Link between epigenetic modifiers and fat metabolism for healthy aging

点击翻译按钮获取中文摘要

PROJECT SUMMARY Chromatin modifiers integrate environmental stimuli to physiological outputs via epigenetic changes, which can be long lasting and even transcend generations. Chromatin remodeling has been found to extend lifespan in several organisms, but how chromatin modifiers promote longevity is unknown. We have made the tantalizing observation that deficiency in the COMPASS methyltransferase complex, which trimethylates histone H3 at lysine 4 (H3K4me3), leads to lifespan extension in C. elegans that is causally coupled to changes in fat metabolism. Intriguingly, H3K4me3 modifiers act in the germline of C. elegans to trigger fat metabolism changes in somatic tissues, suggesting a non-cell autonomous signaling between germline and soma for fat metabolism. Using high throughput mass spectrometry, we find H3K4me3-methyltransferase deficient worms are enriched for several specific mono-unsaturated fatty acids (MUFAs): oleic acid, palmitoleic acid, and cis- vaccenic acid. This fat metabolic switch to MUFAs requires a conserved network involving the transcription factors SPB-1/SREBP1, NHR-49/PPARα, and delta-9 fatty acid desaturases, and remarkably endogenous MUFA accumulation is necessary for lifespan extension. Interestingly, dietary supplementation of individual MUFAs is sufficient to extend lifespan in worms. Excessive fat storage has been associated with diseases such as atherosclerosis and diabetes, but our data suggest fat composition is critical, and that epigenetic remodeling can result in specific fatty acids that increase longevity. Because the genes that generate unsaturated fatty acids are highly conserved throughout evolution, endogenous or dietary MUFAs could promote longevity in humans. Exciting new questions raised by these observations are: how is MUFA metabolism influenced by epigenetic changes and environmental stimuli? How is the communication between germline and somatic tissues orchestrated to influence fat composition? Are the changes in fat composition inherited in the progeny in a transgenerational manner? And how do MUFAs act to extend lifespan? C. elegans is an excellent model for fat metabolism because of its genetic power and because the machinery for conversion of saturated to unsaturated fatty acids is entirely conserved. This proposal will test the hypothesis that epigenetic changes in H3K4me3 in the germline initiates a signal that induces a switch to MUFA accumulation in specific somatic tissues, resulting in lifespan extension. Three specific aims will be developed to test this new idea: 1. To determine how germline H3K4me3 modifiers lead to change in somatic fat composition in parents and progeny. 2. To identify the molecular mechanisms that induce a switch to mono-unsaturated fatty acids and longevity in response to altered germline H3K4me3 and environmental stimuli. 3. To characterize the regulation and mode of action of specific fatty acids that promote longevity. These studies will give mechanistic insights into specific fat metabolism regulation in the germline and potentially discover new signaling molecules that inform the soma of the metabolic status of the germline. Furthermore, the proposed experiments will identify the critical pathways linking epigenetic changes to fat metabolism across generations. Finally, this work in C. elegans will determine how fat metabolism can have benefits on healthspan and lifespan, and provide the foundation to test the conserved role of MUFA metabolism in other species.