Aging, Environment, & DiseaseDNA Methylation and HydroxymethylationHistone ModificationsRegulatory RNA

The Role of Epigenetics in Cognitive Ageing

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Dr. Karen Mather, Genetics & Genomics Group Leader at the Centre for Healthy Brain Ageing (CHeBA), UNSW Australia

As we age, there is a decline in cognitive performance but there is great variability in the rate and degree of cognitive ageing observed across older adults.  The domains of information processing speed, episodic memory (autobiographical memory) and executive function (decision making) are most affected.  However, the biological processes driving this age-related cognitive decline are unclear.  A greater understanding of the causes and correlates of cognitive ageing would assist in identifying individuals at risk of cognitive decline and suggest interventions that may prevent or treat cognitive decline.  This is an important field of research as our population ages.

Epigenetic factors have been linked to neurogenesis (creation of new neurons), synaptic plasticity (the ability of neuronal connections to either strengthen or weaken, which can influence brain function), memory and learning.  There is now some evidence that epigenetic dysregulation may contribute to age-related cognitive performance.  Indeed, the ‘epigenetic hypothesis of ageing-related cognitive dysfunction’ was proposed by Penner and colleagues from the USA in 20101. In our recent review2, we examined the current state of evidence regarding the roles epigenetic factors play in age-related cognitive decline.  The epigenetic factors examined were histone modifications (DNA-associated proteins), non-coding RNAs (that do not encode for protein) and DNA methylation (methylation of DNA cytosine residues).

Epigenetic variation increases with ageing, which is known as epigenetic drift.  This increased variation may disrupt the normal control of gene expression and other essential processes and may contribute to age-related cognitive decline.  Examples of age-related epigenetic dysregulation include changes in modifications to histones, miRNA expression (small non-coding RNAs) and DNA methylation profiles.

Moreover, animal studies suggest changes in histone modifications, DNA methylation and non-coding RNAs are linked to age-related cognitive performance and decline.  Experiments using rodents have yielded the most informative results but whether the results of animal studies is applicable to humans remains to be seen.  Moreover, many of these studies have not been independently replicated.  Of the few human studies that have examined the role of epigenetic factors in age-related cognitive performance, the results in general have been negative.  Another question is whether easily accessible biological samples in humans, such as blood, are informative and useful in epigenetic cognitive ageing studies.  Brain-derived tissue would be the most appropriate sample to use for cognitive studies but cannot be used in living human studies.  A further major complication in human studies is the difficulty in discriminating between individuals showing ‘normal’ age-related decline and those who will develop dementia.

Potential therapies for cognitive ageing include agents that have already been successfully used in cancer treatment such as histone deacetylase inhibitors.  However, their relative non-specificity may be an issue and the development of brain-specific and gene-specific targeted approaches may be necessary.  Another promising avenue for treatment may include the use of RNA interference (RNAi) molecules, which can be targeted to specific non-coding RNAs thereby inhibiting their function.  Lifestyle changes (e.g. exercise) may also influence epigenetic marks, which may potentially lead to improvements in age-related cognitive performance.

Nevertheless, more research is required into firstly improving our fundamental understanding of the epigenetic factors involved in age-related cognitive performance and secondly to investigate possible treatments, including lifestyle changes.  In the future, more human studies investigating cognitive ageing and epigenetics are required, ideally of longitudinal design.  It is important to note that different and dynamic epigenetic mechanisms may be involved, which may interact, and that genetic variation also influences epigenetic marks.  There are still many questions to answer but in the future epigenetic research promises to lead to a better understanding of the factors contributing to age-related cognitive decline.

 

Penner MR, Roth TL, Barnes CA, & Sweatt JD (2010). An epigenetic hypothesis of aging-related cognitive dysfunction. Frontiers in aging neuroscience, 2 PMID: 20552047

Mather KA, Kwok JB, Armstrong N, & Sachdev PS (2014). The role of epigenetics in cognitive ageing. International journal of geriatric psychiatry PMID: 25098266

 

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Karen Mather

Karen Mather