Scientists have managed to restore an ageing liver to a partially youthful state

The results of the gene expression analysis proved particularly striking. Of the 3,313 changes associated with liver ageing, 791 – nearly 24 per cent – were reversed following treatment. However, this does not mean that the liver ‘rejuvenated by 24 per cent’: it refers only to changes in the expression of a specific group of genes. Furthermore, the experiment was carried out on elderly mice using a high dose of the purified substance, rather than on people who ate oranges.

The elderly mice were given the citrus compound for five months

The study was carried out by a team from Yan-Ming Jiaotong National University and other research organisations in Taiwan.

The scientists were interested in hesperetin – a plant-derived flavonoid primarily associated with citrus fruits. Previously, the same research group had already observed its effect on certain signs of ageing and on the activity of the Cisd2 gene in older mice. The new study focused specifically on liver ageing and the molecular mechanism underlying this effect.

The experiment began when the male mice reached 21 months of age — which is already an advanced age for laboratory animals. Over the following five months, they were given hesperetin in their feed at a dose of 100 mg per kilogram of body weight per day. The control group of elderly mice received the same feed without the active substance.

The condition of their livers was then compared with that of both the control group of elderly mice and the young mice.

There was less fat, inflammation and scar tissue in the liver

As the mice aged, their livers exhibited several characteristic changes simultaneously: fat accumulated, inflammatory processes and fibrosis intensified, and blood markers of organ damage worsened.

Following treatment with hesperetin, many of these signs were less pronounced.

The researchers also examined the cells using electron microscopy. In older animals, the mitochondria — the cellular structures responsible for energy production — and the endoplasmic reticulum, which is involved in protein synthesis and processing, were damaged.

Following treatment, their structure more closely resembled that observed in young animals. The authors describe the result as a reduction in age-related liver pathology, rather than a complete reversal of the organ to a youthful state.

Almost a quarter of age-related genetic changes were reversed

The scientists then analysed liver RNA to see how the activity of thousands of genes had changed.

They measured the expression of 10,224 genes and initially compared young mice with older ones. In total, the researchers identified 3,313 genes whose activity differed significantly with age.

After administration of hesperetin, 791 of these genes — 23.9 per cent — showed a shift in activity in the opposite direction to that associated with ageing.

At the level of the entire transcriptome – that is, the totality of active genes – the liver of the treated older mice also shifted towards the profile of young animals.

This is one of the strongest aspects of the study, but it is important to interpret the figure of 23.9% correctly. The researchers did not measure some single ‘degree of ageing’ in the liver, nor did they show that the organ had become a quarter younger. They established that almost a quarter of the age-dependent changes in gene expression identified had reversed direction.

Scientists have found a molecular ‘switch’

The authors also sought to understand why this effect occurs in the first place.

The Cisd2 gene turned out to be at the heart of the mechanism. It plays a role in maintaining normal mitochondrial function, calcium metabolism and cellular homeostasis. In experiments on mice, reduced Cisd2 activity had previously been linked to accelerated ageing, whilst maintaining high levels of its expression was associated with a slower age-related deterioration of tissues.

With age, Cisd2 levels in the liver declined. Hesperetin helped to restore them.

According to the mechanism proposed by the authors, the compound interacts with the Hmgcs2 protein, stabilising it. Hmgcs2 then interacts with the Pparα regulator, and the resulting complex promotes the activation of Cisd2.

This results in the following chain:

hesperetin → Hmgcs2 → Pparα → Cisd2 → protection of liver cells.

The authors consider the elucidation of this sequence to be one of the key findings of their work.

Without Cisd2, the effect was drastically reduced

To test whether Cisd2 really does play a central role, the researchers carried out a further experiment.

They used mice in which this gene had been specifically knocked out in liver cells. These animals were also given hesperetin.

The effect turned out to be significantly weaker.

Genetic and transcriptomic data showed that the majority of the substance’s protective effect depends specifically on the presence of Cisd2. This makes the study more substantial than a simple ‘give the substance – get a better outcome’ type of research: the scientists were able to experimentally interfere with the proposed mechanism and show that, without one of its key components, the effect is substantially reduced.

A similar age-related pattern was also observed in humans

The researchers also studied non-tumour human liver tissue.

With age, the expression of PPARα and CISD2 decreased in this tissue, with higher levels of one being associated with higher levels of the other. This is consistent with the molecular pathway identified in mice.

However, this is where the study reaches a fundamental limitation.

The participants were not treated with hesperetin.

The human samples merely show that certain components of the mechanism under investigation are present and change with age in the human liver. They do not prove that taking hesperetin is capable of ‘rejuvenating’ the human liver in a similar way.

Should we eat more citrus fruits?

Another tempting but incorrect conclusion would be to try to turn the study into a recommendation to eat more citrus fruits.

Hesperetin is indeed a flavonoid found in oranges and other citrus fruits. However, the mice in the experiment did not eat oranges to obtain the active dose. They were given a standardised amount of the purified substance daily — 100 mg/kg body weight.

This is a very significant difference.

The amount of the substance that enters the body from ordinary foods, its form and its bioavailability differ from the experimental administration of the purified compound.

An earlier study by the same team estimated that 100 mg/kg in mice corresponds to approximately 491 mg per day for a 60 kg human, based on standard interspecies dose conversion. However, such a mathematical conversion does not mean that this dose is effective or safe for humans: separate clinical trials are required to establish this.

Therefore, no conclusions can be drawn from the current study regarding either the benefits of eating large quantities of oranges or the need to take supplements containing hesperetin.

We are still a long way from a ‘cure for liver ageing’

The study has several significant limitations.

The main finding was obtained in mice, and the main experiment was conducted on male mice. The human body may metabolise hesperetin differently, react to it differently and regulate the relevant molecular pathways differently.

Furthermore, the study shows an improvement in a number of molecular, biochemical and structural markers of liver ageing, but not the transformation of an aged organ into a young one in every respect.

Finally, the ‘rejuvenation’ of gene expression is not equivalent to a proven increase in human lifespan or protection against age-related liver diseases.

The authors therefore frame their outlook more cautiously: the identified Hmgcs2–Pparα–Cisd2 pathway may serve as a target for the development of future drugs or other interventions aimed at age-related decline in liver function.

Why the finding is nevertheless interesting

Ageing of the liver is accompanied by impaired energy metabolism, fat accumulation, chronic inflammation and a decline in the function of cellular structures. Age also increases the risk of metabolic liver diseases.

This new study is of interest because the researchers not only observed an apparent improvement in several parameters but also traced the putative molecular pathway from hesperetin to the Cisd2 gene — and then genetically disrupted this pathway and observed a reduction in the effect.

Therefore, the most accurate conclusion is, at the same time, quite impressive: in already elderly mice, intervention at a late stage of life was able to partially reverse certain age-related changes in the liver, bringing it closer to the condition seen in young animals.

It is not yet known whether the same approach would work in humans.

Source

Study:“Hesperetin activates the Hmgcs2-Pparα-Cisd2 signalling axis and delays liver ageing”.

Authors: Zhao-Qing Shen, Tsai-Wen Teng, Yi-Long Huang, Jinq-Chyi Lee, Cheng-Heng Kao, Tsai-Yu Tzeng, Chien-Yi Tung, Wei-Cheng Huang, Chun-Wei Tung, Shiu-Feng Huang, Ting-Fen Tsai.

Journal: npj Aging. Published on 12 August 2026.