Leveraging unbiased LC-MS analysis to identify histone post-translational modifications associated with age-related decline of learning and memory

Age-associated cognitive decline is a significant societal challenge, with several neurodegenerative diseases like Alzheimers disease becoming prevalent. Normal ageing is associated with several molecular, cellular, and metabolic hallmarks, including epigenetic mechanisms. In particular, dysregulation of post-translational modifications on histone tails is emerging as a mechanism associated with functional decline. The hippocampus is a region of the brain that is essential for the formation of episodic and spatial memories, which are particularly susceptible to age-related decline. In this perspective manuscript, we have used mass spectrometry as an unbiased method to profile histone tail post-translational modifications both at baseline and after contextual fear conditioning (CFC) from young and aged mouse hippocampi to identify age- and activity-dependent changes. Using this approach, we identify epigenetic marks not widely studied in ageing and in activity-induced learning. We propose a framework on how to integrate these epigenetic marks into current knowledge and discuss how to use this new analysis to formulate novel hypotheses that will broaden this field of ageing research. We believe that this work will be of interest to scientists, clinicians and the wider public by making a significant contribution to our understanding of the molecular mechanisms responsible for age-associated cognitive decline and by reporting the identification of new mechanisms to focus on.