Fight Aging!

In the research noted here, scientists have identified a potential treatment for cataracts based on the details of a rare human mutation that causes cataracts to form in young children. These patients lack lanosterol, and for reasons not yet fully understood that causes cataract formation in the lens of the eye. Following on from that finding researchers demonstrated that providing greater than usual levels of lanosterol in tissues and animals causes cataracts to shrink. The initial results are promising, but it remains to be seen how well it does outside the laboratory: too little is yet understood of the underlying mechanism to be sure that it will do well. Still, this is a good example of the very positive side of genetic studies: using mutational differences between individuals to gain enough insight into poorly understood disease mechanisms to enable the production of better treatments.

Most cataracts are age-related, with no meaningful genetic contribution to their progression, at least not to outweigh the damage you do to yourself through becoming overweight or smoking. In later life cataracts of several varieties can form in the lens of the eye to cause progressively worsening blindness. Some types result from changing structural properties of the lens that lead to damage and loss of transparency, while others involve deposition of opaque waste products or damaged and misplaced versions of the proteins that make up the lens. The present state of the art in treating cataracts is surgery to remove the damaged portions and replace them with prosthetic lens material, but some form of drug-like treatment - as proposed here - to clear out the unwanted compounds blocking vision would be a great improvement for some types of cataract.

Looking at the broader picture, a great deal of aging is a matter of the wrong proteins showing up in the wrong places. Protein aggregates feature prominently in neurodegenerative conditions such as Alzheimer's disease, for example. A large segment of the near future of medical science will involve finding ever more sophisticated methods of safely removing specific proteins from specific locations in our tissues. Many of these errant proteins come into existence as a side-effect of the normal operation of cellular metabolism, so it is perfectly feasible to look to periodic clearance as the basis for rejuvenation treatments. Provided that the level of these proteins is kept fairly low, as it is in young people, they should not cause further damage at a pace high enough to cause the emergence of age-related disease, as is the case today.

Eye drops could dissolve cataracts

Though scientists don't fully understand how cataracts form, they do know that the "fog" often seen by patients is a glob of broken proteins, stuck together in a malfunctioning clump. When healthy, these proteins, called crystallins, help the eye's lens keep its structure and transparency. But as humans and animals alike get older, these crystallin proteins start to come unglued and lose their ability to function. Then they clump together and form a sheathlike obstruction in the lens, causing the signature "steamy glass" vision that accompanies cataracts. Researchers came up with the eye drop idea after finding that children with a genetically inherited form of cataracts shared a mutation that stopped the production of lanosterol, an important steroid in the body. When their parents did not have the same mutation, the adults produced lanosterol and had no cataracts.

So the researchers wondered: What if lanosterol helped prevent or reduce cataracts? The team tested a lanosterol-laden solution in three separate experiments. First, they used human lens cells to test how effectively lanosterol shrank lab models of cataracts. They saw a significant decrease. Then, they progressed to rabbits suffering from cataracts. At the end of the 6-day experiment, 11 of 13 rabbits had gone from having severe or significant cataracts to mild cataracts or no cataracts at all. Finally, the team moved on to dogs with naturally occurring cataracts. The dogs responded just as the researchers hoped to the lanosterol solution, which was given in the form of both eye injections and eye drops. The dogs' lenses showed the same type of dissolving pattern as the human and rabbit lens cells. The improvement was remarkable - researchers could tell just by looking at the dogs' eyes that the cataracts had decreased. But the exact mechanism of how lanosterol manages to disperse the mass of proteins remains unknown.

Lanosterol reverses protein aggregation in cataracts

The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses.

The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs.

Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.