There’s truth to the old adage, “Age is just a number.” People of the same age differ vastly in health and mental capabilities. One 80-year-old may be vibe coding with Claude, while another is gradually forgetting familiar faces and memories.
To better gauge this difference, scientists have been developing “clocks” that measure biological age. Rather than the number of candles on a birthday cake, these tools capture health at the cellular level and are remarkably accurate at estimating disease risk and even life expectancy. But how they work is hard to explain.
Now Harvard scientists and collaborators have released a powerful and more interpretable clock. Using the gene activity of thousands of individuals and animals, the clock predicts biological age in rodents, monkeys, and humans, including how many years they have left.
The analysis involved over 11,000 gene activity profiles across four species, highlighted shared mechanisms during aging, and responded to known anti-aging interventions—such as parabiosis, during which aging animals receive blood from a young donor.
Although the clock isn’t ready for clinical use, it is a boon to scientists working to slow or even reverse the unstoppable progression of time. It “could help researchers to pinpoint which processes are modulated by interventions or diseases,” wrote João Pedro de Magalhães at the University of Birmingham, who was not involved in the work.
Tick, Tock
Biological clocks come in a variety of flavors.
Most rely on AI to make sense of information held in large databases of people. One of these, for example, uses blood proteins related to brain aging to reflect cognition and its decline better than chronological age. Another type, metabolomic age clocks, sorts through protein and fatty acid building blocks to estimate biological age. These clocks correlate well with risk of inflammation, chronic disease, and frailty (where the body struggles to recover from a mild infection or minor fall). More recent multi-omics clocks combine blood measures, metabolism, gene activity, and clinical data for a comprehensive bird’s-eye view of biological age.
But epigenetic clocks remain the field’s defining breakthrough.
As we age, chemical tags accumulate on DNA, switching genes on or off. The pattern of these tags shifts over time and is shaped by everyday life—diet, exercise, stress, sleep quality. Studies have found that the age gaps between biological and lived years measured by the well-known Horvath epigenetic clock, which relies on DNA methylation, were associated with the risk of various types of diseases. Later versions of the Horvath clock could predict maximum lifespan. And other groups have developed “pan-mammalian” epigenetic clocks that work across species.
“One drawback of epigenetic clocks, however, is their limited interpretability,” wrote Magalhães. “The mechanisms that underpin age-related methylation changes are still debated.”
Clocking In
In the new study, the team measured aging by looking at gene activity, or transcriptomics. Transcriptome profiles capture which genes are switched on at any given moment.
Previous studies have linked the aging transcriptome to chronic inflammation, faltering mitochondria, and the gradual breakdown of the extracellular matrix, the molecular scaffolding that supports tissues and organs. With age, these systems go awry.
“Because the signatures reflect changes in the activity of specific genes, transcriptomic biomarkers are more interpretable than are epigenetic ones,” wrote Magalhães. The tradeoff is that gene activity is far more dynamic than DNA methylation, the epigenetic signature used in the Horvath clock. A transcriptome can shift in response to stress, illness, exercise, or even the time of day, making it a less reliable measure of aging.
To make the new clock, the team assembled over 11,000 transcriptomes, heavily relying on data from the Interventions Testing Program, a giant effort to study longevity treatments in mice. The dataset included mice exposed to genetic tweaks, drugs, and dietary therapies known to affect aging and lifespan. The team also added more than 2,600 samples from monkeys, several hundred from rats, and over 4,000 from humans to deliver a cross-species view of aging.
They then built multiple transcriptome clocks that estimated age and mortality risk. To validate the clocks, they turned to an independent dataset that included rodent models of accelerated aging, Alzheimer’s diseases, chronic kidney disease, and other age-related conditions. When applied to individual cells, the clocks yielded older transcriptomic ages in more than 90 percent of the samples, suggesting that aging is deeply rooted at the cellular level.
In humans, the clocks accurately predicted the lifespans of participants enrolled in a large heart health study. They were also sensitive to environmental factors that affect aging, ticking forward after exposure to radiation or chronic diseases and rewinding after treatments such as young-blood transfusion, a strategy shown to rejuvenate elderly rodents.
An analysis of the genes driving the clocks highlighted many of the usual molecular suspects. Aging turned on genes involved in inflammation, cellular energy disfunction, and senescence—where failing cells leak toxic molecules. Many of these signatures appeared across organs and species, suggesting that core aspects of aging have been conserved in mammals.
These findings are especially valuable for longevity researchers, who often work with rodent models. Despite living a fraction of a human lifespan, aging rodents undergo transcriptomic shifts similar to those found in us. The new clock could easily test their biological age after potential anti-aging treatments, capture the immediate effects, and predict lifespan, long before they die. It could, in theory, speed up aging research and the quest for treatments.
But to be clear, like other aging clocks, it isn’t a crystal ball. Scientists don’t know if the transcriptome changes drive aging or merely reflect its aftermath. The signatures could be capturing overall health and resilience, rather than molecular changes associated with aging per se.
That distinction matters. As we grow older, cells activate a variety of protective genes to counter rising stress, inflammation, and damage. Not every age-related transcriptomic change is harmful. Some changes reflect the body’s attempt to fight back. Because transcriptomes capture only a snapshot in time, scientists still need to differentiate genes that contribute to aging from those that help defend against it and learn how those patterns shift over time.
There’s a broader challenge too. Researchers are building more and more biological clocks using different criteria, and they don’t always agree. One may say you’re far older than another. This highlights “the need for any aging biomarker to be validated carefully,” wrote Magalhães.
