Study Highlights Sex-Specific Impact of Keto Diet
A recent study from the lab of David Gius, MD, PhD, and published in Cell Reports reveals that a long-term ketogenic diet leads to the accumulation of aging (senescent) cells and oxidative stress—but only in male mice. Female mice did not show these harmful effects. Interestingly, treating male mice with estrogen or antioxidants prevented these negative outcomes.
Key takeaway: The research underscores the importance of considering biological sex and hormonal status when evaluating the effects of ketogenic diets—suggesting that females may experience protective benefits that males do not.
Dr. Gius is 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 at the Sam and Ann Barshop Institute for Longevity and Aging Studies.
Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence
Sung-Jen Wei, Joseph Schell, Wei Qian, Martin Silguero, Agne Baseviciene, Wan Hsi Chen, Rolando Trevino Jr, 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, Nobuo Horikoshi, David Gius
Cell Rep. 2025 Jul 17;44(8):116026. doi: 10.1016/j.celrep.2025.116026. Online ahead of print.
Abstract:
While a ketogenic diet (KD) can improve certain health parameters, evidence from murine and clinical studies suggests that these effects may be dependent on multiple variables. One understudied variable is the role of sex in the response to a KD. Here, we show that a KD-induced increase in p53, p21, and cellular senescence is only observed in male mice, except when they are given estrogen, and in female mice administered tamoxifen. Male, but not female, mice on a KD exhibit an increase in markers of oxidative stress and acetylation of mitochondrial proteins, including manganese superoxide dismutase (MnSOD). Notably, the increases in p53, p21, cellular senescence, MnSOD acetylation, and oxidative stress in male mice on a KD were all prevented by estrogen treatment. In addition, several established antioxidants and an MnSOD chemical mimetic also prevented KD-induced cellular senescence. These results suggest sex specificity in the effects of a KD, with important clinical implications.
Keywords: CP: Metabolism; MnSOD; SOD2; acetylation; antioxidant; cellular senescence; estrogen; ketogenic diet; oxidative stress; sex difference.