A blend of natural compounds that blocks sugar damage extended lifespan in mice by curbing hunger and improving metabolism in a new study. It hints at a new way to fight obesity, diabetes, and aging without cutting calories.
While it’s a natural chemical reaction, glycation occurs when sugar molecules bind to proteins, fats, or DNA, forming “sticky” harmful compounds called advanced glycation end-products (AGEs) that are thought to drive diabetes, obesity, and aging.
New research led by the Buck Institute for Research on Aging (Buck Institute), California, has tested how a compound made of five natural substances known for their glycation-reducing properties could reduce AGEs, improve metabolic health, and possibly extend lifespan.
“Once formed, AGEs are hard to remove,” said Professor Pankaj Kapahi, PhD, head of the Kapahi Lab at the Buck Institute and the study’s corresponding author. “As we age, our defenses against glycation weaken. Scientists have long suspected that AGEs accelerate many age-related diseases. Our results provide a strong proof-of-concept that glycation isn’t just a bystander in aging; it may be a modifiable target to help people live healthier, longer lives.”
Out in the world, when sugars and proteins interact (usually under heat), that’s what gives us the rich brown color and familiar taste and aroma of toast, seared steak and roasted coffee beans. It’s called the Maillard reaction, and when it happens outside the body, it’s good. Inside the body, though, the Maillard reaction can be problematic. It happens slowly and without heat, as sugars attach themselves to proteins or fats in the blood and tissues. This forms AGEs that, over time, build up and damage cells, blood vessels and organs, contributing to aging and diseases such as diabetes, Alzheimer’s, and cardiovascular disease.
For the present study, the researchers screened 640 natural compounds and found that combining five of them – nicotinamide (a form of vitamin B3), ⍺-lipoic acid (ALA), thiamine (vitamin B1), pyridoxamine (a form of vitamin B6), and piperine – best reduced glycation damage in cell tests done in the lab. They called the mix Gly-Low.
Mice prone to obesity and diabetes were fed Gly-Low for 16 weeks, over which time the researchers measured blood levels of methylglyoxal (MGO) and MG-H1, both harmful byproducts of glycation, alongside food intake, body weight, fat and muscle mass, and blood sugar levels.
In a separate experiment, both male and female healthy mice were given Gly-Low for weeks to months, and the scientists analyzed gene and protein changes in the hypothalamus, hunger-related hormone levels (ghrelin, leptin), glucose and insulin tolerance, and longevity. The hypothalamus is a region of the brain that controls appetite and metabolism.
The researchers found that Gly-Low cut MGO by around 60% and MG-H1 by around 40% in diabetic mice, confirming it lowers glycation stress caused by the formation of AGEs. Mice on Gly-Low also ate less and lost mainly fat, while retaining their muscle mass. These effects weren’t due to increased activity or metabolism; the mice simply appeared to be less hungry. Diabetic mice on Gly-Low had lower fasting blood sugar and less kidney damage. Healthy older mice also showed better glucose control and a stronger insulin response.
Gly-Low didn’t cause food aversion or make food taste bad. It blocked ghrelin signaling, the “hunger hormone” that usually triggers eating. It also inhibited a hunger-promoting enzyme, AMPK, and activated a biological pathway that is linked to fullness and protein synthesis. This brain signaling pattern reduced appetite independently of leptin, another satiety hormone.
“Gly-Low shifted the balance away from ‘feed me’ signals toward satiety,” said the study’s co-lead author, Kiyomi Kaneshiro, PhD, a postdoctoral research fellow. “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.”
When Gly-Low was given to old mice – the equivalent of around 70 human years – it increased lifespan by about 8% and improved coordination and movement. This was notable because most calorie-restriction methods don’t work when started late in life.
“What’s remarkable here is that caloric restriction, the gold-standard longevity intervention, usually fails to extend lifespan if started late in life,” Kapahi said. “Gly-Low, by contrast, succeeded. That suggests its effects go beyond just eating less – it is reversing some of the molecular hallmarks of hypothalamic aging itself.”
The principal limitation of the study is that results in mice don’t automatically apply to humans. Human metabolism and aging are more complex. In addition, most experiments were on male mice; results may differ in females due to hormonal differences. Although unlikely, the study didn’t run a formal “conditioned taste aversion” test, so it’s possible the mice disliked the food slightly. Finally, the specific contributions of each compound that made up Gly-Low weren’t fully separated.
Nonetheless, if similar effects are seen in humans, Gly-Low could help reduce appetite and weight gain naturally, without calorie counting. It could improve insulin sensitivity and blood sugar control, supporting diabetes prevention. And, it offers an aging intervention, potentially improving longevity and brain function.
However, it’s still early-stage research. The researchers recognize that human safety, dosing, and long-term effects would need extensive clinical testing.
“Mice are not humans, and we need rigorous human trials before any clinical use,” Kapahi said. “But the implications are broad. Many age-related diseases, from Alzheimer’s to kidney disease, have high levels of AGEs. If glycation can be safely targeted, it may open new doors to treating a spectrum of conditions at once.”
Several of the study’s authors, including Kapahi, declared a conflict of interest as patent holders of GLYLO, a supplement licensed to Juvify Bio. Kapahi is the founder of Juvify Bio.
The study was published in the journal Cell Reports.
