Glycation is the non-regulated reaction of sugars with proteins leading to a loss of function of these proteins. Glycation is increased in people who have chronic high blood sugar concentrations such as in poorly managed diabetes patients. Diabetics have a higher risk for cardiovascular disease, kidney failure, nerve damage, and loss of eyesight. While other mechanisms besides glycation exist that explain the link between diabetes and these health problems it seems likely that glycation is at least partially responsible. Hence inhibitors that reduce the rate of glycation could have a large therapeutic potential in alleviating the complications of diabetes and ‘normal’ aging.
Testing 3 glycation inhibitors
A team of researchers from the Indian CSIR-National Chemical Laboratory and the Academy of Scientific and Innovative research (AcSIR) have investigated the effect of glycation inhibitors on the lifespan of baker’s yeast. The team used three glycation inhibitors: (i) the gold-standard inhibitor aminoguanidine, (ii) the antidiabetic drug metformin, and (iii) the powerful glycation inhibitor hydralazine. Metformin and aminoguanidine share structural similarity. To determine if the lifespan extension was caused by a decrease in glycation or because the structural similarity causes both to hit the same non-glycation-related target, a third inhibitor of glycation, hydralazine, was tested. Hydralazine does not share any structural similarity with either metformin or aminoguanidine.
Aminoguanidine extended the chronological lifespan of non-calorie restricted yeast by 45-50% while metformin only extended lifespan by 20-25%. The lifespan extension by aminoguanidine is comparable to that of calorie restriction in yeast. Interestingly, aminoguanidine is a more powerful glycation inhibitor hence if lifespan extension was caused by the inhibition of glycation then we would indeed expect that aminoguanidine has a stronger effect on lifespan. The powerful glycation inhibitor hydralazine extended lifespan by 50-55%. These data suggest that the inhibition of glycation might be (partially) responsible for the lifespan extending effect of these three compounds. All three glycation inhibitors were tested to verify that they indeed reduced glycation in yeast.
Next the researchers determined the abundances of all proteins present in the cell through a technique known as SWATH mass spectrometry. Yeast grown in high glucose conditions (2%, non-calorie restriction) have a change (increase or decrease) in the levels of 359 proteins compared to calorie restricted yeast. They found that aminoguanidine changed the expression of these proteins back to a state more similar to calorie restriction. Similar results were obtained with metformin and hydralazine but hydralazine was more efficient than metformin suggesting that the anti-glycation properties may be responsible for the change in protein expression. Many of the proteins that are downregulated by high glucose but rescued by the addition of a glycation inhibitor are involved in mitochondrial respiration.
Glycation inhibitors also affect mitochondrial respiration
Because glycation inhibitors were found to influence mitochondrial respiration the researchers decided to investigate the effect on reactive oxygen species (ROS). Glycation has previously been linked to a higher production of ROS in cells. In the current study the authors showed that all three glycation inhibitors reduced the ROS production. Next, the cells were treated with an inhibitor of complex III of the electron transport chain, antimycin A. Antimycin A reduced cell viability but this was rescued by all three glycation inhibitors. This experiment confirms that mitochondrial respiration plays a role in the lifespan extension by glycation inhibitors.
Kazi RS et al. (2017). Glycation inhibitors extend yeast chronological lifespan by reducing advanced glycation end products and by back regulation of proteins involved in mitochondrial respiration. J Proteomics [Epub ahead of print]