Several pathways influence the aging process in C. elegans.
daf-2,
age-1 and
daf-16 act in an insulin-like signaling pathway that modulates normal life span.
sir-2.1 is involved in chromatin regulation, and overexpression of
sir-2.1 increases lifespan. There may also be a link between stress and aging, since mild stress results in a longer lifespan and longevity mutants are often stress-resistant. What are the molecular mechanisms underlying the increased life spans caused by changes in insulin signaling,
sir-2.1 activity and stress? In order to begin to understand the molecular basis for life span extension in C. elegans, we have used DNA microarrays to profile gene expression changes caused by mutations that affect insulin signaling,
sir-2.1 activity or by stress. Specifically, we have searched for gene expression changes in
daf-2 mutants,
age-1 mutants, a
daf-16;
age-1 double mutant, and a
sir-2.1(lf) mutant. We have also used DNA microarrays to characterize gene expression changes caused by oxidative stress, both in wild-type worms and in
age-1 mutants. The oxidative stress experiments were done because there may be a link between oxidative stress and longevity, and because
age-1 mutants are stress resistant. We have found that expression of
sod-3, which encodes Mn superoxide dismutase, increases in
age-1 and
daf-2 mutants and decreases in
daf-16 mutants, which is consistent with previous results (Honda and Honda, FASEB J. 1999, 13, 1385-93).
sod-3 expression increases in dauers (Wang and Kim, Development 2003, 130, 621-34) and decreases in old worms (Lund et al., Cur. Bio. 2002, 12, 1566-73). We are searching for other genes that also show consistent expression changes during normal aging, in the dauer state and in longevity mutants. One (F45D11.15) encodes a novel protein whose expression increases in
age-1and daf-2 mutants, decreases in
daf-16 mutants, increases in the dauer state, increases in old worms and decreases following heat shock. The consistent change in expression of F45D11.15 in all of these conditions affecting longevity and stress suggest that this gene may play a role in specifying life span. We are continuing to analyze the microarray expression data to find additional genes showing consistent expression changes, and are beginning genetic experiments to understand the function of F45D11.15 in stress and aging.