To identify new genes that control life span, we performed a genetic screen for genes that extend life span when increased in copy number. We reasoned that an increase in dosage of a gene whose activity was rate limiting in the aging process would extend life span. To increase gene dosage, we obtained 35 duplication strains that cover approximately 50% of the genome and measured the life spans of animals carrying the duplications. From this screen, we identified a region on chromosome IV that increased both the mean and maximum life span significantly. This region contained the gene
sir-2.1 , a C. elegans SIR2 homologue (1). Remarkably, in yeast, the dosage of SIR2 alone can determine the life span of yeast mother cells (2). Additionally, yeast SIR2p functions to mediate chromatin silencing due to its NAD-dependent histone deacetylase enzymatic activity (3). The C. elegans genome has four genes with similarity to yeast Sir2p (named
sir-2.1 ,
sir-2.2,
sir-2.3,
sir-2.4) . Of the four genes, the most related to yeast Sir2p is
sir-2.1 (31% identity in the core domain). To test if
sir-2.1 was the gene responsible for the life span extension of animals with the chromosome IV duplication, we made transgenic animals with extra copies of
sir-2.1 on an extrachromosomal array. The life span of the
sir-2.1 transgenic animals was increased by as much as 50% (1). To determine if
sir-2.1 extended life span through one of the known aging pathways, we made strains containing the
sir-2.1 array (either extrachromosomal or integrated) in combination with a
daf-16(
mg50 ),
daf-2(
e1370),
daf-4(
m63), or a
daf-1(
m40) mutation. In combination with a
daf-16(
mg50) mutation, the life span of the
sir-2.1 array animals was almost identical to the
daf-16(
mg50) single mutants. This is similar to
daf-2 or
age-1 mutants where life span extension is completely suppressed by a mutation in
daf-16 . In combination with a
daf-2(
e1370) mutation, the life span of the
sir-2.1 array animals was similar to the
daf-2(
e1370) single mutants. Therefore, there was no synergy between the
sir-2.1 array and a mutation in
daf-2 for life span. Finally, similar to other mutations in the insulin-like signaling pathway such as
daf-2 , the
sir-2.1 array in combination with a mutation in either
daf-1 or
daf-4 (TGF- b receptors) synergized for dauer formation. Therefore, the
sir-2.1 array extends life span through the insulin-like signaling pathway (1). We are interested in determining where
sir-2.1 functions in the insulin-like signaling pathway. To address this issue, we are performing RNAi of
sir-2.1 in the wild type and in various mutant backgrounds and measuring the life span of these worms. Additionally, we are trying to determine the expression pattern of
sir-2.1. Our data suggests that
sir-2.1 may act to couple nutrient availability and developmental decisions, i.e. whether to form dauer larvae and, in animals that proceed to adulthood, how long to live. The demonstration of
sir-2.1 's ability to extend life span may be the first conserved molecular mechanism of aging. 1. Tissenbaum, H. A. and L. Guarente (2001). Nature 410: 227-303. 2. Kaeberlein, M., et al. (1999). Genes Dev 13: 2570-80. 3. Imai, S. et al. (2000). Nature 403:795-800