Genetic variation in glia–neuron signalling modulates ageing rate

The rate of behavioural decline in the ageing population is remarkably variable among individuals. Despite the considerable interest in studying natural variation in ageing rate to identify factors that control healthy ageing, no such factor has yet been found. Here we report a genetic basis for variation in ageing rates in Caenorhabditis elegans. We find that C. elegans isolates show diverse lifespan and age-related declines in virility, pharyngeal pumping, and locomotion. DNA polymorphisms in a novel peptide-coding gene, named regulatory-gene-for-behavioural-ageing-1 (rgba-1), and the neuropeptide receptor gene npr-28 influence the rate of age-related decline of worm mating behaviour; these two genes might have been subjected to recent selective sweeps. Glia-derived RGBA-1 activates NPR-28 signalling, which acts in serotonergic and dopaminergic neurons to accelerate behavioural deterioration. This signalling involves the SIR-2.1-dependent activation of the mitochondrial unfolded protein response, a pathway that modulates ageing. Thus, natural variation in neuropeptide-mediated glia–neuron signalling modulates the rate of ageing in C. elegans. Identifying the gene polymorphisms that are the foundations of variation in glia–neuron signalling in Caenorhabditis elegans provides insight into highly variable age-related declines in worm behaviours. The rate at which we age is highly variable. The roundworm Caenorhabditis elegans also shows variability in lifespan and age-related decline. Shi-Qing Cai and colleagues now show that polymorphisms in regulatory-gene-for-behavioural-ageing-1 (rgba-1) and the neuropeptide receptor gene npr-28 result in changes in the rate at which the worms age. rgba-1 encodes neuropeptides in glial cells that activate receptors encoded by npr-28 in neurons, leading to a reduction of SIR-2.1-mediated activation of UPRmt, which modulates ageing.