By applying principles of physics, a research team at Stony Brook University identified that many proteins associated with aging are damaged and destabilized by a process called oxidation. These findings are important in improving the understanding of the processes that are related to aging and aging-related diseases, like Alzheimer’s and cancer.
Oxidation is a process used to make energy in the body. However, a by-product of the reaction is a special type of oxygen called an oxygen free radical. This free radical can damage proteins and other molecules in the cell by neutralizing positive charges.
Charge is essential to how a protein folds and its overall shape. Take away a charge, like oxidation does, and the protein will no longer fold the same way, altering its structure and function in the cell and body.
When we are young, our bodies have mechanisms to quickly capture and dispose of these free radicals. As we age, however, these mechanisms do not work as well, and the oxygen free radicals can destabilize more proteins. This contributes to the fact that by the age of 80, approximately 50 percent of the proteins in our body will be damaged.
This study, led by Dr. Ken Dill, director of the Laufer Center for Physical and Quantitative Biology, and Adam de Graff, a Laufer junior fellow, aimed to identify how the structure and function of a protein is linked to the level at which the protein is being damaged. They wanted to identify which protein would be most susceptible to damage by oxidation, using a systems biology approach.
Using a mathematical framework and known principles of how free radicals behave, de Graff set out to find the proteins in which oxidation makes a significant impact on stability.
The team found that proteins that are highly charged per unit length are the most susceptible to damage via oxidation. This makes sense because the oxidation is taking away the charge from a protein in which charge plays a significant structural role.
Next, the team looked for overlap between their list of proteins susceptible to oxidative damage and those proteins associated with aging in a database.
They found that 20 proteins previously linked to aging were also at high risk of oxidative damage. These findings help elucidate the role of oxidation in aging.
Many of the 20 proteins are those that interact with DNA, like histones and transcription factors, which are important for gene expression. Since DNA is negatively charged, these proteins are often highly positively charged to facilitate their interaction with DNA.
“Oxidation is going to take away the positive charge, which not only is going to change the stability of the protein, but also change the ability of the protein to bind and do its function,” de Graff said.
The team plans to use this model to continue to understand how organisms age. De Graff also plans to investigate how damaged proteins get rescued by chaperone proteins and how this process changes as we age.
