Biology subjects

MacInnes, A. W.

Publications and source records attributed to MacInnes, A. W..

4 recordsLinked to original sources

bioRxiv2020

Reduced ech-6 Expression Attenuates Fat-induced Premature Aging in C. elegans

Deregulated energy homeostasis represents a hallmark of aging and results from complex gene-by-environment interactions. Here, we discovered that reducing the expression of the gene ech-6 encoding enoyl-CoA hydratase remitted fat diet-induced deleterious effects on lifespan in Caenorhabditis elegans, while a basal expression of ech-6 was important for survival under normal dietary conditions. Lipidomics revealed that supplementation of fat in ech-6-silenced worms had marginal effects on lipid profiles, suggesting an alternative fat utilization for energy production. Transcriptomics further suggest a causal relation between the lysosomal pathway, energy production, and the longevity effect conferred by the interaction between ech-6 and high-fat diets. Indeed, enhancing energy production from endogenous fat by overexpressing lysosomal lipase lipl-4 recapitulated the lifespan effects of high-fat diets on ech-6-silenced worms. Collectively, these results reveal that the gene ech-6 modulates metabolic flexibility and may be a target for promoting metabolic health and longevity.

cell biology↗

bioRxiv2020

The PNUTS-PP1 axis regulates endothelial aging and barrier function via SEMA3B suppression

Age-related diseases pose great challenges to health care systems worldwide. During aging, endothelial senescence increases the risk for cardiovascular disease. Recently, it was described that Phosphatase 1 Nuclear Targeting Subunit (PNUTS) has a central role in cardiomyocyte aging and homeostasis. Here, we determined the role of PNUTS in endothelial cell aging. We confirmed that PNUTS is repressed in senescent endothelial cells (ECs). Moreover, PNUTS silencing elicits several of the hallmarks of endothelial aging: senescence, reduced angiogenesis and loss of barrier function. To validate our findings in vivo, we generated an endothelial-specific inducible PNUTS-deficient mouse line (Cdh5-CreERT2;PNUTSfl/fl), termed PNUTSEC-KO. Two weeks after PNUTS deletion, PNUTSEC-KO mice presented severe multiorgan failure and vascular leakage. We showed that the PNUTS binding motif for protein phosphatase 1 (PP1) is essential to maintain endothelial barrier function. Transcriptomic analysis of PNUTS-silenced HUVECs and lungs of PNUTSEC-KO mice revealed that the PNUTS-PP1 axis tightly regulates the expression of semaphorin 3B (SEMA3B). Indeed, silencing of SEMA3B completely restored barrier function after PNUTS loss-of-function. These results reveal a pivotal role for PNUTS in endothelial homeostasis through a PP1-SEMA3B downstream pathway that provides a potential target against the effects of aging in ECs.

molecular biology↗

bioRxiv2018

Glycine promotes longevity in Caenorhabditis elegans in a methionine cycle-dependent fashion

The deregulation of metabolism is a hallmark of aging. As such, changes in the expression of metabolic genes and the profiles of amino acid levels are features associated with aging animals. We previously reported that the levels of most amino acids decline with age in Caenorhabditis elegans (C. elegans). Glycine, in contrast, substantially accumulates in aging C. elegans. In this study we show that this is coupled to a decrease in gene expression of enzymes important for glycine catabolism. We further show that supplementation of glycine significantly prolongs C. elegans lifespan and ameliorates specific transcriptional changes that are associated with aging. Glycine feeds into the methionine cycle. We find that mutations in components of this cycle, methionine synthase (metr-1) and S-adenosylmethionine synthetase (sams-1), completely abrogate glycine-induced lifespan extension. Strikingly, the beneficial effects of glycine supplementation are conserved when we supplement with serine, also driving the methionine cycle. RNA sequencing of serine- and glycine-supplemented worms reveals similar transcriptional profiles including widespread gene suppression. Taken together, these data uncover a novel role of glycine in the deceleration of aging through its function in the methionine cycle.\n\nAuthor summaryThere are a growing number of studies showing that amino acids function as signal metabolites that influence aging and health. Although contemporary -OMICs studies have uncovered various associations between metabolite levels and aging, in many cases the directionality of the relationships is unclear. In a recent metabolomics study, we found that glycine accumulates in aged C. elegans while other amino acids decrease. The present study shows that glycine supplementation prolongs longevity and drives a genome-wide inhibition effect on C. elegans gene expression. Glycine as a one-carbon donor fuels the methyl pool of one-carbon metabolism composed of folates and methionine cycle. We find that glycine-mediated longevity effect is fully dependent on methionine cycle, and that all of these observations are conserved with supplementation of the other one-carbon amino acid, serine. These results provide a novel role for glycine as a promoter of longevity and bring new insight into the role of one-carbon amino acids in the regulation of aging that may ultimately be beneficial for humans.

systems biology↗

bioRxiv2018

Mitochondrial ubiquinone-mediated longevity is marked by reduced cytoplasmic protein translation

Mutations in the clk-1 gene impair mitochondrial ubiquinone biosynthesis and extend the lifespan of C. elegans. We demonstrate here that this life extension is linked to the repression of cytoplasmic protein translation. Clk-1 mutations inhibit polyribosome formation similarly to daf-2 mutations that dampen insulin signaling. Comparisons of total versus polysomal RNAs in clk-1 mutants reveal a reduction in the translational efficiencies of mRNAs coding for elements of the translation machinery and an increase in those coding for the oxidative phosphorylation and autophagy pathways. Knocking down the transcription initiation factor TAF-4, a protein that becomes sequestered in the cytoplasm during early embryogenesis to induce transcriptional silencing, ameliorates the clk-1 inhibition of polyribosome formation. These results underscore a prominent role for the repression of cytoplasmic protein translation in eukaryotic lifespan extension, and suggest that mutations impairing mitochondrial function are able to exploit this repression similarly to reductions of insulin signaling. Moreover, this report reveals an unexpected role for TAF-4 as a repressor of polyribosome formation when ubiquinone biosynthesis is compromised.

systems biology↗