Research shows ketogenic diets may spark damaging cellular changes in males but not females, pointing to estrogen’s protective role. These results hint at deeper, sex-specific effects of the diet that could shape its clinical use. Credit: Shutterstock

Estrogen protected female mice from harmful effects of a keto diet that affected males.

Could males and females respond differently to a ketogenic diet? Research from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) indicates that they might, with estrogen appearing to shield females from some of the harmful effects, including the build-up of cells showing signs of aging, known as senescence.

The findings showed that male mice on a ketogenic diet developed senescent cells in their organs, while female mice did not. The ketogenic diet, which is high in fat and low in carbohydrates, is widely used to help people with Type 2 diabetes regulate blood sugar and to manage seizures in epilepsy. However, the presence of senescent cells is linked to age-related declines in tissue and organ function.

“These results suggest sex specificity alters the effects of a ketogenic diet, with important clinical implications,” said David Gius, MD, PhD, assistant dean of research and professor with the Department of Radiation Oncology at UT Health San Antonio, associate cancer director for translational research at the institution’s Mays Cancer Center and investigator for its Barshop Institute for Longevity and Aging Studies.

He is the lead author of the study, which was published in the journal Cell Reports.

Broader context of keto diets

Ketogenic diets trigger ketogenesis, a process in which the body produces ketone bodies—water-soluble molecules derived from fat—that serve as an alternative energy source to glucose. These diets have proven effective in managing drug-resistant epilepsy and are under study as potential treatments for several other medical conditions.

David Gius, MD, PhD. Credit: The University of Texas at San Antonio Health Science Center

Over the past few decades, ketogenic diets have also gained wide popularity in North America and Europe as a method for weight loss.

Although they can improve certain health measures, findings from animal research and human studies indicate that their impact may vary depending on several factors, such as consistency of use, individual metabolism, and notably, biological sex. This points to the possibility that hormone status plays a significant role in shaping outcomes.

Hormonal influence on outcomes

Gius says the role of gender in the response to keto diets has been understudied. One reason is that male mice have been used extensively for in vivo basic and translational research because it was assumed that females would give less consistent results due to variability from the estrous cycle. Recent studies, however, suggest that largely is unfounded.

In the new study, Gius’ team observed a keto-diet-induced increase in cellular senescence only in male mice, except when they were given the female hormone estrogen. Male mice on a keto diet also exhibited an increase in markers of oxidative stress, which is known to contribute to senescence in cells.

Estrogen’s protective role

Notably, the researchers found, estrogen or estradiol treatment prevented increases in cell senescence and oxidated stress in male mice on a keto diet, as did several established antioxidants.

They also observed that when females were administered tamoxifen, a “selective estrogen receptor inhibitor” that blocks the effects of estrogen, they then exhibited an increase in oxidative stress and cells expressing senescence markers, the same as male mice. “These results strongly suggest that estrogen is an important variable in the response to a ketogenic diet,” Gius said.

The researchers also found that a high-fat diet – comprising more carbohydrates than a keto diet – also induces cellular senescence in male, but not female, mice.

Reference: “Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence” by Sung-Jen Wei, Joseph Schell, Wei Qian, Martin Silguero, Agne Baseviciene, Wan Hsi Chen, Rolando Trevino, E. Sandra Chocron, Meredith M. Ogle, Mahboubeh Varmazyad, Gloria M. Martinez, Diego Cruz, Brandon Lorenzana, Felix F. Dong, Haiyan Jiang, Alia Nazarullah, Robert A. Beardsley, Kumar Sharma, Jenny Chang, Erin Munkácsy and David Gius, 17 July 2025, Cell Reports.
DOI: 10.1016/j.celrep.2025.116026

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