Folic acid supplementation at lower doses increases oxidative stress resistance and longevity in Caenorhabditis elegans

Abstract

Folic acid (FA) is an essential nutrient that the human body needs but cannot be synthesized on its own. Fortified foods and plant food sources such as green leafy vegetables, beans, fruits, and juices are good sources of FA to meet the daily requirements of the body. The aim was to evaluate the effect of dietary FA levels on the longevity of well-known experimental aging model Caenorhabditis elegans. Here, we show for first time that FA extends organism life span and causes a delay in aging. We observed that FA inhibits mechanistic target of rapamycin (mTOR) and insulin/ insulin growth factor 1 (IGF-1) signaling pathways to control both oxidative stress levels and life span. The expression levels of stress-and life span-relevant gerontogenes, viz. daf-16, skn-1, and sir. 2.1, and oxidative enzymes, such as glutathione S-transferase 4 (GST-4) and superoxide dismutase 3 (SOD-3), were also found to be highly enhanced to attenuate the intracellular reactive oxygen species (ROS) damage and to delay the aging process. Our study promotes the use of FA to mitigate abiotic stresses and other aging-related ailments.

SKN-1-independent transcriptional activation of glutathione S-transferase 4 (GST-4) by EGF signaling

“…7,11,12,15,19,20,23,[26][27][28][29][30][31][32][33] A problem arises, however, when GST-4 is used as the sole readout for SKN-1 activation, in the absence of aforementioned controls. 21,22,24,25 Based on our current observations, the interpretation of gst-4 p ::gfp fluorescence in vivo is indeed not straightforward.…”

“…3 Currently, SKN-1 transcriptional activity is often indirectly assayed via a transcriptional reporter construct of the gst-4 promotor (gst-4 p ::gfp or Pgst-4::gfp; strain CL2166) which shows increased GFP levels when transcription is activated in vivo. 7,11,12,15,[19][20][21][22][23][24][25][26][27][28][29][30] By using gst-4 transcription levels as a proxy for SKN-1 activation, the problem of a low GFP signal is mitigated. Additionally, it is possible to obtain a quantitative indication of the gene's transcription levels, instead of merely being able to discriminate between cytoplasmic or nuclear localization of a transcription factor.…”

Comparison of ESI‐MS/MS and APCI‐MS methods for the quantification of folic acid analogs in C. elegans

“…Caenorhabditis elegans has recently emerged as a facile model organism for studying metabolic processes, fluxes, and disorders . Remarkable metabolic homology between C. elegans and mammals has already yielded key insights into the role of FA deficiency and FA supplementation on organismal physiology, showing effects on host‐microbiome interactions, aging, lipid metabolism, and fertility . Less is known about how gene knockdown of folate cycle components or natural variation impacts global folate status and organismal physiology.…”

“…12 Remarkable metabolic homology between C. elegans and mammals has already yielded key insights into the role of FA deficiency and FA supplementation on organismal physiology, 13 showing effects on host-microbiome interactions, aging, lipid metabolism, and fertility. [14][15][16] Less is known about how gene knockdown of folate cycle components or natural variation impacts global folate status and organismal physiology. Moreover, the investigation of FA in a simple metazoan having only 959 somatic cells may expedite the discovery of new folate-like molecules.…”

ZIP-5/bZIP transcription factor regulation of folate metabolism is critical for aging axon regeneration

“…Unbiased bioinformatics analysis predicted that the human homologs of C. elegans ZIP-5 targets, including those regulating one-carbon metabolism, play a role in neurodegenerative diseases (Supplementary Table 5). In fact, one-carbon metabolism is upregulated in multiple longevity mutants 14 , and folic acid supplementation in wild-type animals increases lifespan 18 , suggesting a central role for folate metabolism in mediating longevity as well as repair. Our work suggests that dietary folate supplementation should be further developed as a novel approach to promote healthy brain aging, and also as a non-invasive treatment for patients with nerve trauma or neurodegenerative diseases associated with aging.…”