Due to the graying of our society and associated increase in the incidence of age-related diseases, understanding healthy aging is of crucial importance. This will expand our overall understanding of biology in order to treat these disorders and help ease the social and economic burden placed on our society. In accordance, the field of biogerentology has shifted its focus from studying pure lifespan interventions to evaluations of healthy aging along the lifespan trajectory. This has unveiled that an increase in lifespan does not always correlate with a proportionate increase in healthspan, defined as the period when an organism is free from disease and in general good health (Bansal et al.,2016, Zhang et al.,2016).
As part of an EU-funded project, Ageing with elegans, we aim is to facilitate the use of C.elegans as a healthspan model. Relying on the ‘WorMotel’, an in-house developed multi-well system for the longitudinal observation of activity of individual animals upon blue light stimulation, we are now performing a genome-wide RNAi screen to identify genes implicated in healthspan control. The observed daily maximal activity of the worms upon stimulation is used to determine life- and healthspan. By defining healthspan as the total amount of days in which the worm shows at least 25% of the highest maximal activity displayed over its lifespan, we select plausible candidates based on the significantly altered healthspan/lifespan (HS/LS) ratio. As such, candidate genes are grouped in 8 classes, established by the relative changes in lifespan and HS/LS ratios, and prioritized for detailed study accordingly.
Here, we present our parameters for the computational analysis and the results of a subset of genetic knockdowns, selected based on the existence of a human ortholog and a known effect on lifespan. In accordance with literature, long-lived populations typically show overall lower HS/LS ratio whereas short-lived groups show higher HS/LS ratio. Still, there are exceptions to this pattern. These interventions are especially interesting for molecular evaluation of their involvement in known (GFP reporter assay of known central regulators) or yet to be discovered pathways (omics analyses). As a part of the consortium, collaborators (UGent, University of Berlin, ETH Zürich) study the role of these genes in other aging-related phenotypes – e.g. sarcopenia-relevant muscle integrity, maintenance of neuronal functionality, lipid content – prior to further study in mice models. As such, we aim to shed more light on the genetics underlying an organism’s healthspan vs. lifespan balance.