A critical goal of aging research is the identification of genes and pathways that modulate somatic and reproductive aging. This information is important for understanding biological principles and may establish a foundation for interventions that can delay human aging. To analyze animal aging, we used C. elegans because it is a complex animal that is relevant to mammals, age-related degenerative changes in reproductive and somatic function are well established, and powerful genetic techniques are available.A forward genetic screen was used to identify mutants with delayed reproductive aging. The mutation am117 causes significant extensions of mated reproductive span and life span. Genetic mapping experiments were used to position the am117 mutation to an interval of chromosome I.We used whole genome sequencing to identify the am117 molecular lesion, a premature stop codon that affects one of several predicted transcripts from the locus. am117 affects a previously uncharacterized gene that encodes a protein that is homologous to human scaffold attachment factor B (SAFB1). am117 mutant animals displayed a 35-70% extension of somatic functions such as lifespan and >50% extension of reproductive span at multiple temperatures. Mutant animals also displayed robust delays of age-related degenerative changes and strong resistance to heat stress. To characterize the relationship with previously identified pathways that influence aging, we analyzed double mutant animals. Mutations that extend lifespan by affecting mitochondria, Insulin/IGF signaling and metabolic transcription factors were additive with am117, suggesting they function through independent mechanisms. By contrast, am117 was not additive with an eat-2(lf) mutation, a genetic model of caloric restriction caused by reduced pharyngeal pumping rates. am117 mutant animals displayed normal pharyngeal pumping rates but abnormal pharyngeal grinder morphology, raising the possibility that bacterial food may be ingested but not effectively absorbed. Consistent with a possible caloric restriction mechanism, we showed that pha-4/FOXOA and skn-1/NRF transcription factors are necessary for extension of lifespan caused by am117. The analysis of am117 may shed new light on caloric restriction, an important and conserved mechanism of lifespan extension.

Affiliation:
- Development Biology, Washington University School of Medicine, St. Louis, MO USA