Citrus compound reverses some signs of liver aging in older mice

Hesperetin, a natural flavonoid found in citrus, acted as a powerful agent in rejuvenating the aging livers of naturally aged mice

The liver is a jack-of-all-trades and a master of all. From removing harmful substances and secreting bile to metabolizing proteins, carbohydrates and fats and managing the immune system, the liver does it all. As we age, liver cells undergo major structural changes, making the body prone to metabolic liver diseases such as fatty liver and inflammation, which, over time, can increase the risk of liver cancer.

A recent study explored ways to protect the liver from age-related damage. The researchers found their answer not in a newly synthesized drug but in a molecule naturally found in citrus fruit on your kitchen counter.

Hesperetin, a natural flavonoid found in citrus, acted as a powerful agent in rejuvenating the aging livers of naturally aged mice. It did so by increasing levels of the protective gene Cisd2, which, together with its two partners Hmgcs2 and Pparα, forms a molecular pathway that controls liver aging.

Gene-activity analysis showed that hesperetin treatment nudged aged livers back toward a younger molecular profile, reversing about 24% of the age-linked gene-expression changes. The findings are published in npj Aging.

Guardians of the liver

The liver, the body's largest internal organ, is the central hub for metabolism, detoxification and immune control. As the liver ages, its cells undergo structural and functional changes, including mitochondrial damage, stress in the protein-making endoplasmic reticulum and overall oxidative stress.

These changes can give rise to severe liver disorders such as metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatohepatitis (MASH).

Although these diseases are common, scientists still do not fully understand the molecular pathways that trigger this aging, so few treatments currently exist to stop it.

Early investigations revealed that Cisd2 (CDGSH iron sulfur domain 2) is a key longevity gene that helps protect mitochondria and maintain cellular balance. In mice, losing Cisd2 accelerated aging, while maintaining high levels of Cisd2 extended lifespan and slowed age-related decline across multiple organs.

A few studies have also highlighted PPARα's liver-shielding role, while hesperetin has shown benefits in aged mice with heart and liver injury.

In this study, the researchers investigated whether a chemical pathway connects these elements and controls the aging process.

The protective pathway

To see how aging and hesperetin affect a whole, living body, the researchers divided healthy, 21-month-old male mice into two dietary groups: a standard diet mixed with hesperetin (100 mg/kg/day) for five months and a neutral control diet.

To test whether hesperetin's benefits depended on the Cisd2 gene, the researchers bred mice that lacked Cisd2 specifically in their liver cells. These mice also received hesperetin, and the researchers tracked them to see if the compound would stop working once the gene was gone.

The team extracted RNA from the mouse livers and used genetic sequencing to measure the activity levels of more than 10,000 genes simultaneously. They then compared active gene patterns in young mice, untreated old mice and hesperetin-treated old mice. This revealed which metabolic and anti-aging pathways the treatment successfully turned back on.

They found that, with age, PPARα and CISD2 levels decreased in mice, and without these protective shields, the aging liver suffered from harmful chemical stress, abnormal fat accumulation and other liver-damaging processes. Introducing hesperetin triggered a molecular chain reaction that helped the liver raise its defenses again.

It began by targeting Hmgcs2 and binding to it, stabilizing the protein so it could interact with Pparα to form the Hmgcs2-Pparα complex. This duo then flipped a genetic switch, encouraging liver cells to produce a fresh supply of the protective Cisd2 protein.

Mice whose diet included hesperetin showed repair of severe, age-related damage to mitochondria and the cell's protein-folding machinery, restoring them toward a healthier state. Hesperetin also brought blood markers of liver damage closer to normal and reduced fatty liver, inflammation and scar tissue.

When researchers removed Cisd2 specifically from liver cells, hesperetin was much less effective, meaning Cisd2 is the primary driver of the repair work triggered by the citrus flavonoid.

The PPARα–CISD2 link to liver health isn't limited to mice. Analysis of nontumor liver tissue from 80 surgical patients showed that both protective genes steadily declined with age, regardless of sex. Patients with higher PPARα levels also had higher CISD2 levels.

Does this mean eating more citrus fruit can help with healthy liver aging? While the study makes no such claim, the researchers believe that hesperetin's potential as a liver anti-aging treatment could help guide the development of drugs or carefully tested nutraceuticals for fatty liver disease in older adults.

Source: MedicalXpress.com