Sphingolipids and lifespan regulation

Abstract

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 sphingolipids 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. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.

Keywords: Aging; Autophagy; Ceramide; Myriocin; Sphingosing-1-phosphate.

Fig. 1

Outline of sphingolipid metabolism. This diagram presents a simplified view of sphingolipid metabolism and more detailed information is available in the literature [12, 13, 16, 34, 119]. Initial steps in sphingolipid synthesis occur in the ER in all eukaryotes that make sphingolipids. Later steps in the synthesis of complex sphingolipids in the Golgi apparatus and that are specific to yeast (Saccharomyces cerevisiae) or mammals are indicated. Shown at the bottom of the figure is one way to generate ceramides and then convert it to sphingosine-1-PO₄.

Fig. 2

Decreasing the rate of yeast sphingolipid synthesis increases lifespan. A. This diagram summarizes known links between inducers (nutrients and stresses), protein kinases and signaling pathways, and cellular processes modulated by myriocin treatment that have known roles in CLS. The cellular processes are based upon GO terms enriched in the myriocin-responsive gene set and which were verified by targeted experiments [48]. Activation, inhibition and repression are not indicated in order to emphasize linkage relationships. Details about signaling pathways can be found in a review [120]. The brown-shaded rectangles indicate up- regulated processes and green-shaded boxes indicate down-regulated processes (Figure adapted from) [48]. B. CLS of DBY746 cells treated myriocin (400 ng/ml) to reduce the rate of sphingolipid synthesis. Data represent the mean ± SEM of surviving cells (* p<0.05, ** p<0.01, No Myr vs 200 and 400 ng/ml Myr). To compensate for the slow growth and extended growth phase of cells treated with 400 ng/ml of myriocin (solid red line), the viability at the 120 hr time point, CLS day 3, was set as CLS day 1 (dashed red line). C. CLS of tetO7-LCB1 cells treated or not treated with doxycycline (100 ng/ml) to reduce gene expression and lower the rate of sphingolipid synthesis. Data show the mean ± SEM of surviving cells (* p<0.05, ** p<0.01, No Dox vs doxycycline). Panels B and C are reproduced with permission [47].

Fig. 3

Drug treatments increase yeast lifespan. A. The CLS of sch9Δ cells (PF102) is enhanced by treating cells with myriocin (Myr). Data represent the mean ± SEM of survival (* p<0.05, ** p<0.01, No Myr vs 300 ng/ml Myr). Reproduced with permission [47]. B. Treatment of wild-type (DBY746) yeast cells with a low dose of myriocin plus rapamycin produces a synergistic enhancement in CLS. Cells were incubated with no drug, 45 ng/ml myriocin (Myr, 112 nM), 450 pg/ml rapamycin (Rap. 0.49 nM), 45 ng/ml Myr plus 450 pg/ml Rap. Data are for the mean ± SEM of viable cells in triplicate cultures. The dotted straight line with an arrowhead indicates an increase in the CLS of cells treated with both drugs that is greater than the additive effect on CLS of each drug treatment compared to untreated cells (additive effect is indicated by a dashed survival curve). The p value for the lifespan increase is computed using the area under the viability curves. Reproduced with permission [74]