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 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.

Demographic and clinical variables affecting mid‐ to late‐life trajectories of plasma ceramide and dihydroceramide species

“…Indeed, it is increasingly recognized at the cellular level that the homeostasis of ceramide metabolism is critical in regulating lifespan and age‐associated diseases (Cutler & Mattson, 2001; Rao et al ., 2007; Huang et al ., 2014). However, given the longer lifespan and greater complexity of sphingolipid metabolism in mammals, fewer studies have translated this cellular work to humans and large‐scale clinical and epidemiological studies of these lipids are lacking.…”

“…Thus, the homeostasis of ceramide metabolism may be critical in regulating lifespan and age‐associated diseases (Cutler & Mattson, 2001; Rao et al ., 2007). Indeed, it has been increasingly recognized, from the cellular to human level, that perturbations in ceramide metabolism are associated with longevity (Yu et al ., 2012; Gonzalez‐Covarrubias et al ., 2013; Cutler et al ., 2014; Huang et al ., 2014) and the development and progression of many age‐related diseases including cancer (Alberg et al ., 2013), atherosclerosis (Ichi et al ., 2006), insulin resistance and diabetes (Holland et al ., 2007; Holland & Summers, 2008; Boon et al ., 2013), Alzheimer's disease (Mielke et al ., 2012), and Parkinson's disease (Mielke et al ., 2013). …”

Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease

“…In this regard, the effects of resveratrol in slowing the progression of age-related diseases are well documented . Interestingly, sphingolipids, such as ceramide and dihydroceramide, have been shown to modulate lifespan of yeast via autophagy and activation of AMPK signaling that is independent of sirtuin activation (Huang et al 2014). Since resveratrol modulates sphingolipid levels, the beneficial effects of resveratrol such as anticancer, antiinflammatory activities, cardio-and neuro-protective properties might be tightly linked with changes in sphingolipid signaling.…”

Ceramide signalling impinges on Sit4p and Hog1p to promote mitochondrial fission and mitophagy in Isc1p-deficient cells

“…Mounting evidence from yeast to mammalian cells suggests that sphingolipids are involved in the regulation of mitochondrial function [17][18][19][20]. Ceramides are central molecules in the metabolism of sphingolipids.…”