Impairing L-Threonine Catabolism Promotes Healthspan through Methylglyoxal-Mediated Proteohormesis

Publication date: Available online 15 March 2018
Source:Cell Metabolism
Author(s): Meenakshi Ravichandran, Steffen Priebe, Giovanna Grigolon, Leonid Rozanov, Marco Groth, Beate Laube, Reinhard Guthke, Matthias Platzer, Kim Zarse, Michael Ristow
Whether and how regulation of genes and pathways contributes to physiological aging is topic of intense scientific debate. By performing an RNA expression-based screen for genes downregulated during aging of three different species, we identified glycine-C-acetyltransferase (GCAT, EC 2.3.1.29). Impairing gcat expression promotes the lifespan of C. elegans by interfering with threonine catabolism to promote methylglyoxal (MGO; CAS 78-98-8) formation in an amine oxidase-dependent manner. MGO is a reactive dicarbonyl inducing diabetic complications in mammals by causing oxidative stress and damaging cellular components, including proteins. While high concentrations of MGO consistently exert toxicity in nematodes, we unexpectedly find that low-dose MGO promotes lifespan, resembling key mediators of gcat impairment. These were executed by the ubiquitin-proteasome system, namely PBS-3 and RPN-6.1 subunits, regulated by the stress-responsive transcriptional regulators SKN-1/NRF2 and HSF-1. Taken together, GCAT acts as an evolutionary conserved aging-related gene by orchestrating an unexpected nonlinear impact of proteotoxic MGO on longevity.

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Teaser

Ravichandran et al. show that the gcat gene is downregulated during normal aging in different species, and show that impairment of GCAT delays aging by promoting formation of methylglyoxal. This diabetes-related and toxic compound unexpectedly also extends healthspan at low concentrations. Both interventions converge at stress-response and proteostasis pathways.


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