Aging Heart Cells Lose Ability to Repair Mutations

As we age, cellular metabolism and reproduction typically undergo more abnormalities than observed throughout the rest of the lifespan. These genetic mutations usually result in harmless mismatched base pairs, often spliced via transcription, but can also result in much more severe conditions, such as heart disease.

Since heart muscle cells, called cardiomyocytes, stop dividing later in the lifespan, they are typically not investigated as deeply for age-related mutations. However, researchers from the Division of Genetics and Genomics at Boston Children’s Hospital decided to investigate these abnormalities in heart muscle cells in more detail, with some surprising results. 

“Because the heart is always pumping, it uses a lot of energy,” says Ming Hui Chen, MD, MMSc, cardiologist in the Division of Genetics and Genomics and Department of Cardiology at Boston Children’s. “This energy production creates chemical byproducts known as reactive oxygen species or ROS. When levels of ROS get too high, they can damage DNA.”

Their work, published in Nature Aging, used single-cell whole-genome sequencing to investigate somatic single-nucleotide variants (sSNVs) in 56 different cardiomyocytes. These cells were derived from 12 individuals across the age spectrum, all of whom died from causes unrelated to heart disease.

The team utilized intricate bioinformatic techniques to identify molecular signatures on these specialized cells to assess the extent of any damage observed. Ultimately, they found that cardiomyocyte sSNVs accumulated faster with aging than that observed with other dividing cell types and neurons. They observed cardiomyocyte mutations occurring faster than other dividing cells, with about 100 new mutations per year, per cell.

“Heart cells also accumulated mutations at rate three times faster than neurons, another cell type that doesn’t divide,” says August Yue Huang, PhD, in the Division of Genetics and Genomics at Boston Children’s.

In addition to DNA repair pathways, mutations affected genes involved in the cytoskeleton, the scaffolding that gives cells their structure, and other essential cell functions.

“As you age and get more mutations, you’re adding deleterious effects that might push the heart past a tipping point into disease,” Chen states. “It may get to a point where so much DNA is damaged that the heart can no longer beat well.”

Notably, the researchers state that, since their study only looked at single-nucleotide variants, they might not have pulled information relating to other types of mutations. Additionally, they only looked at healthy heart cells, so they can’t confirm that these mutations definitively resulted in heart disease. For future studies, they plan to look at mutations in tissue from patients with different cardiovascular diseases.