March 17, 2026 | Aging has increasingly been viewed as a modifiable target for therapeutic intervention, an encouraging idea that was recently reaffirmed with the development of a simple blood test for predicting survival. The biomarkers being measured include five piwi-interacting RNAs (piRNAs), together with high density lipoprotein (HDL) particle number and the ability to do instrumental activities of daily living, such as the ability to independently shop and do housework, according to Virginia Byers Kraus, M.D., Ph.D., professor in the departments of medicine, pathology, and orthopedic surgery at Duke University School of Medicine.
Be it with lifestyle modifications, new drugs, or existing medications, it may be possible to improve aging itself and confirm those beneficial changes with a means to measure the hardest outcome of them all—improving the length of a patient’s life. This is the inescapable conclusion of a study Kraus led that found a handful of molecular markers in blood to be “phenomenal predictors” for two-year survival among nearly 1,300 community-dwelling adults aged 71 years and above. (Aging Cell, DOI: 10.1111/acel.70403).
Their blood samples were repurposed from a previous Duke-led study. Survival outcomes were determined by linking participants to national mortality records.
Six piRNA biomarkers stood out among 828 small RNAs examined and were stronger predictors of survival than age and lifestyle habits as well as every other health measure examined, with accuracy as high as 86% for two-year survival. Five of the six piRNAs made the final cut of predictive measures that provided the “biggest bang for the buck,” says Kraus. And they remained good predictors for five-year survival, but for 10-year survival lifestyle factors seemed to be the most impactful, including smoking habits, alcohol use, and sleep.
Importantly, the piRNAs were “causally related” to survival, she stresses. That’s a critical difference from many prior studies that have been done using blood-based biomarkers of mortality risk and life expectancy.
A few commercially marketed products aim to quantify biological aging, most of which rely on hundreds to thousands of DNA methylation markers, Kraus adds. None of these tests use small non-coding RNA measures, which include piRNAs as well as microRNAs, despite their regulatory role in DNA methylation and gene expression.
“Less is more” when it comes to benefits from the piRNAs that increase chances of two-year survival, says Kraus, which represents both opportunity and intrigue. She and her team will now explore ways of knocking them down to produce survival benefits as well as better understanding their mechanism of action.
Currently, very little is known about piRNAs in the blood, she continues. The literature to date indicates that in tissue piRNAs sit on jumping genes to prevent them from causing mutations, which implies more is better.
It’s perhaps the case that in people who survive longer their piRNAs are “hard at work” in the tissues and therefore not being excreted into circulation, says Kraus. But based on observations made thus far in another study comparing several hundred skeletal muscle tissue and blood sample pairs, very few correlations have been found. Roughly half of the time small RNA levels were higher in the tissue and the other half of the time they were lower, “so it didn’t suggest that there was a smoking gun there.”
Kraus says she suspects another mechanism of action is at play related to functions outside the germline that are poorly understood. “This could be a whole different story in terms of the way [piRNAs] are working and what they’re targeting.”
Demand for a longevity test is likely to be brisk, as suggested by surging interest in wellness globally and the rising number of clinics and methylation metrics popping up to accommodate health-conscious individuals, says Kraus. “I know from having developed biomarkers for many years that they are only
really useful [to physicians] when you have an action item based on them.”
To that end, as part of the latest study, Kraus and her team did a virtual clinical trial. They simulated what might happen if only the survival-related RNAs could be adjusted therapeutically—either lowering their levels when high levels were harmful or increasing them when higher levels were beneficial. By testing these changes across the entire study population, the researchers could estimate their potential impact on survival. The effect was profound for two-, five-, and even ten-year survival, she reports.
Since causal AI methods identified the predictors, validation studies might now be done to learn if they are modifiable with different treatments. Conversations have already begun about potentially partnering with study sponsors to use existing blood samples to get a “snapshot” of how patients have responded to various treatments as indicated by the piRNA biomarkers moving in the direction of survival benefit, says Kraus. It could otherwise be a long wait for such information, since survival studies can take many years if not decades to complete.
In the realm of orthopedic surgery, the traditional predictors used for older adults to determine if they should or shouldn’t undergo a major procedure have been clinically based, she notes. “This would be a much stronger and more reliable predictor and that’s especially important if you’re getting an elective surgery ... [where] you could postpone and try to get into better shape if you knew you weren’t a good candidate or you were a survival risk.”
High-risk individuals having the luxury of a prehabilitation period might, for example, be enrolled in an exercise program for a few months or perhaps take Metformin, one of the GLP-1 medications, or any other drug that would create a beneficial profile prior to their elective procedure, Kraus says. Older adults might also use results of the survival blood test in their decision-making about whether a certain surgery is worth their while based on expected years of remaining life.
Work on the survival blood test emerged from a 12-year labor of love on a systemic biomarker predictor of knee osteoarthritis progression. Joint and cartilage studies by Kraus and her colleagues identified a small group of highly regenerative small RNAs that are shared with organisms that can regenerate whole limbs, like the salamander.
While humans still have this program of regeneration, for some reason they cannot put it into practice for full limb regeneration, she says. “But it happens in the cartilage when the cartilage is stressed, say with something like osteoarthritis, and it happens very robustly in the ankles, but it doesn’t happen robustly in the hips.”
If those small RNAs were regenerating cartilage under stress circumstances, the researchers reasoned that it might also play a role in longevity. So, they took blood samples from a cohort with over 20 years of death data already acquired and looked at their baseline small RNA profiles in circulation to see if they in any way related to survival. “That’s how we stumbled upon these tremendous predictors of this hard and important outcome,” says Kraus.
A half dozen tiny but prediction-mighty RNAs are easy enough to detect with advanced molecular biology techniques such as reverse transcription PCR. The process begins with the isolation of RNA from plasma using a standard commercial RNA isolation kit. An established core lab facility next door to the Kraus lab generally handles the subsequent RNA sequencing steps, returning a dataset listing the amounts of each type of RNA for subsequent analysis.
This typically involves a lot of complex modeling and data transformation work, but the goal here was to create a test that’s easy to deploy in a clinical setting, says Kraus. So, the researchers came up with a method where raw piRNA counts straight off the sequencer produce values for survival risk that are “as good or better” than traditional methods with all the bells and whistles of data normalization and scaling.
This is intended to be a lab-developed test approved for medical purposes by the U.S. Food and Drug Administration (FDA), she says. It could be deployed in wellness clinics prior to the completion of those required regulatory steps.
The high performance of the survival biomarkers in the latest study were demonstrated only in older adults, so the research team is now seeking funding to extend this work to the cohort involved in the longitudinal, multigenerational Physical Performance Across the Lifespan (PALS) study conducted by Duke University Medical Center between 2013 and 2018, Kraus reports. About 1,000 people from North Carolina between 30 and 100 years of age were enrolled in PALS, and their participation involved donating blood.
“We want to evaluate when these [piRNAs biomarkers] start to appear,” she says. “When we’ve looked at other biomarkers in the blood, we have seen some of the adverse biomarker effects start to show up in a subset of people starting in their 30s to 40s.” Identifying problems early on in life opens the possibility of doing something proactive about it.
How survival predictions relate to comorbidities remains to be seen. In the recent study, patients reported various health conditions, and the researchers had data on standard biomarkers, such as those in routine cholesterol and lipid panels. “None of those were informative, and even age for two-year survival wasn’t informative once you knew the piRNA profile,” says Kraus.
“This was a community-based study, so it should be less biased because you’re not waiting for people to come into the doctor’s office,” she adds. “You’re going door to door to try and get people who are representative of the real world.”
Targeting the Troublemakers
In terms of their interest in the preclinical context, Kraus and her team would also like to knock down the molecular survival biomarkers to a low level in different animal models, since the piRNAs are highly conserved across species. The idea is to ensure that the animals make the identical molecules and learn if targeting them can modify their lifespan and healthspan.
“One of the reasons I believe we’re onto something that is causal is an esoteric paper I found about the C. elegans ... where they knocked out all the piRNAs and doubled the lifespan of the worm,” says Kraus. “But we’d like to do a more targeted strike ... with the ones we know are the most predictive of survival and see what [happens].”
It is also now possible to use antisense oligonucleotides (ASOs)—short, synthetic, single-stranded strings of DNA or RNA designed to alter protein expression—to knock down the troublesome piRNAs, she says, noting that there are already 10 FDA-approved ASOs to treat different rare genetic and neurological disorders. If the approach is proven in tissue models, it could perhaps one day be used to achieve health benefits in humans with single or intermittent dosing, or by completely reprogramming the piRNAs one by one.
Kraus says the research team will be putting in a grant this summer in hopes of getting these next steps funded. She has also been talking to a few companies who are interested in pursuing antisense approaches, since they now have a track record with regulators.
The tricky part will be the best gateway to FDA approval, since the agency approves drugs for diseases and not survival, says Kraus. The tie-in could well be how targeting the piRNAs improves the health of different organ systems, she adds.