In Pursuit of Synergistic Lifespan Extension in C. elegans

Abstract

In recent decades, an influx of aging research has unearthed the possibility that aging is a governable process. Hundreds of compounds, environmental factors, and genetic manipulations have already been shown to extend lifespan in invertebrate models as well as some mammalian systems. Since these act through a variety of molecular mechanisms, we have the potential to achieve greater benefits in terms of healthy lifespan extension by combining those that have shown to be successful. Using an automated system for C. elegans lifespan analysis, we first validated the efficacy of twelve compounds previously reported to extend lifespan, then identify double and triple combinations that extend lifespan in C. elegans beyond the impact of the single drugs alone. Of the twelve compounds examined, exposing worms to six—3-hydroxyanthranilic acid (3HAA), bacitracin, rifampicin, resveratrol, or caffeine, or supplementation with higher than standard doses of cholesterol—increased lifespan when dosed independently. Combinations of 3HAA with bacitracin and 3HAA with caffeine led to a further increase in lifespan. Triple combination of bacitracin, rifampicin, and resveratrol surpassed the lifespan extension of each individual drug in that combination. However, none of the combinations were additive nor synergistic. Though we have yet to achieve additional lifespan through our initial trials, due to the small number of compounds tested in combination and the underlying mechanisms mediating lifespan extension not being well understood, we remain open to the possibility that other combinations that optimally target multiple pathways may realize additive or synergistic benefits in the future. In ongoing work, we are beginning to dissect the underlying molecular mechanisms and each drug and drug combination will need to be evaluated in preclinical models to determine if benefits in worms will translate to mammalian systems. The molecular pathways that drive aging are highly conserved between C. elegans and humans, proving some optimism that synergistic pathway activation can be leveraged in humans to elicit greater quality of life and increased lifespan.