In C. elegans, the intestine integrates nutrient uptake and systemic aging signaling. Low food or other stressors lead to the activation of key transcription factors, DAF-16 and SKN-1, initiating a set of adaptations resulting in decreased fecundity and increased lifespan. Recent research suggests that another feeding-induced intestinal process, the periodic calcium wave controlling the defecation cycle, is linked to aging and death. The terminal step of aging, death, is preceded by a fluorescent anthranilate wave (death wave) in the intestine (Coburn et al., 2012). We have investigated mechanisms underlying lifespan extension in an intestinal gap junction mutant, innexin (inx-16), that alters both the defecation calcium wave and the death wave.
In feeding animals, a rapid posterior to anterior calcium wave occurs synchronically with defecation. In the absence of functional inx-16, the intestinal calcium waves are markedly slower and sometimes fail entirely, causing serious defecation defects. Just prior to death, calcium levels rise in anterior intestinal cells leading to necrosis. The calcium and necrosis spread, producing the death wave. inx-16 mutants do not produce these waves (Coburn et al., 2012).
inx-16 mutants exhibit increased lifespan compared to N2 which could be due to failed execution of the necrotic death wave. To determine whether adding functional intestinal INX-16 to adults could restore normal lifespan we performed an adult rescue of the mutant using a vitellogenin promoter. This adult intestinal rescue eliminated defecation defects but failed to normalize lifespan. This suggests that inx-16’s extended lifespan is not due solely to a failure to die. We hypothesize that intestinal and/or nutrient deficiencies in early life induce a longevity program that cannot be altered later. We are investigating the nutritional state and the longevity molecular program in inx-16 mutants. Feeding as measured by pharyngeal pumping rates appears normal. Activation of DAF-16 and/or SKN-1 is being assayed via analysis of nuclear localization in translational fusion lines. No significant increase in nuclear DAF-16 has been found in the mutants’ intestines. Yolk protein production and oocyte uptake is also being scored as a downstream marker of DAF-16 and SKN-1 activation. Fluorescent imaging of vitellogenin::GFP fusions indicate defective yolk protein distribution in inx-16 mutants and likely decreased production. This work will provide valuable insight into links between intestinal cell-cell communication, nutrient uptake and longevity.
Coburn C. et al. (2013) PloS Biology Jul;11(7):e1001613.