Study A long-term ketogenic diet accumulates aged cells in normal tissues (May 2024, mice) Ketogenic diet induces p53-dependent cellular senescence in multiple organs

Michael Harrop

Active member
Jul 6, 2023

"To put this in perspective, 13 million Americans use a ketogenic diet, and we are saying that you need to take breaks from this diet or there could be long-term consequences," said David Gius.


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.
Format correct?
  1. Yes