UC San Diego

Dietary Restriction (DR) and reduced insulin/IGF-1 signaling (IIS) are well known methods of lifespan extension in numerous species. The mechanism by which the response to DR is mediated is largely unknown, yet IIS mediated longevity is more well established. Our lab recently added to this knowledge with the characterization of SMK-1 as a co-regulator required for the forkhead transcription factor, DAF-16, mediated longevity (Wolff et al., 2006). Interestingly, decreased smk-1 also results in the suppression of DR-induced longevity, despite the daf- 16 independence of the DR pathway (Houthoofd et al., 2003). A screen of all existing forkhead transcription factors in C. elegans revealed a second forkhead, pha-4, capable of suppressing the long lifespan observed in animals with either a decreased feeding rate (eat-2 mutant animals) or bona fide DR conditions. pha-4 is specific to DR mediated longevity, as the long lifespans of ETC or IIS deficient animals are not affected by loss of pha-4. pha-4 appears regulated by DR not through sub-cellular localization, but through mRNA levels. The overexpression of daf-16 results in increased lifespan (Henderson and Johnson, 2001) and we find that the overexpression of pha- 4 has similar effects. Interestingly, longevity due to pha -4 overexpression is enhanced in daf-16(mu86) null mutant animals, suggesting a possible competition between the two transcription factors, or redundant functions. Use of a sid-1 rescue tissue-specific RNAi system reveals that pha- 4 expression is required in the intestine for DR longevity, but not in the neurons, muscle, or hypodermis. The discovery of pha-4 as a specific mediator of DR, but not other longevity pathways, provides an important tool for the further identification of genes in the DR pathway and possible mechanisms underlying DR-induced longevity