Plum modulates Myoglianin and regulates synaptic function in D. melanogaster.

Alterations in the neuromuscular system underlie several neuromuscular diseases and play critical roles in the development of sarcopenia, the age-related loss of muscle mass and function. Mammalian Myostatin (MST) and GDF11, members of the TGF-ß superfamily of growth factors, are powerful regulators of muscle size in both model organisms and humans. Myoglianin (MYO), the Drosophila homologue of MST and GDF11, is a strong inhibitor of synaptic function and structure at the neuromuscular junction in flies. Here, we identified Plum, a transmembrane cell surface protein, as a modulator of MYO function in the larval neuromuscular system. Reduction of Plum in the larval body-wall muscles abolishes the previously demonstrated positive effect of attenuated MYO signalling on both muscle size and neuromuscular junction structure and function. In addition, downregulation of Plum on its own results in decreased synaptic strength and body weight, classifying Plum as a (novel) regulator of neuromuscular function and body (muscle) size. These findings offer new insights into possible regulatory mechanisms behind ageing- and disease-related neuromuscular dysfunctions in humans and identify potential targets for therapeutic interventions.

Regulation of the one carbon folate cycle as a shared metabolic signature of longevity.

The metabolome represents a complex network of biological events that reflects the physiologic state of the organism in health and disease. Additionally, specific metabolites and metabolic signaling pathways have been shown to modulate animal ageing, but whether there are convergent mechanisms uniting these processes remains elusive. Here, we used high resolution mass spectrometry to obtain the metabolomic profiles of canonical longevity pathways in C. elegans to identify metabolites regulating life span. By leveraging the metabolomic profiles across pathways, we found that one carbon metabolism and the folate cycle are pervasively regulated in common. We observed similar changes in long-lived mouse models of reduced insulin/IGF signaling. Genetic manipulation of pathway enzymes and supplementation with one carbon metabolites in C. elegans reveal that regulation of the folate cycle represents a shared causal mechanism of longevity and proteoprotection. Such interventions impact the methionine cycle, and reveal methionine restriction as an underlying mechanism. This comparative approach reveals key metabolic nodes to enhance healthy ageing.

Branched chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control.

Elevated branched chain amino acids (BCAAs) are associated with obesity and insulin resistance. How long-term dietary BCAAs impact late-life health and lifespan is unknown. Here, we show that when dietary BCAAs are varied against a fixed, isocaloric macronutrient background, long-term exposure to high BCAA diets leads to hyperphagia, obesity and reduced lifespan. These effects are not due to elevated BCAA per se or hepatic mTOR activation, but rather due to a shift in the relative quantity of dietary BCAAs and other AAs, notably tryptophan and threonine. Increasing the ratio of BCAAs to these AAs resulted in hyperphagia and is associated with central serotonin depletion. Preventing hyperphagia by calorie restriction or pair-feeding averts the health costs of a high BCAA diet. Our data highlight a role for amino acid quality in energy balance and show that health costs of chronic high BCAA intakes need not be due to intrinsic toxicity but, rather, a consequence of hyperphagia driven by AA imbalance.

Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice.

Caloric restriction (CR) increases healthy life span in a range of organisms. The underlying mechanisms are not understood but appear to include changes in gene expression, protein function, and metabolism. Recent studies demonstrate that acute CR alters mortality rates within days in flies. Multitissue transcriptional changes and concomitant metabolic responses to acute CR have not been described. We generated whole genome RNA transcript profiles in liver, skeletal muscle, colon, and hypothalamus and simultaneously measured plasma metabolites using proton nuclear magnetic resonance in mice subjected to acute CR. Liver and muscle showed increased gene expressions associated with fatty acid metabolism and a reduction in those involved in hepatic lipid biosynthesis. Glucogenic amino acids increased in plasma, and gene expression for hepatic gluconeogenesis was enhanced. Increased expression of genes for hormone-mediated signaling and decreased expression of genes involved in protein binding and development occurred in hypothalamus. Cell proliferation genes were decreased and cellular transport genes increased in colon. Acute CR captured many, but not all, hepatic transcriptional changes of long-term CR. Our findings demonstrate a clear transcriptional response across multiple tissues during acute CR, with congruent plasma metabolite changes. Liver and muscle switched gene expression away from energetically expensive biosynthetic processes toward energy conservation and utilization processes, including fatty acid metabolism and gluconeogenesis. Both muscle and colon switched gene expression away from cellular proliferation. Mice undergoing acute CR rapidly adopt many transcriptional and metabolic changes of long-term CR, suggesting that the beneficial effects of CR may require only a short-term reduction in caloric intake.