Novel EGF pathway regulators modulate C. elegans healthspan and lifespan via EGF receptor, PLC-gamma, and IP3R activation

Aging Cell. 2010 Aug;9(4):490-505. doi: 10.1111/j.1474-9726.2010.00575.x. Epub 2010 May 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / enzymology*
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Caloric Restriction
  • Diet
  • Enzyme Activation
  • Epidermal Growth Factor / metabolism*
  • ErbB Receptors / metabolism*
  • Genes, Helminth / genetics
  • Health
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Insulin / metabolism
  • Locomotion / physiology
  • Longevity / physiology*
  • Models, Biological
  • Phospholipase C gamma / metabolism*
  • RNA Interference
  • Signal Transduction


  • Caenorhabditis elegans Proteins
  • Inositol 1,4,5-Trisphosphate Receptors
  • Insulin
  • Epidermal Growth Factor
  • ErbB Receptors
  • Phospholipase C gamma