Insulin/IGF-1 signaling (IIS) regulates longevity, metabolism, development, reproduction and behavior in various organisms. Caenorhabditis elegans
daf-2/insulin/IGF-1 receptor mutants exhibit dramatically increased lifespan and pathogen resistance, but generally display defects in development and reproduction. Whether these pleiotropic phenotypes in
daf-2 mutants can be dissociated at specific steps in the IIS pathway remains poorly understood. Here we show that a specific hypomorhic allele of
daf-18/PTEN phosphatase in
daf-2(
e1370) mutants retains longevity and enhanced immunity compared to wild-type without developmental defects. Through an EMS mutagenesis screen, we identified a missense mutation in
daf-18 [
daf-18(
yh1)], which suppressed constitutive dauer formation in
daf-2 mutants with small impacts on resistance against Pseudomonas aeruginosa, PA14. We showed that the
daf-18(
yh1) caused a mild reduction in its function, but maintained long lifespan, motility span and increased PA14 and stress resistance in
daf-2(
e1370) mutant backgrounds. In contrast,
daf-18(
nr2037), a strong loss of function mutant allele, influenced all these phenotypes indiscriminately. We further demonstrated that
daf-18(
yh1) and
daf-18(
nr2037) differentially affected the activity of DAF-16/FOXO longevity transcription factor, while decreasing the activity of heat shock factor 1 (HSF-1) and SKN-1/NRF indiscriminately. Thus, differential regulation of DAF-16/FOXO activity by
daf-18(
yh1) appears to underlie longevity and immunity in
daf-2 mutant backgrounds, while suppressing developmental and motility impairments. We then functionally characterized individual genes whose expression was robustly down-regulated by
daf-18(
nr2037), but not by
daf-18(
yh1), in
daf-2(
e1370) mutants. We identified two potential candidates that were required for increased PA14 resistance in
daf-2(-);
daf-18(
yh1) animals, and currently characterizing their molecular functions in longevity and immunity. Our research will provide crucial insights into how single component in the evolutionarily conserved IIS pathway differentially regulates distinct physiological processes. Key words: C. elegans, insulin/IGF-1 pathway, PTEN, aging, healthspan