Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence
Summary: 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...
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Elsevier
2025-08-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725007971 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Sung-Jen Wei |
| collection | DOAJ |
| description | Summary: 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. |
| format | Article |
| id | doaj-art-35f634c44fa5424fa75b7ac36b7bbc29 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-35f634c44fa5424fa75b7ac36b7bbc292025-08-20T03:51:09ZengElsevierCell Reports2211-12472025-08-0144811602610.1016/j.celrep.2025.116026Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescenceSung-Jen Wei0Joseph Schell1Wei Qian2Martin Silguero3Agne Baseviciene4Wan Hsi Chen5Rolando Trevino, Jr.6E. Sandra Chocron7Meredith M. Ogle8Mahboubeh Varmazyad9Gloria M. Martinez10Diego Cruz11Brandon Lorenzana12Felix F. Dong13Haiyan Jiang14Alia Nazarullah15Robert A. Beardsley16Kumar Sharma17Jenny Chang18Erin Munkácsy19Nobuo Horikoshi20David Gius21Department 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, USADepartment 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, USAHouston Methodist Cancer Center, Houston, TX, USA; Houston Methodist Research Institute, Houston, TX, USAHouston Methodist Cancer Center, Houston, TX, USA; Houston Methodist Research Institute, Houston, TX, USAHouston Methodist Cancer Center, Houston, TX, USA; Houston Methodist Research Institute, Houston, TX, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment of Pathology, UT Health San Antonio, San Antonio, TX, USAGalera Therapeutics, Inc., 45 Liberty Boulevard, Suite 230, Malvern, PA, USACenter for Precision Medicine, UT Health San Antonio, San Antonio, TX, USA; Division of Nephrology, Department of Medicine, UT Health San Antonio, San Antonio, TX, USAHouston Methodist Cancer Center, Houston, TX, USA; Houston Methodist Research Institute, Houston, TX, USADepartment 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, USADepartment 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, USADepartment 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; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124725007971CP: Metabolism |
| spellingShingle | 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 Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence Cell Reports CP: Metabolism |
| title | Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence |
| title_full | Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence |
| title_fullStr | Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence |
| title_full_unstemmed | Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence |
| title_short | Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence |
| title_sort | divergent sex specific effects on a ketogenic diet male but not female mice exhibit oxidative stress and cellular senescence |
| topic | CP: Metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725007971 |
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