Over one billion people worldwide are over 60, and the population is projected to more than double by 2050. But as more people live into their 60s, 70s, and 80s, healthcare systems across the globe may face new challenges as they attempt to manage associated increases in age-related disease.
Andreas Stahl (center) and members of his lab pose with the organ-on-a-chip system, which features a microfluidic connection between chambers containing fat and liver cells. UC Berkeley photo by Mathew Burciaga
Metabolic biologist Andreas Stahl and preeminent longevity researcher Irina Conboy argue that the greying of the global population underscores the need to understand aging as a biological process, and how it might be slowed or reversed. Longevity therapeutics, however, are expensive to develop, and the lack of rapid, reliable tools to study human aging can make it difficult to test these next-generation therapies. While animal models can provide important data, there are often many caveats when applying those findings to human biology during trials.
“Over $130 billion is spent on drug development each year in the United States, but over 90% end up failing in clinical trials,” explained Stahl, the Ruth Okey Professor in the Department of Metabolic Biology and Nutrition (MBN) and a member of the California Institute for Quantitative Biosciences at UC Berkeley (QB3-Berkeley). “Pharmaceutical developers and regulators such as the US Food and Drug Administration are increasingly realizing that we need to change our drug development pipeline and make it more relevant to human biology.”
But in a first-of-its-kind study published today in Nature Biomedical Engineering, current and former Berkeley scientists detail a way to accelerate the biological age of human fat and liver tissues using a miniaturized organ-on-a-chip system. In as little as four days, researchers were able to mimic—with high physiological accuracy—roughly 40 years of aging on tissue derived from induced pluripotent stem cells. This new technology could make it easier for researchers to understand aging mechanisms and screen longevity therapeutics without waiting years for results.
The study was co-led by Stahl and Irina Conboy, and co-authored by Michael Conboy, Irina’s husband and a research scientist in the Department of Bioengineering and at QB3-Berkeley. Additional co-authors include MBN researchers Lin Qi, Yuchen He, Erzhen Chen, and Yihan Xia; as well as QB3-Berkeley postdoctoral researcher Alexandra Sviercovich, and Bioengineering PhD student Xiaoyue Mei.
Aging Unraveled
The conventional understanding of aging holds that cells in our bodies experience dysfunction with each passing year. In humans, this can manifest as everything from wrinkles and grey hair to changes in physical strength, memory, or metabolism. But Irina Conboy, who was a professor of bioengineering from 2004 to 2025 and a former QB3-Berkeley affiliate, spent most of her UC Berkeley career challenging that notion.
Irina Conboy. Photo by Adam Lau / Berkeley Engineering
In a 2005 study published in Nature, the Conboys pioneered the use of parabiosis—a technique in which two living organisms are surgically connected—to study stem cell aging and systemic rejuvenation in mice. Michael Conboy, who still runs the Conboy lab at Berkeley, noted that the nervous and vascular systems are the only two systems connected to every organ in the body. “But we can’t transplant the nervous or vascular system from a young mouse to an old one, so blood was the easy route out,” he said. Connecting an older mouse to a younger partner led to signs of rejuvenation in the older mouse, the researchers observed, while younger mice aged more rapidly when exposed to older blood.
The researchers demonstrated that aging in mammals is largely regulated by age-elevated systemic proteins circulated by the bloodstream. These proteins are vital to our health at young levels, but become counterproductive at high levels in old age. But because parabiosis is not a clinically feasible method, Irina Conboy said translating those findings from mice to humans is difficult. Subsequent high-impact studies on systemic aging and rejuvenation led by the Conboys showed that diluting the blood plasma of old mice with a saline-albumin mixture (rather than blood or plasma) had rejuvenative effects on the brain, liver, and muscles. They observed a similar result when testing the process in humans: diluting plasma reduced inflammaging—the phenomenon in which, as people age, the immune system promotes inflammation of various tissues at the expense of mounting productive defense against pathogens—and rejuvenated circulating cells and proteins. Their collaboration with Stahl expands these findings to human fat and liver.
“Our collaborative work with Andreas’ lab group strengthened our understanding that aging is not just the progression of time,” said Irina Conboy, who co-founded Generation Lab in 2023 and has served as its Chief Science Officer since 2025. “We are regenerating systems. We are capable of repair.”
A human model, miniaturized
A prototype wafer shows various configurations that the Stahl lab tested before settling on their current design. UC Berkeley photo by Mathew Burciaga
Organ-on-a-chip systems are miniature, cell-filled devices that replicate the architecture, fluid flow, and mechanical forces of living human organs. The idea has been around for decades, but its application to obesity, diabetes, and fatty liver disease has only been recently pioneered by the Stahl lab. During a brainstorming session with QB3-Berkeley colleagues a couple of years ago, Irina Conboy wondered if they could use human blood serum—collected from real people—to age human tissue on a chip? “If you’d asked me the day after she told me about it whether it was going to work, I would have said, ‘No way,’” Stahl recalled. “But it was such a tempting idea to try.”
Fabricated at QB3-Berkeley’s Biomolecular Nanotechnology Center in Stanley Hall, the organ-on-a-chip developed by the Stahl lab mimics the human body’s fat-liver connection. This interplay has major implications for metabolic health, as fat tissue—particularly visceral fat surrounding organs—releases hormones and metabolites that travel directly to the liver via the bloodstream. These signals change with age and contribute to the onset of conditions such as nonalcoholic fatty liver disease, insulin resistance, and type 2 diabetes.
In Stahl’s chips, fat and liver cells derived from human induced pluripotent stem cells are housed in separate but interconnected chambers, allowing the researchers to recreate the organ-to-organ communication. Tiny channels allow nutrient-rich fluid to flow between the two tissues, simulating the way blood carries molecules between organs. The system requires remarkably small amounts of fluid—a fraction of what traditional cell culture methods demand—making it possible to conduct experiments with limited quantities of human blood serum.
The device has separate chambers that contain either fat or liver cells. Small vertical posts allow for interconnection between devices via a microliter-scale tubing system, which attempts to replicate connections found within the human body. UC Berkeley photo by Mathew Burciaga
“The features are tiny, so the flow rates amount to about one milliliter a day,” said Stahl. “Standard tissue culture takes something like 10 to 15 milliliters, and that’s just static—you have to exchange it constantly. Each device can give you between 10 and 100 different readouts with minimum consumption.”
Testing aging on a chip
To test whether the system could accurately replicate human aging, the researchers circulated blood serum from donors aged 62 and older through channels containing newly created fat and liver tissue cells. For comparison, researchers exposed a control group of tissue cells to serum from young donors between the ages of 21 and 34. The results were striking.
Cells exposed to serum from older donors exhibited chronic inflammation, an impaired ability to regulate blood sugar, and disrupted fat metabolism. Many of these changes occur in humans over decades, but in the lab, researchers were able to induce them in as little as four days. The cells also exhibited senescence—where cellular division stops and cells begin secreting inflammatory molecules—and other hallmarks of aging. “My postdoc held this chip up to me, and you could actually see it with the naked eye,” said Stahl, recalling the results of a test that causes senescent cells to turn blue. “No one expected that in four days, you can age freshly differentiated stem cell-derived tissues to the degree that they are now old.”
Equally surprising was the speed at which oxidative DNA damage accumulated. “People assume that it takes time to accumulate damage—that it is a random process,” said Irina Conboy. “But what this paper teaches us is that DNA damage happens all the time, and cells repair this damage, unless they are exposed to old blood serum. The old serum seemingly reduced the capacity for repair.”
To validate their findings, the researchers developed a machine learning model trained on gene-expression data from a database of hundreds of publicly available human tissue samples. The model could determine the age of a sample with 90 to 97% accuracy, depending on tissue type and biological sex. Stem-cell-derived tissues exposed to young serum clustered with samples from people in their 30s, while those exposed to old serum matched profiles from people in their 50s. Further analysis revealed that the top 10 categories of genes altered by aging were identical across the human and stem-cell-derived fat tissues used in the organ-on-a-chip system.
The study also revealed that aging on the chip differs across tissue types. When aged fat tissue was connected to young, healthy liver tissue, the liver cells began to show signs of aging on their own. “These chips were designed with a microfluidic connection between different chambers, similar to how our organs are connected through blood circulation,” explained Irina Conboy. “So the age of one organ propagates forward and establishes the age of another organ. And that’s why, typically, people show signs of aging all over their bodies.”
Co-author Lin Qi, a postdoctoral researcher in the Stahl Lab, sets up an experiment in the device. UC Berkeley photo by Mathew Burciaga
On-chip tests also revealed how aging patterns differ by sex. Despite using genetically identical stem-cell-derived tissues, fat tissues treated with male serum showed stronger inflammatory responses and more pronounced aging markers. Stahl noted that these results are consistent with the well-documented observation that men tend to age faster and have shorter lifespans. Female serum, meanwhile, produced more variable results and lower predictive accuracy in the machine learning model—a finding the researchers attributed to the more complex hormonal landscape of female aging, including the influence of menopause.
A platform for discovery
While researchers have previously used organ-on-a-chip systems to screen drug candidates for the treatment of human genetic diseases, this study marks the first time that scientists have used a chip to evaluate the capacity of specific drug therapies to reduce human tissue aging. Several major candidate anti-aging interventions were tested, including: a class of drugs known as senolytics, which clear senescent cells from the body; rapamycin, which has been the focus of several longevity studies; the hormone oxytocin; and a Transforming Growth-factor beta (TGF-beta) signaling inhibitor. The researchers also tested the effects of diluting old blood serum with young serum.
The Berkeley team found that tissues exposed to oxytocin exhibited reduced inflammation, decreased senescence, and improved insulin sensitivity. The hormone also restored healthy fat and sugar metabolism more comprehensively than any other treatment tested. Stahl said the results are consistent with earlier studies showing that oxytocin can promote fat redistribution and reduce inflammation in mice.
Rapamycin, on the other hand, showed almost no rejuvenative effect—a finding Irina Conboy said has real-world implications. “Some people take rapamycin voluntarily—it’s by far the most broadly used anti-aging therapy,” she said. Stahl added that uncontrolled trials of rapamycin in humans, some spanning a decade or more, have now reported similar results. “We could have told people that this is not going to work based on this system in four days,” he said.
The greatest improvements were achieved by exposing aged fat and liver tissues to serum from young donors, an approach pioneered in genetically identical mice but with very limited translatability to humans. “But even then, there’s a clear memory of the old serum exposure that persists,” Stahl added, suggesting that some damage from exposure to age-related milieux may be difficult to undo entirely. Dilution of old serum also had a beneficial effect, in agreement with the outcomes of therapeutic plasma exchange.
In addition to putting forth this organ-on-a-chip as a potential platform for testing, the research identified 11 novel biomarkers—biological indicators not previously associated with aging—that could serve as targets for future drug development. They also demonstrated, for the first time, that scientists could selectively manipulate gene expression within the organ-on-a-chip. This development could allow scientists to silence or activate individual genes and observe the effects on aging and rejuvenation in real time.
The research team has filed a patent for the technology, and efforts to commercialize the system are underway. Irina Conboy, in her role at Generation Lab, is working to translate over 20 years of research for clinical applications. The company has developed products that determine a person’s biological age using a panel of 460 biomarkers across 19 body systems and is pursuing the development of novel longevity therapeutics—the first of which is expected to enter clinical trials in 2026.
The work was supported by the National Institutes of Health (1UG3DK120004), the National Institute on Aging (R01AG071787), Open Philanthropy, the Congressionally Directed Medical Research Programs (TX230133), the Siebel Stem Cell Institute, and the Gordon and Betty Moore Foundation.
Read More
- Aging in human microphysiological systems closely recreates the in vivo process, expediting evaluation of anti-gerontic strategies (Nature Biomedical Engineering)
- Forever young: Understanding aging through the study of blood (Berkeley Engineer)
- Diluting blood plasma rejuvenates tissue, reverses aging in mice (Berkeley News)