Motivation The analysis of longitudinal datasets and construction of gene regulatory networks provide a valuable means to disentangle the complexity of microRNA-mRNA interactions. However, there are no computational tools that can integrate, conduct functional analysis and generate detailed networks from longitudinal microRNA-mRNA datasets. Results We present TimiRGeN, an R package that uses time point based differential expression results to identify miRNA-mRNA interactions influencing signalling pathways of interest. miRNA-mRNA interactions can be visualised in R or exported to PathVisio or Cytoscape. The output can be used for hypothesis generation and directing in vitro or further in silico work such as gene regulatory network construction. Availability and implementation TimiRGeN is available for download on Bioconductor (https://bioconductor.org/packages/TimiRGeN) and requires R v4.0.2 or newer and BiocManager v3.12 or newer. Supplementary information Supplementary data is available at Bioinformatics online.

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SummaryAgeing results from the gradual loss of homeostasis, and there are currently many hypotheses for the underlying initial causes, such as molecular damage accumulation. However, few if any theories directly connect comprehensive, underlying biological mechanisms to specific age-related diseases. We recently demonstrated how a specific maintenance system impeding overactivity disorders such as cancer might undergo positive selection while still resulting in a gradual homeostatic shift toward slower metabolism. Here we connect this metabolic slowdown, via a series of unavoidable homeostatic shifts, to the hallmarks of ageing, including mitochondrial dysfunction, insulin resistance (IR), weight gain, basal inflammation, and age-related diseases such as atherosclerosis. We constructed the fuel and energy model (FEM) based on these shifts and found that ageing via metabolic slowdown could explain not only the effects of anti-ageing interventions such as rapamycin and calorie restriction, but many of the paradoxes of ageing that currently defy alternative theories.