipofuscin granules were found in RPE cells of untreated versus treated animals respectively ( p = 9,9E-08). Photoreceptors facing depigmented RPE appeared normal.
Conclusion: Our results demonstrate that administration of THPE induces lipofuscin elimination from RPE cells in a dose-dependent manner by degradation in RPE cells and/or transfer to macrophages. Although the mechanism is still unknown, this is an important finding which disproves the dogma of undegradable and unremovable lipofuscin from RPE cells and has the potential to serve as an active ingredient in the treatment of AMD, particularly the dry form.

<br>
Cytoprotective. Used in the treatment of ulcers.<br><a href="http://www.google.ru...=bookclip"><img src="http://www.google.ru...5&edge=0"/></a>

Edited by okok, 12 February 2012 - 03:09 PM.

[niner]

Wow! This is starting to look good. I would really like to know what the heart muscle looked like in those monkeys. Tubingen group has demonstrated that an oral compound can remove lipofuscin, and at least as far as the abstract goes, the toxicity was acceptable.

Cytoprotective. Used in the treatment of ulcers.

Anyone know if there are human-approved drugs in this class?

[Googoltarian]

(7R, 8R, 9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imi-dazo [1,2-h] [1,7] naphthyridine

 correct structure.GIF   3.75KB   5 downloads

[eighthman]

Here's the deal as I see it: Some lunatics (OK, helpful visionaries) suggested laser ablation to get rid of lipofuscin! There is also evidence from mice that autophagy plus cyclic antilipolytic drugs can wipe out defective proteins and membrane material in the liver.

At some point, if we can get rid of all this various age-related cellular gunk, how does an old cell differ from a young one? Indeed, how could we even tell which was which? Does aging stop then?

[Danail Bulgaria]

Well, the lipofuscin and the "cellular gunk" are not all of the changes, that happen with the cells during aging. If not anything else tt least DNA damage accumulates too. Moreover, some scientists suggest, that the damage of the DNA and the corresponding with it "wrong proteins" is a main factor for the accumulation of "all the cellular gunk", and they suppose, that even after the removal of the "gunc", it will accumulate again if the DNA remains damaged. So, the aged and the young cell will still have differences.
As long as for "the lunatics", who suggestes, that laser ablation may help to get rid of the lipofuscin in the age related macular degeneration, I must say you, that today exists laser treatments of the eye, including the retina, the age related macular degeneration is uncurable so far and it leads to non reversible blindness, and according to the oppinion of eye doctors, who know much more than you about this topic, everything, connected with the macular degeneration may appear to be helpful, including the direct ablation of the lipofuscin and the money are the only thing, that stops the development of this topic.

[Mind]

My question is about the mechanism. What happens, according to what I have read and learned, is that the lypofuscin builds up within lysosomes and these lysosomes become non-functional. The lypofuscin just sits there in the lysosome until the cell dies. Is the compound helping the lysosome degrade the lypofuscin, or is it triggering the death of lypofuscin rich cells.

[Danail Bulgaria]

This question should be answered from a biochemist or from cell biologist.

[niner]

At some point, if we can get rid of all this various age-related cellular gunk, how does an old cell differ from a young one? Indeed, how could we even tell which was which? Does aging stop then?

No, there are other forms of age related damage. Aging won't stop until we can slow the degradation to a level that our natural repair mechanisms can keep up with. However, with each form of damage that we learn to repair, the functionality of the cells, and thus the organism, should improve. I anticipate a future where aging simply looks different than it does today. New characteristic problems might crop up at ages beyond what anyone has reached so far. Eventually, when we can fix all of them, aging will have been conquered.

[Elus]

Am I allowed to post the paper? If not, just delete the post and lemme know...

I put it on mediafire: http://www.mediafire...a3lzc8443a1yapz

[eighthman]

Uh..... direct ablation of lipofuscin by laser? And I wonder what happens to the cells? Apoptosis, perhaps? Miniature steam explosions?

As for the rest of age related damage, I think some studies of very long lived animals suggest that DNA damage may not be that much of a deal, however logical that stuff might seem as a cause.

I think the remaining main obstacle would be crosslinking as a cause of hemoragic stroke. Get that out of the way (and there was talk about this being possible as demonstrated in baboons) and we might be there. At some point, we might want to list all the critical areas of damage to be overcome, if guys like DeGrey haven't done so, specifically.

Keep in mind too, that there could very well be synergistic effects between various improvements as shown by recent studies regarding removal of senescent cells.

Hey, it could happen, dudes.

[okok]

Thanks Elus for the paper.
Remofuscin - interesting, there's already a generic name. I agree, this looks promising. For safety data, we'd probably have to turn to Altana Chem. Research. The 1982 patent i.a. reads

In their excellent properties, the compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art in various models in which the antiulcerogenic and the antisecretory properties are determined. On account of these properties, the compounds of the formula and their pharmacologically tolerable salts are outstandingly suitable for use in human and veterinary medicine, where they are used, in particular, for the treatment and/or prophylaxis of disorders of the stomach and/or intestine.

To summarize the article, lipofuscin as recently discovered is mainly composed of oxidized lipid fragments and bisretinoids.
Remofuscin probably works by exocytosis and subsequent macrophage clearance.
Recently, several small molecules have been shown to decrease the new formation of bisretinoid lipofuscin. Horseradish peroxidase also degrades it.

This would make for an interesting future podcast episode. Mind?

[nowayout]

Creatine inhibits lipofuscin accumulation in mice:

http://www.neurobiol...0111-X/abstract

[Mind]

Nice to know, but the real "killer app" is getting rid of it.

Creatine inhibits lipofuscin accumulation in mice:

http://www.neurobiol...0111-X/abstract

Edited by Mind, 13 February 2012 - 11:34 PM.

[Mind]

To summarize the article, lipofuscin as recently discovered is mainly composed of oxidized lipid fragments and bisretinoids.
Remofuscin probably works by exocytosis and subsequent macrophage clearance.
Recently, several small molecules have been shown to decrease the new formation of bisretinoid lipofuscin. Horseradish peroxidase also degrades it.

This would make for an interesting future podcast episode. Mind?

Thanks for the idea. I will look into it.

[Mind]

Just to follow up on my first post (because last night I wasn't thinking straight). Three possibilities here:

1. The drug activates the lysosome in some manner that it could not operate before and it digests the previously undigestible lipofuscin (unlikely).
2. The drug selectively kills lipofuscin-rich cells.
3. The drug is taken up by the lysosome and directly dissolves the lipofuscin. This would be the easiest to test. Put lipofuscin in a dish. Add the tetrahydropyridoethers drug. See what happens. Since the drug is over 30 years old, patent protection should have run out, correct?

[nowayout]

Well, perhaps creatine does get rid of it, as opposed to preventing it. We are unable to see which from that study though.

Nice to know, but the real "killer app" is getting rid of it.

Creatine inhibits lipofuscin accumulation in mice:

http://www.neurobiol...0111-X/abstract

[eighthman]

If the monkeys eyesight was unimpaired in the study (I'm not sure how that gets determined), then it would be number 1 - it triggers something to dissolve the gunk within the cell or just expel the lipofuscin - totally best outcome. Maybe it ends up in the lymphatic system. Such an ability could be beyond even rockfish (200+yrs), from what I've read!!

[steampoweredgod]

Well, the lipofuscin and the "cellular gunk" are not all of the changes, that happen with the cells during aging. If not anything else tt least DNA damage accumulates too. Moreover, some scientists suggest, that the damage of the DNA and the corresponding with it "wrong proteins" is a main factor for the accumulation of "all the cellular gunk", and they suppose, that even after the removal of the "gunc", it will accumulate again if the DNA remains damaged. So, the aged and the young cell will still have differences.

Some cells do escape significant nuclear damage as evidence in the fact that you can clone a whole new young organism from an adult organism's cell.

Though would be interesting to see how mitochondria are preserved in women oocyte. Even old women can have healthy young children, and presumably all the mitochondria should've been subjected to damage from decades of being subjected to background levels of metabolic activity.

3. The drug is taken up by the lysosome and directly dissolves the lipofuscin. This would be the easiest to test. Put lipofuscin in a dish. Add the tetrahydropyridoethers drug. See what happens. Since the drug is over 30 years old, patent protection should have run out, correct?

Another possibility is to cause the lysosome to merge with the external membrane and thus expel all material within it to the extracellular environment. It may be a function that lies dormant in this cell type but other cells may use. Neurons presumably given their high metabolic activity(even while not sending messages) and century plus lifespan may be doing this, but maybe not at a sufficient rate to halt accumulation.

Edited by steampoweredgod, 19 February 2012 - 02:33 AM.

[Danail Bulgaria]

By the way, if someone wants to put lipofuscin in a dish, where he would get the lipofuscin?

[Mind]

Another possibility is to cause the lysosome to merge with the external membrane and thus expel all material within it to the extracellular environment. It may be a function that lies dormant in this cell type but other cells may use. Neurons presumably given their high metabolic activity(even while not sending messages) and century plus lifespan may be doing this, but maybe not at a sufficient rate to halt accumulation.

I didn't know that this was possible. Do you know of any good resource where I could read about this process of merging with the cell membrane?

Edited by Mind, 19 February 2012 - 03:31 PM.

[steampoweredgod]

Another possibility is to cause the lysosome to merge with the external membrane and thus expel all material within it to the extracellular environment. It may be a function that lies dormant in this cell type but other cells may use. Neurons presumably given their high metabolic activity(even while not sending messages) and century plus lifespan may be doing this, but maybe not at a sufficient rate to halt accumulation.

I didn't know that this was possible. Do you know of any good resource where I could read about this process of merging with the cell membrane?

I'm not sure if the lysosome can do it in all cases(like say when filled with intractable garbage.), but it appears that such fusion is the process for some forms of membrane maintenance and repair. Fusion of internal membrane compartments is also the process used when releasing neurotransmitters and some other substances(for example, the vesicles containing neuron transmitter merge with the cellular membrane and the contents are expelled). The process is called exocytosis.

The organelle known as the golgi apparatus appears to function via generating vesicles, that fuse with the membranes of various other cellular compartments, and also the cellular membrane for secretion of extracellular substances. It has been likened to a post office, iirc, there are molecular tags indicating the destination of vesicles(specific internal organelles, extracellular membrane, etc).

The following paper suggests it may be possible for exocytosis to occur involving lysosomes.

We further demonstrate that lysosomal exocytosis mediates the resealing of primary skin fibroblasts wounded during the contraction of collagen matrices. These findings reveal a fundamental, novel role for lysosomes: as Ca2+-regulated exocytic compartments responsible for plasma membrane repair.-cell

Regarding neurons:

We quantitatively demonstrate that lipofuscin, accrued through normal ageing, can be lost from neural tissue. The mechanism of loss probably involves exocytosis and possibly blood transport. If non-disruptive ways to accelerate lipofuscin removal can be found, our results suggest that therapeutic reversal of this most universal manifestation of cellular ageing may be possible.-link

Of course there is or was controversy regarding this possibility, a review of several studies would be needed to fully clarify the issue.

Though at least some harmful aggregates have been dealt with in other species. It would be interesting to know the mechanisms involved.

In the study, researchers at Case Western Reserve University School of Medicine gave mice mega-doses of bexarotene, a drug used to treat a type of skin cancer called cutaneous T-cell lymphoma. Within 72 hours, the mice showed dramatic improvements in memory and more than 50% of amyloid plaque -- a hallmark of Alzheimer's disease -- had been removed from the brain.

"I want to say as loudly and clearly as possible that this was a study in mice, not in humans," he said. "We've fixed Alzheimer's in mice lots of times, so we need to move forward expeditiously but cautiously."-cnn

The following video shows inner cellular function, golgi apparatus, and membrane transport and fusion with commentary
http://www.youtube.com/watch?v=GigxU1UXZXo&feature=related

Edited by steampoweredgod, 19 February 2012 - 08:31 PM.

[Musli]

This is great news. Hopefully, scientists will build on this momentum.

[Mind]

I will try to contact the UKT (where the research was performed).

[manofsan]

Interesting discussion - I suppose there's more than one way to "skin a cat".

ie. Suppose all the stem cell research leads to mastery over stem cells? Then these could be introduced into the body over and over, to supplant existing aged tissue. Suppose science comes up with a "streamlined" stem cell (ie. one with a more efficient genome, having extraneous parts relating to fetal development removed). It's possible that Man might improve on Nature, given that Man has more self-centred goals in mind.

As some here have said, perhaps there's no one approach that will do it all, but it will rather be a cocktail or combination of approaches which will yield the desired results.

[N.T.M.]

Wow, this has incredible implications. It's very exciting.

[Mind]

Wow, yes, but how can we move this research forward? I sent an email to the UKT but no response. Anyone out there willing to get some lipofuscin and the chemical and do some tests?

[niner]

Wow, yes, but how can we move this research forward? I sent an email to the UKT but no response. Anyone out there willing to get some lipofuscin and the chemical and do some tests?

I think it's unlikely that the chemical is dissolving the lipofuscin in a physical manner. It would be very difficult to get that much of a small molecule into the lysosome. I think it's far more likely to be a receptor-mediated process. It would probably be more productive to obtain some old cells that contain lipofuscin, and to experiment with them in vitro. I'm not sure what's the best way to get old cells with lipofuscin- punch biopsies from cutaneous 'age spots' from elderly humans? If some elderly person wanted to be adventurous, they could self-experiment with topical application. Just looking at the molecule, it doesn't look too scary, and it's already been in monkeys.

It might be tricky to get the compound. The fact that it has the suggestive name "remofuscin" tells me that someone has already been planning on marketing it, so it will probably be tied up in a lot of IP red tape. You could probably find a storefront synthesis house somewhere in China that would make it. When I was a kid, there was a business like that in my home town. They were really cool and would give me chemicals. I was about 12 then. That would never happen today. Thinking about it, I'm kind of surprised it happened then...