Insecticide resistance is driven by distinct metabolic mechanisms across the lifespan of the major malaria vector Anopheles arabiensis

Insecticide resistance among Anopheles malaria vectors is entrenched across sub-Saharan Africa, yet resistance phenotyping is routinely performed on 3–5-day old mosquitoes, not older cohorts responsible for malaria transmission. To identify age-specific insecticide resistance mechanisms, we performed whole transcriptomic sequencing of wild permethrin-resistant An. arabiensis at 3, 6, and 11 days old. We observed age-specific expression of detoxification enzymes, cuticular proteins, salivary glands, and gustatory and odorant receptors, which was generally highest in 3-day old mosquitoes and declined over time. In younger mosquitoes, CYP6P3, which metabolises permethrin and deltamethrin in vitro, was highly over-expressed (>100 fold) alongside CYP6M2, CYP6Z3, CYP4H19, CYP6Z2 and CYP4H17, COEJHE2E, and GSTD7. CYP4H17 only demonstrated increased overexpression in 11-day old An. arabiensis, representing a putative marker of transcriptional age grading. Dynamic transcriptomic profiles of permethrin resistant An. arabiensis of different ages indicates that insecticide resistance is driven by distinct metabolic mechanisms across the malaria vector lifespan.