Access Type

Open Access Dissertation

Date of Award

January 2024

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Nutrition and Food Science

First Advisor

Ahmad A. Heydari

Abstract

Folate (Vitamin B9) is an essential cofactor in one-carbon transfer reactions. It is involved in multiple critical processes including DNA synthesis, DNA methylation, protein synthesis and antioxidant defense mechanisms. Inadequate intake and availability of folate is a known risk factor for several diseases. The effect of folate deficiency in causing adverse health outcome is well documented. Recently, excess folate exposure has been associated with deleterious effects on health in humans and animal models. However, the underlying mechanisms involved in mediating such effects are poorly understood, requiring extensive investigations. This work was conducted to understand the effect of excess folate on health and lifespan in mice and C. elegans with an emphasis on investigating the role of the microbiome in mediating folate’s effects. Reduction of folate production in the gut using the antibiotic SST resulted in distinct bacterial clustering at various taxa levels, downregulation of mTOR signaling and an upregulation of antioxidant genes, suggesting a direct link between folate and aging. To further elucidate the mechanistic effects of folates on lifespan and health span, we used the well characterized C. elegans aging model. Excess folate resulted in the reduction of median lifespan and oxidative stress resistance in wild type C. elegans. Furthermore, NAC administration failed to rescue oxidative stress under excess folate suggesting that cytosolic oxidative stress is not the main driver of excess folate induced aging phenotype. Our results suggest that dietary folate availability is an important conserved regulator of lifespan. The results from this study are critical to human health because consumption of excess FA through fortification and supplementation can potentially impact health and lifespan in humans.

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