As we get older, our cognitive ability declines, especially our memory. Although aging-related cognitive impairment occurs naturally, humans have been fascinated since ancient times with uncovering a “fountain of youth” to ensure that our beauty, minds, and youthful qualities stay with us forever. What if we could stave off or protect our brain function as we age? With new research in epigenetics, we may be closer to finding out what’s behind memory loss and cognitive impairment. A study published in Scientific Reports reveals a link between a specific epigenetic mark and cognitive decline in a rat model. These findings help progress our understanding of the biological repercussions of getting older and could bring us closer to potential therapies for slowing down or even remedying this degeneration.
Epigenetic mechanisms, such as DNA methylation, are known to control the regulation of several genes directly responsible for the formation and maintenance of memory. Earlier research has shown that aberrant DNA methylation changes are linked to cognitive decline, such as impaired spatial memory. On the other hand, a DNA methyltransferase known as Dnmt3a2 has been shown to restore cognitive function in older mice, potentially boosting their memory.
In this study, a research team from Peking University in China assessed whether DNA methylation of protein kinase Mζ (PKMZ), a key molecule found in the brain that is involved in establishing long-term memory, is connected to aging-related memory loss. This molecule has also been previously connected to Alzheimer’s, a dementia-related disease that afflicts as many as 5.4 million Americans. After the group conducted various learning and memory-related assessments on young, adult, and elderly rats, including the Morris water maze, contextual fear conditioning, and novel object recognition test, the researchers collected prelimbic cortex samples. Then, they bisulfite-converted the rats’ DNA for quantitative real-time PCR to investigate the difference in methylation between the rat age groups.
The group of researchers performed bisulfite conversion of DNA using the BisulFlash DNA Modification Kit (EpiGentek), converting unmethylated cytosine to uracil so that methylated cytosine could be detected. This kit is geared specifically for fast bisulfite conversion followed by methylation-specific PCR (MSP) or post-bisulfite based NGS applications. Using this assay, the researchers were able to bisulfite convert the rat brain DNA samples quickly and with high conversion efficiency and accuracy. The team focused on the DNA methylation status of PKMZ genes, specifically, the promoter region.
Overall, they found that hypermethylation of PKMZ DNA was connected to memory impairment in aged rats. Typically, hypermethylation occurs at CpG islands in the promoter region and is associated with gene inactivation. They reported that “associative learning decreased the level of methylated PKMZ DNA in all age groups during [long-term memory] retention, and increased the level of unmethylated PKMZ DNA only in young and adult rats but not in aged rats.”
When the rats were exposed to environmentally enriched housing, the hypermethylation of PKMZ was reversed and the aged rats’ cognitive performance was restored. Environmentally enriched housing consisted of larger cages with running wheels, dwellings, ramps, toys, and other engaging items. Other research has linked enriched surroundings to improved spatial memory, although the underlying biological mechanisms are unclear. The researchers indicated that PKMZ protein and unmethylated PKMZ DNA were upregulated and methylated PKMZ DNA expression was downregulated, which led to an improvement in memory retention. The team suggested that it’s possible that “both passive and active mechanisms of DNA demethylation may be involved.” Notably, they found that an increase in endogenic PKMZ expression was “required for the potentiating effect of environmental enrichment on cognitive function in aged rats.”
This study contributes to our knowledge of memory retention and to our understanding of epigenetic mechanisms that might explain the benefits of environmental enrichment, especially as we age. These results bring forth more questions about the epigenetics behind aging and the possibility of staving off or reversing cognitive decline. For now, these questions remain unanswered as current epigenetic research explores the endless mysteries surrounding aging and continues to pursue our fascination of staying physically and mentally “forever young.”
Source: Chen C, et al. (2016). Epigenetic modification of PKMζ rescues aging-related cognitive impairment. Scientific Reports, 6: 22096.