Early Inflammation , Immunopathology and Aging 1 2

1 7 1 8 Age-related diseases are often attributed to immunopathology, which results in self-1 9 damage caused by an inappropriate inflammatory response. Immunopathology 2 0 associated with early-life inflammation also appears to cause faster ageing, although 2 1 we lack direct experimental evidence for this association. To understand the 2 2 interactions between ageing, inflammation and immunopathology, we used the 2 3 mealworm beetle Tenebrio molitor as a study organism. We hypothesized that 2 4 phenoloxidase (PO), an important immune effector in insect defence, may impose 2 5 substantial immunopathological costs by causing tissue damage, in turn accelerating 2 6 aging. In support of this hypothesis, we found that RNAi knockdown of PO 2 7 transcripts in young adults reduced inflammation-induced autoreactive tissue damage 2 8 to Malpighian tubules, and increased adult lifespan. Our work thus provides empirical 2 9 evidence for a causative link between immunopathological costs of early life 3 0 inflammation and faster ageing. We also reasoned that if natural selection weakens 3 1 with age, older individuals should display increased immunopathological costs 3 2