Aging is often associated with declines in cognitive function and neuronal plasticity and an increased risk of neurodegenerative disease. However, the factors causing age-dependent changes in the nervous system remain largely unknown. We have used laser axotomy on PLM axons to study the age-dependent responses to axonal injury. We axotomized PLM axons of animals aged from L4 stage to day 10 of adulthood and then measured the regrowth 24 hours after the surgery. As previously reported (Wu et al., 2007), PLM axons of L4 or young adult animals show robust regenerative regrowth in the first 24 hours. We find PLM regrowth significantly declines in adult animals after 3 days of adulthood (A3). In addition, regrowing axons of older animals show a higher percentage of growth cones and secondary neurites formation, as well as an increased rate of proximal to distal process fusion events compared to L4 animals. Calcium and cAMP play critical roles in the neuronal regenerative response. Genetic mutations that increase neuronal calcium or cAMP improve regeneration in L4 animal (Ghosh-Roy et al., 2010). However, we find that simply elevating calcium or cAMP has little effect on the regrowth extent in older animals. Mutations increasing the lifespan of C. elegans, such as
daf-2 or
eat-2 can delay some age associated phenotypes and improve learning and memory performance in aging animals (Kauffman et al., 2010). However, we find that these long-lived mutants show the same regeneration profile as wild type animals. Our results suggest that the adult decline in regenerative axonal regrowth is independent of organismal aging or health, and that mechanisms intrinsic to the neuron itself are likely responsible for the regenerative decline. In our screen of stress resistance and metabolism genes, we find several mutants in which the L4 to A3 regeneration decline is abolished. Preliminarily, we find that loss of function in
akt-2,
rsks-1 or
isp-1 attenuates the age-dependent regeneration decline. We are currently investigating whether they act cell-autonomously as well as whether an age-dependent decline in neuronal mitochondrial respiration is responsible for the decline in adult axon regeneration.