Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence

  • Cell Rep. 2025 Aug 26;44(8):116026. doi: 10.1016/j.celrep.2025.116026.
Sung-Jen Wei  1 ,  Joseph Schell  1 ,  Wei Qian  2 ,  Martin Silguero  2 ,  Agne Baseviciene  2 ,  Wan Hsi Chen  1 ,  Rolando Trevino Jr  1 ,  E Sandra Chocron  1 ,  Meredith M Ogle  1 ,  Mahboubeh Varmazyad  1 ,  Gloria M Martinez  1 ,  Diego Cruz  1 ,  Brandon Lorenzana  1 ,  Felix F Dong  1 ,  Haiyan Jiang  1 ,  Alia Nazarullah  3 ,  Robert A Beardsley  4 ,  Kumar Sharma  5 ,  Jenny Chang  2 ,  Erin Munkácsy  1 ,  Nobuo Horikoshi  1 ,  David Gius  6
Affiliations
  • 1. Department of Radiation Oncology, Mays Cancer Center at UT Health San Antonio MD Anderson, Joe R. and Teresa Lozano Long School of Medicine, San Antonio, TX, USA; Barshop Institute for Longevity and Aging Studies, UT Health San Antonio, San Antonio, TX, USA.
  • 2. Houston Methodist Cancer Center, Houston, TX, USA; Houston Methodist Research Institute, Houston, TX, USA.
  • 3. Department of Pathology, UT Health San Antonio, San Antonio, TX, USA.
  • 4. Galera Therapeutics, Inc., 45 Liberty Boulevard, Suite 230, Malvern, PA, USA.
  • 5. Center for Precision Medicine, UT Health San Antonio, San Antonio, TX, USA; Division of Nephrology, Department of Medicine, UT Health San Antonio, San Antonio, TX, USA.
  • 6. Department of Radiation Oncology, Mays Cancer Center at UT Health San Antonio MD Anderson, Joe R. and Teresa Lozano Long School of Medicine, San Antonio, TX, USA; Barshop Institute for Longevity and Aging Studies, UT Health San Antonio, San Antonio, TX, USA. Electronic address: [email protected].
PMID: 40682777 DOI: 10.1016/j.celrep.2025.116026
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.
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