Switch On Memory

The painful reality is that age-related cognitive decline often begins in your late 40s. Diet, exercise, nutraceuticals, and other longevity treatments may help delay this deterioration, which is particularly pronounced in declarative memory — the ability to recall facts and experiences — but age eventually takes its toll. Changes occur in gene expression in the brain’s hippocampus and frontal lobe. However, the molecular mechanisms underlying these changes in gene regulation are not completely known.

A new study published in Science sheds some light on how “memory disturbances” in an aging mouse brain are associated with altered “hippocampal chromatin plasticity” — the combination of DNA, histones, and other proteins that make up the chromosomes associated with the hippocampus. Specifically, the study describes an acetyl genetic switch that produces memory impairment in aging 16-month-old mice. Because the acetyl wasn’t present in young 3-month-old mice, the study concludes that it acts as a switch for a cluster of learning and memory genes.

The research was led by André Fischer of the European Neuroscience Institute in Göttingen, Germany, and reported in New Scientist. Three-month-old mice had to find their way around a new environment and were then assessed on their ability to associate an electric shock with a particular location. The result was much higher genetic expression of over 1500 genes known to make proteins needed for the creation of new neurons. Older 16-month-old mice were given the same tasks and did not exhibit the same gene expression. They also did not do as well as the younger mice at spatial learning and memory tasks.

The genetic switch involves acetylation, the introduction of an acetyl group into a molecule at the DNA level of chromatin resulting in genetic transcription. Here’s a video that animates the acetylation of histone proteins in the regulation of gene expression in cancer cells:

It wasn’t long ago that the idea that genes could be switched on and off was revolutionary: gene regulatory proteins, and the specific DNA sequences that these proteins recognize, turn genes on and off in response to a variety of signals. Dr. Fischer’s research shows that when young mice are learning, an acetyl group binds to a particular point on the histone protein. The cluster of learning and memory genes on the surrounding DNA ends up close to the acetyl group. This acetyl group was missing in the older mice that had been given the same tasks. By injecting an enzyme known to encourage acetyl groups to bind to any kind of histone molecule, Fischer’s team flipped the acetyl genetic switch to the “on” position in the older mice and their learning and memory performance became similar to that of 3-month-old mice.

Ultimately, Dr. Fischer’s team is interested in understanding the impairment associated with normal aging, as well as the origins of mental and neurodegenerative diseases such as anxiety disorders and Alzheimer’s disease. Their hope is that the study of hippocampal chromatin plasticity and gene regulation in mice will help them to identify therapeutic strategies to encourage neuroplasticity (the formation of new neural networks in the brain), to improve learning behavior, and to recover seemingly lost long-term memories in human patients.

Switch on memory? What’s not clear is why the switch flips “off” as we get older. It might help us cope with oxidative stress at the cellular level as we age. Turning the switch “on” might have damaging side effects. But, then again, you just might be able to remember where you left those darn keys.