Novel EGF pathway regulators modulate C. elegans healthspan and lifespan via EGF receptor, PLC-gamma, and IP3R activation.
Improving health of the rapidly growing aging population is a critical medical, social, and economic goal. Identification of genes that modulate healthspan, the period of mid-life vigor that precedes significant functional decline, will be an essential part of the effort to design anti-aging therapies. Because locomotory decline in humans is a major contributor to frailty and loss of independence and because slowing of movement is a conserved feature of aging across phyla, we screened for genetic interventions that extend locomotory healthspan of Caenorhabditis elegans. From a group of 54 genes previously noted to encode secreted proteins similar in sequence to extracellular domains of insulin receptor, we identified two genes for which RNAi knockdown delayed age-associated locomotory decline, conferring a high performance in advanced age phenotype (Hpa). Unexpectedly, we found that hpa-1 and hpa-2 act through the EGF pathway, rather than the insulin signaling pathway, to control systemic healthspan benefits without detectable developmental consequences. Further analysis revealed a potent role of EGF signaling, acting via downstream phospholipase C-gammaplc-3 and inositol-3-phosphate receptor itr-1, to promote healthy aging associated with low lipofuscin levels, enhanced physical performance, and extended lifespan. This study identifies HPA-1 and HPA-2 as novel negative regulators of EGF signaling and constitutes the first report of EGF signaling as a major pathway for healthy aging. Our data raise the possibility that EGF family members should be investigated for similar activities in higher organisms.
Iwasa
Hiroaki
H
Department of Medical Biochemistry, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
Yu
Simon
S
Xue
Jian
J
Driscoll
Monica
M
D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D031204:Caloric Restriction; D004032:Diet; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D017238:Genes, Helminth / Q000235:genetics; D006262:Health; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D008124:Locomotion / Q000502:physiology; D008136:Longevity / Q000502:physiology*; D008954:Models, Biological; D051966:Phospholipase C gamma / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction
D029742:Caenorhabditis elegans Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007328:Insulin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D051966:Phospholipase C gamma