Aging--Molecular aspects.

Caenorhabditis elegans optionally enter into a dauer diapause phase that results
in a prolonged life in a semi-dormant state. Entry into and recovery from dauer diapause
includes many physical changes in body structure, physiology, and gene expression.
Entry into dauer diapause is regulated by several signaling pathways including
transforming growth factor (TGF-β). Autophagy plays an important role in dauer
formation and recover. During dauer transformation autophagy is up-regulated and may
play a role in remodeling the molecular structure for long term survival during dauer
diapause. This research helps determine the role of autophagy in dauer development and
recovery mediated through the TGF-β signaling pathway. This research also determines
in which tissue autophagy is necessary for dauer formation and recovery through TGF-β signaling. This research is shedding light on the function of autophagy in the TGF-β
signaling pathway, both processes of which have been linked to tumorigenesis, heart
disease and cancer.

In the round worm C. elegans, it has recently been shown that autophagy, a highly
conserved lysosomal degradation pathway that is present in all eukaryotic cells, is
required for maintaining healthspan and for increasing the adult lifespan of worms fed
under dietary restriction conditions or with reduced IGF signaling. It is currently
unknown how extracellular signals regulate autophagy activity within different tissues
during these processes and whether autophagy functions cell-autonomously or nonautonomously.
We have data that for the first time shows autophagy activity in the
neurons and intestinal cells plays a major role in regulating adult lifespan and the
longevity conferred by altered IGF signaling and dietary restriction, suggesting
autophagy can control these phenotypes cell non-autonomously. We hypothesize that
autophagy in the neurons and intestinal cells is an essential cellular process regulated by
different signaling pathways to control wild type adult lifespan, IGF mediated longevity and dietary restriction induced longevity. Excitingly we also have found that in animals
with reduced IGF signaling autophagy can control longevity in only a small subset of
neurons alone. Autophagy in either specific individual chemosensory neurons or a small
group of them is completely sufficient to control IGF mediated longevity. This work
provides novel insight to the function and regulation of autophagy which will help shed
light on understanding this essential process in higher organisms, including mammals.

The inevitable aging process can be partially attributed to the accumulation of
oxidative damage that results from the action of free radicals. Methionine sulfoxide
reductases (Msr) are a class of enzymes that repair oxidized methionine residues. The
two known forms of Msr are MsrA and MsrB which reduce the R- and S- enantiomers of
methionine sulfoxide, respectively. Our lab has created the first genetic animal model
that is fully deficient for any Msr activity. Previously our lab showed that these animals
exhibit a 20 hour delay in development of the third instar larvae (unpublished data). My
studies have further shown that the prolonged third-instar stage is due to a reduced
growth rate associated with slower food intake and a markedly slower motility. These
Msr-deficient animals also exhibit decreased egg-laying that can be attributed to a lack of
female receptivity to mating.