Posted on 18 May 2020
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DNA damage that accumulates throughout life is thought to be an important driver of age-related disease. DNA is continually damaged by chemicals produced in normal cellular metabolism, as well as bythat originates from the Sun and the Earth. We have evolved alongside these threats, and so cells are equipped with highly effective repair mechanisms to safeguard against DNA damage. However, as we age, these repair mechanisms become less effective.
In this study, researchers identify an important role for the enzyme HDAC1 in repairing DNA damage to certain genes, specifically those involved in memory and other cognitive functions. HDAC1 levels are reduced both in Alzheimer’s disease and normal ageing, so HDAC1-activating drugs could have potential for slowing age-related cognitive decline and neurodegeneration.
In a study of mice, the researchers showed that when HDAC1 is lost, a specific type of DNA damage builds up as the mice age. They also showed that they could reverse this damage and improve cognitive function with a drug that activates HDAC1.
The study suggests that restoring HDAC1 could have positive benefits for both Alzheimer’s patients and people who suffer from age-related cognitive decline, the researchers say.
Several years ago, [Li-Huei Tsai, (Massachusetts Institute of Technology)] and Stephen Haggarty of Harvard Medical School, who is also an author of the new study, screened libraries of small molecules in search of potential drug compounds that activate or inhibit members of the HDAC family.
In the new paper, Tsai and Pao used one of these drugs, called exifone, to see if they could reverse the age-related DNA damage they saw in mice lacking HDAC1. […] they found that the drug reduced the levels of oxidative DNA damage in the brain and improved the mice’s cognitive functions, including memory.
Exifone was approved in the 1980s in Europe to treat dementia but was later taken off the market because it caused liver damage in some patients. Tsai says she is optimistic that other, safer HDAC1-activating drugs could be worth pursuing as potential treatments for both age-related cognitive decline and Alzheimer’s disease.
Tsai’s lab is now exploring whether DNA damage and HDAC1 also play a role in the formation of Tau tangles – misfolded proteins in the brain that are a signature of Alzheimer’s and other neurodegenerative diseases.
Li-Huei Tsai, Study Senior Author and Director, Massachusetts Institute of Technology Picower Institute for Learning and Memory