Ketogenic diet induces p53-dependent cellular senescence in multiple organs

Area of Science:

• Biochemistry
• Cell Biology
• Physiology

Background:

• Ketogenic diets (KD) are high-fat, low-carbohydrate diets known for weight loss and improving certain health conditions.
• However, potential detrimental effects of ketogenic diets require further investigation.
• Cellular senescence, a state of irreversible cell cycle arrest, is implicated in aging and age-related diseases.

Purpose of the Study:

• To investigate the impact of ketogenic diets on cellular senescence in multiple organs.
• To elucidate the molecular mechanisms underlying KD-induced senescence.
• To explore potential interventions for mitigating KD-associated senescence.

Main Methods:

• Mice were fed two different ketogenic diets at various ages.
• Analysis involved assessing cellular senescence markers in organs, utilizing knockout mice (p53, caspase-2), and employing specific inhibitors (AMPK, p21, caspase-2).
• Senescence-associated secretory phenotype (SASP) biomarkers were measured in mouse serum and human patient plasma from a KD clinical trial.

Main Results:

• Ketogenic diets induced cellular senescence in the heart and kidney of mice.
• This effect was mediated by the adenosine monophosphate-activated protein kinase (AMPK) pathway, caspase-2 inactivation of mouse double minute 2 (MDM2), leading to p53 accumulation and p21 induction.
• Elevated SASP biomarkers were observed in mice and humans on ketogenic diets, which was reversible with senolytics or an intermittent KD.

Conclusions:

• Ketogenic diets can promote cellular senescence through specific molecular pathways.
• Intermittent KD and senolytic treatments show potential for preventing or reversing KD-induced senescence.
• The findings highlight the contextual effects of ketogenic diets, emphasizing the need for personalized approaches.