Cool core-body temperature promotes longevity in mammals, fishes, flies and worms. Molecular mechanisms underlying this cool-mediated longevity are not well understood. Mutations in the
daf-2 gene increase adult lifespan. In C. elegans, wild-type adult maximal lifespan is doubled at 15 deg C compared to 25 deg C, but this pattern is aberrant in adults bearing mutations in the
daf-2 gene. We investigated the gene by environment interaction using microarrays on samples from wild-type or
daf-2(
m577,
m41,
e1370,
m579 or
m596) adults acclimated to 15 deg C or 25 deg C. Differentially expressed (DE) genes revealed five categories: pro-longevity, pro-aging, context-specific-pro-longevity, context-specific-pro-aging, and irrelevant.
DE genes lower at 25 deg C than 15 deg C included particular protein synthesis and lysosomal proteolysis genes. Adult lifespan was increased at 25 deg C and decreased lifespan at 15 deg C when treated with pharmacological lysosomal inhibitors. Lysosomal protease RNAi caused paralysis in middle-aged adults only at 15 deg C. RNAi of protein synthesis genes caused an increased lifespan in wild-type adults only at 25 deg C and vulval herniation or paralysis in middle-aged adults only at 15 deg C. Together, these results indicate that temperature-dependent regulation of the proteostatic network is adaptive for long-term healthy adult survival.
Aspects of temperature regulation were retained in
daf-2 adults. These mutants were hyper-responsive to temperature at the molecular level. There were 338 temperature-responsive genes in wild type, whereas the number in the mutants ranged from 902 to 3410 DE genes. Of the wild-type DE protein synthesis genes, 22 of 26 showed temperature regulation in the mutants, with four elevated at 25 deg C rather than lowered. There were 615 temperature DE genes shared in mild
daf-2 alleles and 653 genes in severe
daf-2 alleles. An additional 38 genes became DE in
daf-2 mutants. Temperature regulation of 10 of 15 lysosomal proteases was lost in
daf-2 mutants with elevated levels at 25 deg C correlating with allele severity. RNAi of protein synthesis genes in
daf-2 mutants dramatically increased lifespan at 25 deg C with no increase in lifespan at 15 deg C. RNAi of a lysosomal protease increased lifespan in the
daf-2 mutants at 15 deg C and decreased lifespan at 25 deg C. This suggests one consequence of the dysregulated
daf-2 transcriptome results in a pro-aging liability at both temperatures. In summary, we have identified proteostatis network profiles which favor long-term healthy survival given a genotype and environmental condition.