Ketogenic diet induces p53-dependent cellular senescence in multiple organs

Sung Jen Wei, Joseph R. Schell, E. Sandra Chocron, Mahboubeh Varmazyad, Guogang Xu, Wan Hsi Chen, Gloria M. Martinez, Felix F. Dong, Prethish Sreenivas, Rolando Trevino, Haiyan Jiang, Yan Du, Afaf Saliba, Wei Qian, Brandon Lorenzana, Alia Nazarullah, Jenny Chang, Kumar Sharma, Erin Munkácsy, Nobuo HorikoshiDavid Gius

Research output: Contribution to journalArticlepeer-review


A ketogenic diet (KD) is a high-fat, low-carbohydrate diet that leads to the generation of ketones. While KDs improve certain health conditions and are popular for weight loss, detrimental effects have also been reported. Here, we show mice on two different KDs and, at different ages, induce cellular senescence in multiple organs, including the heart and kidney. This effect is mediated through adenosine monophosphate–activated protein kinase (AMPK) and inactivation of mouse double minute 2 (MDM2) by caspase-2, leading to p53 accumulation and p21 induction. This was established using p53 and caspase-2 knockout mice and inhibitors to AMPK, p21, and caspase-2. In addition, senescence-associated secretory phenotype biomarkers were elevated in serum from mice on a KD and in plasma samples from patients on a KD clinical trial. Cellular senescence was eliminated by a senolytic and prevented by an intermittent KD. These results have important clinical implications, suggesting that the effects of a KD are contextual and likely require individual optimization.

Original languageEnglish (US)
Article numbereado1463
JournalScience Advances
Issue number20
StatePublished - May 2024

ASJC Scopus subject areas

  • General


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