Fight Aging — Extracellular Aggregates

Little protein clumps called amyloids

Scientists at the SENS Research Foundation have been working on obliterating unhealthy extracellular aggregates, which is junk that accumulates between cells to cause dysfunction and early death. Also referred to as “amyloids,” these toxic little protein clumps can cause big problems.

The human body maintains the structure of the proteins and other structures of which it is composed in a delicate balance. Complex physiological functions ensure that its tissues retain their composition — proteins that are intended to remain in a form that keeps them soluble in body fluids, for example, while the proteins in bones stay stiff and solid.

As the human body ages, however, some of the structures underlying our physiological functions begin to decline. Particularly, proteins that should have remained dissolved in our bodily fluids suffer damage and, consequently, begin to take on a clumped form known as an amyloid. These amyloid clumps are toxic and difficult to break down. In time, amyloid clumps accumulate in tissues and organs, negatively affecting the structure and function of those body parts.

TTR Aggregation

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. When TTR is warped into aggregates, the negative health effects of its accumulation begin to appear at middle age, causing dysfunction in the kidneys, lungs, heart, and other organs.

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.

SENS Research Foundation Investigates the Cause and Treatment of TTR Aggregates

Age is a common cause of amyloid formation but genetics may play a role in their formation as well. A mutation in the gene that controls TTR can produce a form of protein that can easily twist itself into an amyloid. One mutation in particular, which affects 3 — 4 percent of African Americans, is known to cause heart failure. People with these genetic mutations can begin to feel the negative health effects of amyloids as early as age 30.

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. Dr. Paul is also investigating ways to trap the best catabodies in an effort to optimize catabody activity.

Someday, physicians may supplement the natural defenses of the body’s immune system with catabodies specific to the type of damage caused by TTR accumulation. Physicians can introduce these catabodies through intravenous injection or through gene therapy.

SENS Research Foundation is dedicated to developing the industry of restorative medicine by targeting the underlying causes of aging and early death. Their efforts begin with proof-of-concept work but their ultimate goal is to develop biotechnologies capable of curing age-related diseases.