Diseases including cancer, type 2 diabetes, cardiovascular and immune dysfunction and neurodegeneration become more prevalent as we age, and combined with the increase in average human lifespan, place an ever increasing burden on the health care system. In this chapter we focus on finding ways of modulating sphingolipids to prevent the development of age-associated diseases or delay their onset, both of which could improve health in elderly, fragile people. Reducing the incidence of or delaying the onset of diseases of aging has blossomed in the past decade because of advances in understanding signal transduction pathways and cellular processes, especially in model organisms, that are largely conserved in most eukaryotes and that can be modulated to reduce signs of aging and increase health span. In model organisms such interventions must also increase lifespan to be considered significant, but this is not a requirement for use in humans. The most encouraging interventions in model organisms involve lowering the concentration of one or more sphingolipid so as to reduce the activity of key signaling pathways, one of the most promising being the Target of Rapamycin Complex 1 (TORC1) protein kinase pathway. Other potential ways in which modulating sphingolipids may contribute to improving the health profile of the elderly is by reducing oxidative stresses, inflammatory responses and growth factor signaling. Lastly, perhaps the most interesting way to modulate sphingolipids and promote longevity is by lowering the activity of serine palmitoyltransferase, the first enzyme in the de novo sphingolipid biosynthesis pathway. Available data in yeasts and rodents are encouraging and as we gain insights into molecular mechanisms the strategies for improving human health by modulating sphingolipids will become more apparent.

Summary Studies of aging and longevity are revealing how diseases that shorten life can be controlled to improve the quality of life and lifespan itself. Two strategies under intense study to accomplish these goals are rapamycin treatment and calorie restriction. New strategies are being discovered including one that uses low-dose myriocin treatment. Myriocin inhibits the first enzyme in sphingolipid synthesis in all eukaryotes and we showed recently that low-dose myriocin treatment increases yeast lifespan at least in part by down-regulating the sphingolipid-controlled Pkh1/2-Sch9 (ortholog of mammalian S6 kinase) signaling pathway. Here we show that myriocin treatment induces global effects and changes expression of approximately forty percent of the yeast genome with 1252 genes up-regulated and 1497 down-regulated (p < 0.05) compared to untreated cells. These changes are due to modulation of evolutionarily conserved signaling pathways including activation of the Snf1/AMPK pathway and down-regulation of the Protein Kinase A (PKA) and Target of Rapamycin Complex 1 (TORC1) pathways. Many processes that enhance lifespan are regulated by these pathways in response to myriocin treatment including respiration, carbon metabolism, stress resistance, protein synthesis and autophagy. These extensive effects of myriocin match those of rapamycin and calorie restriction. Our studies in yeast together with other studies in mammals reveal the potential of myriocin or related compounds to lower the incidence of age-related diseases in humans and improve health span.

Survival of Saccharomyces cerevisiae cells, like most microorganisms, requires switching from a rapidly dividing to a non-dividing or stationary state. To further understand how cells navigate this switch, we examined sphingolipids since they are key structural elements of membranes and also regulate signaling pathways vital for survival. During and after the switch to a non-dividing state there is a large increase in total free and sphingolipid-bound long chain-bases and an even larger increase in free and bound C20-long-chain bases, which are nearly undetectable in dividing cells. These changes are due to intrinsic factors including Orm1 and Orm2, ceramide synthase, Lcb4 kinase and the Tsc3 subunit of serine palmitoyltransferase as well as extrinsic factors including glucose and iron. Lowering the concentration of glucose, a form of calorie restriction, decreases the level of LCBs, which is consistent with the idea that reducing the level of some sphingolipids enhances lifespan. In contrast, iron deprivation increases LCB levels and decreases long term survival; however, these phenomena may not be related because iron deprivation disrupts many metabolic pathways. The correlation between increased LCBs and shorter lifespan is unsupported at this time. The physiological rise in LCBs that we observe may serve to modulate nutrient transporters and possibly other membrane phenomena that contribute to enhanced stress resistance and survival in stationary phase.