Implications of Sphingolipids on Aging and Age-Related Diseases

Aging is a process leading to a progressive loss of physiological integrity and homeostasis, and a primary risk factor for many late-onset chronic diseases. The mechanisms underlying aging have long piqued the curiosity of scientists. However, the idea that aging is a biological process susceptible to genetic manipulation was not well established until the discovery that the inhibition of insulin/IGF-1 signaling extended the lifespan of C. elegans. Although aging is a complex multisystem process, López-Otín et al. described aging in reference to nine hallmarks of aging. These nine hallmarks include: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Due to recent advances in lipidomic, investigation into the role of lipids in biological aging has intensified, particularly the role of sphingolipids (SL). SLs are a diverse group of lipids originating from the Endoplasmic Reticulum (ER) and can be modified to create a vastly diverse group of bioactive metabolites that regulate almost every major cellular process, including cell cycle regulation, senescence, proliferation, and apoptosis. Although SL biology reaches all nine hallmarks of aging, its contribution to each hallmark is disproportionate. In this review, we will discuss in detail the major contributions of SLs to the hallmarks of aging and age-related diseases while also summarizing the importance of their other minor but integral contributions.