CaMKII Oxidation in Heart Function as an Example of Antagonistic Pleiotropy
CaMKII can be oxidized readily in mammals, but not in flies. This is a small change in DNA sequence, but it produces a greater physical capacity in youth, coupled to a greater vulnerability and loss of tissue function in the environment of chronic oxidative stress characteristic of old age. This is a good example of antagonistic pleiotropy, a concept at the center of the consensus on how evolution reliably leads to the production of species that undergo aging. Individuals that reproduce successfully early in life are favored, and thus mutations - such as CaMKII vulnerability to oxidation - that provide an advantage in youth at the cost of degeneration in later life are readily selected.
The evolutionary conservation of genes that enable the young to run faster and respond robustly to "fight or flight" responses makes sense: It helps them to catch prey or evade predators, thereby ensuring their reproductive success. However, some of these genes carry a steep price that animals need to pay when they grow older. Research shows that turning on CaMKII through a chemical reaction caused by adding oxygen, known as oxidation, strengthens these survival responses for young animals. However, oxidative stress increases with aging, which leads to excessive activation of CaMKII. Elevated CaMKII activity has long been linked to tissue damage seen in heart failure, atrial fibrillation, cancer, lung diseases, and neurodegenerative diseases.
Researchers genetically engineered mice so their CaMKII is resistant to oxidation. They then used mouse-sized treadmills to compare the athletic performance of mice with and without CaMKII oxidation. They found that mice with oxidized CaMKII were able to run, on average, about 150 meters further and about 5 meters per minute faster than the mice with oxidation-resistant CaMKII. Further experiments showed that CaMKII activity in the mouse muscle tissue increased the expression of cellular pathways related to inflammation, diabetes, enlarged heart, seizures, and obesity.
Researchers then used a gene-cutting and insertion tool called CRISPR to add the oxidation site characteristic of mammalian CaMKII to the CaMKII gene in fruit fly DNA, normally lacking that site. In one experiment, the flies were placed into glass tubes and allowed to climb to the top of the tube. The researchers found that flies genetically modified to have the oxidizable CaMKII climbed higher and 5mm per second faster than flies with the oxidation-resistant CaMKII. Despite having better physical performance and cardiac function, the genetically modified flies experienced a more rapid age-related decline and they died at a younger age. The hearts of the genetically modified flies are more vulnerable to damaging effects of excessive oxidants.