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

Abstract

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.

Lactate and pyruvate promote cellular stress resistance and longevity through ROS signaling

“…These observations are in line with mitohormesis, a concept described in multiple organisms 18,57 whereby a moderate increase in ROS production, in the low micromolar range (Fig. 3f), promotes stress resistance and longevity 20,58 . This hypothesis is supported by recent literature pointing to the signaling role of ROS 16,17 .…”

Modulation of caveolae by insulin/ IGF ‐1 signaling regulates aging of Caenorhabditis elegans

“…Next, we asked whether these transcription factors are also needed for the promotion of proteostasis by reducing the cav-1 expression levels. Importantly, all three transcription factors were shown to promote proteostasis in previous studies [13,45] and inhere (Appendix Fig S4). Ab worms were treated with mixtures of RNAi toward cav-1 and each transcription factor as described above, and the rates of paralysis within the worm populations were recorded.…”

“…Importantly, all three transcription factors were shown to promote proteostasis in previous studies [13,45] and inhere (Appendix Fig S4). Importantly, all three transcription factors were shown to promote proteostasis in previous studies [13,45] and inhere (Appendix Fig S4).…”

The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality

“…Loss of function of GLOD-4, on the other hand, shortens lifespan which is exacerbated under high glucose conditions in C. elegans (Chaudhuri et al, 2016). Interestingly, a recent study has shown that low concentrations of MGO, formed via inactivation of the enzyme glycine-C-acetyltransferase (GCAT) involved in threonine catabolism, can promote lifespan through proteohormesis (Ravichandran et al, 2018). Reduction of age-related accumulation of AGEs by the FDA-approved (for the treatment of tuberculosis (TB)) drug Rifampicin also enhances worm lifespan through activation of DAF-16/FOXO (Golegaonkar et al, 2015).…”