Why This Matters to Us
As longevity enthusiasts, we are always on the lookout for ways to extend not only lifespan but also healthspan—the years we spend living free of disease and frailty. This study highlights a fascinating potential breakthrough: a diabetes drug already in clinical use could help combat the processes of aging at a cellular level.
The possibility of repurposing an existing drug to reduce frailty, slow down cellular aging, and improve lifespan is exciting and holds promise for accelerating the availability of anti-aging therapies. Additionally, glibenclamide’s potential to improve mitochondrial function and reduce key signs of cellular aging makes it a significant development in the longevity field.
The Detail
A recent study published in the journal Signal Transduction and Targeted Therapy revealed that glibenclamide, a drug commonly used to treat type 2 diabetes, could have surprising effects on aging. The researchers explored how this drug impacts cellular senescence—the process by which cells stop dividing and contribute to aging and inflammation.
How Aging and Cellular Senescence Work
At the centre of this study is the relationship between histone proteins and aging. Histones are key parts of our DNA packaging system, and they influence which genes are turned "on" or "off." Specifically, the histone changes named H3K4me3 and H3K27me3 play opposing roles in the aging process. H3K4me3 activates genes tied to aging (like p21 and p16), while H3K27me3 silences these genes.
Think of it like a traffic light system: H3K4me3 keeps the light green for aging-related processes, and H3K27me3 puts up a red light to stop them. Problems arise when the green light shines too often with age, and cellular senescence accelerates.
Research has shown that instead of directly fixing these histones (which is challenging), targeting metabolism can influence them indirectly. Since histones are closely tied to how the body uses energy and nutrients, drugs like glibenclamide can tweak this metabolic system.
Why Glibenclamide Is Important
In their earlier work, the researchers noticed that a related compound (chlorpropamide) reversed signs of aging in worms. Building on this, they investigated how glibenclamide might act in more complex organisms.
Starting in human lung cells, the team discovered that a key protein, MDH2, was involved. MDH2 is essential in energy production inside cells, especially in mitochondria—the "power plants" of our cells. When MDH2 was suppressed, key markers of senescence, including SA-β-gal and p16, decreased. When it was boosted, the opposite happened, confirming that MDH2 significantly impacts aging.
Among the diabetes drugs tested, glibenclamide had the strongest effect on MDH2, substantially reducing cellular aging markers. The drug was even reported to lower specific inflammatory signals (a hallmark of aging), like interleukin IL-1β, that were unaffected by other diabetes drugs like metformin.
Effects on Mice and Longevity
The researchers then moved to tests in mice, a well-known model for studying human aging. They gave glibenclamide to a group of middle-aged mice and compared them to those receiving either NMN (a popular longevity supplement) or no treatment.
Remarkably, the mice on glibenclamide experienced reduced frailty as they aged. By the end of the study, they lived significantly longer than their untreated peers.
Of course, durability and quality of life are just as essential as longevity. Another test on older mice revealed that glibenclamide also decreased liver fibrosis—a scarring process linked to aging—and reduced cellular senescence in liver cells. Interestingly, while it increased certain protective histones like H3K27me3, it didn’t affect others like H3K9me3, showing that its influence is selective and targeted.
Unexpected Findings: Mitochondrial Oxidative Stress
While glibenclamide had many positive effects, the study highlighted an unexpected downside. In human lung cells, the drug caused a spike in reactive oxygen species (ROS)—damaging molecules that result from oxygen metabolism. This happened because the drug altered the mitochondria's energy production cycle, forcing cells to use oxygen-burning pathways.
Although increased ROS is generally harmful, the researchers believe this side effect is essential to glibenclamide’s benefits. The drug interferes with the methionine cycle—a process critical to histone methylation—and this may outweigh the negatives of increased ROS.
What Next?
While promising, this research remains in its early stages, focusing primarily on mice and human cells. The next step will be to examine how glibenclamide affects aging in humans before it can be officially repurposed as an anti-aging therapy.
Since glibenclamide is already an FDA-approved and widely prescribed drug, clinical trials may face fewer regulatory hurdles. The researchers also suggest that tailoring glibenclamide or creating new drugs targeting MDH2 might lead to even better results.
This study provides hope that solutions to cellular senescence and aging could be closer than we think, bringing us one step closer to a future where healthspan and lifespan significantly increase.