Compound blend ‘Gly-Low’ is shown to slow ageing and reduce obesity in mouse models

A study has shown that a combination of common metabolic compounds – known as Gly-Low – reduced hunger, improved insulin sensitivity and extended lifespan in mice. The findings suggest that targeting glycation, the same chemical process responsible for the browning of toast, could lead to therapies to combat ageing and metabolic disease

The same chemical reaction that makes toasted bread smell good also occurs in the human body but with less desirable consequences. The Maillard reaction, in which sugars react with proteins to form brown, sticky compounds in a process known as glycation, is increasingly suspected to be a hidden driver of obesity, diabetes and accelerated ageing. Scientists at the Kapahi Laboratory, part of the Buck Institute of Novato, California have reported a way to mitigate this process in mouse models by feeding them a combination of glycation-lowering compounds.

In the study the team demonstrated that a combination of nicotinamide, α-lipoic acid, thiamine, pyridoxamine and piperine – collectively termed Gly-Low – reduced hunger, lowered insulin resistance and extended lifespan in mice. The treatment acted by reducing levels of advanced glycation end-products (AGEs), which are sticky, plaque-like molecules formed as a by-product of glycation.

“Once formed, AGEs are hard to remove. As we age, our defences against glycation weaken. Scientists have long suspected that AGEs accelerate many age-related diseases,” said Professor Pankaj Kapahi who compared it to rust on corroded iron.

“Our results provide strong proof of concept that glycation is not merely a bystander in ageing; it may be a modifiable target to help people live healthier, longer lives.”

The study was led by Lauren A. Wimer, a former graduate student, and postdoctoral fellow Dr Kiyomi Kaneshiro. Wimer investigated how Gly-Low influenced normal physiology and feeding behaviour in both diabetic and non-diabetic mice. She found that the compound combination affected hypothalamic ghrelin signalling, with ghrelin being the so-called ‘hunger hormone’. This led to a reduction in feeding behaviour, thereby diminishing glycation stress and counteracting obesity.

Kaneshiro examined the hypothalamic transcriptome of Gly-Low-treated mice and discovered that the combination altered signalling through the cellular energy sensor adenosine monophosphate-activated protein kinase (AMPK), activating the mammalian target of rapamycin/S6 (mTOR/S6) pathway in the hypothalamus.

“Gly-Low shifted the balance away from ‘feed me’ signals towards satiety,” said Kaneshiro.

“The effect was profound; the mice voluntarily ate less food while maintaining muscle mass. Our data suggest that, rather than simple food aversion, the biology of hunger was being rewired.”

The treated mice also showed lower fasting and random blood glucose levels, improved insulin sensitivity and reduced fat accumulation in their livers.

Professor Kapahi stated that one of the most promising outcomes of the research was Gly-Low’s efficacy when introduced late in life. In one set of experiments, Kaneshiro began treatment in mice aged 24 months, equivalent to roughly 70 years in humans. According to Kapahi, the compounds enabled older mice to regulate blood sugar surges more effectively. The ageing animals also demonstrated enhanced motor coordination and longer lives, with Gly-Low extending their remaining lifespan by nearly 60 per cent.

“What is remarkable here is that caloric restriction, the gold standard longevity intervention, usually fails to extend lifespan if started late in life. Gly-Low, by contrast, succeeded,” said Kapahi.

“That suggests its effects go beyond simply eating less; it appears to reverse some of the molecular hallmarks of hypothalamic ageing itself.”

He added that transcriptomic analyses revealed that genes which typically change with age were shifted back towards youthful expression patterns in Gly-Low-treated mice.

Kapahi explained that each compound in the Gly-Low formulation is known to influence metabolism or glycation to some extent.

“Individually, some of these compounds can modestly affect appetite or glucose balance. But together, they act synergistically to dramatically reduce glycation stress and alter feeding behaviour,” he said.

Extending his analogy with toast, Kapahi remarked that the older people become, the more ‘browned’ their biology tends to be. He expressed hope that Gly-Low might alleviate some of that internal ‘toasting’, while acknowledging that the research remains at an early stage.

“Mice are not humans, and we need rigorous human trials before any clinical use,” he said.

“But the implications are broad. Many age-related diseases, from Alzheimer’s to kidney disease, are associated with high levels of AGEs. If glycation can be safely targeted, it may open doors to treat a spectrum of conditions at once.”

For further reading please visit: 10.1016/j.celrep.2025.116422