Aging and Those Little Protein Clumps Called Amyloids
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One of the fundamental ways in which old tissue is different from young tissue is the presence of deposits of misfolded proteins between cells. In their normal form these proteins should remain dissolved in tissue fluids, but with age ever more precipitate to form the strands and fibrils known as amyloid. There are a number of different types of amyloid, each corresponding to a particular protein that is prone to this outcome. For many of these types the research community cannot yet explain exactly why and how the amyloid contributes to the age-related conditions it is associated with, or indeed why and how this is an age-related phenomenon. Is it a failure in clearance mechanisms caused by other forms of damage, perhaps? For some forms of amyloid a great deal is known, however: take Alzheimer's disease, for example. If the average fellow in the street has heard of amyloid at all, it is probably in connection with Alzheimer's research and the present focus of treatment.

There is another arguably equally important condition and form of amyloid, one that appears to act as a limiting factor on human life span, and receives far less attention and funding than does Alzheimer's disease. The results of autopsies performed on supercentenarians, people who lived to be 110 years of age or older, suggest that those of us who survive or evade every other potential fatal age-related condition are eventually felled by the buildup of transthyretin amyloid, leading to a condition known as TTR amyloidosis, or senile systemic amyloidosis when referring to the age-related condition rather than the genetic disease that can cause similar early-life buildup of amyloid.

Since there is all too little work taking place on senile system amyloidosis, this is one of the areas in which the SENS Research Foundation has stepped into accelerate matters in the past couple of years. One of the key insights that led to the existence of the Foundation is that we don't in fact have to have a complete understanding of the mechanisms involved in any particular cause of aging to effectively treat it. What we do need is a comprehensive list of differences between old tissue and young tissue, a good identification of which of those differences are fundamental - primary causes versus secondary effects - and a plan to reverse those differences.

In the case of amyloids we have all of these items: it doesn't matter that researchers cannot yet explain how and why some forms of amyloid cause harm if the development community can build the means to remove these amyloids. We should just remove them, as they are not a feature of young tissue. Much of the work of the Alzheimer's research community, for example, will hopefully be broadly applicable to forms of amyloid other than that associated with the condition. Progress by Alzheimer's researchers towards immune therapies that can attack and break down amyloid is watched with interest in a number of other fields.

Here is a piece by Jason Hope, a philanthropist who has contributed meaningfully to some of the SENS Research Foundation programs:

Fight Aging  -  Extracellular Aggregates

Aggregation of one specific protein causes problems in many parts of body but inflicts special harm to the heart in particular. Transthyretin, or TTR, is a transporter protein that carries thyroid hormones to the various parts of the body that need it. By the time they reach the age of 70 years, 10 percent of people suffer significant accumulations of TTR amyloids. The condition becomes nearly universal as people reach the century mark. TTR amyloid may prevent a body from reaching its destiny as a "supercentenarian" who lives more than 110 years.

To date, there is no approved treatment for amyloids aside from organ transplant to replace organs damaged by amyloids. The SENS Research Foundation-funded TTR Extracellular Aggregates collaboration is working to develop antibodies that identify and safely remove TTR amyloid deposits from body tissues. The antibodies do this by binding to TTR. Physicians could someday use these antibodies to diagnose and treat both age-induced and genetic forms of TTR.

To create these antibodies, Dr. Brian O'Nuallain and his collaborators immunized three strains of mice with three different TTR-containing substances intended to provoke an immune response. Exposure to these substances triggered an immune response in the mice  -  each group of mice created unique antibodies that would target different types of aggregating TTR. This means the scientists created antibodies already armed to fight only clumping TTR, ignoring any TTR remaining in a form that can remain dissolved in body fluids. Seven of these antibodies show diagnostic and therapeutic potential. All seven bind strongly to clumped TTR and ignore soluble TTR well. O'Nuallain is collaborating with Dr. Sudhir Paul to learn if these antibodies can facilitate the breakdown of TTR amyloids.

Dr. Paul works on developing catalytic antibodies, known as catabodies for short, which break down TTR amyloids. Catabodies do not just bind to TTR amyloids and carry them away  -  catabodies destroy TTR amyloids. In earlier research, Dr. Paul identified naturally occurring catabodies that break down TTR amyloids found in the brains of patients with Alzheimer's disease. Today, with funding from SENS Research Foundation, he has identified catabodies that completely dissolve TTR amyloids in a test tube without damaging TTR proteins that are functioning correctly.

This is important work on the foundations of human rejuvenation, and I look forward to hearing of further advances towards clinical application. Given the present structure of medical regulation that will probably involve development of a treatment of the genetic version of TTR amyloidosis however - it remains the case that regulators at the FDA do not recognize aging as a condition to be treated, and there is thus no path to approval for treatments for aging. This roadblock echoes all the way back down the research and development pipeline, which goes some way towards explaining why there is still comparatively little funding for work on amyloidosis and other necessary portions of a rejuvenation toolkit.

That said, it is good to see progress in the laboratory towards targeted and focused methods of designing treatments: attack the problem molecule and only the problem molecule. We live in an age of biotechnology, and ongoing work should absolutely be far above and beyond the old school drug development programs in which compounds from the natural world are thrown at the problem until something is found that causes more good than harm. Sadly there is still all too much of that going on today.

Comments

Some potential treatments for TTR amyloidosis -

Tafamidis for transthyretin amyloidosis
http://www.ncbi.nlm.nih.gov/pubmed/22645721

Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study
http://informahealthcare.com/doi/abs/10.3109/13506129.2012.678508

Safety and Effect of Doxycycline in Patients With Amyloidosis
http://clinicaltrials.gov/show/NCT01677286

Posted by: Lou Pagnucco at February 6, 2014 12:22 PM

Hello Reason,

Excellent commentary.
One question: is it transthyretin or glucosepane that does in the
the pre-supercentarian elderly?

Regards,
Sam

Posted by: Samuel Stewart at February 6, 2014 3:12 PM

@Samuel Stewart: The younger elderly are done in by a combination of factors, including amyloid and glucosepane build up, but also the other array of first causes outlined in the SENS proposals.

What system or organ fatally fails first is a stochastic result of the interplay of that damage, some genetic influences, and environmental circumstances.

Posted by: Reason at February 6, 2014 4:19 PM

I take comfort in knowing that it is absolutely 100% certain that we will have a treatment for what kills people over the age of 110, long before I reach that age. Almost certainly before my parents reach that age too. There is every reason to think that some people living now will still be living past 122.

Unfortunately, that still leaves the problem of all the other forms of aging damage that kill most people (especially people with my genes) long before they reach that age.

Posted by: Carl at February 8, 2014 2:14 AM
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