New epigenetic clock measures intrinsic capacity, predicting mortality and offering a potential route through regulatory deadlock.
For all the advances in aging biomarkers, the field has long been hampered by a persistent misalignment: we have been remarkably good at measuring age, but far less adept at measuring how well people are aging. DNA methylation clocks have proliferated; some track lifespan, others offer proxy measures for inflammation, disease risk or all-cause mortality. But few – if any – have addressed what matters most to the people experiencing aging: how well they can live, move, think and adapt.
That gap is what a team of researchers from the Buck Institute for Research on Aging and the IHU HealthAge in France set out to close. Their new study, published in Nature Aging, introduces the IC Clock – the first epigenetic clock trained not on chronological age or mortality data, but on function. Specifically, on intrinsic capacity, a framework introduced by the World Health Organization (WHO) to describe the sum of an individual’s cognitive, physical, sensory and psychological abilities [2].
Longevity.Technology: This new epigenetic clock represents a meaningful advancement in aging biomarkers – not simply because it introduces a new measurement, but because it targets what matters most in clinical and personal aging trajectories: function. By predicting intrinsic capacity, the IC Clock quantifies the physical and cognitive abilities that underpin independence and quality of life. It offers a practical framework for assessing aging through a functional lens – one that aligns with the priorities of both older adults and health systems aiming to shift from reactive to preventative care.
One of the teams competing in the global XPRIZE Healthspan competition – led by the Buck Institute and University of Toulouse – is using the IC Clock to track participant outcomes, a choice that reflects the tool’s operational relevance. The competition itself is centered on function-based endpoints – improvements in mobility, cognition and immune response – and the IC Clock provides a molecular readout that maps directly onto those goals. Importantly, it has been validated in blood and shows strong correlation in saliva samples, with development underway for dried blood spot testing – a move that could enable lower-cost, decentralized deployment. With intrinsic capacity already recognized as a diagnosable condition by the WHO, the IC Clock also offers a credible pathway for regulatory and clinical adoption – particularly in contexts where the FDA has yet to fully engage with aging as a targetable domain.
Biology meets real-world relevance
Developed using data from the French INSPIRE-T cohort of over 1,000 individuals aged 20 to 102, the IC Clock is trained on five core domains – cognition, psychological health, vitality, locomotion and sensory function. These metrics, collectively, define an individual’s intrinsic capacity. A DNA methylation-based predictor was built using elastic-net regression, identifying 91 CpG sites strongly associated with function rather than simply with age [1].
“Maintaining function during the aging process is what matters to older adults. Function should inform medical care instead of focusing on getting patients to some disease-free state,” said senior author David Furman, PhD, Buck associate professor and director of the Buck Bioinformatics and Data Science Core.
In validating the model, the researchers turned to the Framingham Heart Study, a well-established longitudinal cohort in the US. Here, the IC Clock proved a stronger predictor of all-cause mortality than first- and second-generation epigenetic clocks – including PhenoAge and GrimAge – despite not being trained on survival data. Those with low IC scores had higher mortality risk across multiple age-related conditions, including cardiovascular disease, stroke and congestive heart failure. In fact, based on survival curves, individuals with high DNAm IC (that is high intrinsic capacity measured epigenetically) lived an average of 5.5 years longer [1].
The hallmarks have function
While many biological age clocks focus on composite longevity signals, the IC Clock traces the hallmarks of aging through a functional lens. Higher scores correlated with lower levels of inflammatory markers such as CRP and IL-6, lower iAge, and improved immune signatures – including increased CD28 expression, a key co-stimulatory molecule lost during T-cell senescence. Conversely, lower IC scores were associated with signs of immune exhaustion and elevated inflammatory gene expression [1].
Perhaps most intriguing is the IC Clock’s ability to differentiate the biological mechanisms associated with each domain of function. For instance, vitality was linked with mitochondrial electron transport; psychological health with DNA damage response; locomotion with Notch signaling; and sensory capacity with immune regulation [1]. These associations give the clock both interpretability and mechanistic weight – a valuable feature in a field where black-box models often dominate.
Accessible biology
Beyond its conceptual strengths, the IC Clock may have practical benefits in deployment. Unlike performance-based assessments of intrinsic capacity, which require trained staff and in-person testing, the IC Clock is based on methylation data from blood or saliva. Early work suggests that a dried blood spot version could soon be viable – reducing the barrier to access for large-scale monitoring or population-level aging studies, particularly in lower-resource settings.
The team is also clear-eyed about the translational potential. The WHO now includes age-related decline in intrinsic capacity in the ICD-11, opening a route for diagnostic recognition. While the FDA has not yet acknowledged aging as a treatable condition, this new tool could provide a way forward – measuring something functionally meaningful, molecularly grounded and clinically relevant.
A functional future?
The IC Clock’s adoption in the XPRIZE Healthspan competition – where it will help track the effects of interventions designed to restore function by up to 20 years in adults aged 50 to 80 – may accelerate this process. The Buck-Toulouse team’s chosen intervention, a combination of daily ketone ester supplementation and a personalized lifestyle protocol called ICOPE-INTENSE, will be assessed in part using the clock as a primary outcome. It is a rare example of a longevity intervention being measured by function first – and biology second.
The field has been waiting for a way to connect what aging feels like with what it looks like in the lab. A clock built on capacity, rather than chronology, could be one way to do just that.
[1] https://www.nature.com/articles/s43587-025-00883-5
[2] https://www.who.int/publications/i/item/WHO-FWC-ALC-18-1
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