Scientists have found a potential remedy for liver protection in citrus fruits

The natural flavonoid hesperetin, found in citrus fruits, partially reversed age-related changes in the liver of elderly mice. The substance restored the activity of the protective Cisd2 gene, improved the condition of mitochondria, and reduced fat accumulation, inflammation, and scar tissue formation. This was reported on August 20 by Medical Xpress with reference to a study published in the journal npj Aging.

How aging changes the liver

The liver is involved in almost all key metabolic processes in the body. It neutralizes potentially dangerous substances, produces bile, regulates the metabolism of proteins, fats and carbohydrates, and also performs a number of immune functions.

As we age, structural and functional disorders accumulate in the cells of the organ. In particular, the mitochondria that provide cells with energy are damaged, oxidative stress increases, and the endoplasmic reticulum, a cellular structure responsible for protein synthesis and proper folding, is disrupted.

Such changes increase the likelihood of developing metabolically associated fatty liver disease and metabolically associated steatohepatitis. These conditions are accompanied by fat accumulation, inflammation, and gradual tissue damage. Over time, the pathological process can lead to fibrosis, cirrhosis and an increased risk of liver cancer.

At the same time, the molecular mechanisms of organ aging have not yet been fully studied. That is why researchers from the National Yang-Ming Jiaotong University and the National Institutes of Health Research of Taiwan have tried to identify a signaling pathway that can control age-related liver changes.

What substance was found in citrus fruits

Previous animal experiments have shown that the loss of Cisd2 accelerates age-related changes. Maintaining its activity, on the contrary, slowed down the deterioration of a number of organs and increased the lifespan of mice. However, it remained unclear which molecular mechanisms regulate the activity of Cisd2 in the liver and whether it is possible to influence them with the help of chemical compounds.

The authors of the new study found that with age, the activity in the liver decreases not only Cisd2, but also PPARa, a protein receptor that regulates fatty acid metabolism, inflammatory processes and energy balance. A decrease in the levels of these protective factors was accompanied by fat accumulation, mitochondrial damage, and increased cellular stress.

How the experiment was conducted

Healthy male mice aged 21 months were used in the experiment. The animals were divided into two groups. The first received a standard feed with the addition of hesperetin for five months at the rate of 100 mg per 1 kg of body weight per day. The second was on a control diet without the test substance.

The scientists also bred mice in which Cisd2 was disabled directly in liver cells. These animals were also given hesperetin to test whether its effect would persist without the protective gene.

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After completing the experiment, the experts examined liver tissue, blood chemistry, and the activity of more than 10,000 genes. The data obtained were compared with the results of young mice, elderly animals from the control group, and old mice treated with hesperetin.

The analysis showed that the treatment partially brought the molecular profile of the old liver closer to that of the young animals. Hesperetin reversed approximately 24% of age-related changes in gene expression. We are not talking about complete rejuvenation of the organ, but about restoring the activity of some of the genetic programs disrupted during the aging process.

How hesperetin affected cells

The researchers concluded that hesperetin triggers a sequence of molecular reactions involving three components — Hmgcs2, Ppara, and Cisd2. The first target of the substance was Hmgcs2— an enzyme involved in liver energy metabolism and the formation of ketone bodies. Hesperetin bound to this protein and stabilized it, after which Hmgcs2 could interact with Ppara.

The resulting complex affected a special region in the Cisd2 regulatory region and enhanced the activity of the gene. As a result, liver cells began to produce more of the protective protein CISD2, the level of which decreased as the animals aged.

The condition of mitochondria and the cellular system responsible for protein formation improved in mice treated with hesperetin. The biochemical parameters of liver damage in the blood approached normal values. In addition, the researchers recorded a decrease in body fat, inflammatory changes, and fibrosis.

The results of experiments on animals with Cisd2 disabled in liver cells turned out to be especially important. In this case, the positive effect of hesperetin was significantly weakened. This indicated that Cisd2 is one of the main mediators providing the detected protective effect.

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What did the study of human tissues show?

The authors additionally analyzed healthy, tumor-free liver samples from 80 patients who underwent surgery. The levels of PPARa and CISD2 in the tissues gradually decreased with age, regardless of the gender of the participants.

At the same time, patients with higher PPARa activity, as a rule, had higher CISD2 levels. The data obtained are consistent with the results of experiments on mice and indicate the possible existence of a similar protective mechanism in the human liver.

However, this part of the study was observational in nature. The patients were not given hesperetin, so it is impossible to determine from the results of the analysis whether the substance will be able to affect the human body in the same way.

Is it possible to slow down liver aging with oranges?

The study does not prove that increasing the amount of oranges, lemons or other citrus fruits in the diet can rejuvenate the human liver. In the experiments, the mice received a certain dose of isolated hesperetin, rather than the fruits themselves. It is also impossible to transfer the dosage directly from animals to humans.

The work is still at the preclinical stage. Scientists will study the safety of hesperetin, its absorption, optimal doses and possible side effects, and then test the effectiveness of the substance in controlled clinical trials.

Nevertheless, the results allow us to consider the HMGCS2–PPARa–CISD2 signaling chain as a potential target for future drugs. Exposure to it may become one of the directions for the development of remedies against age-related deterioration of liver function and metabolic diseases in the elderly.

The authors believe that hesperetin can be used as a starting point for creating medicines or carefully tested nutraceuticals. However, it is premature to perceive the substance as a ready-made remedy against liver aging until evidence of its effectiveness in humans appears.