Hypercapnia (high CO2 levels) occurs in a number of lung diseases and it is associated with worse outcomes in patients with chronic obstructive lung disease (COPD). However, it is largely unknown how hypercapnia is sensed and responds in nonneuronal cells. Here, we used C. elegans to study the response to nonanesthetic CO 2 levels and show that levels exceeding 9% induce aberrant motility that is accompanied by age-dependent deterioration of body muscle organization, slowed development, reduced fertility and increased life span. These effects occur independently of the IGF-R, dietary restriction, egg laying or mitochondrial-induced aging pathways. Transcriptional profiling analysis shows specific and dynamic changes in gene expression after 1, 6, or 72 h of exposure to 19% CO 2 including increased transcription of several 7-transmembrane domain and innate immunity genes and a reduction in transcription of many of the MSP genes. Together, these results suggest specific physiological and molecular responses to hypercapnia, which appear to be independent of early heat shock and HIF mediated pathways.aging ͉ gene expression ͉ hypercapnia ͉ muscle deterioration ͉ physiology T he internal environment of a living organism self-regulates CO 2 /H ϩ . In mammals the lungs are the organs that dispose of excess CO 2 produced in the different tissues by adjusting the ventilatory pattern. Hypercapnia occurs in a number of lung disease states and usually reflects hypoventilation inadequate gas exchange. Some investigators have proposed that high CO 2 levels had beneficial effects in models of acute lung injury and proposed the term ''permissive hypercapnia'' and even ''therapeutic hypercapnia'' (1, 2). However, more recent studies have suggested that high pCO 2 can cause oxidative stress in the lung, and injury (3). More recently it has been reported that in rat lungs and human epithelial cells, high pCO 2 decreased alveolar fluid clearance independently of pH and ROS (4, 5). In some reports it has been shown that CO 2 uptake involves the aquaporin and RH1 channels (6, 7). In red blood cells, the RH1 complex also functions as an ammonium transporter (8). The sensing of CO 2 levels in the brain involves CO 2 /H ϩ chemoreceptors. CO 2 chemoreceptors were also identified in the central and peripheral nervous system and pulmonary vascular tissues (9, 10). However, very little is known about what senses the CO 2 levels and how these tissues respond to hypercapnia. The effect of low pH (acidosis) in kidney and lung cells can be altogether separated from that of high CO 2 /HCO 3 Ϫ (4, 11). The genetically tractable model organism, C. elegans, is a very powerful system in which to investigate cellular sensing and response to CO 2 . Despite being an invertebrate, C. elegans has differentiated tissues including hypodermis, epidermis, muscle, nervous system and others. Also demonstrated is the importance of evolutionary conserved genes in studying diseases and specific biological processes including hypoxia, longevity, and others.Recent ...