Rapamycin deregulated genes as new targets for antiaging interventions

Rapamycin is currently considered one of the leading candidate compounds for delaying aging and age-related diseases in Homo sapiens. Evidence from multiple model organisms indicates that early-life interventions can have long-lasting effects on aging trajectories, and short rapamycin exposure during postnatal early life has been shown to extend lifespan in both Mus musculus and Drosophila melanogaster. To identify genes involved in mediating these effects, we analyzed gene expression profiles from mouse livers transiently treated with rapamycin during early life. Among the differentially expressed genes, we identified Nr1i3, which encodes the nuclear hormone receptor constitutive androstane receptor (CAR), and whose functional homolog in Drosophila melanogaster is dHR96. In Drosophila, dHR96 is a key regulator of midgut lipid uptake, metabolic homeostasis, and xenobiotic stress responses. Consistent with a conserved role in lifespan regulation, transient upregulation of dHR96 in newly eclosed flies results in a robust extension of lifespan. Given that Nr1i3 is upregulated in mice following transient rapamycin exposure, we further investigated whether dHR96 mediates rapamycin-induced lifespan extension in Drosophila melanogaster. Notably, dHR96 mutant animals fail to respond to rapamycin, suggesting that dHR96 is an essential component of the rapamycin response and a key mediator of its longevity effects. Furthermore, dHR96 acts in glial cells to extend lifespan in male flies and is associated with reduced expression of alkaline phosphatase, whose downregulation has also been linked to increased longevity. Based on this rationale and leveraging the genetic tools available in Drosophila, it will be of interest to investigate additional genes upregulated during the acute phase of rapamycin treatment. This approach may facilitate the identification of novel molecular targets and, ultimately, the development of interventions that retain the beneficial effects of rapamycin while minimizing its adverse outcomes.