Molecular and Cellular Evidence for Age by Disease Interactions: Updates and Path Forward

Characterization of age-associated gene expression changes shows that the brain engages a specific set of genes and biologic pathways along a continuous life-long trajectory and that these genes and pathways overlap with those associated with brain-related disorders. Based on this correlative observation, we have suggested a model of age-by-disease interaction by which brain ageing promotes biologic changes associated with diseases and where deviations from expected age-related trajectories, due to biologic and environmental factors, contribute to defining disease risk or resiliency. In this review, we first evaluate various biomarkers that can be used to study age-by-disease interactions and then focus on transcriptome analysis (i.e., the set of all expressed genes) as a useful tool to explore this interaction. Using the specific example of brain-derived neurotrophic factor and brain-derived neurotrophic factor-associated genes, we then describe molecular events and mechanisms potentially contributing to age-by-disease interactions. Finally, we suggest that long-term biologic adaptations within distinct cellular components of cortical microcircuits, as determined by transcriptome analysis, may integrate and mediate the effects of ageing and diseases. Moving forward, we suggest that analysis of transcriptome similarities between ageing and small molecule-induced system perturbations may lead to novel therapeutics discovery.