Lipid metabolism and lipid signals in aging and longevity

Abstract

Lipids play crucial roles in regulating aging and longevity. In the past few decades, a series of genetic pathways have been discovered to regulate lifespan in model organisms. Interestingly, many of these regulatory pathways are linked to lipid metabolism and lipid signaling. Lipid metabolic enzymes undergo significant changes during aging and are regulated by different longevity pathways. Lipids also actively modulate lifespan and health span as signaling molecules. In this review, we summarize recent insights into the roles of lipid metabolism and lipid signaling in aging and discuss lipid-related interventions in promoting longevity.

Keywords: aging; lipid metabolism; lipid signals; longevity.

Figure 1.. Different classes of lipid species

Fatty acids are building blocks of all lipids. Palmitic, oleic, and α-linolenic acid are shown as examples for saturated, monounsaturated, and polyunsaturated FAs, respectively. For storage lipids, triglycerides consist of three FAs attached to a glycerol, whereas cholesterol esters consist of a fatty acid attached to a cholesterol. Glycerophospholipids are lipids with a polar group attached to one of the positions on the glycerol backbone and FAs attached to the other two. For example, phosphatidylcholines have a choline attached to the third position on the glycerol. Other than choline, the head group could be ethanolamine, inositol, serine, and glycerol. Sphingolipids have a sphingoid base attached to one fatty acid. For example, ceramides have sphingosine attached to a fatty acid. For signaling lipids, N-acetylethanolamides (e.g., oleoylethanolamide) and cholesterol-derived bile acids (e.g., cholic acid) are shown as examples.

Figure 2.. Lipid metabolic changes associated with aging

Specific lipid metabolic enzymes localize to different cellular organelles. The activities of those enzymes are shown to influence lifespan and health span in various model organisms, as well as humans. Age-associated changes are also detected in specific lipid profiles.

Figure 3.. Pro-longevity signaling pathways regulating lipid metabolism

Molecular characterization of conserved pro-longevity signaling mechanisms, including IIS, mTOR signaling, and germline endocrine signals, have uncovered interesting mechanistic links between lipid metabolism and longevity. In C. elegans, multiple transcription factors/mediators and nuclear receptors act in these pathways to regulate different lipid metabolic processes.

Figure 4.. Lipid signaling in longevity regulation

Lipid messengers linked with the longevity regulation are summarized, which can act through GPCRs and TRP channels on the membrane and nuclear receptors. Lipid chaperones, including FABPs and apolipoproteins (LBPs and vitellogenins in C. elegans), facilitate intracellular and intercellular transportation of lipids and their signaling effects. Although not shown in the figure, changes in the membrane lipid environment and lipid modifications of GPCRs and TRP channels also modulate their activities.