The liver is one of the most notable organs in the human body. This multitasking dynamo performs around 500 vital functions, including processing nutrients and filtering harmful substances from the blood. Despite the chemical toxins it has to deal with daily, the liver is preternaturally young, thanks to its unique ability to regenerate. However, not even the trusty liver is immortal. As the body begins to age, so does the liver. And as it decreases, you become susceptible to various forms of fatty liver disease. But what if there was a way to help restore an aging liver to its youthful state? In a new study published in npj Aging, scientists got one step closer to that, using a compound found in citrus fruits to slow and even reverse signs of liver aging in mice. Your liver, pictured at three years old. (SciePro/Getty Images) In one experiment, a team led by first author and molecular biologist Zhao-Qing Shen of National Yang Ming Chiao Tung University in Taiwan investigated hesperetin, a natural flavonoid found in lemons, limes, oranges, and other citrus fruits, which has shown promise for a variety of potential pharmacological effects, including several anti-inflammatory, anti-aging, and neuroprotective properties. Hesperetin has previously been identified as an activator of a longevity-associated gene called CISD2 (or Cisd2 in mice), which is known to support liver and metabolic health. “In the liver, Cisd2 deficiency promotes steatohepatitis [fatty liver disease] and hepatocellular carcinoma [liver cancer]while increasing Cisd2 expression preserves youthful metabolic profiles and attenuates age-related liver dysfunction,” the researchers explain in their paper. “In particular, Cisd2 expression decreases during aging, suggesting that restoring its expression may represent a promising strategy to delay liver aging and prevent age-related liver diseases.” To test their hypothesis, the researchers gave naturally old mice (21 months old) a daily dose of hesperetin for five months, while that a control group received an inactive dose substitute. Comparison of mouse livers, showing young mice (three months old, left), control mice (26 months old, center), and hesperetin mice (26 months old, right) (Shen et al., npj Aging, 2026). Hesperetin daily had Cisd2 levels in the liver comparable to those in young mice as young as three months old. Several other markers of liver aging and deterioration were also reduced, including fat deposits, damaged liver cells, and inflammation. “Taken together, these results demonstrate that hesperetin consumption alleviates pathological liver damage and delays liver aging in elderly mice, an effect that closely correlates with the upregulation of Cisd2 expression,” the researchers write. RNA sequencing to compare gene activity showed that the citric compound had shifted gene expression in the treated animals toward a more youthful state, reversing a number of age-associated gene expression changes that were seen in control animals. A separate experiment showed that mice genetically engineered to lack Cisd2 in the major functional cells of their livers (which as a result were already showing signs of poor liver health at three months of age) did not respond to hesperetin treatment. In mouse liver cells, the citric compound relies heavily on Cisd2 to function and is mostly ineffective in its absence, although the researchers also found some changes in gene expression independent of Cisd2. According to the researchers, hesperetin appears to work through a signaling pathway that involves two different proteins, called Hmgcs2 and Pparα, which together increase the activity of Cisd2. safe way similar effects to improve human liver health, the beginnings of the pathway could exist. Related: The clearest evidence yet that a common plastic increases the risk of fatty liver disease In the study, the research team analyzed non-tumor liver samples from 80 patients who had undergone surgery for liver cancer or benign tumors, and found that the expression of PPARα and CISD2 decreased with age in human liver tissues. Reduced Cisd2 levels seen in mice could also be occurring in older people. And if that’s the case, perhaps boosting that pathway with hesperetin could also help rejuvenate the human liver. “These findings, taken together, provide strong evidence that hesperetin is a potent anti-aging treatment for the liver and form the basis for future clinical interventions using hesperetin as a potent liver activator. Cisd2 and as a functional food derived from citrus fruit peels,” the researchers write. “age-related fatty liver disease.” The findings are reported in npj Aging. This article was fact-checked by Rebecca Dyer and edited by Rebecca Dyer. While we take pride in our process, we are human. If you spot an error, please let us know.
