New Sterols Clear Amyloid Protein Aggregates in Cataracts
Some types of cataract involve the formation of amyloid deposits in the lens of the eye made up of damaged crystallin. Researchers have made progress of late in finding sterols that clear this form of amyloid. This is of general interest as there are many types of amyloid that form in tissues in increasing amounts with advancing age, some of which are clearly linked to the pathology of specific age-related conditions. Progress towards effective means of clearance for any one amyloid might turn out to be the starting point for the development of a broader technology platform for therapies, so it is worth paying attention. Here is an update on the development of sterol compounds targeting crystallin amyloid:
In order for our lenses to function well, a permanent, finite reservoir of crystallins must maintain both the transparency of fiber cells and their flexibility, as the eyes' muscles constantly stretch and relax the lens to allow us to focus on objects at different distances. The crystallins accomplish these duties with the help of aptly named proteins known as chaperones, which act "kind of like antifreeze, keeping crystallins soluble in a delicate equilibrium that's in place for decades and decades." This state-of-affairs is "delicate" because pathological, clumped-together configurations of crystallins are far more stable than properly folded, healthy forms, and fiber-cell chaperones must continually resist the strong tendency of crystallins to clump. A similar process underlies other disorders related to aging, such as Alzheimer's disease, but in each of these diseases the specific protein that clumps together and the place in the body that clumping occurs is different. In all cases, these clumped-together proteins are called amyloids.Because the melting point of amyloids is higher than that of normal crystallins, the team focused on finding chemicals that that lowered the melting point of crystallin amyloids to the normal, healthy range. The group began with 2,450 compounds, eventually zeroing in on 12 that are members of a chemical class known as sterols. One of these, known as lanosterol, was shown to reverse cataracts, but because lanosterol has limited solubility the group who published that study had to inject the compound into the eye for it to exert its effects. Using lanosterol and other sterols as a clue, the researchers assembled and tested 32 additional sterols, and eventually settled on one, which they call "compound 29," as the most likely candidate that would be sufficiently soluble to be used in cataract-dissolving eye drops. In laboratory dish tests, the team confirmed that compound 29 significantly stabilized crystallins and prevented them from forming amyloids. They also found that compound 29 dissolved amyloids that had already formed. Through these experiments, "we are starting to understand the mechanism in detail. We know where compound 29 binds, and we are beginning to know exactly what it's doing."
In addition to compound 29's potential for cataract treatment, the insights gained through the research could have broader applications. "If you look at an electron micrograph at the protein aggregates that cause cataracts, you'd be hard-pressed to tell them apart from those that cause Alzheimer's, Parkinson's, or Huntington's diseases. By studying cataracts we've been able to benchmark our technologies and to show by proof-of-concept that these technologies could also be used in nervous system diseases, to lead us all the way from the first idea to a drug we can test in clinical trials."
Link: http://universityofcalifornia.edu/news/clearing-cataracts-eye-drops
Since these crystallins help with lens flexibility, this might also improve presbyopia symptoms.
I've had LASIK surgery (which I strongly recommend for anyone with any conventional myopia), and I'm worried about getting hit by presbyopia within the next decade. As usual, I'd love to be the guinea pig for safety trials of Compound 29.
I thought that glucosepane crosslinks accumulating over time were also an important factor in loss of lens flexibility.
Him: not glucosepane, no: glucosepane forms in collagen, and the lens is composed of crystallins. The dominant AGE in lens is K2P; I'm not aware of any evidence on the magnitude of its effect on lens flexibility with age.
Well, I was going to comment on how this might help presbyopia, one of the big annoyances of getting old, but I see I've been beat to the punch.
So I'm posting this anyways.... just because.
@Michael
So if we can ablate K2P this is direct repair of the underlying damage isnt it and proof of SENS strategy?
Also if so then the same applies to glucosepane and its removal stops TGF-beta and NK-fb running amok and causing stem cell dysfunction and inflammation etc...
Obviously we do not currently have a way to remove AGE but with the Conboys testing ALK-5 to mitigate the results of AGE is this what you mean by their work allows you to see what you get for "free" if AGE is removed?
I am currently trying to get the Major Mouse Testing Project to test ALK-5, Senlyotics as well as mTOR in separate and combination groupings in lifespan studies on old mice (16-18 months old to begin).
Steve H: So if we can ablate K2P this is direct repair of the underlying damage isnt it and proof of SENS strategy?
I take it you mean "cleave," not "ablate." It would be an implementation of the SENS strategy; it would really only be a proof (of concept) if it resulted in rejuvenation of the tissue. Since (as I said) I'm not aware of any evidence on the magnitude of K2P's effect on lens flexibility with age, I'm not convinced that it is a sufficiently important contributor to age-related loss of lens flexibility to meaningfully restore such function and thus constitute such a PoC.
Of course, there are multiple PoCs of the SENS strategy already extant for other forms of cellular and molecular damage, as we've discussed before.
Steve H: Also if so then the same applies to glucosepane and its removal stops TGF-beta and NK-fb running amok and causing stem cell dysfunction and inflammation etc...
You mean in the context of the downstream benefits as you allude below? Yes.
Steve H: Obviously we do not currently have a way to remove AGE but with the Conboys testing ALK-5 to mitigate the results of AGE is this what you mean by their work allows you to see what you get for "free" if AGE is removed?
(Note that the Conboys are testing an ALK-5 inhibitor: I trust they aren't transducing anything with ALK-5!). What do you mean here by "this"? Using an ALK-5 inhibitor isn't such an example — repairing underlying damage wouldn't suddenly cause an animal (including a human) to suddenly start biosynthesizing ALK-5 inhibitors — but you can predict that repairing sufficient amounts of the relevant forms of damage will restore normal, youthful signaling through the TGF-β pathway, thus garnering the benefits of ALK-5 inhibitors "for free" but without the inevitable side-effects of using a drug to force the matter.
(And no, I can't point to any specific side-effects associated with pharmacological ALK-5 inhibition — but it's inescapable that they will emerge. No drug is going to regulate TGF-β signaling as well as the evolved function of a healthy young body's regulatory networks, and to the extent that you succeed, simply restoring youthful TGF-β signaling in the context of a still-damaged body is not going to do the job of repairing the damage and having the signaling environment normalize in response, just as turning off inflammation while you are still fighting off an infection is a bad idea. Nor is its application going to give the full range of benefits of concomitant normalization of multiple other pathways that will accompany thoroughgoing damage-repair).
@Michael
Michael: "What do you mean here by "this"? Using an ALK-5 inhibitor isn't such an example "
Sorry I meant that Alk-5 inhibiting treats a consequence of AGE but not the cause. However inhibiting TGF-beta using ALK-5 does show some of the benefits we would get if we cleaved AGE. I am asking if this shows what we get for "free" if we just tackle AGE? You seem to have confirmed this above.
Michael:"And no, I can't point to any specific side-effects associated with pharmacological ALK-5 inhibition — but it's inescapable that they will emerge. No drug is going to regulate TGF-β signaling as well as the evolved function of a healthy young body's regulatory networks, and to the extent that you succeed, simply restoring youthful TGF-β signaling in the context of a still-damaged body is not going to do the job of repairing the damage and having the signaling environment normalize in response, just as turning off inflammation while you are still fighting off an infection is a bad idea. Nor is its application going to give the full range of benefits of concomitant normalization of multiple other pathways that will accompany thoroughgoing damage-repair)."
I agree with you I think the primary damage source is the key here. AGE effects multiple networks not just TGF-beta. I am stunned cleaving it is not a much higher priority in general. I also suspect that if you inhibited the TGF-beta the AGE would continue to build up and compromise that or change the system in other ways to compensate, eventually. Might we see a lifespan.io campaign for this vital work?
You also know I am working with the Major Mouse Testing Program, we have ALK-5 inhibiting on our potential test list (Mike Conboys suggestion) plus senolytics. Is testing them for lifespan of any interest to SENS (given we see the "free" effect from ALK-5) or to put it another way what can we do to help SENS?
We are going to be fundraising for this soon so obviously we want to ensure what we are doing is meaningful and useful to the field.
Hey great ideas I have a bad cataract in one eye and I am going to try lanosterol before I get surjury
then I had a thought why wouldn't lanosterol cure parkinsons
it looks like a lack of squalene in my body might be the reason I don't have enough lanosterol to prevent cataracts
Squalene breaks down into lanosterol
hey= hope to see more good reads about curing things with sterols