An example of a signaling network for peroxide-induced premature senescence in human fibroblasts, demonstrating major and minor ‘hubs’; the former are possible target sites of five different putative microRNAs. This network was constructed by the Ingenuity functional clustering software, with lead proteins identified as differing in concentration between young replicating WI-38 human fibroblasts and their senescent counterparts exposed to peroxide, and their prematurely senescent counterparts (induced by peroxide). The five major hubs, represented here as yellow color-filled circles, are: High-mobility group box 1 (HMGB1), Annexin A2 (ANXA2), Vimentin (Vim), Heat-shock protein B1 (HSPB1 or Hsp27), and Stress-induced phosphoprotein (STIP1); and the two minor hubs, represented here as two gray color-filled circles, are histone 1 (H4d) and interleukin (IL). In this model each of the five major hubs is targeted by one of five putative microRNAs, i.e. miR-X, miR-Y, miR-α, miR-β, and miR-γ. However, not shown here are the two potential scenarios that: 1. an individual ‘hub’ may be targeted by multiple microRNAs; and 2. miR-X may target not only HMGB1 but also HSPB1, according to the multi-miR/multi-target pair principle.