Could Oxidative Damage To Proteins Be Involved In Aging?

Posted on 19 February 2016

Oxidation leads to formation of rust, or iron oxide, but it also modifies proteins too 

Oxidation leads to formation of rust, or iron oxide, but it also modifies proteins too 

Proteins are responsible for countless biological functions from transport of nutrients, communication between cells to the copying of the DNA. Proteins are polymers, long chains, made up of dozens to hundreds of individual building blocks called amino acids. There are 20 different amino acids and the order in which these are put inside the protein determines the eventual 3D structure, properties and function of the resulting protein. Small regions of a protein are responsible for conducting the function of the protein while the rest is there as a scaffold to keep the active pieces in the right spacial orientation.

The importance of charge  

In a paper published in the journal Structure researchers from the Stony Brook University introduced a theoretical model to investigate the effect of oxidative damage on the stability of proteins. The researchers discovered that oxidative damage to amino acids with charged side chains is especially harmful on protein structure. Next the researchers looked at a list of proteins known to be involved in aging and found that many were enriched in charged amino acids and hence are expected to be particularly susceptible to structural instability from oxidative damage. Among the proteins involved in aging that have many charged amino acids we find telomerase, SIRT1 (the famous target of resveratrol), and histones (the proteins around which the DNA is wrapped). 

The effects of oxidative stress are complicated

The oxidative stress theory of aging is one of the oldest theories dating back to a paper by Denham Harman in 1956. According to the oxidative stress theory, oxidative damage to DNA, proteins and lipids accumulates with age and eventually leads to dysfunction, pathology, and death. Indeed, levels of oxidative damage increase with age and higher levels of oxidative damage is found in several human diseases such as Alzheimer’s disease and atherosclerosis. In recent years the oxidative stress theory has received its share of criticism as several experiments put doubt on the validity of this theory. For example, when the roundworm C. elegans is exposed to pro-oxidative substances its lifespan is extended rather than reduced. Furthermore, while some mutants that have increased levels of antioxidative enzymes live longer, others do not and conversely not all mutants that have reduced levels of antioxidative enzymes live shorter as the oxidative stress theory would predict. However, none of these experiments have conclusively disproven the oxidative stress theory, so the jury is still out.     

Graff AMR, Hazoglou MJ, Dill KA (2016). Highly charged proteins: The achilles’ heel of aging proteomes. Structure 24: 329-336.

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