Folate receptor (FR) alpha (FOLR1) and beta (FOLR2) are membrane-anchored folate transporters that are expressed at low levels in normal tissues, while their expression is strongly increased in several cancers. Intriguingly, although the function of these receptors in, for example, development and cancer has been studied intensively, their role in aging is still unknown. To address this, we utilized Caenorhabditis elegans, in which FOLR-1 is the sole ortholog of folate receptors. We found that the loss of FOLR-1 does not affect reproduction, physical condition, proteostasis or lifespan, indicating that it is not required for folate transport to maintain health. Interestingly, we found that FOLR-1 is detectably expressed only in uterine-vulval cells, and that the histone-binding protein LIN-53 inhibits its expression in other tissues. Furthermore, whereas knockdown of lin-53 is known to shorten lifespan, we found that the loss of FOLR-1 partially rescues this phenotype, suggesting that elevated folr-1 expression is detrimental for health. Indeed, our data demonstrate that overexpression of folr-1 is toxic, and that this phenotype is dependent on diet. Altogether, this work could serve as a basis for further studies to elucidate the organismal effects of abnormal FR expression in diseases such as cancer.

叶酸受体 (FR) α (FOLR1) 和 β (FOLR2) 是膜锚定的叶酸转运蛋白，在正常组织中表达水平较低，而在多种癌症中表达量大幅增加。有趣的是，尽管这些受体在发育和癌症等方面的功能已被深入研究，但它们在衰老中的作用仍然未知。为了解决这个问题，我们利用了秀丽隐杆线虫，其中 FOLR-1 是叶酸受体的唯一直系同源物。我们发现 FOLR-1 的丢失不会影响生殖、身体状况、蛋白质稳态或寿命，这表明叶酸运输不需要它来维持健康。有趣的是，我们发现 FOLR-1 仅在子宫外阴细胞中可检测到表达，并且组蛋白结合蛋白 LIN-53 抑制其在其他组织中的表达。此外，虽然已知敲低lin-53会缩短寿命，但我们发现 FOLR-1 的缺失部分挽救了这种表型，这表明folr-1表达升高对健康有害。事实上，我们的数据表明folr-1的过度表达是有毒的，并且这种表型依赖于饮食。总而言之，这项工作可以作为进一步研究的基础，以阐明异常 FR 表达对癌症等疾病的机体影响。