Research Paper Advance Articles
Methylglyoxal-induced glycation stress promotes aortic stiffening: putative mechanistic roles of oxidative stress and cellular senescence
- 1 Buck Institute for Research on Aging, Novato, CA 94945, USA
- 2 University of Colorado Boulder, Boulder, CO 80309, USA
- 3 College of Chemistry, University of Berkely, Berkely, CA 94720, USA
- 4 R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA
- 5 University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Received: June 27, 2025 Accepted: October 30, 2025 Published: November 14, 2025
https://doi.org/10.18632/aging.206335How to Cite
Copyright: © 2025 Singh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Here, we assessed the role of the advanced glycation end-product (AGE) precursor methylglyoxal (MGO) and its non-crosslinking AGE MGO-derived hydroimidazolone (MGH)-1 in aortic stiffening and explored the potential of a glycation stress-lowering compound (Gly-Low) to mitigate these effects.
Methods: Young (3–6 month) C57BL/6J mice were supplemented with MGO (in water) and Gly-Low (in chow). Aortic stiffness was assessed in vivo via pulse wave velocity (PWV) and ex vivo through elastic modulus. Putative mechanisms underlying MGO- and MGH-1-induced aortic stiffening were explored using complementary experimental approaches in aortic tissue and cultured human aortic endothelial cells (HAECs). Moreover, aortic stiffness was assessed in old C57BL/6J (24 month) mice after consumption of Gly-Low-enriched chow.
Results: MGO-induced glycation stress increased PWV in young mice by 21% (P<0.05 vs. control), which was prevented with Gly-Low (P=0.93 vs. control). Ex vivo, MGO increased aortic elastic modulus ~100% (P<0.05), superoxide production by ~40% (P<0.05), and MGH-1 expression by 50% (P<0.05), which were all mitigated by Gly-Low. Chronic MGO exposure elevated biomarkers of cellular senescence in HAECs, comparable to a known senescence inducer Doxorubicin, an effect partially blocked by Gly-Low. Moreover, elevated aortic elastic modulus induced by Doxorubicin (P<0.05 vs. control) was prevented with Gly-Low (P=0.71 vs. control). Aortic RNA sequencing implicated preservation of endogenous cellular detoxification pathways with Gly-Low following exposure to MGH-1. Old mice supplemented with Gly-Low had lower PWV (P<0.05) relative to old control mice.
Conclusions: MGO-induced glycation stress contributes to aortic stiffening and glycation stress lowering compounds hold promise for mitigating these effects.
Abbreviations
AGEs: Advanced glycation end products; Cdkn1a: Cyclin-dependent kinase inhibitor 1A (p21); Cdkn2a: Cyclin-dependent kinase inhibitor 2A (p16); CVDs: Cardiovascular diseases; DMEM: Dulbecco's Modified Eagle Medium; DOXO: DOXOrubicin; Glo-1: Glyoxalase-1; Gly-Low: Glycation-lowering compound; HAECs: Human aortic endothelial cells; Lmnb1: Lamin B1; MGH-1: Methylglyoxal-derived hydroimidazolone isomer-1; MGO: Methylglyoxal; PWV: Pulse wave velocity; ROS: Reactive oxygen species; SA-β-gal: Senescence-associated β-galactosidase; Serpine1: Plasminogen activator inhibitor-1 (PAI-1); TEMPOL: 4-Hydroxy-TEMPO (a superoxide scavenger)..