Abstract
The increasing prevalence of age-related diseases and resulting healthcare insecurity and emotional burden require novel treatment approaches. Several promising strategies seek to limit nutrients and promote healthy aging. Unfortunately, the human desire to consume food means this strategy is not practical for most people but pharmacological approaches might be a viable alternative. We previously showed that myriocin, which impairs sphingolipid synthesis, increases lifespan in Saccharomyces cerevisiae by modulating signaling pathways including the target of rapamycin complex 1 (TORC1). Since TORC1 senses cellular amino acids, we analyzed amino acid pools and identified 17 that are lowered by myriocin treatment. Studying the methionine transporter, Mup1, we found that newly synthesized Mup1 traffics to the plasma membrane and is stable for several hours but is inactive in drug-treated cells. Activity can be restored by adding phytosphingosine to culture medium thereby bypassing drug inhibition, thus confirming a sphingolipid requirement for Mup1 activity. Importantly, genetic analysis of myriocin-induced longevity revealed a requirement for the Gtr1/2 (mammalian Rags) and Vps34-Pib2 amino acid sensing pathways upstream of TORC1, consistent with a mechanism of action involving decreased amino acid availability. These studies demonstrate the feasibility of pharmacologically inducing a state resembling amino acid restriction to promote healthy aging.
Highlights
Aging is the prime risk factor for fatal diseases including cardiovascular disease, diabetes, dementias and cancers [1,2,3,4]
Myr treatment acutely inhibits transport function at the plasma membrane (PM). These findings suggest that an acute effect of Myr treatment is diminished function of amino acid transporters (AATs) at the PM, resulting in lower amino acid availability in the cytosol that promotes longevity
Trafficking of Mup1-green fluorescent protein (GFP) to the PM 1 h after the media shift was not impaired by any concentration of Myr (Figure 4A). In these assays Vph1-MARS served as a visual marker for the vacuolar membrane to track the internal pool of Mup1-GFP localized to the lumen of the vacuole. Consistent with these observations, we found that yeast cells grown to stationary phase [67] and inoculated into methionine-deficient SC medium exhibited delivery of newly-synthesized Mup1-GFP to the PM within 1 h, which was unaffected by Myr treatment (Figure 4B)
Summary
Aging is the prime risk factor for fatal diseases including cardiovascular disease, diabetes, dementias and cancers [1,2,3,4]. Strategies to slow the aging process and improve heath in older people are being investigated. There is a critical need for alternative strategies to achieve nutrient restriction as few humans can limit nutrient intake to the degree required to improve health. As we show here, Myr lowers the free pool of most amino acids including ones known to enhance lifespan. These results pose the tantalizing question: How does slowing sphingolipid synthesis rewire metabolism and promote longevity?
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
