Protect neurons from aging

Anti-aging enzyme of neurons found in mice

Tatiana Matveeva, "Scientific Russia"

Neurologists from Cambridge and the Massachusetts Institute of Technology (USA) have found that when the HDAC1 enzyme (histone deacetylase 1) is "lost" in mice, a certain type of DNA damage accumulates with age. Scientists have managed to prevent this damage in rodents. It is assumed that the restoration of the HDAC1 enzyme can also help patients with Alzheimer's disease and elderly people suffering from cognitive impairment, the MIT press service reports. The results of the study are published in the journal Nature Communications (Pao et al., HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer's disease).

"It seems that HDAC1 is really an anti–aging molecule," says Li–Hui Tsai, director of the Picower Institute of Learning and Memory at the Massachusetts Institute of Technology (MIT) and senior author of the study.

There are several members of the HDAC enzyme family, and their main function is to modify histones, proteins around which DNA is wound. These modifications control gene expression by preventing genes in certain DNA regions from being copied into RNA.

In 2013, Tsai's lab published two papers that linked HDAC1 to DNA repair in neurons. And in their latest work, the researchers studied what happens when HDAC1-mediated recovery does not occur. To do this, they removed this enzyme from some mice in neurons and other types of brain cells called astrocytes.

During the first few months of the mice's life, there were no noticeable differences in their levels of DNA damage or behavior compared to the control group. However, as the rodents aged, the differences became more and more obvious. DNA damage began to accumulate in mice with HDAC1 deficiency, and they also lost some of their ability to change the strength of connections between neurons (synaptic plasticity). Older mice lacking HDAC1 also showed impairments in memory and spatial orientation tests.

Neurons in the lower row that lack the HDAC1 gene show a higher level of DNA damage (green) than normal neurons. Image provided by researchers. The team found that the loss of HDAC1 leads to a certain type of DNA damage called 8-oxo-guanine damage, which is a sign of oxidative DNA damage.

Studies of patients with Alzheimer's disease have also shown a high level of DNA damage of this type, which is often caused by the accumulation of harmful metabolic byproducts. The brain's ability to purify these byproducts often weakens with age.

An enzyme called OGG1 is responsible for repairing this type of oxidative DNA damage. As the researchers found, HDAC1 is necessary for the activation of OGG1. When HDAC1 is absent, OGG1 is not turned on and DNA damage is not repaired.

Scientists have also discovered that there are drugs that activate or stop the work of enzymes from the HDAC family. They used exifone to see if they could reverse the age-related DNA damage they saw in mice lacking HDAC1.

The researchers used exifone to treat mice with Alzheimer's disease, as well as healthy aged mice. In all cases, they found that the drug reduced 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 for the treatment of dementia, but was later withdrawn from the market because it caused liver damage in some patients. The authors of the study hope that other, safer HDAC1-activating drugs can help in the treatment of both age-related cognitive decline and Alzheimer's disease in humans.

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