Insulin regulates aging and oxidative stress in Anopheles stephensi

Abstract

SUMMARYObservations from nematodes to mammals indicate that insulin/insulin-like growth factor signaling (IIS) regulates lifespan. As in other organisms, IIS is conserved in mosquitoes and signaling occurs in multiple tissues. During bloodfeeding, mosquitoes ingest human insulin. This simple observation suggested that exogenous insulin could mimic the endogenous hormonal control of aging in mosquitoes, providing a new model to examine this phenomenon at the organismal and cellular levels. To this end, female Anopheles stephensi mosquitoes were maintained on diets containing human insulin provided daily in sucrose or three times weekly by artificial bloodmeal. Regardless of delivery route, mosquitoes provided with insulin at 1.7ϫ10 -4 and 1.7ϫ10 -3 ·mol·l -1 , doses 0.3-fold and 3.0-fold higher than non-fasting blood levels, died at a faster rate than controls. In mammals, IIS induces the synthesis of reactive oxygen species and downregulates antioxidants, events that increase oxidative stress and that have been associated with reduced lifespan. Insulin treatment of mosquito cells in vitro induced hydrogen peroxide synthesis while dietary supplementation reduced total superoxide dismutase (SOD) activity and manganese SOD activity relative to controls. The effects of insulin on mortality were reversed when diets were supplemented with manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP), a cell-permeable SOD mimetic agent, suggesting that insulin-induced mortality was due to oxidative stress. In addition, dietary insulin activated Akt/protein kinase B and extracellular signal-regulated kinase (ERK) in the mosquito midgut, suggesting that, as observed in Caenorhabditis elegans, the midgut may act as a ʻsignaling centerʼ for mosquito aging.

ERK signaling couples nutrient status to antiviral defense in the insect gut

“…4C and SI Appendix, Fig. S25), similar to previous reports in the vector mosquito Anopheles stephensi (34). Furthermore, we found that oral administration of insulin did not alter feeding behavior or increase mortality compared with vehicle-fed flies within the time course of our assays (SI Appendix, Fig.…”

“…Because ERK signaling can be activated in the mosquito digestive tract by nutrients and insulin in the blood meal (30,34), we reasoned that the ERK pathway may couple signals in the meal with antiviral defense to protect insects from orally acquired viral infections, including arboviruses. To determine whether ERK activity in the gut impacts local viral susceptibility, we took advantage of U0126 to inhibit ERK signaling in the gut.…”

“…The food contained 5% (vol/vol) sucrose plus dye in addition to the indicated treatment. Bovine insulin (83.5 μM) was used as described (34), and mixing experiments demonstrated no change in infectivity of VSV when mixed with insulin (SI Appendix, Fig. S30).…”

Human IGF1 extends lifespan and enhances resistance to Plasmodium falciparum infection in the malaria vector Anopheles stephensi

“…The most vulnerable point of the malaria parasite life cycle is the transition from the human blood stream to the mosquito midgut. During this transition, hormones, growth factors and cytokines in infected blood can regulate aspects of mosquito physiology and lifespan that directly affect parasite development (Kang et al, 2008;Luckhart et al, 2003;Luckhart and Riehle, 2007;Pakpour et al, 2012;Surachetpong et al, 2009;Surachetpong et al, 2011).…”

“…The blood meal is stored and digested in this organ, and it is the site of crucial phases in malaria parasite development in the mosquito host. Activation of midgut IIS can shorten mosquito lifespan and enhance susceptibility to P. falciparum infection in A. stephensi (Kang et al, 2008;Surachetpong et al, 2009). In particular, Pakpour et al (Pakpour et al, 2012) showed that insulin-induced susceptibility is due to the sustained activation of the phosphatidylinositol 3-kinase (PI3K)/Akt branch of the A. stephensi IIS, which in turn inhibits NF-κB-regulated immune gene expression.…”