Natural accelerated proteomic ageing in the red-tailed phascogale mirrors human ageing trajectories

Proteomic studies across large human cohorts have defined conserved ageing signatures, including mitochondrial dysfunction, loss of proteostasis, immune dysregulation, extracellular matrix remodelling, and impaired DNA repair. Here, we report that the red-tailed phascogale (Phascogale calura), a semelparous marsupial in which males die after a single reproductive season, exhibits proteomic changes that closely parallel human ageing signatures. Comparative proteomics revealed that breeders (adult male, AMB) show upregulation of mitochondrial enzymes (e.g., SDHB), ER stress chaperones (HSPA5), and cytoskeletal proteins (MYL4, keratins), alongside suppression of DNA repair (DTL), apoptosis regulation (APAF1), detoxification enzymes (MGST3), and synaptic/ECM proteins (NCKAP1, TNR). These changes reproduce, in compressed form, the gradual proteomic drift observed over decades in humans. Our findings establish the phascogale as a unique natural model of accelerated proteomic ageing, offering insights into the trade-off between reproduction and longevity and providing a platform to study interventions that bolster health span.