Image by master1305 on Freepik

In recent years, the low-carb ketogenic diet (KD) has gained worldwide popularity for its weight loss benefits and specific health improvements. During the ketogenic diet (KD), minimal carbohydrate intake triggers the liver to produce ketones, which are then used as an alternative energy source. KD has been proven effective in treating refractory epilepsy and may also have beneficial effects on cancer and neurodegenerative diseases.

Furthermore, several studies using mouse models have shown that the ketogenic diet has anti-inflammatory properties, can promote longevity, improve middle-age health, optimize metabolism, and even combat obesity. However, on the other hand, there is also evidence suggesting that low-carbohydrate diets may exacerbate inflammation in mice and increase the risk of heart fibrosis and kidney damage. The mechanisms behind these differing results, which individuals might be at risk of adverse effects, or whether any interventions could mitigate these risks, remain inconclusive.

Current theories suggest that the beneficial or harmful effects of a ketogenic diet (KD) depend on specific variables of both the diet and the individual undergoing dietary intervention. Key factors include the person’s age, the duration of the diet, and its specific composition. Multiple studies indicate that the age at which dietary intervention begins can be crucial.

For instance, mice that started a KD at 12 months old showed reduced middle-age mortality, improved memory, and better skeletal muscle maintenance. In contrast, mice that began the diet at 3 weeks old exhibited developmental issues. Long-term use of KD has also been associated with potential side effects, especially in children with refractory epilepsy who benefit significantly from KD. However, those who used KD for more than six years were found to have increased risks of kidney stones, fractures, and growth retardation.

Recently, researchers from the Joe R. and Teresa Lozano Long School of Medicine published an article in Science Advances titled "Ketogenic diet induces p53-dependent cellular senescence in multiple organs." This study uncovered that a ketogenic diet can trigger p53-dependent cellular aging across various organs.

The research team utilized two different mouse models under varying conditions and found that a ketogenic diet led to signs of cellular aging in multiple organs, including the heart and kidneys, across different age groups.

Two Distinct Methods of Inducing Cellular Senescence by KDS

Credit: https://pubmed.ncbi.nlm.nih.gov/38758782/

The process of cellular aging occurs in the following way: initially, a protein known as AMP kinase and an enzyme called caspase-2 work together to inactivate another protein named MDM2. When MDM2 becomes nonfunctional, it leads to the accumulation of P53 protein and an increase in P21 protein, which triggers the aging of cells.

Additionally, research has shown that both mice on a ketogenic diet and individuals participating in ketogenic diet clinical trials exhibited elevated levels of aging-related biomarkers in their blood. This indicates that the ketogenic diet does indeed affect cellular aging. However, the good news is that this aging can be mitigated by specific drugs known as senolytics, and intermittent ketogenic dieting can also help to halt the aging process.

This study indicates that intermittent ketogenic diets (IKD) can help prevent the accumulation of cellular aging problems that may arise from long-term ketogenic diets (KD). This supports the idea that IKD might be more beneficial than continuous KD, as it could help lower inflammation risks. These findings are significant for practical medical applications because they suggest that prolonged KD in treating childhood epilepsy might be associated with long-term side effects due to cellular aging.

The research team also investigated whether the levels of aging-related biomarkers could quickly return to normal after a 7-day KD. The results showed that one week after resuming a regular diet, the levels of aging markers P53, P21, and SA-β-GAL decreased. This implies that IKD could be a better alternative to consider in clinical practice.

Combining this mouse study with other research, we see that the effects of ketogenic diets are multifaceted, with benefits and drawbacks varying per individual based on factors like age, dietary habits, genetics, and overall health. Therefore, it is recommended to adopt a personalized approach when using a ketogenic diet, evaluating each patient's unique situation carefully to determine who would benefit and to devise the most suitable treatment plan.

References:

[1] Wei, Sung-Jen et al. “Ketogenic diet induces p53-dependent cellular senescence in multiple organs.” Science advances vol. 10,20 (2024): eado1463. doi:10.1126/sciadv.ado1463