Aging

A Fast-Aging Fish Reveals How a Familiar Drug Preserves Youthful Kidney Function

A Fish That Ages in Months, Not Years

The African turquoise killifish is one of the fastest-aging vertebrates known, completing its entire lifespan in just a few months. In a breakthrough report in Kidney International, an international team of 13 scientists at MDI Biological Laboratory, Hannover Medical School and Colby College demonstrate that the fish’s physiological response to aging closely mirrors that of humans as they age — particularly with respect to classic hallmarks of kidney aging and disease.

Because the African turquoise killifish (ATK) condenses its lifetime into just four to six months, it offers biomedical researchers an exceptional new model for studying aging-related changes that normally take years to observe in mammals such as mice. This compressed timeline allows scientists to follow the full arc of organ aging and test interventions far more quickly.

Hermann Haller, M.D., the article’s senior author (and President of MDI Bio Lab) says the research exemplifies the Lab’s dual focus on basic research and real-world applications.

“We knew these fish could speed research on varied mechanisms of aging and on therapeutic pathways. And with sustained help from the Morris Discovery Fund, we were able to prove it.”

A Familiar Drug, Seen in a New Light

Once the researchers established the model, they were able to demonstrate its usefulness in less than two years of work, as documented in the new article. They developed a colony of killifish on the MDI Bio Lab campus, in the Kathryn W. Davis Center for Renegenerative Biology and Aging, combining classical pathology methods and cutting-edge molecular tools to study aging in the kidney. They then examined the effects of drugs that inhibit a protein called sodium-glucose cotransporter 2, or SGLT2.

At left, the kidney of a young, healthy African turquoise killifish (ATK) shows a dense and multi-branched capillary system. Center, as it ages kidney vasculature in a typical ATK loses density, with a reduction in the number of vessels and branches. But at right, kidneys of older fish that were treated over time with SGLT2 inhibitors retained a dense and multi-branched capillary system, similar to that seen in young, untreated fish. (Hannah Somers, Anastasian Paulmann, M.D., MDI Bio Lab)

The human health benefits of drugs that inhibit SGLT2 are well documented, which is why they are FDA-approved and widely prescribed for conditions such as diabetes-associated heart disease and chronic kidney disease (for example, Jardiance^® and Farxiga^®).  While their clinical benefits are clear, the biological mechanisms underlying those benefits have not been fully understood.

Clinically, SGLT2 inhibitors are already known to slow progression of chronic kidney disease in both diabetic and non-diabetic patients. This study suggests that their benefit may extend further upstream to the biological processes of kidney aging itself, reframing SGLT2 inhibitors as protectors of the aging kidney’s underlying functionality.

Protecting the Kidney’s Most Vulnerable Systems

Upstream effects seen in aging fish treated over time included the persistence of healthier blood vessel networks within the kidney — especially the tiniest vessels, or capillaries — while improving the integrity of the kidney’s filtration barrier. Treated fish also showed better management of cellular energy, stronger cell-to-cell communication and less inflammatory activity at the genetic level.

Together, these findings suggest that SGLT2 inhibitors may help preserve kidney structure and function by protecting the kidney’s blood supply and energy balance during aging, offering a mechanistic basis for their growing role in preventing age-related renal decline. The findings provide the first direct evidence that SGLT2 inhibition can help to preserve kidney structure and function during aging in a living vertebrate model.

“It’s long been thought though that SGLT2 inhibition operates mostly as a regulator of glucose levels in the blood stream,” Haller said. “These upstream effects align with clinical observations that benefits often exceed what would be expected from glucose control alone,” he continued. “They offer a unifying biological explanation for why SGLT2 inhibitors consistently reduce kidney and cardiovascular events across diverse patient populations.”

From Rapid Discovery to Human Health

Anastasia Paulmann, M.D., a former postdoctoral researcher at MDI Bio Lab, and the article’s first author, says she believes the African turquoise killifish now presents a significant new opportunity to speed investigations of the mysteries of aging and development of medical therapies to extend healthier lifespans.

“Seeing these effects emerge so clearly in a rapid-aging model like our killifish was striking,” Paulmann, who also holds a clinical position at Hannover Medical School. “What impressed me most was how a seemingly ‘simple’ drug influences so many interconnected systems within the kidney — from microvascular maintenance to inflammation, metabolism and overall function.”

One key insight from the study is that, in both killifish and humans, the loss of tiny blood vessels in aging kidneys is associated with a fundamental shift in how cells produce and manage energy. As capillaries are lost, kidney cells rely less on efficient, mitochondria-based energy production and more on less efficient backup pathways.

Among the most visually striking results are microscopy images showing that capillaries become fewer and farther between in untreated fish as they age — a process known as vascular rarefaction — while remaining noticeably denser and more intact in treated animals.

After documenting these structural changes, the researchers took a deep dive into the genetic mechanisms behind them, using tools that track which genes are turned on or off as aging progresses — an emerging field known as transcriptomics.

African Turquoise killifish at MDI Bio Lab. (Hannah Somers, Anastasian Paulmann, M.D.,MDI Bio Lab.)

They found that, as in aging human kidneys, loss of capillaries in older killifish was accompanied by changes in gene activity related to cellular energy use and inflammation. In contrast, fish treated with SGLT2 inhibitors retained a more “youthful transcriptional profile.” The sets of genes active in older treated animals more closely resembled those seen in younger fish and showed lower levels of inflammatory signaling than in untreated older animals.

Paulmann began her career as a clinical physician caring for patients recovering from kidney transplant surgery, and she says her work remains closely tied to patient needs.

“In the end, it’s whether you can take a finding like this from the lab to the clinic,” Paulmann says. “How can we make it as easy and accessible for as many people as possible?”

By enabling researchers to observe decades’ worth of kidney aging biology within months, Paulmann and the team have built a vertebrate aging model that serves as a fast, practical pipeline for evaluating how therapies affect organ resilience with age, helping to prioritize the most promising candidate drugs before they reach human trials.

She adds that new experiments planned to begin at MDI Bio Lab this spring will explore whether SGLT2 inhibition can help restore kidney tissue after age-related damage has already occurred, and how timing and treatment duration influence long-term outcomes.

That research will be made possible by the renovation and expansion of two MDI Bio Lab buildings to support the growing use of African turquoise killifish, as part of the Lab’s MDI Bioscience initiative focused on translational research.