SGLT2 Inhibitors Slow Kidney Aging in Rapid-Aging Fish

In a new study published in Kidney International, researchers report that drugs known as SGLT2 inhibitors prevented age-related deterioration of kidney structure and function in the African turquoise killifish, a vertebrate that completes its entire lifespan in just a few months. The findings reveal specific biological mechanisms that may help explain why these drugs consistently protect kidney and cardiovascular health in people, beyond their original role in lowering blood sugar.

The work establishes the African turquoise killifish as a powerful new model for studying how organs age—and for testing therapies that may help maintain organ resilience as the body grows older.

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A Fish That Ages in Months, Not Years

The African turquoise killifish is one of the fastest-aging vertebrates known, completing its full lifespan in four to six months. In the new study, an international team of 13 scientists from MDI Biological Laboratory, Hannover Medical School, and Colby College showed that the fish’s kidneys undergo structural and functional changes with age that closely mirror those seen in humans.

These include loss of tiny blood vessels, breakdown of the kidney’s filtration barrier, increased inflammation, and disruptions in how kidney cells generate and manage energy—classic hallmarks of kidney aging and disease.

Because the killifish compresses decades of human-like kidney aging into a matter of months, the model allows researchers to observe the full arc of organ aging and evaluate interventions far more quickly than is possible in longer-lived animals such as mice.

A Familiar Drug, Seen in a New Light

Once the researchers established the killifish aging model, they used it to examine the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors—a class of drugs widely prescribed to treat diabetes-associated heart disease and chronic kidney disease.

“These drugs are already known to protect the heart and kidneys in patients with and without diabetes,” said Hermann Haller, M.D., senior author of the study and President of MDI Biological Laboratory. “What has been less clear is how they do so.”

The team found that killifish treated with SGLT2 inhibitors retained healthier kidney structure as they aged, including denser networks of tiny blood vessels called capillaries, improved integrity of the kidney’s filtration barrier, and more stable cellular energy production.

Importantly, the treatment also preserved communication between different kidney cell types and reduced age-associated inflammatory signaling at the genetic level.

“Together, these upstream effects provide a biological explanation for clinical observations that the benefits of SGLT2 inhibitors often exceed what would be expected from glucose control alone,” Haller said. “They help explain why these drugs consistently reduce kidney and cardiovascular events across diverse patient populations.”

Protecting the Kidney’s Most Vulnerable Systems

Age-related loss of capillaries—known as vascular rarefaction—emerged as a central feature of kidney decline in untreated fish. As these vessels disappeared, kidney cells shifted away from efficient, mitochondria-based energy production toward less efficient backup pathways.

By contrast, kidneys from SGLT2-treated fish retained healthier capillary networks and showed gene-expression patterns that more closely resembled those of younger animals. These “youthful transcriptional profiles” were associated with improved energy metabolism and lower inflammatory activity.

Taken together, the results provide direct evidence that SGLT2 inhibition can preserve kidney structure and function during aging in a living vertebrate model.

From Rapid Discovery to Human Health

The study’s first author, Anastasia Paulmann, M.D., a former postdoctoral researcher at MDI Bio Lab who also holds a clinical position at Hannover Medical School, established and raised the new killifish colony in the Lab’s Kathryn W. Davis Center for Regenerative Biol0gy and Aging. She says the killifish model offers a new way to accelerate aging research with direct relevance to human health.

“Seeing these effects emerge so clearly in a rapid-aging model like our killifish was striking,” Paulmann said. “What impressed me most was how a seemingly simple drug influences so many interconnected systems within the kidney—from blood vessels and energy metabolism to inflammation and overall function.”

By allowing researchers to observe decades’ worth of kidney aging biology within months, the model provides a fast, practical pipeline for evaluating how existing or experimental therapies affect organ resilience with age—helping to prioritize the most promising candidate drugs before they advance to human trials.

The team is now planning follow-up studies to investigate whether SGLT2 inhibition can help restore kidney tissue after age-related damage has already occurred, and how the timing and duration of treatment influence long-term outcomes.

That work will be supported by the renovation and expansion of laboratory facilities at MDI Bio Lab, as part of the institution’s MDI Bioscience initiative focused on translating fundamental discoveries into strategies that improve human health.

Reference: Paulmann A, Cox MD, Boewer T, et al. Sodium-glucose co-transporter 2 inhibition improves age-dependent kidney microvascular rarefaction. Kidney Int. 2025:S0085253825010208. doi: 10.1016/j.kint.2025.12.011

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