D-Glucosamine supplementation extends life span of nematodes and of ageing mice

Abstract

D-Glucosamine (GlcN) is a freely available and commonly used dietary supplement potentially promoting cartilage health in humans, which also acts as an inhibitor of glycolysis. Here we show that GlcN, independent of the hexosamine pathway, extends Caenorhabditis elegans life span by impairing glucose metabolism that activates AMP-activated protein kinase (AMPK/AAK-2) and increases mitochondrial biogenesis. Consistent with the concept of mitohormesis, GlcN promotes increased formation of mitochondrial reactive oxygen species (ROS) culminating in increased expression of the nematodal amino acid-transporter 1 (aat-1) gene. Ameliorating mitochondrial ROS formation or impairment of aat-1-expression abolishes GlcN-mediated life span extension in an NRF2/SKN-1-dependent fashion. Unlike other calorie restriction mimetics, such as 2-deoxyglucose, GlcN extends life span of ageing C57BL/6 mice, which show an induction of mitochondrial biogenesis, lowered blood glucose levels, enhanced expression of several murine amino-acid transporters, as well as increased amino-acid catabolism. Taken together, we provide evidence that GlcN extends life span in evolutionary distinct species by mimicking a low-carbohydrate diet.

Glucosamine decreases the stemness of human ALDH+ breast cancer stem cells by inactivating STAT3

“…In the study reported by Song et al (37), using a xenograft mouse lung tumor model, glucosamine was required to be introduced at a concentration as high as 500 mg/kg body weight in order to achieve a significant benefit of glucosamine. Furthermore, Weimer et al (38) reported that the plasma level of glucosamine in a mouse model may be increased up to ~2 µM. Notably, it was observed that the effects of glucosamine on ALDH + breast CSC viability are increased after 24 h of treatment, compared with after 48 h; however, the glucosamine treatments for longer durations were not performed in the present study due to MCF7 cells not surviving in serum-free treatment medium for ≥48 h. If the effect of stemness suppression is only short-term, it may indicate that glucosamine treatment should be repeated as necessary to replenish the effect.…”

Hexosamine pathway and (ER) protein quality control

“…HP activation might lead to energy imbalance by consuming metabolites, triggering a stress response. This view receives support from the observation that glucosamine (GlcN) supplementation causes a ROS response [18 ] that extends worm and mouse lifespan through a hormetic mechanism.…”

Lifespan extension by peroxidase and dual oxidase-mediated ROS signaling through pyrroloquinoline quinone in C. elegans

“…Low concentrations of paraquat, which is toxic at high concentrations, were reported to extend lifespan of C. elegans by generating ROS from mitochondria (Yang and Hekimi, 2010a). D-Glucosamine extends the lifespan of C. elegans by impairing glucose metabolism, and increases the mitochondria biogenesis that triggers mtROS generation (Weimer et al, 2014). The mood stabilizer lithium extends the lifespan of Drosophila through inhibition of GSK3 and activation of Nrf2 (also known as Cap-ncollar in flies) (Castillo-Quan et al, 2016).…”

“…Various stimuli, such as mitochondrial dysfunction, calorie restriction, acute impairment of insulin signaling, glucose restriction or absence of a germline, can release mtROS to extend lifespan (Lee et al, 2010;Schaar et al, 2015;Schulz et al, 2007;Wei and Kenyon, 2016;Xie and Roy, 2012;Yang and Hekimi, 2010a,b;Zarse et al, 2012). The hypoxia inducible factor 1 (HIF-1), the stress-activated transcriptional factor SKN-1 (Nrf2 or NFE2L2 in mammals), AMP-activated protein kinase (AMPK) and molecules in the intrinsic apoptosis pathway including CED-4 (Apaf1 in mammals) also participate in mtROSmediated longevity signaling (Castillo-Quan et al, 2016;Hwang et al, 2014;Lee et al, 2010;Wei and Kenyon, 2016;Weimer et al, 2014;Xie and Roy, 2012;Yee et al, 2014;Zarse et al, 2012).…”