Beta Cyclodextrins as a Possible Treatment for the Build Up of Lipofuscin

Liposfucin is the name given to a mix of hardy metabolic waste compounds that build up in long-lived cells over the years, such as the vital cell populations of the retina. Cells are not equipped with suitable tools to remove this gunk, but they try anyway and so it ends up concentrated in the cellular recycling structures known as lysosomes. This leads to bloated, poorly functional lysosomes and a decline in cellular housekeeping, which in turn causes cell dysfunction and loss of tissue function. In the retina this process contributes meaningfully to a number of progressive blindness conditions such as age-related macular degeneration.

Here researchers report on a possible drug candidate that renders harmless some fraction of a few of the important lipofuscin constituent compounds when used on retinal cells:

Lipofuscin accumulation in the retinal pigment epithelium (RPE) is a hallmark of aging. Accumulation of lipofuscin bisretinoids (LBs) in the RPE is the alleged cause of retinal degeneration in genetic blinding diseases (e.g., Stargardt) and a possible etiological agent for age-related macular degeneration. Currently, there is no treatment to prevent and/or revert lipofuscin-driven retinal degenerative changes. Hence agents that efficiently remove LBs from RPE would be valuable therapeutic candidates.

In this study, we report that beta cyclodextrins (β-CDs), cyclic sugars composed of seven glucose units, can bind retinal lipofuscin, prevent its oxidation and remove it from RPE. Computer modeling and biochemical data are consistent with the encapsulation of the retinoid arms of lipofuscin bisretinoids (LBs) within the hydrophobic cavity of β-CD. Importantly, β-CD treatment reduced by 73% and 48% the LB content of RPE cell cultures and of eyecups obtained from [mice], respectively. Furthermore, intravitreal administration of β-CDs reduced significantly the content of bisretinoids in the RPE of [mice].

Thus, our results demonstrate the effectiveness of β-CDs to complex and remove LB deposits from RPE cells and provide crucial data to develop novel prophylactic approaches for retinal disorders elicited by LBs. This study opens an avenue to develop small drugs against, currently untreatable lipofuscin-associated blinding disorders.

Link: http://dx.doi.org/10.1073/pnas.1400530111

Comments

I thought the components of Lipofucin were supposed to be too tough for the body to break down and would require enzymes from bacterial species or something? This is like discovering a small simple molecule that can remove oxized LDL from foam cells.

Pretty unexpected as the other types of damage that the body doesn't bother to repair all seem to have big evolutionary humps to get over so any mutants in those directions would be penalties at first. A bunch of sugar like substances being able to remove lipofuscin bisretinoids seems like something that evolution could come up with quite easily. On the other hand fish that dwell in caves are blind because eyes have no use in the permanent darkness, not because re-evolving site would be difficult or disadvantageous initially.

Hopefully some of the other components of lipofuscin turn out to be as straight forward to deal with.

Posted by: Jim at July 15th, 2014 6:03 PM

Answering Jim's question ...

So, to start at the beginning:
the other types of damage that the body doesn't bother to repair all seem to have big evolutionary humps to get over so any mutants in those directions would be penalties at first. A bunch of sugar like substances being able to remove lipofuscin bisretinoids seems like something that evolution could come up with quite easily.

I'm guessing that when you wrote your first sentence, you were thinking of cases like the remaining 13 mitochondrially-encoded proteins which evolution has not yet moved into the "safe harbor" of the nucleus, which certainly do face greater challenges than the ones it has succeeded in relocating (the discrepancy in the actual code of the mitochondrial vs. nuclear genome, and the great hydrophobicity of these proteins). You may also have been thinking of mutations involved in extending the lifespan of mice and invertebrates, which typically come at a very high cost to fertility (and, under wild conditions, fecundity) and other aspects of fitness. But it isn't necessarily particularly "hard" in terms of the engineering required, or even obviously risky, to make an organism more resistant to degenerative aging in general, and even less so to make it more resistant to specific diseases of aging. As a salient example, people with loss-of-function mutations in the gene encoding PCSK9 (a protein involved in degrading cell-surface LDL receptors, which increase uptake and excretion of cholesterol by the liver and thereby lower circulating LDL cholesterol levels) have an astounding 88% reduction in the risk of coronary heart disease; others with milder missense sequence variation have a 47% reduction in risk. And while research on these people is still in its early days, so far there's no evidence of a phenotype that is life-threatening in our modern environment.

Rather, in most cases the real reason that evolution has not made us more resistant to aging generally or individual pathologies that aging drives is lack of selective pressure to do it. Remember, evolution is not driven to relentlessly make one more and more resistant to degenerative aging changes generally — just to build an organism that is sufficiently robust that it can strongly be expected to survive as long as it can reasonably do granted the extrinsic sources of mortality in its evolutionary niche (injury, predation, exposure, infection, etc). We are already quite well-defended against the ravages of aging by this standard: average life expectancy in the Paleolithic period was under 30 years, with infant and child mortality a far greater threat to the organism's chances of passing on its genes than atherosclerosis, Alzheimer's, or macular degeneration. We are already far less susceptible to all of these disorders than a mouse (leaving aside atherosclerosis, which mice don't get for unrelated reasons), which is why we can in a sheltered environment live for over 70 years, while a mouse will only live for two. To make us even more resistant to CHD or macular degeneration than we are, there would have to be many generations of people being frustrated in their intentions and capacity to reproduce at ages pushing up against the onset of these diseases — a situation which is only just now beginning to emerge, and is being bypassed with reproductive technologies, thus alleviating all selective pressure.

Also:

-even if the molecule is quite simple, coming up with an entirely novel structure like β-cyclodextrin as a defense against age-related disease (as you seem to envision) is an inherently very substantial evolutionary challenge;

- the costs of such a genetic change to people in our Paleolithic evolutionary context may not manifest in people leading sheltered modern lives with the benefits of heating, cooling, clean water, a reliable food supply, etc;

-costs can be quite subtle: the sheer energy and resources required to synthesize a protein can be quite taxing on the organism, particularly if it has to be constantly expressed.

-there are at least some obvious potential risks to β-cyclodextrin (or a molecule that acts like it). β-cyclodextrin solubilizes sterols nonselectively, effecting their efflux from cells and their desorption (stripping) from cell membranes. Both of those could be very harmful to cells under normal physiological conditions.

-there may be risks to mobilizing these bisretinoid lipofuscins out of cells. Certainly A2E, the poster child of such, is extremely toxic, particularly if exposed to UV in the eye. Cramming these molecules into the retinal pigmented epithelial cell lysosme is an (initially) "safe" way to sequester them; mobilizing them out into the retina again may well prove to be more acutely harmful than beneficial in normally-aging mice or humans.

All that said: we're on this and are exploring it. The SENS Reasearch Foundation-funded team working on therapeutic clearance of intracellular aggregates in the macrophage/foam cell at Rice University has been working with β-cyclodextrin for over a year now, and has some interesting early results which will be discussed in our upcoming Annual Report and may lead to an eventual publication, and coincidentally our in-house team working on novel hydrolases against intracellular aggregates in macular degeneration have just started using it too (though in the latter case it's mostly for laboratory convenience rather than for any therapeutic potential).

Remember, finally, that even if β-cyclodextrin is entirely safe and highly successful as a treatment to delay atherosclerosis or macular degeneration, it will not get us to the goal, any more than statins or BP meds have. The general feature of such approaches is that because they rely on reducing the rate at which biomolecules become damaged by the metabolic processes (or alternatively, at which damaged molecules accumulate), they can only delay to some small degree the point at which the burden of such damage begins to impair function and threaten survival — not arrest or reverse its course. This limits their effectiveness, particularly in people older than middle age, in whom significant aging damage has already accumulated.

Rejuvenation biotechnology is based on a different heuristic: that therapies should directly remove, repair, replace, or render harmless the inert molecular and cellular damage itself, without interfering with the metabolic regime that has ensured our development, survival, and decades of healthy function. Returning those essential biomolecules to their youthful fidelity will restore and eventually indefinitely sustain youthful tissue function, health, vigor, and vitality.

Posted by: Michael at July 15th, 2014 9:48 PM

Thanks the the incredibly detailed explanation once again Michael. I feel a bit guilty that you are writing this to the readers on this blog. I hope I am not distracting you guys from doing the actual science with interested amateur questions.

"Remember, finally, that even if β-cyclodextrin is entirely safe and highly successful as a treatment to delay atherosclerosis or macular degeneration, it will not get us to the goal, any more than statins or BP meds have. The general feature of such approaches is that because they rely on reducing the rate at which biomolecules become damaged by the metabolic processes (or alternatively, at which damaged molecules accumulate), they can only delay to some small degree the point at which the burden of such damage begins to impair function and threaten survival — not arrest or reverse its course. This limits their effectiveness, particularly in people older than middle age, in whom significant aging damage has already accumulated."

I didn't realize from reading the article and Reason's blog post above that β-cyclodextrin doesn't remove all of the lipofuscin bisretinoids from lysosomes and instead just slows the rate at which it accumulates.

On a side note, if SENS is successful in adapting a bacterial enzyme to completely remove oxidized LDL from foam cells than surely that will upset a few apple carts amongst big Pharma? They are spending billions on developing monoclonal antibodies to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface e.g. Evolocumab. You guys technology, if safe and effective, could make these redundant along with Statin drugs.

Posted by: Jim at July 16th, 2014 5:38 AM

As someone only in their 30s, but genetically positive for macular degeneration, I find this subject fascinating as well as personally relevant. Enjoyed the article, the discourse in the comments, and looking forward to your eventual publication. Best of luck!

Posted by: Michelle at April 27th, 2022 1:28 AM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.