Gene expression analysis after RNAi treatment of different isoforms of vab-3 in C.elegans

Progredient accumulation of body fat occurs in diverse species with increasing age, and is linked to reduced longevity in humans. Independently, changes in the relative expression of genetic isoforms have recently been associated with aging, while the functional significance of isoform usage in longevity and healthy aging remains to be elucidated. We here find that modulation of the evolutionarily conserved splicing factor skp-1 improves physical fitness and lifespan in adult C. elegans. By opposing usage of the corresponding promoters, this factor modulates the expression of different isoforms of nematodal vab-3, an orthologue of the endocrine transcription factor Pax6 in mammals. Specifically, preferential usage of the short vab-3c isoform is functionally epistatic to skp-1, and promotes expression of the peroxisomal acox-1.2 gene. Increasing ACOX1 activates AMP-dependent protein kinase (AMPK) to promote healthspan in a redox-dependent manner, but also protects from both lipotoxicity as well as organismal triglyceride accumulation. Accordingly, in human adipose tissue expression of SNW1, the human orthologue of skp-1, is positively correlated with age, and inversely correlated with ACOX1 expression. Moreover, increased ACOX1 expression correlates with decreased adipose tissue mass and improved glucose tolerance in BXD mice. Taken together, these findings indicate that ACOX1 may serve as promising therapeutic targets for ameliorating type 2 diabetes and obesity in an aging population. 8 samples in 3 groups: Control: 2 samples, Vab3 isoform A/N2: 3 samples, RNAi Vab3 isoform C/N2: 3 samples