Scientists have been closely studying the impacts of the ketogenic diet (KD), a regimen high in fats and low in carbohydrates that shifts the body to use ketones as its primary energy source. While KD is lauded for its potential benefits, including weight loss, improved epilepsy management, and possible neuroprotective effects, a recent study conducted by Sung-Jen Wei and colleagues published in "Science Advances" on May 17, 2024, unwraps some unforeseen consequences involving cellular senescence and aging.

The research team demonstrated that a KD, regardless of its specific fatty acid makeup—whether it's based on Crisco or cocoa butter—precipitates cellular senescence in multiple organs, including the heart and kidneys. These effects are not reliant on the subject's age as mice, ranging from young to old, showed similar senescence markers when fed with a KD for 21 days.

These outcomes are believed to cascade from the activation of adenosine monophosphate–activated protein kinase (AMPK), leading to inactivation of MDM2—a key regulator of the p53 tumor suppressor pathway—and consequent accumulation of p53 protein with the induction of cellular senescence.

Interestingly, the researchers found that cellular senescence was accompanied by heightened levels of the senescence-associated secretory phenotype (SASP)—markers of inflammation—in both mice on the KD and human patients participating in a KD clinical trial, suggesting a potentially pro-inflammatory state induced by sustained KD.

Further experimentation with genetically modified mice lacking p53 or caspase-2 and with mice treated with inhibitors to AMPK, p21 (cell cycle regulator), and caspase-2 (caspase involved in MDM2 processing) solidified p53 and caspase-2's pivotal roles in KD-induced cellular senescence.

Nonetheless, the study brings good news—interventions such as senolytics, that clear senescent cells, and an intermittent KD may mitigate these adverse effects, offering new avenues for the dietary regimen's application in clinical practice.

In essence, while the KD has shown promise in treating certain conditions and aiding in weight loss, it also carries implications for increased cellular aging and may need to be tailored on an individual basis. These findings open up important discussions for considering KD within the scope of personalized medicine.

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Jeff Caba, DHSc, PA-C.

Jeff brings to Buoy over 20 years of clinical experience as a physician assistant in urgent care and internal medicine. He also has extensive experience in healthcare administration, most recently as developer and director of an urgent care center. While completing his doctorate in Health Sciences at A.T. Still University, Jeff studied population health, healthcare systems, and evidence-based medi...

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References

Wei, S.-J., Schell, J. R., Chocron, E. S., Varmazyad, M., Xu, G., Chen, W. H., Martinez, G. M., Dong, F. F., Sreenivas, P., Trevino, R. Jr., Jiang, H., Du, Y., Saliba, A., Qian, W., Lorenzana, B., Nazarullah, A., Chang, J., Sharma, K., Munkácsy, E., Horikoshi, N., Gius, D. (2024). Ketogenic diet induces p53-dependent cellular senescence in multiple organs. Science Advances, 10(20), eado1463.