Glycation-lowering compounds inhibit ghrelin signaling to reduce food intake, lower insulin resistance, and extend lifespan

You can’t get anything close to enough B6 to significantly inhibit glycation from diet alone. Supplements are the only way to get high enough doses for that.

From Pankaj:

correct - but they are inter convertible - in our metabolomics all B6 metabolites go up - same is true for NAD

I think too much is made about one form or the other - partly to sell one version or the other - experimentally I think the difference is subtle

This response from Pankaj sounds like an excuse. Yes the B6 forms are interconvertible but the other forms are clearly not being converted into pyridoxamine in great amounts or else pyridoxamine wouldn’t be obviously more effective than the other forms in vivo. Also him saying the differences between the forms are subtle, I disagree with that. Pyridoxamine is clearly better. In addition, it is also safer than the other forms, so you can afford to take higher doses of it without risking neurotoxicity, which is the main side effect that limits the amount of anti-glycation effects you can get from taking B6.

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Good news, Pankaj is getting millions $ to continue research on glycation-reducing compounds;

Using glycation to understand how hallmarks of aging interact with each other

The Kapahi lab will use glycation, which occurs when sugar binds to proteins or lipid molecules, and its toxic methylglyoxal (MGO) byproduct to understand the interplay between three hallmarks of aging: dysregulated nutrient sensing, a loss of protein homeostasis and cellular senescence. In thanking Hevolution for their funding, Kapahi added, “It’s crucial that we understand the hierarchy of these detrimental processes. What comes first? Where should we target interventions? Glycation burden connects all three of these hallmarks giving us a unique opportunity to expand our understanding of age-related pathology.”

Kapahi’s team will investigate the connection between MGO-induced protein glycation, insulin resistance and cellular senescence in the context of type 2 diabetes. The first aim is focused on investigating the direct role of MGOs in regulating insulin synthesis and secretion. Pancreatic β-cells from mice will be used to mechanistically assess the cell-autonomous effect of different doses of GLYLO, a novel glycation-reducing compound on glucose metabolism and insulin synthesis. The second aim is directed at investigating the role of various dosages of dietary MGOs in regulating glucose homeostasis and insulin resistance in fat tissue, while validating targets that might ameliorate the resulting damage.

The team will bring the research together by investigating the interplay between MGO-induced protein glycation, insulin resistance and cellular senescence. “One hypothesis is that in overweight people type 2 diabetes is driven by inflammation caused by cellular senescence in belly fat,” said Kapahi. “Type 2 diabetes can also be driven in the pancreas. What’s the connection? Does senescence in the fat tissue also affect insulin secretion in the pancreas? What comes first?” Kapahi’s team will also test a senolytic drug to see if reducing the burden of senescent cells has an impact on MGO-mediated insulin resistance and release. They will also combine treatment with a senolytic and glycation-reducing GLYLO to determine if alleviating two hallmarks of aging, protein homeostasis and senescence, can show additional protection to lower insulin resistance and enhance survival in mice on a high fat diet.

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I’m glad they got funding for this. However, I am not a fan of them testing GLYLO as a means to examine the effects of glycation. First of all because I don’t think GLYLO is necessary primarily a glycation inhibitor, therefore any effects caused by GLYLO cannot necessarily be intepreted as being a result of reduced glycation. Note that we already know that lipoic acid, which is one of the main ingredients in GLYLO, improves insulin sensitivity, so if GLYLO were to improve insulin sensitivity, that effect would likely be caused primarily by the lipoic acid and have nothing directly to do with glycation. GLYLO is effectively similar to a dirty drug with various effects and targets. That must be kept in mind when interpreting the results.

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