All forms of life, from those that live in the icy water of the Arctic Circle to those inhabiting the boiling hot sands of the Kalahari Desert, share one thing in common: their physiology and longevity are affected by environmental temperature. One might assume that this is simply a thermodynamic process, in which temperature alters the rates of biochemical reactions and thus establishes how quickly cells or tissues age. However, studies in a simple roundworm, Caenorhabditis elegans, and in mice suggest that it is the nervous system that regulates the effects of temperature on longevity. Chun-Liang Pan’s group at the Institute of Molecular Medicine, NTU, recently identified key neuronal signals from C. elegans neurons that counteract the adverse effects of high temperature on life span. Yen-Chih Chen and Hung-Jhen Chen, two Master’s program students at the time of the study, found that AFD thermosensory neurons in C. elegans relay temperature information through phosphorylation of CRH-1/CREB, a transcription factor well known for its importance in neuronal memory. Formation of this putative “temperature memory” in AFD neurons leads to the synthesis of FLP-6, a short peptide, the release of which from thermosensory neurons is stimulated by a rise in temperature. Loss of CRH-1 or FLP-6 shortens lifespan, and, strikingly, an increase in CRH-1 or FLP-6 activity extends longevity at a warm temperature. Thus, modulation of a single gene overrides the unwanted aging effects resulting from a high environmental temperature. However, thermosensory neurons do not act alone. Data suggest that the FLP-6 peptide targets AIY interneurons, which communicate with AFD neurons via chemical signals. How do a total of four neurons (two AFDs and two AIYs) globally alter the speed at which an animal ages? By profiling gene expression patterns using high-throughput messenger RNA sequencing, the Pan group found that signals from the AFD-AIY neural circuit dampen the activity of INS-7, an insulin-like peptide, as well as other genes that also engage insulin-related pathways. As activity of the insulin signaling pathway affects the lifespan of animals ranging from C. elegans to primates, the finding that this thermosensory circuit counteracts high temperature by gauging the level of insulin signaling suggests that such a neural mechanism is likely a conserved theme in the sensory regulation of lifespan. The study by Pan’s group posits a provocative hypothesis whereby part of the plasticity of lifespan is essentially a physiological interpretation of the sensory environment in which the animal lives. This hypothesis also raises several intriguing questions. As the longevity of C. elegans at a cool temperature is also genetically regulated, it will be interesting to investigate whether a dedicated neural circuit also regulates lifespan at lower temperature as well as the neuronal signals involved in this regulation. “The NTU C. elegans community (a total of seven labs) had been making great scientific discoveries over the years,” said Pan as he showed his sincere gratitude for his fellow worm scientists on the campus. “For those who aim to answer big questions, starting from a humble tiny organism proves to be a fantastic idea.” Reference Yen-Chih Chen, Hung-Jhen Chen, Wei-Chin Tseng, Jiun-Min Hsu, Tzu-Ting Huang, Chun-Hao Chen, Chun-Liang Pan. A C. elegans Thermosensory Circuit Regulates Longevity through crh-1/CREB-Dependent flp-6 Neuropeptide Signaling. Dev. Cell 2016, 39: 209-223. DOI:10.1010/j.devcel.2016.08.021. Epub 2016 Oct 6. Associate Professor Chun-Liang Pan Institute of Molecular Medicine chunliangpan@gmail.com Reference Yen-Chih Chen, Hung-Jhen Chen, Wei-Chin Tseng, Jiun-Min Hsu, Tzu- Ting Huang, Chun-Hao Chen, Chun- Liang Pan. (2016). A C. elegans Thermosensory Circuit Regulates Longevity through crh-1/CREBDependent flp-6 Neuropeptide Signaling. Developmental Cell, 39, 209-223. DOI:10.1010/ j.devcel.2016.08.021. Epub 2016 Oct 6. Associate Professor Chun-Liang Pan Institute of Molecular Medicine chunliangpan@gmail.com