Early-life inflammation, immune response and ageing

Abstract

Age-related diseases are often attributed to immunopathology, which results in self-damage caused by an inappropriate inflammatory response. Immunopathology associated with early-life inflammation also appears to cause faster ageing, although we lack direct experimental evidence for this association. To understand the interactions between ageing, inflammation and immunopathology, we used the mealworm beetle as a study organism. We hypothesized that phenoloxidase, an important immune effector in insect defence, may impose substantial immunopathological costs by causing tissue damage to Malpighian tubules (MTs; functionally equivalent to the human kidney), in turn accelerating ageing. In support of this hypothesis, we found that RNAi knockdown of phenoloxidase (PO) transcripts in young adults possibly reduced inflammation-induced autoreactive tissue damage to MTs, and increased adult lifespan. Our work thus suggests a causative link between immunopathological costs of early-life inflammation and faster ageing. We also reasoned that if natural selection weakens with age, older individuals should display increased immunopathological costs associated with an immune response. Indeed, we found that while old infected individuals cleared infection faster than young individuals, possibly they also displayed exacerbated immunopathological costs (larger decline in MT function) and higher post-infection mortality. RNAi-mediated knockdown of PO response partially rescued MTs function in older beetles and resulted in increased lifespan after infection. Taken together, our data are consistent with a direct role of immunopathological consequences of immune response during ageing in insects. Our work is also the first report that highlights the pervasive role of tissue damage under diverse contexts of ageing and immune response.

Age‐dependent variation in the terminal investment threshold in male crickets

“…Alternatively, older males could be shifting toward a more proinflammatory state with age (e.g., see Khan et al. ).…”

Immune deployment increases larval vulnerability to predators and inhibits adult life‐history traits in a dragonfly

“…Predator‐mediated costs of immune deployment thus probably stemmed more from trade‐offs with escape performance and emergence time. While the substantial energetic costs of immune deployment seem likely to primarily underlie these trade‐offs (Freitak et al ., ; Ardia et al ., ), evaluating any additional contribution of autoreactive tissue damage (Sadd & Siva‐Jothy, ; Khan et al ., ) or shared reliance on transport proteins (Adamo et al ., ) remains necessary. Nevertheless, as trade‐offs between performance and immune deployment have also been observed in other organisms (Adamo et al ., ; Otti et al ., ; Zamora‐Camacho et al ., ), predator‐dependent costs of immune deployment like those observed here could commonly constrain the evolutionary maximization of immune responses.…”

“…While the energetic costs of the subsequent encapsulation response are known to be substantial (e.g. Freitak et al ., ; Ardia et al ., ), incidental tissue damage caused by auto‐immunity may also contribute to the total costs observed here (Sadd & Siva‐Jothy, ; Khan et al ., ). For a control treatment, we inserted an implant but then removed it immediately.…”

“…The persistent threat of parasites and pathogens should favour increasingly robust immunity, yet immune function is often imperfect and highly variable among individuals within and across populations (Sheldon & Verhulst, ; Rolff & Siva‐Jothy, ). One important constraint on the evolutionary maximization of immune function may be the inherent trade‐offs between mounting immune responses and other important traits that arise due to resource limitations (Zuk & Stoehr, ; Schmid‐Hempel, ; McKean et al ., ) and/or incidental tissue damage (‘self‐harm’ or ‘autoreactivity’, Sadd & Siva‐Jothy, ; Khan et al ., ). Indeed, the deployment of a robust immune response often comes at a substantial cost to traits such as locomotor performance (Adamo et al ., ; Zamora‐Camacho et al ., ), investment in offspring size (Uller et al ., ), sexual displays (Jacot et al ., , ) and longevity (Armitage et al ., ; Krams et al ., ; Khan et al ., ).…”

“…This melanin‐based immune response is energetically costly (Freitak et al ., ; Ardia et al ., ; González‐Santoyo & Córdoba‐Aguilar, ) and highly sensitive to environmental conditions (including predation risk: Stoks et al ., ; Duong & McCauley, ), making it likely to be involved in many allocation trade‐offs within life stages. Because of the cytotoxic properties of the melanin‐synthesis pathway, this nonspecific immune response can also result in considerable incidental tissue damage (Nappi & Vass, ; Sadd & Siva‐Jothy, ; Khan et al ., ). Moreover, the functioning of the melanin‐synthesis pathway directly carries over from the larval to the adult life stage in arthropods (Debecker et al ., ) and is used in the production of sexually selected coloration (Hooper et al ., ; Lawniczak et al ., ; Wittkopp & Beldade, ), making the overall encapsulation response likely to affect fitness components across life stages as well.…”