Ketogenic diet induces p53-dependent cellular senescence in multiple organs.
Level 5 - mechanism / opinion, no new human data
Preclinical animal mechanistic study with correlative human plasma biomarker analysis
PubMed 38758782 · doi:10.1126/sciadv.ado1463
What was done
Mice of varying ages were placed on two different ketogenic diets to evaluate cellular senescence across multiple organs, including heart and kidney. The molecular pathway was interrogated using p53 and caspase-2 knockout mice alongside pharmacological inhibitors of AMPK, p21, and caspase-2. Senescence-associated secretory phenotype (SASP) biomarkers were assayed in mouse serum and human plasma samples from an existing ketogenic diet clinical trial. Interventions including a senolytic agent and intermittent ketogenic feeding schedules were tested in mice.
What was found
Ketogenic diets induced organ cellular senescence via an AMPK and caspase-2-dependent inactivation of MDM2, driving p53 accumulation and p21 induction. SASP biomarkers increased in both mouse serum and human plasma. Cellular senescence was cleared with a senolytic and prevented by an intermittent ketogenic diet regimen. The abstract reported no specific numerical values, sample sizes, or effect estimates.
Why it matters
This study highlights a potential risk of continuous ketogenic dieting through pro-senescent signaling in vital organs, suggesting continuous regimens may require optimization or intermittent schedules.
Limits
The mechanistic evidence is primarily derived from animal models, and human data are limited to circulating biomarker measurements from an unspecified clinical trial sample size. No numerical data, confidence intervals, or clinical outcomes are provided in the abstract.
Cited by
- supports A 2024 mouse study found that a continuous ketogenic diet drove cellular senescence in heart and kidney tissues through the p53 molecular pathway, while intermittent ketogenic feeding did not.