Folate receptor overexpression shortens C. elegans lifespan by impeding adaptation to microbial metabolism

Folate receptor (FR) alpha and beta (FR and FR{beta}) 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, FR, 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 utilized Caenorhabditis 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 to folr-1 depletion, folr-1 overexpression shortens lifespan in a cocultured E. coli strain-dependent manner. Furthermore, we found that folr-1 overexpression blunts the lifespan extension upon treatment with sulfamethoxazole, a sulfonamide that promotes longevity by limiting folate in E. coli. These data suggest that animals overexpressing folr-1 are 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 utilizing C. elegans, we show that FOLR-1 (FR homolog in C. elegans) is not required to maintain normal physiology, whereas its overexpression shortens lifespan through a mechanism dependent on cocultured bacteria. Since cocultured bacteria constitute the C. elegans gut microbiota, this study places elevated FR expression as a link between gut commensal bacteria and organisms lifespan, raising the intriguing question of whether the same mechanism applies in cancer.