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- Title
Novel EGF pathway regulators modulate C. elegans healthspan and lifespan via EGF receptor, PLC-γ, and IP3R activation.
- Authors
Hiroaki Iwasa; Simon Yu; Jian Xue; Driscoll, Monica
- Abstract
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-γ plc-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.
- Subjects
LIFE spans; CAENORHABDITIS elegans; GENES; AGING; INSULIN receptors; MUSCULOSKELETAL system
- Publication
Aging Cell, 2010, Vol 9, Issue 4, p490
- ISSN
1474-9718
- Publication type
Article
- DOI
10.1111/j.1474-9726.2010.00575.x