Good Ol' Fat: Links between Lipid Signaling and Longevity

Abstract

Aging is the single greatest risk factor for the development of disease. Understanding the biological molecules and mechanisms that modulate aging is therefore critical for the development of health-maximizing interventions for older people. The effect of fats on longevity has traditionally been disregarded as purely detrimental. However, new studies are starting to uncover the possible beneficial effects of lipids working as signaling molecules on health and longevity. These studies highlight the complex links between aging and lipid signaling. In this review we summarize accumulating evidence that points to changes in lipid metabolism, and in particular lipid signaling, as an underlying mechanism for healthy aging.

Keywords: aging; lipid signaling; lipidomics; longevity; nuclear receptors.

Figure I. Worm life cycle.

Representation of C. elegans life cycle at 22ºC. Numbers along the arrows represent the hours (hrs) necessary to transition from one stage to the next.

Figure 1. Reduced insulin insulin-like signaling (IIS) extends lifespan in a DAF-16/DAF-12/NSBP-1 dependent manner.

In wild type C. elegans, IIS phosphorylates and negatively regulates NSBP-1, a cholesterol binding protein, and DAF-16 transcription factor. Under reduced IIS, these proteins become dephosphorylated and migrate into the nucleus and interact in a cholesterol-dependent manner to modulate the transcription of pro-longevity genes. Extension of lifespan by lowered IIS is also dependent on DAF-12 and its ligand DA. Worms with reduced IIS cannot maximize lifespan-extension in the absence of DA or excess of cholesterol. I: Insulin; P: Phosphate; C: Cholesterol; DA; Dafachronic Acids

Figure 2. Different dietary restriction (DR) paradigms promote longevity in ways that depend on lipid signals.

While different DR interventions in C. elegans have at least partially independent mechanisms for lifespan extension, they all seem to rely on the regulation of transcription factors that act in response to putative lipid signals. Hence, increased lifespan from eat-2 mutation relies on NHR-49 and NHR-62, although their respective lipid ligands (if they have one) remain unknown. NHR-62 is also involved in extension of lifespan by BDR, at least at low food concentrations, and NHR-8 and DA are also required, although the nature of their interaction is unclear. IF relies on DAF-16 and AP-1 to achieve maximum lifespan extension, but whether NSBP-1 may play a role here remains unknown.

Figure 3. Germline ablation increases lifespan by modulating lipid metabolism.

Germ cells inhibit the production of DA. We propose that, as a consequence, the transcriptional activity of both DAF-16 and DAF-12 is dampened. Conversely, removal of germ cells allows production of DA and transcription of pro-longevity genes by DAF-16 and DAF-12, including genes involved in lipid metabolism. These changes promote the generation of putative lipid signals, which in turn activate downstream factors such as NHR-49, NHR-80 and SKN-1 that promote longevity through different transcriptional programs. However, these putative lipid signals remain unknown. Whether Oleoylethanolamide (OEA) serves as a NHR-80 ligand under germline ablation remains unclear. FA stands for fatty acids.