Twelve candidate aging rate indicators could offer faster route to testing geroprotective drugs – and to understanding what slow aging means.
The search for interventions that slow aging has an awkward experimental problem built into it: aging takes time. A mouse lifespan study can require three to four years and cost $100,000–$300,000; in humans, waiting for sufficiently convincing changes in healthspan or lifespan makes the timescale considerably less accommodating.
A new article in Frontiers in Science proposes a different way of reading the biology. Researchers from the University of Alabama at Birmingham and University of Michigan have identified 12 candidate “aging rate indicators” (ARIs) – molecular and physiological characteristics shared across mouse models in which aging has been slowed by drugs, dietary interventions or genetic mutations. Rather than estimating how much aging has accumulated, an ARI would ideally reveal whether an animal has entered a slow-aging state after an intervention.
Longevity.Technology: Geroscience has become increasingly adept at asking how old biology looks; the more consequential question for drug development is whether an intervention has actually persuaded it to age more slowly. The authors’ distinction is a useful one – aging biomarkers are closer to an odometer, recording biological miles accumulated, while an ARI is intended to behave more like a speedometer, revealing the rate of travel now. If that speedometer proves reliable, the prize is not merely faster, cheaper studies; shared changes induced by rapamycin, calorie restriction and other lifespan-extending interventions could help reveal what a slow-aging state actually is – turning measurement into a route toward mechanism, rather than simply better scorekeeping.
For now, however, these are candidate ARIs, with considerable validation required before anyone starts fitting speedometers to humans. That caution feels especially pertinent in a marketplace already rather fond of selling consumers a biological age; the authors themselves are unusually forthright about commercial aging tests and the distance between some claims and their validation. Perhaps longevity does not need another number telling us how old we supposedly are. What it needs is a rigorous way of knowing whether we have changed the trajectory – and why.
Finding the slow-aging signature
The proposal grows out of results from the National Institute on Aging-supported Interventions Testing Program (ITP), which evaluates candidate longevity interventions in genetically heterogeneous mice. Fourteen agents or combinations have significantly increased lifespan in ITP studies; eight have produced increases of at least 12% in one or both sexes, including rapamycin, acarbose, canagliflozin and 17α-estradiol.
What interests the researchers is the biological overlap. Interventions that are quite different in origin and mechanism nevertheless produce some parallel changes in signaling, metabolism, inflammation and tissue physiology.
The proposed indicators include mTORC1 activity, MEK/ERK and MEK3/p38 signaling, UCP1 in adipose tissue, inflammatory and anti-inflammatory macrophage balance, circulating irisin and GPLD1, as well as BDNF and doublecortin in the hippocampus. Importantly, no individual ARI is expected to explain aging; the working criterion is simply that it differs consistently between normal and multiple varieties of slow-aging mice [1].
Senior author Professor Richard A Miller said: “We hope aging rate indicators (ARIs) will advance the search for antiaging drugs in three ways. First, they may provide a quicker and less expensive way to select drugs that deserve testing in mice. Second, they may allow us to see which drugs can induce patterns of change in healthy people that make them more similar to slow aging mice, and therefore give clues about drugs that may slow aging in people. Lastly, the ARI panel can give us clues about the changes shared by many – perhaps all – antiaging drugs, and in this way select way targets and new drug families to work on.”
Compressing the experimental clock
Most ARI data so far come from studies in which mice began receiving drugs or calorie restriction at four months and were assessed eight months later, using groups of just 10–20 animals of each sex. If those measurements can reliably distinguish interventions that ultimately extend lifespan from those that do not, the authors estimate experiments could run around four times faster and at roughly one-twentieth the cost of full lifespan studies.
That would make ARIs useful as a screening layer rather than a substitute for lifespan and healthspan studies – allowing researchers to discard unpromising candidates earlier and reserve longer, more expensive experiments for interventions carrying a stronger biological signal.
“The biggest challenge in translating the biology of aging into better health is knowing whether an intervention actually affects the rate of aging,” said co-author Dr Matt Kaeberlein. “Developing and validating aging rate indicators could give us the tools to answer that question on a practical timescale, rather than waiting years or decades for lifespan outcomes. If we can do that rigorously, it will fundamentally change our ability to find interventions that extend healthy lifespan.”
Mice first, humans later
There is some distance to travel. Much of the published evidence comes from a single laboratory group using one genetically heterogeneous mouse stock, making independent replication an immediate priority. Only two of the published ARIs, irisin and GPLD1, are currently measurable in plasma; developing a broader blood-based panel will be important if the approach is to move into longitudinal animal studies and eventually human trials.
The translational roadmap therefore runs through other mammals. The authors highlight companion dogs, which share human environments and develop many comparable age-related conditions, and common marmosets, whose shorter lifespans make them potentially valuable intermediary models between rodents and humans [1].
There is another encouraging wrinkle. Several ITP interventions remain effective when treatment begins relatively late in mouse life.
“The surprising discovery in mice that many effective antiaging drugs remain fully active even when started in late adulthood suggests that similar therapies could perhaps benefit people in middle age, which is an exciting possibility,” said lead author Professor Steven Austad.
“ARIs could play a pivotal role in advancing these preventative therapies, culminating – eventually – in human clinical trials that can be completed in far shorter timeframes to speed access to new antiaging drugs.”
Beyond the clock face
The authors are deliberately cautious about equating correlation with measurement: as they put it, “currently we have no way to measure biological age or biological aging rate.” ARIs will have to earn their status by predicting outcomes that matter.
If they do, the shift could be subtle but important. Geroscience would have something more useful than another estimate of biological age: an experimentally testable signal that biology has changed direction. The speedometer still needs calibrating; knowing where the accelerator and brake are would be more interesting still.
[1] https://www.frontiersin.org/journals/science/articles/10.3389/fsci.2026.1821393
