Ageing liver and metabolic fatty liver diseases

Chronological ageing is an established risk factor for metabolic and viral end-stage liver diseases, and progression to cirrhosis remains the most common indication for liver transplantation. With metabolic dysfunction-associated fatty liver disease (MAFLD) now affecting roughly one in three adults worldwide – more than one billion people – the need for effective therapies has never been greater. Yet available drugs only marginally improve fibrosis, none is effective once cirrhosis develops, and none prevents adverse liver outcomes.

Our group studies why the liver becomes progressively resistant to therapy as disease progress. A central insight from our work is that age drives this loss of therapeutic responsiveness: a 60-year-old person with advanced fatty liver can have a liver that is biologically 80 or 90 years old. We use systems medicine, single-cell and spatial multi-omics, and disease modelling to map the perturbed biological networks underlying advanced disease, and we design modular, multi-stage interventions – including CRISPR-based gene therapies – to correct them and reinstate liver homeostasis.

Our research rests on two linked discoveries. First, ageing reshapes crosstalk between the liver and the bone marrow haematopoietic stem and progenitor cells (HSPCs) whose myeloid progeny infiltrate the liver and drive inflammation and fibrosis. Second, the ageing liver loses its cellular identity. We are testing whether rejuvenating hepatocyte identity and normalising the liver–bone marrow axis can reverse end-stage disease.

About the Group Leader

Dr Saeed Esmaili leads a multidisciplinary, translational research program investigating liver–bone marrow crosstalk in the pathogenesis of fatty liver disease and liver cancer. Medically trained (MBBS, Tehran University of Medical Sciences, 2003), he completed his PhD in Medicine at the University of Sydney in 2014 and is a senior research scientist at the Westmead Institute for Medical Research. His work spans human metabolic disease and pre-clinical models, with a focus on MAFLD, liver cancer, and haematopoiesis, integrating clinical, single-cell, and spatial genomics data. He is committed to advancing this emerging field and to mentoring the next generation of translational scientists, having supervised numerous PhD students and postdoctoral researchers.

Research Themes

1. Liver–bone marrow crosstalk in ageing and fatty liver disease

We have shown that, unlike young mice, old mice fail to reverse liver injury and fibrosis when switched from a fatty-liver diet to a healthy one, and that a fatty-liver diet expands inflammatory bone marrow HSPCs whose responses also fail to normalise with age. We discovered that bile acids mediate this liver–bone marrow crosstalk, and we are using single-cell and spatial multi-omics to define the aged, inflammatory HSPC clones that perpetuate liver disease.

2. Reversing hepatocyte ageing and restoring liver identity

As the liver ages and disease progresses, hepatocytes gradually lose their identity and function. We are using CRISPR technology to reactivate lost regulatory circuits, with the aim of rebuilding the hepatocyte programme, restoring bile acid homeostasis, and reversing fibrosis, rather than simply treating its downstream consequences.

3. CRISPR-based therapeutic discovery

We use high-throughput CRISPR perturbation screens to identify and validate ageing-responsive genes in hepatocytes and immune cells.

4. Translating to people: blood-based markers of liver biological ageing

Because liver biopsy cannot be used to assess biological ageing at scale, we profile blood by single-cell multi-omics as an accessible readout of age-related immune dysfunction.