Folate receptor overexpression shortensC. eleganslifespan by impeding adaptation to microbial metabolism

Abstract

AbstractFolate receptor (FR) alpha and beta (FRα and FRβ) are membrane-anchored transporters that mediate folate uptake through endocytosis. Unlike other folate transporters, FRs are expressed at low levels in normal tissues, while their expression is strongly increased in several cancers. In addition to its canonical role in folate transport, FRα, the most studied FR, also regulates signaling pathways unrelated to folate- or one-carbon metabolism. Nevertheless, it is not known how loss of folate receptors, or their overexpression, affects health- and lifespan. To elucidate this, we utilizedCaenorhabditis elegans, in which FOLR-1 is the sole homolog of folate receptors. Interestingly, loss of FOLR-1 does not affect reproduction, fitness, proteostasis or lifespan, indicating that it is not required for folate transport to maintain health. Strikingly, in contrast tofolr-1depletion,folr-1overexpression shortens lifespan in a coculturedE. colistrain-dependent manner. Furthermore, we found thatfolr-1overexpression blunts the lifespan extension upon treatment with sulfamethoxazole, a sulfonamide that promotes longevity by limiting folate inE. coli. These data suggest that animals overexpressingfolr-1are deficient in their ability to adapt to changes in microbial metabolism, thus revealing an intriguing and non-canonical role of FR in lifespan regulation. Therefore, this work could serve as a basis for further studies to elucidate the organismal effects of abnormal FR expression in diseases such as cancer.Author SummaryFolate receptors (FRs) differ from other folate transporters based on, for example, these two things: their expression is strongly restricted, and they can regulate intracellular cellular processes independently of folate- and one-carbon metabolism (OCM). Interestingly, FRs have an essential role in embryonic development, but on the other hand, their overexpression in cancer have been shown to reduce patient survival. Apart from development and disease, the role of FRs in aging remains unknown. By utilizingC. elegans, we show that FOLR-1 (FR homolog inC. elegans) is not required to maintain normal physiology, whereas its overexpression shortens lifespan through a mechanism dependent on cocultured bacteria. Since cocultured bacteria constitute theC. elegansgut microbiota, this study places elevated FR expression as a link between gut commensal bacteria and organism’s lifespan, raising the intriguing question of whether the same mechanism applies in cancer.