Research published in the Science Advances journal reveals that following a ketogenic or keto diet over a long period can accelerate the aging of our organ cells, increasing the risk of heart disease, kidney disease, and cancer.

However, different experiments with mice also found that this aging can be reversed by switching to a standard diet and can even be prevented by following a keto diet on an intermittent basis.

Ketogenic diet induces p53-dependent cellular senescence in multiple organs was a study conducted by more than 20 researchers at the University of Texas Health Science Center at San Antonio (UT Health San Antonio) led by David Gius, a professor in the Department of Radiation Oncology at the School of Medicine and Associate Cancer Center Director of Translational Research at the Mays Cancer Center. 

First, what is senescence? Biologically, it refers to the aging of cells until they stop dividing but do not die, entering a kind of “zombie state.”

These cells remain in the tissues, accumulate over time in greater quantities and “release harmful substances that may cause inflammation and damage to nearby healthy cells. Senescence may play a role in the development of cancer and other diseases,” states the U.S. National Cancer Institute website.

Second, what do the researchers mean by p53? Known as the “guardian of the genome” or “tumor suppressor,” it is a gene that produces a protein found in the nucleus of cells that is activated when cells suffer DNA damage, by activated oncogenes and in response to certain stress signals. 

“It normally helps prevent the development of cancer, and mutations in the p53 gene are one of the most common genetic abnormalities in human cancers,” states the University of Navarra website.

Having clarified these concepts, let’s address the ketogenic diet, based on a high-fat (over 70%) and low-carbohydrate intake, which has proven effective in the treatment of refractory epilepsy and is being investigated for its positive effects on neurodegenerative diseases, though it has been gaining popularity for some decades due to its effect on weight loss.

How Did the Study Reveal That the Keto Diet Accelerates Aging?

According to a story published on the UT Health San Antonio website, research leader David Gius says that 13 million Americans follow a keto diet. Together with his team, he aimed to understand the impact this dietary plan has on the p53 gene and its implications for cellular senescence.

During the research, mice of different ages (6, 16, 24, and 52 weeks) were fed for three weeks on a ketogenic diet, in which 90% of their calories came from fat and less than 1% from carbohydrates. 

Also, a control group was fed a standard diet in which 17% of calories came from fat and 58% from carbohydrates. 

Tissue samples from their hearts, kidneys, livers, and brains were then analyzed to determine the condition of their cells. 

Mice on a ketogenic diet, regardless of age, had higher levels of the protein released by p53, which can be activated by stress, and had more senescent cells in their organs than those on a standard diet.

For example, animals fed a ketogenic diet had on average four times the amount of a cellular senescence marker in their kidneys than those on a regular diet.

As senescent cells increase with age, the results of this research suggest that the ketogenic diet may accelerate organ aging, increasing the risk of heart disease, cancer, and type 2 diabetes. 

Is Keto-Induced Senescence Reversible?

Yes. According to this research, keto diet-induced cellular senescence is time-dependent and reversible: We subjected mice to this regimen for seven days, then returned them to a normal diet and observed that after one week the levels of p53, p21 and SA-β-gal (which induce senescence) decreased and continued to drop to the control range after two to three weeks. 

The study also revealed that administering a senolytic (a pharmaceutical) selectively eliminates senescent cells by binding to and inhibiting multiple anti-apoptotic proteins in mice that had been on a ketogenic diet for 21 days. 

The results showed that when the drug was applied for seven days immediately after the end of the keto diet, most of the senescent cells were successfully eliminated but those who were treated one week after the end of the diet still had high levels of senescence. 

Finally, the researchers tested whether an intermittent ketogenic diet would prevent p53 activation and cellular senescence. They fed the mice a keto diet for four days and alternated with a standard diet for three cycles of seven days. 

Two other groups were fed a ketogenic diet (positive control) and a standard diet (negative control) for 31 days. Contrary to the sustained keto diet, the intermittent diet did not increase p53 or cellular senescence. 

Why Is This Research Important?

Although such dietary plans have proven positive for treating certain diseases, there is controversy over their long-term effects. 

Citing a 2020 study, the University of Texas researchers highlight that in the short term, the keto diet can improve metabolism by activating resident, tissue-specific immune cells, although continued over the long term, it induces systemic inflammation, obesity, and glucose intolerance. 

Based on this paper, the researchers aimed to investigate further the detrimental long-term effects: “Our experiments have shown that a ketogenic diet can induce p53 signaling through AMPK activation combined with inactivation of MDM2 by caspase-2 cleavage, ultimately leading to an increase in p21 and cellular senescence in multiple organs.”

“Because we observed these changes in key organs such as the heart and kidneys, where the accumulation of senescent cells can contribute to systemic inflammation and toxicity, we believe that they have important clinical implications.”

Another important finding of this research is that the keto diet applied intermittently may be easier for patients to adhere to and improve health parameters without the risk of cellular senescence that occurs with long-term keto diets. 

Gius and his team acknowledge that more studies are needed to add to this research “to determine whether an intermittent ketogenic diet might be beneficial in humans and for which conditions, as well as the optimal regimen for each patient.”

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