Buck Institute team shows that reducing glycation can extend lifespan in mice and may translate to human metabolic health.
The same chemical process that turns toast golden brown also takes place in our bodies, with far less appetizing results. Glycation – the non-enzymatic binding of sugars to proteins, lipids and DNA – produces sticky advanced glycation end-products (AGEs) that accumulate over time, disrupting molecular structure and driving chronic inflammation.
Researchers at the Buck Institute for Research on Aging believe this chemistry can be slowed. Their newly published Cell Reports paper describes how a mix of five glycation-lowering compounds, dubbed Gly-Low, reduced food intake, improved glucose balance and extended lifespan in mice – even when treatment began late in life. The study, led by Professor Pankaj Kapahi and colleagues, links metabolic control, hunger signalling and longevity through modulation of the hypothalamus, the brain’s energy-regulating hub [1].
Longevity.Technology: Glycation has long been the biochemical elephant in the room – the sticky, browning chemistry we’d rather not think about as our proteins slowly caramelize. Yet, the Kapahi lab’s work on Gly-Low makes it difficult to keep ignoring. By lowering methylglyoxal and other glycation products, these compounds appear to unpick part of the metabolic knot that ties together aging, appetite and insulin resistance. It’s elegant work, suggesting that the cellular ‘rust’ of glycation may be not only measurable but modifiable – and that tackling it could move the late-life needle in ways caloric restriction and clean living no longer can. Gly-Low’s multi-compound synergy – nicotinamide, α-lipoic acid, thiamine, pyridoxamine and piperine acting together rather than alone – hints that aging may demand combination therapy rather than a single silver bullet.
That Gly-Low works even when introduced to mice in their dotage is especially intriguing; geroscience rarely gives us interventions that arrive fashionably late and still make an impact. If these results translate, the implications reach beyond one compound cocktail – they hint at a broader shift in thinking, from managing aging’s sequelae to editing its chemistry. Glycation has always lurked in the background of the hallmarks of aging, present but unglamorous; perhaps it deserves promotion to a more central role. The study also blurs the lines between metabolic disease and aging biology – a reminder that obesity and senescence are often fellow travellers on the same biochemical road. Of course, we’ve been singed by murine miracles before, and glycation’s complexity resists easy victories; but as metabolic and neuroendocrine control begin to converge in the lab, this line of research may mark the start of something less sugary and far more substantial.
Unpicking hunger’s signal
The authors report that Gly-Low reduced levels of methylglyoxal (MGO), a reactive by-product of glycolysis and a key precursor to AGEs. Mice given Gly-Low ate less food, lost body fat while retaining muscle mass, and displayed improved insulin sensitivity. Importantly, their metabolic rate did not fall, suggesting that appetite regulation, not energy expenditure, drove the effects [1].
Postdoctoral fellow Kiyomi Kaneshiro found that the compounds acted on ghrelin signalling – ghrelin being the so-called ‘hunger hormone’ – within the hypothalamus. “Gly-Low shifted the balance away from ‘feed me’ signals toward satiety,” she says. “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.”
At the molecular level, the combination appeared to suppress activation of AMP-activated protein kinase (AMPK) while enhancing mTOR/S6 signalling in the hypothalamus – a pattern associated with reduced hunger and improved energy homeostasis. The authors note that ghrelin-stimulated food intake was blunted in Gly-Low-treated mice, confirming that hypothalamic control of appetite had been altered rather than bypassed [1].
Late-life benefit
Perhaps the most striking data came from late-life experiments. When treatment began at 24 months – roughly equivalent to a human age of seventy – the remaining lifespan of the mice increased by nearly 60 percent. The older animals also showed better glucose control and motor coordination.
Senior author Pankaj Kapahi says the results challenge the belief that metabolic interventions must begin early to work. “Once formed, AGEs are hard to remove,” he explains. “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.”
Each of the compounds in the Gly-Low mixture – nicotinamide, α-lipoic acid, thiamine, pyridoxamine and piperine – has prior links to metabolism or antioxidant pathways. Kapahi believes their combination is key. “Individually some of these compounds can modestly affect appetite or glucose balance,” he says. “But together they act synergistically to dramatically reduce glycation stress and alter feeding behavior.”
From bench to bedside
While the data are compelling, translation to humans will require care. The Buck Institute is now launching the GAP (Gly-Low Aging Pilot) study, a small double-blind, placebo-controlled trial in which participants will take the supplement for twelve weeks. The team will monitor changes in glycation biomarkers, glucose control and other metabolic indicators to assess feasibility for larger clinical studies.
Kaneshiro says the move into human testing is a critical step. “By examining the effects of glycation-lowering therapies in people, we will obtain crucial data needed for translation of geroscience discoveries into clinical interventions.”
The study will also provide early safety and tolerance data for the Gly-Low formulation, which is closely related to GLYLO, a supplement licensed by Buck to Juvify Bio – a commercial link openly disclosed in the paper.
Bridging metabolic and aging research
The potential of glycation control reaches beyond metabolic disease. AGEs have been implicated in neurodegeneration, kidney disease and vascular stiffness – all hallmarks of aging tissues. Reducing their accumulation could, in principle, modulate multiple aging pathways at once. The paper’s authors suggest that lowering glycation might reduce not only damage formation but also restore cellular detoxification and proteostasis capacity, helping tissues maintain function for longer [1].
If borne out in humans, glycation-lowering strategies could join a growing toolkit that includes senolytics, mitochondrial modulators and caloric restriction mimetics. Unlike most interventions, Gly-Low operates through appetite regulation and hypothalamic signalling – a central node rather than a downstream repair mechanism.
Chemistry, appetite and time
The biology of aging rarely yields to single-pathway explanations; yet, as glycation emerges from the background, it offers a bridge between metabolic regulation, nutrient sensing and cellular maintenance. Whether Gly-Low will prove effective in people remains to be seen, but it has already expanded the conversation – from sugar control to age control, and from metabolic clean-up to the chemistry of longevity.
[1] https://www.cell.com/cell-reports/fulltext/S2211-1247(25)01193-3
