The Cross-Talk Between Sphingolipids and Insulin-Like Growth Factor Signaling: Significance for Aging and Neurodegeneration

Abstract

Bioactive sphingolipids: sphingosine, sphingosine-1-phosphate (S1P), ceramide, and ceramide-1-phosphate (C1P) are increasingly implicated in cell survival, proliferation, differentiation, and in multiple aspects of stress response in the nervous system. The opposite roles of closely related sphingolipid species in cell survival/death signaling is reflected in the concept of tightly controlled sphingolipid rheostat. Aging has a complex influence on sphingolipid metabolism, disturbing signaling pathways and the properties of lipid membranes. A metabolic signature of stress resistance-associated sphingolipids correlates with longevity in humans. Moreover, accumulating evidence suggests extensive links between sphingolipid signaling and the insulin-like growth factor I (IGF-I)-Akt-mTOR pathway (IIS), which is involved in the modulation of aging process and longevity. IIS integrates a wide array of metabolic signals, cross-talks with p53, nuclear factor κB (NF-κB), or reactive oxygen species (ROS) and influences gene expression to shape the cellular metabolic profile and stress resistance. The multiple connections between sphingolipids and IIS signaling suggest possible engagement of these compounds in the aging process itself, which creates a vulnerable background for the majority of neurodegenerative disorders.

Sphingolipids in neuroinflammation: a potential target for diagnosis and therapy

“…Some researchers have reported that ceramides play pro-inflammatory roles in various diseases, such as pulmonary edema, airway inflammation, cystic fibrosis, and inflammatory bowel disease (4), although another study revealed conflicting findings pertaining to anti-inflammatory effects of ceramides in macrophages, neutrophils, and corneal epithelial cells (12 (20,21). A study on primary rat astrocytes revealed that ceramide stimulates the expression of pro-inflammatory molecules (TNF-, iNOS, IL-1, and IL-6) and activation of NF-B (22).…”

New Insights for nicotinamide Metabolic disease autophagy and mTOR

“…mTOR, a 289-kDa serine/threonine protein kinase, is increasingly being recognized as a critical pathway for nicotinamide given the ability of this vitamin to control cellular metabolism and the programmed death pathways of autophagy and apoptosis. mTOR also is known as the mammalian target of rapamycin and the FK506-binding protein 12-rapamycin complex-associated protein 1 (203,212) and is encoded by a single gene FRAP1 (213)(214)(215). The target of rapamycin (TOR) was initially discovered in Saccharomyces cerevisiae with the genes TOR1 and TOR2 (216).…”

“…mTOR is the principal component of the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2). mTORC1 is composed of Raptor, the proline rich Akt substrate 40 kDa (PRAS40), Deptor (DEP domain-containing mTOR interacting protein), and mammalian lethal with Sec13 protein 8, termed mLST8 (mLST8) (214). mTORC2 is composed of Rictor, mLST8, Deptor, the mammalian stress-activated protein kinase interacting protein (mSIN1), and the protein observed with Rictor-1 (Protor-1).…”

Rosemary Flowers as Edible Plant Foods: Phenolic Composition and Antioxidant Properties in Caenorhabditis elegans

“…The life-extending effect could be due to up-regulating stress-resistance-associated genes such as DAF-16 and HSP-1, associated with the insulin/IGF (insulin-like growth factor) signaling (IIS) pathway [35,[37][38][39]. The IIS pathway is a key regulator of aging and longevity in many organisms, including C. elegans [40].…”