Dietary restriction-limitation of caloric intake without deleterious reduction in essential nutrients-extends lifespan and reduces the incidence of age-associated disease across species. Identification of regulators of the DR state that might bypass the calorie limitation requirement but nonetheless engage metabolism to promote healthy aging are of considerable interest. We previously identified a unique fluorimetric signature for the C. elegans DR state (Excitation maximum peak shift for naturally fluorescent age pigments and lipofuscin[1]) that is not found in other long-lived mutant strains. We exploited this discovery to screen through the available miRNA deletion mutants to identify mir mutants that might persist in a constitutive DR-like state.
We identified a single mir mutant, affecting the conserved
mir-80 gene, which robustly exhibits the fluorimetric DR signature and lives longer than wild type.
mir-80 mutants also exhibit reduced fecundity and appear pale and thin. Like DR-animals,
mir-80(nDf53) is hypersensitive to the DR mimetic drug metformin, which is the drug response expected for animals that are already in DR (pushed over the edge into starvation)[2]. Interestingly, a transcriptional GFP reporter for
mir-80 is responsive to food (upregulated in the presence of food and down-regulated in absence of food) and a key molecular reporter of DR, the transcription factor
skn-1, is activated by
mir-80 deletion. We will present preliminary data on several genes that are needed for
mir-80(nDf53)-regulated DR benefits.
In conclusion, we will provide evidence that miR-80 negatively regulates genes that are involved in DR metabolism. We report the first instance of a metazoan microRNA that affects longevity through dietary restriction.
1.Gerstbrein, B., et al., In vivo spectrofluorimetry reveals endogenous biomarkers that report healthspan and dietary restriction in Caenorhabditis elegans. Aging Cell, 2005. 4(3): p. 127-137. 2.Onken, B. and M. Driscoll, Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1. PLoS ONE, 2010. 5(1): p.
e8758.