University of Southern California
Ray R. Irani Hall
Molecular and Computational Biology
Seminar Series
Malene Hansen
Sanford-Burnham Medical Research Institute
Program of Development & Aging
“A role for TOR-regulated processes in
C. elegans lifespan ”
Abstract:
Dietary restriction (limited food intake) extends lifespan in multiple organisms, at least in part, by down-regulation of the TOR pathway. In C. elegans, both dietary restriction and TOR pathway inhibition reduce protein translation and extend lifespan via a mechanism independent of the FOXO transcription factor DAF-16 (a key downstream effector of the insulin/IGF-1 longevity pathway). Even though we and others have found that inhibition of protein translation extends lifespan, it remains unclear if this is the sole process by which dietary restriction and TOR pathway inhibition could promote longevity or whether this is also an independent avenue of regulation. Besides protein translation, TOR also regulates autophagy. This cellular process of cytoplasmic degradation is generally induced following nutritional deprivation. To get insights into the molecular mechanisms underlying dietary restriction and TOR pathway inhibition, we addressed the longevity role of autophagy in C. elegans.
We find that dietary restriction and TOR pathway inhibition trigger autophagy in this organism, and that inhibiting genes required for autophagy during adulthood, e.g., bec-1, the worm ortholog of the yeast and mammalian autophagy gene ATG6/VPS30/beclin 1, prevents dietary restriction and TOR pathway inhibition from extending lifespan (Hansen et al., PLoS, 2008). The longevity response to dietary restriction in C. elegans is not a passive consequence of reduced energy levels, because it is known to require transcription, in part through the PHA-4/FOXA transcription factor. Interestingly, we find that the autophagic response to dietary restriction also requires PHA-4 activity, indicating that autophagy in relation to lifespan, too, is a transcriptionally-regulated response to food limitation. Interestingly, and in contrast to the longevity role observed for autophagy in dietary restriction and in the TOR pathway, lifespan extensions produced by direct inhibition of protein translation does not seem to involve autophagy. Thus, autophagy might not be necessary for all C. elegans longevity mutants to live long. Furthermore, TOR regulates multiple processes, each of which is likely to play complex roles in modulating organismal lifespan.
Friday, February 19, 2010
12:00 pm
RRI 101
Host: John Tower
