Activating this enzyme could repair age-associated DNA damage in neurons and improve cognition
Scientists from MIT found stimulating activity of enzyme HDAC1 could improve cognition in mice with age-related cognitive decline.(whitehoune | iStock)
Age-related cognitive decline from normal aging and Alzheimer’s disease continue to increase in prevalence. In 2014, an estimated 5 million people 65 years of age and older had Alzheimer’s disease in the US. This number is expected to increase to 14 million people by the year 2060. These numbers illustrate the importance of research to determine treatments for these patients.
Researchers from the Massachusetts Institute of Technology (MIT) found that the loss of an enzyme, HDAC1, leads to DNA damage as mice age. With exifone, a drug that activates HDAC1, the team reversed the DNA damage and improved cognition in mice. The study published in Nature Communications on May 18, indicates restoration of HDAC1 could benefit Alzheimer’s patients and people who suffer from cognitive decline with aging.
“It seems that HDAC1 is really an anti-aging molecule,” says Li-Huei Tsai, the director of MIT’s Picower Institute for Learning and Memory in a press release from the school. “I think this is a very broadly applicable basic biology finding, because nearly all of the human neurodegenerative diseases only happen during aging. I would speculate that activating HDAC1 is beneficial in many conditions.”
The researchers found HDAC1 loss led to DNA damage called 8-oxo-guanine lesions, which come from cellular stress termed oxidative DNA damage. In studies of Alzheimer’s disease, patients also show high levels of 8-oxo-guanine lesions, typically caused by the buildup of harmful byproducts from metabolism. The brain loses its ability to clear these by-products with aging.
Another enzyme, OGG1, repairs oxidative DNA damage, and the researchers found cells need HDAC1 to activate OGG1. Without HDAC1, OGG1 doesn’t activate and DNA damage does not get repaired. The researchers found many of the genes susceptible to this type of DNA damage play critical roles in the function of synapses, connections between neurons.
The researchers treated mice without HDAC1 with exifone and found improved memory. The team measured improvements in memory with contextual fear conditioning, where the mice would freeze if they remembered receiving a shock in a specific environmental setting. When comparing mice without HDAC1, those treated with exifone performed better on this memory task — they froze more than those without exifone treatment.
Although Exifone restored HDAC1 and improved the memory of mice, the drug has been withdrawn from the market due to having toxic effects on the liver in humans. In the future, developing safe alternative drugs that target HDAC1 can be a promising pharmaceutical intervention in age-related cognitive decline.
“This study really positions HDAC1 as a potential new drug target for age-related phenotypes, as well as neurodegeneration-associated pathology and phenotypes,” said Tsai in the same press release.