Frontiers in Science · Sep 17, 2026
Catching aging in motion
By McGaunn JP, Baur JA
Can the right biomarkers provide a snapshot of how fast someone is aging at a given moment? Austad, Kaeberlein, and Miller argue that such biomarkers, termed aging rate indicators (ARIs), likely exist, and that identifying and testing them is a critical priority for aging research (Austad et al., 2026). ARIs differ from traditional biomarkers of biological age, which attempt to measure the cumulative effects of aging on the body and compare them with expected values for a given chronological age. By analogy, when purchasing a used car, one can check the year (chronological age) and odometer (biological age); but to know how much wear is currently being put on the car, it is more useful to check the speedometer (ARIs).The advantages of ARIs become especially clear when considering candidate longevity interventions. Testing whether an intervention affects lifespan requires waiting a lifespan.Biological age measures improve the situation by allowing proxy measurements in living individuals, but they still require enough time for a detectable difference in biological age to emerge. In contrast, ARIs could quickly reveal whether an intervention has changed the current pace of aging-similar to how pressing the brake or accelerator rapidly changes the dial on a car's speedometer. (Austad et al., 2026). This list begins to highlight some of the ambiguities and questions that will need to be addressed.Many candidate ARIs, while responding to interventions that promote longevity, will also be affected by factors unrelated to longevity. For example, one candidate, UCP1 in adipose tissue, responds strongly to cold (Cutler et al., 2025), but cold exposure does not positively affect longevity in rodents (Vaanholt et al., 2009). Candidate ARIs are expected to respond to multiple, but not all, longevity interventions, raising the question of how many ARIs would need to respond for a result to be considered positive. It is also not clear whether the proposed ARIs can distinguish between male and female responses to drugs that produce sexspecific effects on longevity, such as acarbose, canagliflozin, and 17-alpha-estradiol (Austad et al., 2026). Each potential explanation highlights another consideration: correct predictions from the ARIs could be masked by a separate, harmful effect of the same drug, or ARIs may be specific to a sex or genetic background.Finally, there is no guarantee that a given biomarker will be purely an ARI or purely an indicator of biological age. Parameters such as blood pressure and stress hormones worsen with age on average, serving as conventional biomarkers (albeit poor ones), but may simultaneously act as ARIs. Although these examples are based on physiology, an ARI need not change with age or be directly connected to pathology; it is a statistical construct.As a case in point, Belsky and colleagues established that an ARI-like measure, termed DunedinPACE, can be extracted from DNA methylation data obtained from a blood draw, using data collected over two decades from 1,037 patients born in 1972-1973 in Dunedin, New Zealand (Belsky et al., 2022). Importantly, the authors demonstrated associations between DunedinPACE values and morbidity, disability, and mortality in both the Normative Aging Study and Framingham Heart Study cohorts, whose measurements were obtained far from the location of the training data. Whether this measure will successfully predict the results of acute interventions, and whether the strategy can be applied to other types of "clock" data (i.e., mRNA, protein, metabolite levels) remains to be seen.Recent evidence suggests an additional caveat: not all organs may "age" at the same rate within an individual, and the most rapidly "aging" organ or organs may vary from person to person (Oh et al., 2023). This raises questions not only about the sensitivity of ARIs to changes in aging rates, but also about their specificity: which organs' aging rates are represented by a given ARI? The best individual ARIs will predict morbidity, mortality, and disability at the scale of the whole organism, but an aggregate of tissue-specific ARIs may ultimately have greater predictive value and clinical utility than a single whole-organism marker. With a bewildering and growing array of potential ARIs available, prioritization and validation will be significant challenges.Ultimately, an ARI would be validated by its successful use to identify a new longevity intervention, but gaining the confidence to move forward with such an experiment is a difficult challenge. Austad, Kaeberlein, and Miller suggest a subset of molecular markers based on their consistency across several models of slow-aging mice (Austad et al., 2026). This approach could be extended to find markers that correlate with longevity across an increasing range of conditions. The current most promising set, or a more refined future set, could then be used to screen a variety of treatments in mice and prioritize those with strong ARI responses for testing in conventional lifespan and healthspan assays. However, whether the ARIs themselves-or the interventions they identify-will be relevant to humans will need to be tested separately.Alternatively, starting with human data gives up the ability to use data from validated longevity interventions, but allows candidate ARIs to be tested directly in human datasets. DunedinPACE provides a good example of extracting a potential ARI from natural variation rather than intervention. Although it has already been replicated in independent cohorts, this measure, like any candidate ARI, should be validated with as many genetic ancestries, environmental exposures, and lifestyles represented as possible. Additionally, an ideal ARI would indicate that the "pace of aging" is much faster in patients with genetic causes of rapid aging, such as progeria, whose rates of functional decline, morbidity, and mortality are all much greater at younger ages. Although genetic diseases of rapid aging may not affect all processes involved in typical aging, they may serve as a natural experiment to help validate whether putative ARI markers do indeed predict lifespan, disease risk, and functional decline.Finally, to be useful in the clinic, any ARI should ideally be detectable in an accessible tissue or biofluid, such as skin, saliva, or blood. The bar is high for developing a clinically useful ARI, but any candidate marker that meets these criteria could greatly benefit patients, scientists, and therapeutic development both in and beyond aging and translational geroscience.While the development of ARIs is an exciting prospect, it should not be overlooked that they would come with risks. Using ARIs that are not sufficiently validated could waste more time than they were intended to save. In addition, the short-term nature of ARI-based experiments runs the risk of failing to identify long-term harms. For example, drugs that mildly accelerate cancer or neurodegeneration would be unlikely to raise red flags in an ARI-based screen.Perhaps the most insidious risk, however, is siloing. If we develop ARIs based only on the pathways that we already know influence aging, we may blind ourselves to interventions that work through other mechanisms. We do not know what we do not know, and limiting biomarkers at this stage could stifle further discoveries if we assume that a lack of change in one, or even a panel of, ARIs indicates no change in the rate of aging. Therefore, we would advocate for ARIs as an important complement to, but not as a replacement for, conventional studies of healthspan and longevity; any ARI-based signal should ultimately be corroborated by direct measurements of clinical benefit in populations of interest. Austad, Kaeberlein, and Miller (Austad et al., 2026) make a compelling argument for the concept and utility of ARIs, but much work remains to be done before such markers can be used successfully to validate gerotherapeutics in the clinic. We applaud them for opening this important conversation and look forward to the essential work and discussion ahead as the field endeavors to identify and test putative ARIs in the pursuit of our shared goal of extending healthy lifespan.None