Abstract
A growing body of evidence suggests that changes in fat metabolism may have a significant effect on lifespan. Accumulation of lipid deposits in non-adipose tissue appears to be critical for age-related pathologies and may also contribute to the aging process itself. We established a model of lipid storage in muscle cells of C.elegans to reveal a mechanism that promotes longevity non-cell-autonomously. Here, we describe how muscle-specific activation of adipose triglyceride lipase (ATGL) and the phospholipase A2 (PLA2) ortholog IPLA-7 collectively affect inter-tissular communication and systemic adaptation that requires the activity of AMP-dependent protein kinase (AMPK) and a highly conserved nuclear receptor outside of the muscle. Our data suggest that muscle-specific bioactive lipid signals, or "lipokines," are generated following triglyceride breakdown and that these signals impinge on a complex network of genes that modify the global lipidome, consequently extending the lifespan.
Highlights
The worldwide spike in the frequency of obesity and the number of patients suffering from insulin resistance, type II diabetes, and metabolic syndrome have called into question the role of diet and, the negative effects of dietary lipid consumption
This dichotomy is clearly demonstrated in C. elegans, where longevity can be achieved by increasing the expression of genes involved in lipid metabolism (Chen et al, 2009; Wang et al, 2008)
We observed an accumulation of lipid droplets (LDs) in body wall muscle in aged hermaphrodites that was dramatically increased when the animals were grown on glucose-supplemented bacteria, indicating that lipid accumulation in non-storage tissue occurs in C. elegans as a function of both age and diet (Figures S2A–S2D)
Summary
The worldwide spike in the frequency of obesity and the number of patients suffering from insulin resistance, type II diabetes, and metabolic syndrome have called into question the role of diet and, the negative effects of dietary lipid consumption. The role of fat intake has been suggested to contribute to the etiology of several diseases, the data remain inconclusive, and numerous studies do not corroborate any causal link between fat intake and any of these diseases (Del Razo Olvera et al, 2017; Melanson et al, 2009; Mozaffarian and Ludwig, 2010) In addition to these diseases, evidence suggests that alterations in lipid metabolism may contribute to systemic aging (Hansen et al, 2013). Long-lived mutants often possess increased levels of lipids, again challenging the claim that increased lipid abundance systematically has negative effects on overall lifespan (O’Rourke et al, 2009; Yen et al, 2010)
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