Ageing rewrites every organ differently, and one molecular pathway could be the key to slowing it 

A landmark study of more than 15,000 tissue samples has revealed that ageing leaves a distinct molecular fingerprint in nearly every organ and identified a potential target for therapies that could slow the process. 

Scientists have produced the most comprehensive map to date of how ageing alters the human ​epi​genome across 17 different organs, uncovering patterns that could reshape the search for treatments that slow or reverse biological decline. 

The study, published today in Nature Aging and led by Dr Macsue Jacques and Professor Nir Eynon at the Australian Regenerative Medicine Institute (ARMI), analysed more than 15,000 tissue samples from organs including the brain, liver, lung, heart, skin and skeletal muscle. It found that ageing does not affect the body uniformly – each organ accumulates a distinct molecular signature over time – but that certain changes occur in almost all of them. 

The research focuses on DNA methylation, a process by which small chemical tags attach to the genome and control which genes are switched on or off. These tags shift predictably with age, and scientists have used them to develop so-called biological clocks – tools that estimate how old a person’s body is at the cellular level, independent of how many years they have lived. 

Until now, most of that research relied heavily on blood samples. This study is the first to systematically map methylation changes across a range of tissues throughout the adult lifespan.

Postdoctoral researcher Dr Macsue Jacques said the atlas answers a question that blood-based research could never fully address. “Blood studies are helpful, but it’s one tissue being extrapolated to the whole body,” she said. “What we wanted to know was whether ageing occurs uniformly across all organs. The answer is: it doesn’t, it depends entirely on the organ. Some tissues accumulate enormous numbers of methylation changes. Others hardly change at all.” 

A genome growing quieter with age 

Across nearly all tissues examined, the study found a consistent trend: regions of the genome that carry few or no methylation tags in younger people tend to accumulate them with age. The effect is a move towards gene silencing – parts of the genome that were active earlier in life are progressively switched off. 

The brain, liver and lung showed the largest number of age-related changes, with the brain alone registering more than 180,000 altered sites. Other organs, including the prostate and pancreas, showed far fewer changes, though this could be due to smaller numbers of prostate and pancreas samples in the study. 

One gene family, every tissue 

Dr Jacques found that a gene family called PCDHG, specifically a gene known as PCDHGA1, was consistently linked to ageing across multiple organs. PCDHG genes encode proteins that help cells recognise and communicate with one another, a function long associated with neural development and brain organisation. PCDHG genes have previously been linked to reduced brain white matter, a marker of accelerated cognitive decline. 

The appearance of PCDHG genes as a central player across non-neural tissues – including blood, muscle and fat – was unexpected. Professor Eynon, the senior author on the study, said computer simulations showed that switching off this gene family disrupted more than half of the processes it was involved in, suggesting it plays a central role in how cells coordinate as the body ages. 

“PCDHG genes are best known for their role in brain development,” Professor Eynon said. “Finding them at the centre of ageing in tissues such as muscle and fat tells us that the breakdown of communication between cells may be a shared mechanism of ageing, not one confined to the brain. That changes how we think about where to look for interventions that target cognitive and muscle decline. We are ​​currently ​​verifying these changes in multiple cells using gene editing and cell imaging techniques, in collaboration with researchers at ARMI and the Monash Biomedicine Discovery Institute.”​​ ​​ 

A window for intervention 

The study also identified one metabolic pathway that behaved differently to the rest. Most age-related changes proved difficult to reverse in simulation and often grew worse when disrupted. 

One of the few exceptions​ ​was a pathway linked to NAD⁺, a molecule essential to energy production and DNA repair, which responded positively to simulated intervention.  

NAD⁺ levels fall substantially with age, a decline associated with mitochondrial dysfunction, reduced cellular repair capacity and accelerating tissue deterioration. The new findings provide molecular evidence to support NAD⁺-based therapies, which are already being trialled for their potential to slow age-related decline in the brain, muscle and heart. 

An open resource 

The full dataset – covering all 17 tissues, three analytical frameworks and the cross–tissue network models – has been made publicly available through an interactive atlas accessible at https://bioinformatics.erc.monash.edu/apps/human-aging-atlas/. 

The next steps for the research team are to validate the computational findings experimentally and to determine whether the methylation signatures identified in this study can serve as reliable biomarkers of organ-specific biological age – markers that could one day guide clinical decisions about when and how to intervene in the ageing process. 

The study was conducted in collaboration with researchers from Victoria University, Deakin University, Harvard Medical School, the University of Sydney, the University of Copenhagen and institutions across Finland, Norway and China. 

This research was funded by the National Health and Medical Research Council of Australia, the Australian Research Council, the Research Council of Finland, the Research Council of Norway, Wallonia–Brussels International, the National Heart Foundation of Australia, the Medical Research Future Fund (Australia), the National Natural Science Foundation of China, the National Institute on Aging (USA), Hevolution and the American Federation for Aging Research. 

About ARMI 
The Australian Regenerative Medicine Institute (ARMI), based at Monash University in Melbourne, is a world leader in regenerative biology and stem cell research. ARMI works at the frontier of science, translating discovery into hope for people living with conditions like cancer, arthritis, dementia, neurodegenerative disease, rare disease and injury. 

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