Abstract
The Insulin/IGF-like signalling (IIS) pathway plays an evolutionarily conserved role in ageing. In model organisms reduced IIS extends lifespan and ameliorates some forms of functional senescence. However, little is known about IIS in nervous system ageing and behavioural senescence. To investigate this role in Drosophila melanogaster, we measured the effect of reduced IIS on senescence of two locomotor behaviours, negative geotaxis and exploratory walking. Two long-lived fly models with systemic IIS reductions (daGAL4/UAS-InRDN (ubiquitous expression of a dominant negative insulin receptor) and d2GAL/UAS-rpr (ablation of insulin-like peptide producing cells)) showed an amelioration of negative geotaxis senescence similar to that previously reported for the long-lived IIS mutant chico. In contrast, exploratory walking in daGAL4/UAS-InRDN and d2GAL/UAS-rpr flies declined with age similarly to controls. To determine the contribution of IIS in the nervous system to these altered senescence patterns and lifespan, the InRDN was targeted to neurons (elavGAL4/UAS-InRDN), which resulted in extension of lifespan in females, normal negative geotaxis senescence in males and females, and detrimental effects on age-specific exploratory walking behaviour in males and females. These data indicate that the Drosophila insulin receptor independently modulates lifespan and age-specific function of different types of locomotor behaviour. The data suggest that ameliorated negative geotaxis senescence of long-lived flies with systemic IIS reductions is due to ageing related effects of reduced IIS outside the nervous system. The lifespan extension and coincident detrimental or neutral effects on locomotor function with a neuron specific reduction (elavGAL4/UAS-InRDN) indicates that reduced IIS is not beneficial to the neural circuitry underlying the behaviours despite increasing lifespan.
Highlights
The IGF-like signalling (IIS) pathway is ubiquitous in multicellular animals [1] and mutations that alter IIS can have pleiotropic effects on growth, development, metabolic homoeostasis and reproduction [2,3,4,5,6]
To initially determine if the amelioration of locomotor senescence in long-lived chico mutant flies is a common feature of lifespan extending systemic IIS reductions, we measured the senescence of negative geotaxis behaviour in two long-lived fly models with systemically reduced IIS —daGAL4/UAS-InRDN flies ubiquitously express a dominant negative form of the insulin receptor under the control of the daughterlessGAL4 driver [32] and d2GAL/UAS-rpr flies have reduced levels of circulating Drosophila insulin-like peptides (Dilps) 2, 3 and 5 due to the ablation of insulin producing cells (IPCs) in the brain [31]
As lifespan extension due to reductions in IIS is dependent on the presence of Wolbachia [32, 39], it was confirmed that all strains used in all experiments were positive for this endosymbiont (S1 Fig)
Summary
The IIS pathway is ubiquitous in multicellular animals [1] and mutations that alter IIS can have pleiotropic effects on growth, development, metabolic homoeostasis and reproduction [2,3,4,5,6]. Despite the potential for severe detrimental effects, such as diabetes in mammals, reduced IIS has been identified as an evolutionarily conserved method of extending lifespan and some measures of age-related health in nematode worms, fruit flies and mice. Drosophila lacking chico, the single fly insulin receptor substrate are long-lived [7] and show slower age-related decline in negative geotaxis locomotor function [8, 9]. Mice lacking the insulin receptor substrate 1 (IRS1) are long-lived and show improvements in skin, bone, immune and motor function, and glucose homeostasis with age compared to controls [10]. It is important to fully evaluate the health and function of long-lived model organisms as they age, to determine if interventions that extend lifespan have the potential to delay or attenuate ageing-related disease and functional senescence in humans
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