Life(span) in balance: oxygen fuels a sophisticated neural network for lifespan homeostasis in C. elegans.

A key finding of modern ageing research is that our limitation in lifespan is more than the result of accumulated organismal decay. Lifespan is regulated by genetically defined chemosensory and endocrine pathways, which integrate signals that reflect the internal and external status of the animal. New findings by Liu and Cai unravel a role for the environmental gases oxygen and carbon dioxide in the regulation of lifespan homeostasis and thus a novel function of oxygen-chemosensory neurons in C. elegans. Which factors define our lifetime? Along the quest for answers, the soil nematode C. elegans has become a popular model to address this question, as is demonstrated by the rapidly growing number of journal articles on lifespan regulation solely in C. elegans. Importantly, due to evolutionary conservation of the implicated genes, these findings are transferable to higher organisms including humans. Environmental circumstances such as nutrient availability and temperature directly feed into endocrine mechanisms that regulate lifespan. The importance of chemosensation in these processes has long been understood and efforts were focused on elucidating its various roles affecting longevity. For instance, ablating specific sensory neurons involved in the detection of stress and starvation pheromones causes pronounced effects on lifespan, both positive and negative (Alcedo and Kenyon, 2004). Specifically, functional loss of neuron classes called ASI or ASG promotes lifespan, an effect which is suppressed by ablation of other neuron classes called ASJ and ASK. This lifespan modulation was found to be dependent on hormonal signalling via the insulin receptor homologue DAF-2, which negatively regulates the FOXO transcription factor DAF-16. The hypoxia-inducible factor 1 (HIF-1) transcriptional pathway presents another well-described mechanism affecting longevity. Although predominantly known for its importance for survival of hypoxic conditions, HIF-1 has gained recognition as a key player in lifespan regulation. Activation of HIF-1 promotes longevity via the classical hypoxic response pathway (Mehta et al, 2009), whilst functional loss of HIF-1 promotes lifespan in a temperatureand DAF16-dependent manner (Leiser et al, 2011). Generally, DAF-16 proved to play a leading role in lifespan regulation, both dependent and independent of DAF-2. For instance, recent work demonstrated that cold-induced longevity via DAF-16 occurs independent of DAF-2 and is initiated by the activation of the temperature-sensitive TRP family ion channel TRPA-1 in cold-sensitive neurons and the intestine (Xiao et al, 2013).